ILLUSTRATIVE CASE

A 60-year-old man comes to your office for a follow-up visit to talk about his congestive heart failure. He has New York Heart Association Class III heart failure with a left ventricular ejection fraction of 30%. You notice that he is downcast, and after evaluation, including a score of 17 on a self-administered 9-item Patient Health Questionnaire (PHQ-9), you determine that he is having a concomitant major depressive episode. Should you start him on a selective serotonin reuptake inhibitor (SSRI)?

Depression is widely recognized as an independent risk factor for both the development of cardiovascular disease (CVD), as well as adverse outcomes in patients with known CVD.^2-5 Previous studies have identified poor health behaviors as the primary underlying mechanisms linking depression and the risk of CVD.^2,6 Conversely, a recent systematic review suggests that positive constructs—mediated primarily through lifestyle behaviors—may have a protective effect on CVD outcomes.⁷

As a result, researchers have focused on the treatment of depression to improve CVD outcomes in recent years, including in patients with heart failure. While some randomized studies have shown that SSRIs are a safe and effective treatment for depression in patients with coronary disease, they have not demonstrated improvement in CVD outcomes.^8,9 However, a post hoc analysis of the ENRICHD (Enhancing Recovery in Coronary Heart Disease) trial did suggest that SSRI treatment may improve mortality and morbidity post-myocardial infarction.¹⁰

The prevalence of depression among patients with heart failure ranges from 10% to 40%, depending on disease severity.¹¹ Depression is associated with worse quality of life, poorer treatment adherence, and higher rates of rehospitalization among patients with heart failure, and is an independent predictor of mortality in this patient population.¹ Until recently, only one randomized controlled trial (RCT), the SADHART-CHF (Sertraline Against Depression and Heart Disease in Chronic Heart Failure) study, looked at treatment with SSRIs in patients with heart failure and depression.¹² In this trial, sertraline, when compared with placebo, did not improve depression or CVD outcomes over 12 weeks, but the study period may have been insufficiently long to capture the impact on long-term outcomes.

STUDY SUMMARY

SADHART-CHF, but better

In the MOOD-HF (The effects of selective serotonin re-uptake inhibition on morbidity, mortality, and mood in depressed heart failure patients) study, investigators sought to determine whether SSRI treatment for depression in patients with heart failure could improve CVD outcomes over a longer study period (up to 24 months).¹ Specifically, this RCT assessed whether treatment with escitalopram vs placebo could reduce the increased morbidity and mortality risk in patients with comorbid chronic systolic heart failure and depression.

Using SSRIs for depression treatment to affect chronic disease outcomes that are likely lifestyle-related may not be cost-effective or patient-centered.

This double-blind, placebo-controlled trial was conducted at 16 tertiary medical centers in Germany between 2009 and 2014. Adult patients established at heart failure clinics with New York Heart Association class II to IV heart failure and left ventricular ejection fractions <45% were screened for depression using the PHQ-9. Individuals with PHQ-9 scores ≥12 underwent a structured psychiatric interview with a psychiatrist or psychosomatic specialist. Those who received a diagnosis of major depression were invited to participate in the trial. Patients with recent SSRI use and/or psychotherapy were excluded from participation.

Eligible participants were randomized to receive either escitalopram (10-20 mg/d) or placebo for up to 24 months in addition to standard heart failure care. The starting dose of 5 mg was increased to 10 to 20 mg as tolerated until week 12 of the study; the dose at 12 weeks was considered the maintenance dose. Psychiatric and medical assessments were performed every 6 months during the study period. Depression severity was assessed using the 10-item Montgomery-Åsberg Depression Rating Scale (MADRS).

Outcomes. The primary study outcome was time to a first event of the composite of all-cause death or hospitalization. Secondary outcomes included MADRS score at 12 weeks, anxiety as assessed by the Generalized Anxiety Disorder 7-item scale (GAD-7), and health-related quality of life (QoL) as assessed by the Kansas City Cardiomyopathy Questionnaire (KCCQ). The sample size was calculated to achieve 80% power for the primary outcome. Baseline characteristics between the intervention and placebo groups were balanced after randomization, and the modified intention-to-treat study population included participants who took at least one dose of the study medication.¹

Results. Ultimately, 372 participants were included in the analysis (185 in the escitalopram group and 187 in the placebo group). A primary endpoint event occurred in 116 participants (63%) in the escitalopram group and in 119 participants (64%) in the placebo group (hazard ratio [HR]=0.99; 95% confidence interval [CI], 0.76 to 1.27]; P=.92).¹ No differences were found between treatment groups for the primary endpoints in either adjusted or unadjusted analyses.

The mean (SD) MADRS score changed from 20.2 (8.6) at baseline to 11.2 (8.1) at 12 weeks with escitalopram and from 21.4 (8.8) to 12.5 (7.6) in the placebo group (between-group difference = -0.9; 95% CI, -2.6 to 0.7; P =.26).¹⁰ Overall, participants in the 2 treatment groups had comparable daily doses of study medications, as well as mean treatment duration (18 months), and both groups demonstrated partial remission of depression symptoms over the study period, as well as improved health status and QoL as measured by KCCQ.

Interestingly, QoL as assessed by the KCCQ symptom score was significantly improved in the placebo group at 12 months.¹ There were no between-group differences in adverse events or safety measures.¹ The trial was discontinued prematurely on February 28, 2014, based on futility after a recommendation from the data and safety monitoring committee.

WHAT’S NEW

Longer study period/different SSRI doesn’t change earlier finding

The MOOD-HF trial directly addresses the major criticism of the SADHART-CHF trial by looking at SSRI treatment of patients with heart failure and depression over a much longer study duration (up to 24 months vs 12 weeks). Also, in contrast to SADHART-CHF, this trial studied escitalopram, rather than sertraline, because some evidence indicates that escitalopram is superior at treating primary depression.¹³ Despite these differences, the results of MOOD-HF are consistent with the findings of SADHART-CHF: treating patients with both heart failure and depression with an SSRI did not improve the elevated morbidity and mortality risk seen with these comorbid conditions.

Also consistent with SADHART-CHF findings, participants in both groups in the MOOD-HF trial had partial remission of depressive symptoms over the study period, with no significant difference between those treated with escitalopram vs placebo. Given that this high-quality trial, with a much longer treatment period and a possibly more effective SSRI, replicated the findings of SADHART-CHF, the results of MOOD-HF should put to rest the practice of initiating SSRI treatment in depressed patients with heart failure in an attempt to affect CVD outcomes.

CAVEATS

There are other SSRI fish in the sea

There are other SSRIs, besides escitalopram and sertraline, available for use. However, it is likely that this is a class effect.

Additionally, none of the patients in this trial had severe depression, as their PHQ-9 scores were all below 19. Therefore, it remains to be determined if treating patients with severe depression has an impact on cardiovascular outcomes.

Although there are other SSRIs besides escitalopram and sertraline, it is likely that this is a class effect.

Lastly, and most importantly, this study only looked at screening patients for depression and initiating SSRIs in the setting of heart failure. The trial did not include patients already taking SSRIs for pre-existing depression. Thus, the results do not imply evidence for discontinuing SSRIs in patients with heart failure.

Treating comorbid depression and CVD to improve the elevated risk for adverse clinical outcomes remains nuanced and elusive. In fact, the same can be said of non-CVD chronic conditions—such as diabetes—based on recent systematic reviews.¹³ The summation of these studies suggests that a traditional screen-and-treat approach utilizing SSRIs for depression treatment to affect chronic disease outcomes (that are likely lifestyle-related) may not be cost-effective or patient-centered.

The publication of a recent study showing that cognitive behavioral therapy did improve depression—but not heart failure—among patients with both conditions¹⁴ reaffirms that teasing out the impact of depression on lifestyle behaviors and chronic disease outcomes among multimorbid patients is more complex than previously thought. Nevertheless, this is an area of research that should continue to be explored, given the obvious increased risk for poorer chronic disease outcomes in the presence of depression.

CHALLENGES TO IMPLEMENTATION

Changing the tide can be difficult

As with any behavior change among providers, we expect that it will be a challenge to convince providers to stop screening for depression and initiating treatment with an SSRI to affect CV outcomes in patients with heart failure. This is especially so given the body of evidence for depression as a risk factor for increased morbidity and mortality in this population.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 60-year-old man comes to your office for a follow-up visit to talk about his congestive heart failure. He has New York Heart Association Class III heart failure with a left ventricular ejection fraction of 30%. You notice that he is downcast, and after evaluation, including a score of 17 on a self-administered 9-item Patient Health Questionnaire (PHQ-9), you determine that he is having a concomitant major depressive episode. Should you start him on a selective serotonin reuptake inhibitor (SSRI)?

Depression is widely recognized as an independent risk factor for both the development of cardiovascular disease (CVD), as well as adverse outcomes in patients with known CVD.^2-5 Previous studies have identified poor health behaviors as the primary underlying mechanisms linking depression and the risk of CVD.^2,6 Conversely, a recent systematic review suggests that positive constructs—mediated primarily through lifestyle behaviors—may have a protective effect on CVD outcomes.⁷

As a result, researchers have focused on the treatment of depression to improve CVD outcomes in recent years, including in patients with heart failure. While some randomized studies have shown that SSRIs are a safe and effective treatment for depression in patients with coronary disease, they have not demonstrated improvement in CVD outcomes.^8,9 However, a post hoc analysis of the ENRICHD (Enhancing Recovery in Coronary Heart Disease) trial did suggest that SSRI treatment may improve mortality and morbidity post-myocardial infarction.¹⁰

The prevalence of depression among patients with heart failure ranges from 10% to 40%, depending on disease severity.¹¹ Depression is associated with worse quality of life, poorer treatment adherence, and higher rates of rehospitalization among patients with heart failure, and is an independent predictor of mortality in this patient population.¹ Until recently, only one randomized controlled trial (RCT), the SADHART-CHF (Sertraline Against Depression and Heart Disease in Chronic Heart Failure) study, looked at treatment with SSRIs in patients with heart failure and depression.¹² In this trial, sertraline, when compared with placebo, did not improve depression or CVD outcomes over 12 weeks, but the study period may have been insufficiently long to capture the impact on long-term outcomes.

STUDY SUMMARY

SADHART-CHF, but better

In the MOOD-HF (The effects of selective serotonin re-uptake inhibition on morbidity, mortality, and mood in depressed heart failure patients) study, investigators sought to determine whether SSRI treatment for depression in patients with heart failure could improve CVD outcomes over a longer study period (up to 24 months).¹ Specifically, this RCT assessed whether treatment with escitalopram vs placebo could reduce the increased morbidity and mortality risk in patients with comorbid chronic systolic heart failure and depression.

Using SSRIs for depression treatment to affect chronic disease outcomes that are likely lifestyle-related may not be cost-effective or patient-centered.

This double-blind, placebo-controlled trial was conducted at 16 tertiary medical centers in Germany between 2009 and 2014. Adult patients established at heart failure clinics with New York Heart Association class II to IV heart failure and left ventricular ejection fractions <45% were screened for depression using the PHQ-9. Individuals with PHQ-9 scores ≥12 underwent a structured psychiatric interview with a psychiatrist or psychosomatic specialist. Those who received a diagnosis of major depression were invited to participate in the trial. Patients with recent SSRI use and/or psychotherapy were excluded from participation.

Eligible participants were randomized to receive either escitalopram (10-20 mg/d) or placebo for up to 24 months in addition to standard heart failure care. The starting dose of 5 mg was increased to 10 to 20 mg as tolerated until week 12 of the study; the dose at 12 weeks was considered the maintenance dose. Psychiatric and medical assessments were performed every 6 months during the study period. Depression severity was assessed using the 10-item Montgomery-Åsberg Depression Rating Scale (MADRS).

Outcomes. The primary study outcome was time to a first event of the composite of all-cause death or hospitalization. Secondary outcomes included MADRS score at 12 weeks, anxiety as assessed by the Generalized Anxiety Disorder 7-item scale (GAD-7), and health-related quality of life (QoL) as assessed by the Kansas City Cardiomyopathy Questionnaire (KCCQ). The sample size was calculated to achieve 80% power for the primary outcome. Baseline characteristics between the intervention and placebo groups were balanced after randomization, and the modified intention-to-treat study population included participants who took at least one dose of the study medication.¹

Results. Ultimately, 372 participants were included in the analysis (185 in the escitalopram group and 187 in the placebo group). A primary endpoint event occurred in 116 participants (63%) in the escitalopram group and in 119 participants (64%) in the placebo group (hazard ratio [HR]=0.99; 95% confidence interval [CI], 0.76 to 1.27]; P=.92).¹ No differences were found between treatment groups for the primary endpoints in either adjusted or unadjusted analyses.

The mean (SD) MADRS score changed from 20.2 (8.6) at baseline to 11.2 (8.1) at 12 weeks with escitalopram and from 21.4 (8.8) to 12.5 (7.6) in the placebo group (between-group difference = -0.9; 95% CI, -2.6 to 0.7; P =.26).¹⁰ Overall, participants in the 2 treatment groups had comparable daily doses of study medications, as well as mean treatment duration (18 months), and both groups demonstrated partial remission of depression symptoms over the study period, as well as improved health status and QoL as measured by KCCQ.

Interestingly, QoL as assessed by the KCCQ symptom score was significantly improved in the placebo group at 12 months.¹ There were no between-group differences in adverse events or safety measures.¹ The trial was discontinued prematurely on February 28, 2014, based on futility after a recommendation from the data and safety monitoring committee.

WHAT’S NEW

Longer study period/different SSRI doesn’t change earlier finding

The MOOD-HF trial directly addresses the major criticism of the SADHART-CHF trial by looking at SSRI treatment of patients with heart failure and depression over a much longer study duration (up to 24 months vs 12 weeks). Also, in contrast to SADHART-CHF, this trial studied escitalopram, rather than sertraline, because some evidence indicates that escitalopram is superior at treating primary depression.¹³ Despite these differences, the results of MOOD-HF are consistent with the findings of SADHART-CHF: treating patients with both heart failure and depression with an SSRI did not improve the elevated morbidity and mortality risk seen with these comorbid conditions.

Also consistent with SADHART-CHF findings, participants in both groups in the MOOD-HF trial had partial remission of depressive symptoms over the study period, with no significant difference between those treated with escitalopram vs placebo. Given that this high-quality trial, with a much longer treatment period and a possibly more effective SSRI, replicated the findings of SADHART-CHF, the results of MOOD-HF should put to rest the practice of initiating SSRI treatment in depressed patients with heart failure in an attempt to affect CVD outcomes.

CAVEATS

There are other SSRI fish in the sea

There are other SSRIs, besides escitalopram and sertraline, available for use. However, it is likely that this is a class effect.

Additionally, none of the patients in this trial had severe depression, as their PHQ-9 scores were all below 19. Therefore, it remains to be determined if treating patients with severe depression has an impact on cardiovascular outcomes.

Although there are other SSRIs besides escitalopram and sertraline, it is likely that this is a class effect.

Lastly, and most importantly, this study only looked at screening patients for depression and initiating SSRIs in the setting of heart failure. The trial did not include patients already taking SSRIs for pre-existing depression. Thus, the results do not imply evidence for discontinuing SSRIs in patients with heart failure.

Treating comorbid depression and CVD to improve the elevated risk for adverse clinical outcomes remains nuanced and elusive. In fact, the same can be said of non-CVD chronic conditions—such as diabetes—based on recent systematic reviews.¹³ The summation of these studies suggests that a traditional screen-and-treat approach utilizing SSRIs for depression treatment to affect chronic disease outcomes (that are likely lifestyle-related) may not be cost-effective or patient-centered.

The publication of a recent study showing that cognitive behavioral therapy did improve depression—but not heart failure—among patients with both conditions¹⁴ reaffirms that teasing out the impact of depression on lifestyle behaviors and chronic disease outcomes among multimorbid patients is more complex than previously thought. Nevertheless, this is an area of research that should continue to be explored, given the obvious increased risk for poorer chronic disease outcomes in the presence of depression.

CHALLENGES TO IMPLEMENTATION

Changing the tide can be difficult

As with any behavior change among providers, we expect that it will be a challenge to convince providers to stop screening for depression and initiating treatment with an SSRI to affect CV outcomes in patients with heart failure. This is especially so given the body of evidence for depression as a risk factor for increased morbidity and mortality in this population.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 60-year-old man comes to your office for a follow-up visit to talk about his congestive heart failure. He has New York Heart Association Class III heart failure with a left ventricular ejection fraction of 30%. You notice that he is downcast, and after evaluation, including a score of 17 on a self-administered 9-item Patient Health Questionnaire (PHQ-9), you determine that he is having a concomitant major depressive episode. Should you start him on a selective serotonin reuptake inhibitor (SSRI)?

Depression is widely recognized as an independent risk factor for both the development of cardiovascular disease (CVD), as well as adverse outcomes in patients with known CVD.^2-5 Previous studies have identified poor health behaviors as the primary underlying mechanisms linking depression and the risk of CVD.^2,6 Conversely, a recent systematic review suggests that positive constructs—mediated primarily through lifestyle behaviors—may have a protective effect on CVD outcomes.⁷

As a result, researchers have focused on the treatment of depression to improve CVD outcomes in recent years, including in patients with heart failure. While some randomized studies have shown that SSRIs are a safe and effective treatment for depression in patients with coronary disease, they have not demonstrated improvement in CVD outcomes.^8,9 However, a post hoc analysis of the ENRICHD (Enhancing Recovery in Coronary Heart Disease) trial did suggest that SSRI treatment may improve mortality and morbidity post-myocardial infarction.¹⁰

The prevalence of depression among patients with heart failure ranges from 10% to 40%, depending on disease severity.¹¹ Depression is associated with worse quality of life, poorer treatment adherence, and higher rates of rehospitalization among patients with heart failure, and is an independent predictor of mortality in this patient population.¹ Until recently, only one randomized controlled trial (RCT), the SADHART-CHF (Sertraline Against Depression and Heart Disease in Chronic Heart Failure) study, looked at treatment with SSRIs in patients with heart failure and depression.¹² In this trial, sertraline, when compared with placebo, did not improve depression or CVD outcomes over 12 weeks, but the study period may have been insufficiently long to capture the impact on long-term outcomes.

STUDY SUMMARY

SADHART-CHF, but better

In the MOOD-HF (The effects of selective serotonin re-uptake inhibition on morbidity, mortality, and mood in depressed heart failure patients) study, investigators sought to determine whether SSRI treatment for depression in patients with heart failure could improve CVD outcomes over a longer study period (up to 24 months).¹ Specifically, this RCT assessed whether treatment with escitalopram vs placebo could reduce the increased morbidity and mortality risk in patients with comorbid chronic systolic heart failure and depression.

Using SSRIs for depression treatment to affect chronic disease outcomes that are likely lifestyle-related may not be cost-effective or patient-centered.

This double-blind, placebo-controlled trial was conducted at 16 tertiary medical centers in Germany between 2009 and 2014. Adult patients established at heart failure clinics with New York Heart Association class II to IV heart failure and left ventricular ejection fractions <45% were screened for depression using the PHQ-9. Individuals with PHQ-9 scores ≥12 underwent a structured psychiatric interview with a psychiatrist or psychosomatic specialist. Those who received a diagnosis of major depression were invited to participate in the trial. Patients with recent SSRI use and/or psychotherapy were excluded from participation.

Eligible participants were randomized to receive either escitalopram (10-20 mg/d) or placebo for up to 24 months in addition to standard heart failure care. The starting dose of 5 mg was increased to 10 to 20 mg as tolerated until week 12 of the study; the dose at 12 weeks was considered the maintenance dose. Psychiatric and medical assessments were performed every 6 months during the study period. Depression severity was assessed using the 10-item Montgomery-Åsberg Depression Rating Scale (MADRS).

Outcomes. The primary study outcome was time to a first event of the composite of all-cause death or hospitalization. Secondary outcomes included MADRS score at 12 weeks, anxiety as assessed by the Generalized Anxiety Disorder 7-item scale (GAD-7), and health-related quality of life (QoL) as assessed by the Kansas City Cardiomyopathy Questionnaire (KCCQ). The sample size was calculated to achieve 80% power for the primary outcome. Baseline characteristics between the intervention and placebo groups were balanced after randomization, and the modified intention-to-treat study population included participants who took at least one dose of the study medication.¹

Results. Ultimately, 372 participants were included in the analysis (185 in the escitalopram group and 187 in the placebo group). A primary endpoint event occurred in 116 participants (63%) in the escitalopram group and in 119 participants (64%) in the placebo group (hazard ratio [HR]=0.99; 95% confidence interval [CI], 0.76 to 1.27]; P=.92).¹ No differences were found between treatment groups for the primary endpoints in either adjusted or unadjusted analyses.

The mean (SD) MADRS score changed from 20.2 (8.6) at baseline to 11.2 (8.1) at 12 weeks with escitalopram and from 21.4 (8.8) to 12.5 (7.6) in the placebo group (between-group difference = -0.9; 95% CI, -2.6 to 0.7; P =.26).¹⁰ Overall, participants in the 2 treatment groups had comparable daily doses of study medications, as well as mean treatment duration (18 months), and both groups demonstrated partial remission of depression symptoms over the study period, as well as improved health status and QoL as measured by KCCQ.

Interestingly, QoL as assessed by the KCCQ symptom score was significantly improved in the placebo group at 12 months.¹ There were no between-group differences in adverse events or safety measures.¹ The trial was discontinued prematurely on February 28, 2014, based on futility after a recommendation from the data and safety monitoring committee.

WHAT’S NEW

Longer study period/different SSRI doesn’t change earlier finding

The MOOD-HF trial directly addresses the major criticism of the SADHART-CHF trial by looking at SSRI treatment of patients with heart failure and depression over a much longer study duration (up to 24 months vs 12 weeks). Also, in contrast to SADHART-CHF, this trial studied escitalopram, rather than sertraline, because some evidence indicates that escitalopram is superior at treating primary depression.¹³ Despite these differences, the results of MOOD-HF are consistent with the findings of SADHART-CHF: treating patients with both heart failure and depression with an SSRI did not improve the elevated morbidity and mortality risk seen with these comorbid conditions.

Also consistent with SADHART-CHF findings, participants in both groups in the MOOD-HF trial had partial remission of depressive symptoms over the study period, with no significant difference between those treated with escitalopram vs placebo. Given that this high-quality trial, with a much longer treatment period and a possibly more effective SSRI, replicated the findings of SADHART-CHF, the results of MOOD-HF should put to rest the practice of initiating SSRI treatment in depressed patients with heart failure in an attempt to affect CVD outcomes.

CAVEATS

There are other SSRI fish in the sea

There are other SSRIs, besides escitalopram and sertraline, available for use. However, it is likely that this is a class effect.

Additionally, none of the patients in this trial had severe depression, as their PHQ-9 scores were all below 19. Therefore, it remains to be determined if treating patients with severe depression has an impact on cardiovascular outcomes.

Although there are other SSRIs besides escitalopram and sertraline, it is likely that this is a class effect.

Lastly, and most importantly, this study only looked at screening patients for depression and initiating SSRIs in the setting of heart failure. The trial did not include patients already taking SSRIs for pre-existing depression. Thus, the results do not imply evidence for discontinuing SSRIs in patients with heart failure.

Treating comorbid depression and CVD to improve the elevated risk for adverse clinical outcomes remains nuanced and elusive. In fact, the same can be said of non-CVD chronic conditions—such as diabetes—based on recent systematic reviews.¹³ The summation of these studies suggests that a traditional screen-and-treat approach utilizing SSRIs for depression treatment to affect chronic disease outcomes (that are likely lifestyle-related) may not be cost-effective or patient-centered.

The publication of a recent study showing that cognitive behavioral therapy did improve depression—but not heart failure—among patients with both conditions¹⁴ reaffirms that teasing out the impact of depression on lifestyle behaviors and chronic disease outcomes among multimorbid patients is more complex than previously thought. Nevertheless, this is an area of research that should continue to be explored, given the obvious increased risk for poorer chronic disease outcomes in the presence of depression.

CHALLENGES TO IMPLEMENTATION

Changing the tide can be difficult

As with any behavior change among providers, we expect that it will be a challenge to convince providers to stop screening for depression and initiating treatment with an SSRI to affect CV outcomes in patients with heart failure. This is especially so given the body of evidence for depression as a risk factor for increased morbidity and mortality in this population.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

EVIDENCE SUMMARY

A 2015 meta-analysis by Liu et al of 5 RCTs from 2010 to 2015 (446 patients, range 35 to 194 per trial) evaluated the effect of CPAP on 24-hour ambulatory BP in adults with OSA and moderate to severe resistant hypertension.¹ Resistance was defined as hypertension despite optimally dosed 3-drug regimens or adequate control of BP achieved with a 4-drug regimen.

Treatment groups received at least 4 hours of CPAP nightly in addition to previously prescribed pharmacotherapy; control groups received either sham CPAP or no CPAP in addition to their regimen of antihypertensive medications. Reported drug regimens included primarily diuretics, angiotensin converting enzyme inhibitors, calcium channel blockers, and aldosterone receptor blockers.

Prestudy systolic BP ranged from 129 mm Hg to 148 mm Hg; diastolic BP ranged from 75 mm Hg to 88 mm Hg. Participants were followed from 2 to 6 months. Pooled data from all 5 studies indicated an overall decrease in mean 24-hour ambulatory systolic BP of 4.8 mm Hg (95% confidence interval [CI], −8.0 to −1.6) and an overall decrease in diastolic BP of 3 mm Hg (95% CI, −5.4 to −0.5) in CPAP-treated patients compared with controls.

An earlier meta-analysis also shows BP reductions with CPAP

Another 2015 meta-analysis by Hu et al of 7 RCTs from 2006 to 2014 evaluated the effect of CPAP on hypertension in 794 patients with OSA.² Subgroup analysis of 4 of these studies (351 patients, range 35 to 194 per trial) evaluated outcomes in patients with a previous diagnosis of resistant hypertension. This subgroup had 3 trials in common with the Liu et al meta-analysis and one not included in that study. Two other studies in the Liu et al meta-analysis were published after the search dates of this meta-analysis.

Baseline BP wasn’t reported, and treatment resistance was not explicitly defined. Treatment groups received CPAP for 3 to 6 months in addition to their pharmacotherapy regimen, but duration of nightly use was not reported; control groups received only pharmacotherapy. The number and type of antihypertensive medications used was not reported.

Pooled data from the subgroup noted a significant difference in 24-hour mean ambulatory BPs in the CPAP group compared with controls. Systolic BP decreased by 3.9 mm Hg (95% CI, −6.6 to −1.2) and diastolic BP decreased by 3.7 mm Hg (95% CI, −5.2 to −2.1).

EVIDENCE SUMMARY

A 2015 meta-analysis by Liu et al of 5 RCTs from 2010 to 2015 (446 patients, range 35 to 194 per trial) evaluated the effect of CPAP on 24-hour ambulatory BP in adults with OSA and moderate to severe resistant hypertension.¹ Resistance was defined as hypertension despite optimally dosed 3-drug regimens or adequate control of BP achieved with a 4-drug regimen.

Treatment groups received at least 4 hours of CPAP nightly in addition to previously prescribed pharmacotherapy; control groups received either sham CPAP or no CPAP in addition to their regimen of antihypertensive medications. Reported drug regimens included primarily diuretics, angiotensin converting enzyme inhibitors, calcium channel blockers, and aldosterone receptor blockers.

Prestudy systolic BP ranged from 129 mm Hg to 148 mm Hg; diastolic BP ranged from 75 mm Hg to 88 mm Hg. Participants were followed from 2 to 6 months. Pooled data from all 5 studies indicated an overall decrease in mean 24-hour ambulatory systolic BP of 4.8 mm Hg (95% confidence interval [CI], −8.0 to −1.6) and an overall decrease in diastolic BP of 3 mm Hg (95% CI, −5.4 to −0.5) in CPAP-treated patients compared with controls.

An earlier meta-analysis also shows BP reductions with CPAP

Another 2015 meta-analysis by Hu et al of 7 RCTs from 2006 to 2014 evaluated the effect of CPAP on hypertension in 794 patients with OSA.² Subgroup analysis of 4 of these studies (351 patients, range 35 to 194 per trial) evaluated outcomes in patients with a previous diagnosis of resistant hypertension. This subgroup had 3 trials in common with the Liu et al meta-analysis and one not included in that study. Two other studies in the Liu et al meta-analysis were published after the search dates of this meta-analysis.

Baseline BP wasn’t reported, and treatment resistance was not explicitly defined. Treatment groups received CPAP for 3 to 6 months in addition to their pharmacotherapy regimen, but duration of nightly use was not reported; control groups received only pharmacotherapy. The number and type of antihypertensive medications used was not reported.

Pooled data from the subgroup noted a significant difference in 24-hour mean ambulatory BPs in the CPAP group compared with controls. Systolic BP decreased by 3.9 mm Hg (95% CI, −6.6 to −1.2) and diastolic BP decreased by 3.7 mm Hg (95% CI, −5.2 to −2.1).

EVIDENCE SUMMARY

A 2015 meta-analysis by Liu et al of 5 RCTs from 2010 to 2015 (446 patients, range 35 to 194 per trial) evaluated the effect of CPAP on 24-hour ambulatory BP in adults with OSA and moderate to severe resistant hypertension.¹ Resistance was defined as hypertension despite optimally dosed 3-drug regimens or adequate control of BP achieved with a 4-drug regimen.

Treatment groups received at least 4 hours of CPAP nightly in addition to previously prescribed pharmacotherapy; control groups received either sham CPAP or no CPAP in addition to their regimen of antihypertensive medications. Reported drug regimens included primarily diuretics, angiotensin converting enzyme inhibitors, calcium channel blockers, and aldosterone receptor blockers.

Prestudy systolic BP ranged from 129 mm Hg to 148 mm Hg; diastolic BP ranged from 75 mm Hg to 88 mm Hg. Participants were followed from 2 to 6 months. Pooled data from all 5 studies indicated an overall decrease in mean 24-hour ambulatory systolic BP of 4.8 mm Hg (95% confidence interval [CI], −8.0 to −1.6) and an overall decrease in diastolic BP of 3 mm Hg (95% CI, −5.4 to −0.5) in CPAP-treated patients compared with controls.

An earlier meta-analysis also shows BP reductions with CPAP

Another 2015 meta-analysis by Hu et al of 7 RCTs from 2006 to 2014 evaluated the effect of CPAP on hypertension in 794 patients with OSA.² Subgroup analysis of 4 of these studies (351 patients, range 35 to 194 per trial) evaluated outcomes in patients with a previous diagnosis of resistant hypertension. This subgroup had 3 trials in common with the Liu et al meta-analysis and one not included in that study. Two other studies in the Liu et al meta-analysis were published after the search dates of this meta-analysis.

Baseline BP wasn’t reported, and treatment resistance was not explicitly defined. Treatment groups received CPAP for 3 to 6 months in addition to their pharmacotherapy regimen, but duration of nightly use was not reported; control groups received only pharmacotherapy. The number and type of antihypertensive medications used was not reported.

Pooled data from the subgroup noted a significant difference in 24-hour mean ambulatory BPs in the CPAP group compared with controls. Systolic BP decreased by 3.9 mm Hg (95% CI, −6.6 to −1.2) and diastolic BP decreased by 3.7 mm Hg (95% CI, −5.2 to −2.1).

The Centers for Disease Control and Prevention (CDC) recently reported details of the 2016-2017 influenza season in Morbidity and Mortality Weekly Report¹ and at the June meeting of the Advisory Committee on Immunization Practices. The CDC monitors influenza activity using several systems, and last flu season was shown to be moderately severe, starting in December in the Western United States, moving east, and peaking in February.

During the peak, 5.1% of outpatient visits were attributed to influenza-like illnesses, and 8.2% of reported deaths were due to pneumonia and influenza. For the whole influenza season, there were more than 18,000 confirmed influenza-related hospitalizations, with 60% of these occurring among those ≥65 years.¹ Confirmed influenza-associated pediatric deaths totaled 98.¹

The predominant influenza strain last year was type A (H3N2), accounting for about 76% of positive tests in public health laboratories (FIGURE).¹ This was followed by influenza B (all lineages) at 22%, and influenza A (H1N1), accounting for only 2%. However, in early April, the predominant strain changed from A (H3N2) to influenza B. Importantly, all viruses tested last year were sensitive to oseltamivir, zanamivir, and peramivir. No antiviral resistance was detected to these neuraminidase inhibitors.

Good news and bad news on vaccine effectiveness. The good news: Circulating viruses were a close match to those contained in the vaccine. The bad news: Vaccine effectiveness at preventing illness was estimated to be just 34% against A (H3N2) and 56% against influenza B viruses.¹ There has been no analysis of the relative effectiveness of different vaccines and vaccine types.

The past 6 influenza seasons have revealed a pattern of lower vaccine effectiveness against A (H3N2) compared with effectiveness against A (H1N1) and influenza B viruses. While vaccine effectiveness is not optimal, routine universal use still prevents a great deal of mortality and morbidity. It’s estimated that in 2012-2013, vaccine effectiveness (comparable to that in 2016-2017) prevented 5.6 million illnesses, 2.7 million medical visits, 61,500 hospitalizations, and 1800 deaths.¹

More good news: Vaccine safety studies are reassuring

The CDC monitors influenza vaccine safety by using several sources, including the Vaccine Adverse Event Reporting System and the Vaccine Safety Datalink.² Studies were conducted using the Datalink network to assess incidences of anaphylaxis, Bell’s palsy, encephalitis, Guillain-Barré syndrome, seizures, and transverse myelitis. No increases in any of these conditions were found to be related to the influenza vaccine; nor were any new safety concerns detected.

Changes for the 2017-2018 influenza season

The composition of influenza vaccine products for the 2017-2018 season will differ slightly from last year’s formulation in the H1N1 component. Viral antigens to be included in the trivalent products are A/Michigan (H1N1), A/Hong Kong (H3N2), and B/Brisbane.³ Quadrivalent products will add B/Phuket to the other 3 antigens.³ A wide array of influenza vaccine products is available. Each one is described on the CDC Web site.⁴

Two minor changes in the recommendations were made at the June ACIP meeting.⁵ Afluria is approved by the FDA for use in children starting at age 5 years. ACIP had recommended that its use be reserved for children 9 years and older because previous influenza seasons had raised concerns about increased rates of febrile seizures in children younger than age 9. These concerns have been resolved, however, and the ACIP recommendations are now in concert with those of the FDA for this product.

Influenza immunization with an inactivated influenza vaccine product has been recommended for all pregnant women. Safety data are increasingly available for other product options as well, and ACIP now recommends vaccination in pregnancy with any age-appropriate product except for live attenuated influenza vaccine. ⁵

Antivirals: Give as needed, even before lab confirmation

The CDC recommends antiviral medication for individuals with confirmed or suspected influenza who have severe, complicated, or progressive illness, who require hospitalization, or who are at high risk of complications from influenza (TABLE⁶). Start treatment without waiting for laboratory confirmation for those with suspected influenza who are seriously ill. Outcomes are best when antivirals are started within 48 hours of illness onset, but they can be started even after this “window” has passed.

Once antiviral treatment has begun, make sure the full 5-day course is completed regardless of culture or rapid-test results.⁶ Use only neuraminidase inhibitors, as there is widespread resistance to adamantanes among influenza A viruses.

Influenza can occur year round

Rates of influenza infection are low in the summer, but cases do occur. Be especially alert if patients with influenza-like illness have been exposed to swine or poultry; they may have contracted a novel influenza A virus. Report such cases to the state or local health department so that staff can facilitate laboratory testing of viral subtypes. Follow the same protocol for patients with influenza symptoms who have traveled to areas where avian influenza viruses have been detected. The CDC is interested in detecting novel influenza viruses, which can start a pandemic.

Prepare for the 2017-2018 influenza season

Family physicians can help prevent influenza and its associated morbidity and mortality in several ways. Offer immunization to all patients, and immunize all health care personnel in your offices and clinics. Treat with antivirals those for whom they are recommended. Prepare office triage policies that prevent patients with flu symptoms from mixing with other patients, ensure that clinic infection control practices are enforced, and advise ill patients to avoid exposing others.⁷ Finally, stay current on influenza epidemiology and changes in recommendations for treatment and vaccination.

The Centers for Disease Control and Prevention (CDC) recently reported details of the 2016-2017 influenza season in Morbidity and Mortality Weekly Report¹ and at the June meeting of the Advisory Committee on Immunization Practices. The CDC monitors influenza activity using several systems, and last flu season was shown to be moderately severe, starting in December in the Western United States, moving east, and peaking in February.

During the peak, 5.1% of outpatient visits were attributed to influenza-like illnesses, and 8.2% of reported deaths were due to pneumonia and influenza. For the whole influenza season, there were more than 18,000 confirmed influenza-related hospitalizations, with 60% of these occurring among those ≥65 years.¹ Confirmed influenza-associated pediatric deaths totaled 98.¹

The predominant influenza strain last year was type A (H3N2), accounting for about 76% of positive tests in public health laboratories (FIGURE).¹ This was followed by influenza B (all lineages) at 22%, and influenza A (H1N1), accounting for only 2%. However, in early April, the predominant strain changed from A (H3N2) to influenza B. Importantly, all viruses tested last year were sensitive to oseltamivir, zanamivir, and peramivir. No antiviral resistance was detected to these neuraminidase inhibitors.

Good news and bad news on vaccine effectiveness. The good news: Circulating viruses were a close match to those contained in the vaccine. The bad news: Vaccine effectiveness at preventing illness was estimated to be just 34% against A (H3N2) and 56% against influenza B viruses.¹ There has been no analysis of the relative effectiveness of different vaccines and vaccine types.

The past 6 influenza seasons have revealed a pattern of lower vaccine effectiveness against A (H3N2) compared with effectiveness against A (H1N1) and influenza B viruses. While vaccine effectiveness is not optimal, routine universal use still prevents a great deal of mortality and morbidity. It’s estimated that in 2012-2013, vaccine effectiveness (comparable to that in 2016-2017) prevented 5.6 million illnesses, 2.7 million medical visits, 61,500 hospitalizations, and 1800 deaths.¹

More good news: Vaccine safety studies are reassuring

The CDC monitors influenza vaccine safety by using several sources, including the Vaccine Adverse Event Reporting System and the Vaccine Safety Datalink.² Studies were conducted using the Datalink network to assess incidences of anaphylaxis, Bell’s palsy, encephalitis, Guillain-Barré syndrome, seizures, and transverse myelitis. No increases in any of these conditions were found to be related to the influenza vaccine; nor were any new safety concerns detected.

Changes for the 2017-2018 influenza season

The composition of influenza vaccine products for the 2017-2018 season will differ slightly from last year’s formulation in the H1N1 component. Viral antigens to be included in the trivalent products are A/Michigan (H1N1), A/Hong Kong (H3N2), and B/Brisbane.³ Quadrivalent products will add B/Phuket to the other 3 antigens.³ A wide array of influenza vaccine products is available. Each one is described on the CDC Web site.⁴

Two minor changes in the recommendations were made at the June ACIP meeting.⁵ Afluria is approved by the FDA for use in children starting at age 5 years. ACIP had recommended that its use be reserved for children 9 years and older because previous influenza seasons had raised concerns about increased rates of febrile seizures in children younger than age 9. These concerns have been resolved, however, and the ACIP recommendations are now in concert with those of the FDA for this product.

Influenza immunization with an inactivated influenza vaccine product has been recommended for all pregnant women. Safety data are increasingly available for other product options as well, and ACIP now recommends vaccination in pregnancy with any age-appropriate product except for live attenuated influenza vaccine. ⁵

Antivirals: Give as needed, even before lab confirmation

The CDC recommends antiviral medication for individuals with confirmed or suspected influenza who have severe, complicated, or progressive illness, who require hospitalization, or who are at high risk of complications from influenza (TABLE⁶). Start treatment without waiting for laboratory confirmation for those with suspected influenza who are seriously ill. Outcomes are best when antivirals are started within 48 hours of illness onset, but they can be started even after this “window” has passed.

Once antiviral treatment has begun, make sure the full 5-day course is completed regardless of culture or rapid-test results.⁶ Use only neuraminidase inhibitors, as there is widespread resistance to adamantanes among influenza A viruses.

Influenza can occur year round

Rates of influenza infection are low in the summer, but cases do occur. Be especially alert if patients with influenza-like illness have been exposed to swine or poultry; they may have contracted a novel influenza A virus. Report such cases to the state or local health department so that staff can facilitate laboratory testing of viral subtypes. Follow the same protocol for patients with influenza symptoms who have traveled to areas where avian influenza viruses have been detected. The CDC is interested in detecting novel influenza viruses, which can start a pandemic.

Prepare for the 2017-2018 influenza season

Family physicians can help prevent influenza and its associated morbidity and mortality in several ways. Offer immunization to all patients, and immunize all health care personnel in your offices and clinics. Treat with antivirals those for whom they are recommended. Prepare office triage policies that prevent patients with flu symptoms from mixing with other patients, ensure that clinic infection control practices are enforced, and advise ill patients to avoid exposing others.⁷ Finally, stay current on influenza epidemiology and changes in recommendations for treatment and vaccination.

The Centers for Disease Control and Prevention (CDC) recently reported details of the 2016-2017 influenza season in Morbidity and Mortality Weekly Report¹ and at the June meeting of the Advisory Committee on Immunization Practices. The CDC monitors influenza activity using several systems, and last flu season was shown to be moderately severe, starting in December in the Western United States, moving east, and peaking in February.

During the peak, 5.1% of outpatient visits were attributed to influenza-like illnesses, and 8.2% of reported deaths were due to pneumonia and influenza. For the whole influenza season, there were more than 18,000 confirmed influenza-related hospitalizations, with 60% of these occurring among those ≥65 years.¹ Confirmed influenza-associated pediatric deaths totaled 98.¹

The predominant influenza strain last year was type A (H3N2), accounting for about 76% of positive tests in public health laboratories (FIGURE).¹ This was followed by influenza B (all lineages) at 22%, and influenza A (H1N1), accounting for only 2%. However, in early April, the predominant strain changed from A (H3N2) to influenza B. Importantly, all viruses tested last year were sensitive to oseltamivir, zanamivir, and peramivir. No antiviral resistance was detected to these neuraminidase inhibitors.

Good news and bad news on vaccine effectiveness. The good news: Circulating viruses were a close match to those contained in the vaccine. The bad news: Vaccine effectiveness at preventing illness was estimated to be just 34% against A (H3N2) and 56% against influenza B viruses.¹ There has been no analysis of the relative effectiveness of different vaccines and vaccine types.

The past 6 influenza seasons have revealed a pattern of lower vaccine effectiveness against A (H3N2) compared with effectiveness against A (H1N1) and influenza B viruses. While vaccine effectiveness is not optimal, routine universal use still prevents a great deal of mortality and morbidity. It’s estimated that in 2012-2013, vaccine effectiveness (comparable to that in 2016-2017) prevented 5.6 million illnesses, 2.7 million medical visits, 61,500 hospitalizations, and 1800 deaths.¹

More good news: Vaccine safety studies are reassuring

The CDC monitors influenza vaccine safety by using several sources, including the Vaccine Adverse Event Reporting System and the Vaccine Safety Datalink.² Studies were conducted using the Datalink network to assess incidences of anaphylaxis, Bell’s palsy, encephalitis, Guillain-Barré syndrome, seizures, and transverse myelitis. No increases in any of these conditions were found to be related to the influenza vaccine; nor were any new safety concerns detected.

Changes for the 2017-2018 influenza season

The composition of influenza vaccine products for the 2017-2018 season will differ slightly from last year’s formulation in the H1N1 component. Viral antigens to be included in the trivalent products are A/Michigan (H1N1), A/Hong Kong (H3N2), and B/Brisbane.³ Quadrivalent products will add B/Phuket to the other 3 antigens.³ A wide array of influenza vaccine products is available. Each one is described on the CDC Web site.⁴

Two minor changes in the recommendations were made at the June ACIP meeting.⁵ Afluria is approved by the FDA for use in children starting at age 5 years. ACIP had recommended that its use be reserved for children 9 years and older because previous influenza seasons had raised concerns about increased rates of febrile seizures in children younger than age 9. These concerns have been resolved, however, and the ACIP recommendations are now in concert with those of the FDA for this product.

Influenza immunization with an inactivated influenza vaccine product has been recommended for all pregnant women. Safety data are increasingly available for other product options as well, and ACIP now recommends vaccination in pregnancy with any age-appropriate product except for live attenuated influenza vaccine. ⁵

Antivirals: Give as needed, even before lab confirmation

The CDC recommends antiviral medication for individuals with confirmed or suspected influenza who have severe, complicated, or progressive illness, who require hospitalization, or who are at high risk of complications from influenza (TABLE⁶). Start treatment without waiting for laboratory confirmation for those with suspected influenza who are seriously ill. Outcomes are best when antivirals are started within 48 hours of illness onset, but they can be started even after this “window” has passed.

Once antiviral treatment has begun, make sure the full 5-day course is completed regardless of culture or rapid-test results.⁶ Use only neuraminidase inhibitors, as there is widespread resistance to adamantanes among influenza A viruses.

Influenza can occur year round

Rates of influenza infection are low in the summer, but cases do occur. Be especially alert if patients with influenza-like illness have been exposed to swine or poultry; they may have contracted a novel influenza A virus. Report such cases to the state or local health department so that staff can facilitate laboratory testing of viral subtypes. Follow the same protocol for patients with influenza symptoms who have traveled to areas where avian influenza viruses have been detected. The CDC is interested in detecting novel influenza viruses, which can start a pandemic.

Prepare for the 2017-2018 influenza season

Family physicians can help prevent influenza and its associated morbidity and mortality in several ways. Offer immunization to all patients, and immunize all health care personnel in your offices and clinics. Treat with antivirals those for whom they are recommended. Prepare office triage policies that prevent patients with flu symptoms from mixing with other patients, ensure that clinic infection control practices are enforced, and advise ill patients to avoid exposing others.⁷ Finally, stay current on influenza epidemiology and changes in recommendations for treatment and vaccination.

International travel, whether for business, pleasure, child adoption, medical tourism, or adventure, continues to grow. In 2015, more than 70 million US citizens traveled internationally.¹ Many individuals contact family physicians first about their plans for travel and questions about travel-related health advice. This article provides an overview of the vaccines recommended for travelers headed to international destinations. Because country-specific vaccination recommendations and requirements for entry and departure change over time, check the Centers for Disease Control and Prevention (CDC) Web site for up-to-date requirements and recommendations (www.cdc.gov/travel).

Vaccine schedules vary according to destination and individual risks

There is no single vaccination schedule that applies to all travelers. Each schedule should be individualized based on the traveler’s destination, risk assessment, previous immunizations, health status, and time available before departure.^2,3 Pregnant or immunocompromised travelers should seek advice from an experienced travel medicine consultant on the immunization recommendations specifically meant for them.^4,5

Travel vaccines (TABLE⁶) are generally categorized as routine, required, or recommended.

1. Routine vaccines are the standard child and adult immunizations recommended by the Advisory Committee on Immunization Practices (ACIP). These include such vaccines as diphtheria-tetanus toxoids-acellular pertussis (DTaP), inactivated polio vaccine (IPV), Haemophilus influenzae type b (Hib), hepatitis B, rotavirus and pneumococcal vaccines, and human papillomavirus (HPV).
2. Required vaccines—eg, yellow fever and meningococcal vaccines—must be documented on the International Certificate of Vaccination before entry into certain countries.
3. Recommended vaccines are advised based on the travel destination and anticipated activities. These would include vaccines for typhoid, rabies, Japanese encephalitis, and polio (adult booster).

Routine vaccinations may need to be accelerated

Pre-travel patient encounters are an opportunity to update routine vaccinations.^7,8 Immunization against childhood diseases remains suboptimal in developing countries, where vaccine-preventable illnesses occur more frequently.⁹

Routine vaccines may be administered on an accelerated basis depending on geographic destination, seasonal disease variations, anticipated exposures, and known outbreaks at the time of travel.

MMR vaccine. Measles is still common in many parts of the world, and unvaccinated or incompletely vaccinated travelers are at risk of acquiring the disease and importing it to the United States (see “Measles: Why it’s still a threat,” 2017;66:446-449.) In 2015, a large, widespread measles outbreak occurred in the United States, linked to an amusement park in California, likely originating with an infected traveler who visited the park.¹⁰

Flu vaccine is recommended for all travelers ≥6 months of age, as flu season varies internationally.

All children older than 12 months should receive 2 doses of measles-mumps-rubella (MMR) vaccine separated by at least 28 days before departure (regardless of their destination). Infants between 6 and 11 months are at risk for high morbidity and may therefore receive a single dose of MMR earlier than the routinely recommended age of 12 to 15 months. Adolescents and adults without evidence of immunity against measles should get 2 doses of MMR separated by at least 28 days.¹¹ Acceptable presumptive evidence of immunity against measles includes written documentation of adequate vaccination, laboratory evidence of immunity, laboratory confirmation of measles, or birth before 1957.

Varicella vaccine. Children, adolescents, and young adults who have received only one dose of varicella should get a second dose prior to departure. For children 7 to 12 years, the recommended minimum interval between doses is 3 months. For individuals 13 years or older, the minimum interval is 4 weeks.^7,8

Influenza vaccine is routinely recommended for all travelers 6 months of age or older, as flu season varies geographically. Flu season in the Northern Hemisphere may begin as early as October and can extend until May. In the Southern Hemisphere, it may begin in April and last through September. Travelers should be vaccinated at least 2 weeks before travel in order to develop adequate immunity.^12,13

Required vaccinations: Proof is needed before traveling

Yellow fever (YF) is a mosquito-borne viral illness characterized by fever, chills, headache, myalgia, and vomiting. The disease can progress to coagulopathy, shock, and multisystem organ failure.¹⁴ YF vaccine is recommended for individuals 9 months or older who are traveling to or living in areas of South America or Africa where YF virus transmission is common (map: http://www.cdc.gov/yellowfever/maps/).

YF vaccine is a live-attenuated virus formulation and, therefore, should not be given to individuals with primary immunodeficiencies, transplant recipients or patients on immunosuppressive and immunomodulatory therapies, or patients with human immunodeficiency virus (HIV) whose CD4 count is below 200/mL. Other contraindications to YF vaccine are age younger than 6 months, allergy to a vaccine component, and thymic disorders. Serious adverse reactions to the vaccine are rare, but include 2 syndromes: YF-associated neurotropic disease and YF vaccine-associated viscerotropic disease.¹⁵

In many YF-endemic countries, vaccination is legally required for entry, and proof of vaccination must be documented on an International Certificate of Vaccination or Prophylaxis (ICVP). Additionally, some countries may require proof of vaccination before allowing travel through an endemic region, to prevent introduction of the disease elsewhere. Travelers with a specific contraindication to YF vaccine should obtain a waiver from a physician before traveling to a country requiring vaccination.¹⁶

The vaccination certificate is valid beginning 10 days after administration of YF vaccine. Immunity after a single dose is long lasting and may provide lifetime protection. Previously, re-vaccination was required every 10 years; however, in February 2015, ACIP approved a new recommendation stating a single dose of YF vaccine is adequate for most travelers.¹⁷

Many countries in which yellow fever is endemic don't allow entry without proof of vaccination on an International Certificate of Vaccination or Prophylaxis.

Although ACIP no longer recommends booster doses of YF vaccine for most travelers, clinicians and travelers should review the entry requirements for destination countries because changes to the International Health Regulations have not yet been fully implemented. Once this change is instituted, a completed ICVP will be valid for the lifetime of the vaccine.^18,19 Country-specific requirements for YF can be found at http://www.cdc.gov/yellowfever/maps/. (Click on the link below the appropriate map.) In the United States, the YF vaccine is distributed only through approved vaccination centers. These designated clinics are listed in a registry on the CDC travel Web site at https://wwwnc.cdc.gov/travel/yellow-fever-vaccination-clinics/search.

Meningococcal disease. ACIP recommends routine vaccination against meningococcal disease for people 11 to 18 years of age and for individuals with persistent complement component deficiency, functional or anatomic asplenia, and HIV. Vaccination is recommended for travelers who visit or reside in areas where meningococcal disease is hyperendemic or epidemic, such as the meningitis belt of sub-Saharan Africa during the dry season of December to June (map: http://wwwnc.cdc.gov/travel/yellowbook/2016/infectious-diseases-related-to-travel/meningococcal-disease). Travelers to Saudi Arabia during the annual Hajj and Umrah pilgrimages are required to have a certificate of vaccination with quadrivalent (serogroups A, C, Y, W-135) meningococcal vaccine issued within 3 years (and not less than 10 days) before entry.

Several meningococcal vaccines are available in the United States. The quadrivalent vaccines are Menactra (MenACWY-D, Sanofi Pasteur) and Menveo (MenACWY-CRM, GSK). A bivalent (serogroups C and Y) conjugate vaccine MenHibrix (Hib-MenCY-TT, GSK) is also licensed for use in the United States, but infants traveling to areas with high endemic rates of meningococcal disease who received this vaccine are not protected against serogroups A and W and should receive quadrivalent meningococcal conjugate vaccine. Serogroup B vaccination is not routinely recommended for travelers. Approximately 7 to 10 days are required after vaccination for the development of protective antibody levels.^7,8,20,21

Polio. Although polio has been nearly eradicated, as of the time this article was written, the disease has not been eliminated in Afghanistan, Guinea, Laos, Nigeria, or Pakistan. Other countries, such as Cameroon, Chad, and Ukraine remain vulnerable to international transmission.²² The CDC recommends that adults who are traveling to areas where wild polio virus (WPV) has circulated in the last 12 months and who are unvaccinated, incompletely vaccinated, or whose vaccination status is unknown should receive a series of 3 doses of IPV to prevent ongoing spread.²³ Adults who completed the polio vaccine series as children and are traveling to areas where WPV has circulated in the last 12 months should receive a one-time booster dose of IPV.²³

Infants and children in the United States should be vaccinated against polio as part of a routine age-appropriate series. If a child cannot complete the routine series before departure and is traveling to an area where WPV has circulated in the last 12 months, an accelerated schedule is recommended. Vaccination should be documented on the ICVP, as countries with active spread of poliovirus may require proof of polio vaccination upon exit. A list of the countries where the polio virus is currently circulating is available at http://polioeradication.org/polio-today/polio-now/wild-poliovirus-list/.

Both routine and accelerated vaccination schedules for children and adults are published annually by the CDC and are available at http://www.cdc.gov/vaccines/schedules/hcp/index.html.

Recommended vaccines

Japanese encephalitis (JE) is endemic throughout most of Asia and parts of the Western Pacific region (map: http://www.cdc.gov/japaneseencephalitis/maps/). JE vaccine is recommended for travelers who plan to spend more than a month in endemic areas during the JE virus transmission season. (In temperate areas of Asia, JE virus transmission is seasonal and usually peaks in the summer and fall. In the subtropics and tropics, transmission can occur year-round, often with a peak during the rainy season.)

Adults who completed the polio vaccine series as children and are traveling where wild polio virus has circulated in the last 12 months should receive a one-time booster dose of IPV.

This recommendation includes recurrent travelers or expatriates who are likely to visit endemic rural or agricultural areas during a high-risk period of JE virus transmission. Risk is low for travelers who spend less than a month in endemic areas and for those who confine their travel to urban centers. Nevertheless, vaccination should be considered if travel is planned for outside an urban area and includes such activities as camping, hiking, trekking, biking, fishing, hunting, or farming. Inactivated Vero cell culture-derived vaccine (Ixiaro) is the only JE vaccine licensed and available in the United States. Ixiaro is given as a 2-dose series, with the doses spaced 28 days apart. The last dose should be given at least one week before travel.²⁴

Typhoid fever. Vaccination against typhoid fever is recommended for travelers to highly endemic areas such as the Indian subcontinent, Africa, and Central and South America. Two typhoid vaccines are available: Vi capsular polysaccharide vaccine (ViCPS) administered intramuscularly (IM), and oral live attenuated vaccine (Ty21a). Ty21a is a live vaccine and should not be given to immunocompromised people or those taking antibiotics, as it may reduce immunogenicity. Ty21a must be kept refrigerated at 35.6° F to 46.4° F (2° C - 8° C) and administered with cool liquid no warmer than 98.6° F (37° C). Both vaccines are only 50% to 80% efficacious, making access to clean food and water essential.^3,5,25

Hepatitis A vaccine should be given to all children older than one year traveling to areas where there is an intermediate or high risk of the disease. Children younger than one year who are traveling to high-risk areas can receive a single dose of immunoglobulin (IG) 0.02 mL/kg IM, which provides protection for up to 3 months. One 0.06 mL/kg-dose IM provides protection for 3 to 5 months.

If travel continues, children should receive a second dose after 5 months. IG does not interfere with the response to YF vaccine, but can interfere with the response to other live injected vaccines (such as MMR and varicella).²⁶

Hepatitis B vaccination should be administered to all unvaccinated travelers who plan to visit an area with intermediate to high prevalence of chronic hepatitis B (HBV surface antigen prevalence ≥2%). Unvaccinated travelers who may engage in high-risk sexual activity or injection drug use should receive hepatitis B vaccine regardless of destination. Additionally, travelers who access medical care for injury or illness while abroad may also be at risk of acquiring hepatitis B via contaminated blood products or medical equipment.²⁷

Serologic testing and booster vaccination are not recommended before travel for immunocompetent adults who have been previously vaccinated. The combined hepatitis A and B vaccine provides effective and convenient dual protection for travelers and can be administered with an accelerated 0-, 7-, and 21-day schedule for last-minute travelers.^7,8

Rabies remains endemic in developing countries of Africa and Asia, where appropriate post-exposure prophylaxis is limited or non-existent.²⁸ Consider pre-exposure rabies prophylaxis for traveling patients based on the availability of rabies vaccine and immunoglobulin in their destination area, planned duration of stay, and the likelihood of animal exposure (eg, veterinarians, animal handlers, cavers, missionaries). Advise travelers who decline vaccination to avoid or minimize animal contact during travel. In the event the traveler sustains an animal bite or scratch, immediate cleansing of the wound substantially reduces the risk of infection, especially when followed by timely administration of post-exposure prophylaxis.

In the event of an animal bite or scratch, immediate cleansing of the wound significantly reduces the risk of rabies infection.

Post-exposure prophylaxis for unvaccinated individuals consists of local infiltration of rabies immunoglobulin at the site of the bite and a series of 4 injections of rabies vaccine over 14 days, or 5 doses over one month for immunosuppressed patients. The first dose of the 4-dose course should be administered as soon as possible after exposure. Two vaccines are licensed for use in the United States: human diploid cell vaccine (HDCV, Imovax Rabies, Sanofi Pasteur) and purified chick embryo cell vaccine (PCECV, RabAvert, Novartis Vaccines and Diagnostics). The vaccine should never be administered in the gluteal area, as this may result in lower antibody titers.²⁹

Additionally, promising new vaccines against malaria and dengue fever are under clinical development and may be available in the near future.

CORRESPONDENCE
Vini Vijayan, MD, Division of Infectious Diseases, Arkansas Children's Hospital, 1 Children's Way, Slot 512-11, Little Rock, AR 72202; [email protected]. 

International travel, whether for business, pleasure, child adoption, medical tourism, or adventure, continues to grow. In 2015, more than 70 million US citizens traveled internationally.¹ Many individuals contact family physicians first about their plans for travel and questions about travel-related health advice. This article provides an overview of the vaccines recommended for travelers headed to international destinations. Because country-specific vaccination recommendations and requirements for entry and departure change over time, check the Centers for Disease Control and Prevention (CDC) Web site for up-to-date requirements and recommendations (www.cdc.gov/travel).

Vaccine schedules vary according to destination and individual risks

There is no single vaccination schedule that applies to all travelers. Each schedule should be individualized based on the traveler’s destination, risk assessment, previous immunizations, health status, and time available before departure.^2,3 Pregnant or immunocompromised travelers should seek advice from an experienced travel medicine consultant on the immunization recommendations specifically meant for them.^4,5

Travel vaccines (TABLE⁶) are generally categorized as routine, required, or recommended.

1. Routine vaccines are the standard child and adult immunizations recommended by the Advisory Committee on Immunization Practices (ACIP). These include such vaccines as diphtheria-tetanus toxoids-acellular pertussis (DTaP), inactivated polio vaccine (IPV), Haemophilus influenzae type b (Hib), hepatitis B, rotavirus and pneumococcal vaccines, and human papillomavirus (HPV).
2. Required vaccines—eg, yellow fever and meningococcal vaccines—must be documented on the International Certificate of Vaccination before entry into certain countries.
3. Recommended vaccines are advised based on the travel destination and anticipated activities. These would include vaccines for typhoid, rabies, Japanese encephalitis, and polio (adult booster).

Routine vaccinations may need to be accelerated

Pre-travel patient encounters are an opportunity to update routine vaccinations.^7,8 Immunization against childhood diseases remains suboptimal in developing countries, where vaccine-preventable illnesses occur more frequently.⁹

Routine vaccines may be administered on an accelerated basis depending on geographic destination, seasonal disease variations, anticipated exposures, and known outbreaks at the time of travel.

MMR vaccine. Measles is still common in many parts of the world, and unvaccinated or incompletely vaccinated travelers are at risk of acquiring the disease and importing it to the United States (see “Measles: Why it’s still a threat,” 2017;66:446-449.) In 2015, a large, widespread measles outbreak occurred in the United States, linked to an amusement park in California, likely originating with an infected traveler who visited the park.¹⁰

Flu vaccine is recommended for all travelers ≥6 months of age, as flu season varies internationally.

All children older than 12 months should receive 2 doses of measles-mumps-rubella (MMR) vaccine separated by at least 28 days before departure (regardless of their destination). Infants between 6 and 11 months are at risk for high morbidity and may therefore receive a single dose of MMR earlier than the routinely recommended age of 12 to 15 months. Adolescents and adults without evidence of immunity against measles should get 2 doses of MMR separated by at least 28 days.¹¹ Acceptable presumptive evidence of immunity against measles includes written documentation of adequate vaccination, laboratory evidence of immunity, laboratory confirmation of measles, or birth before 1957.

Varicella vaccine. Children, adolescents, and young adults who have received only one dose of varicella should get a second dose prior to departure. For children 7 to 12 years, the recommended minimum interval between doses is 3 months. For individuals 13 years or older, the minimum interval is 4 weeks.^7,8

Influenza vaccine is routinely recommended for all travelers 6 months of age or older, as flu season varies geographically. Flu season in the Northern Hemisphere may begin as early as October and can extend until May. In the Southern Hemisphere, it may begin in April and last through September. Travelers should be vaccinated at least 2 weeks before travel in order to develop adequate immunity.^12,13

Required vaccinations: Proof is needed before traveling

Yellow fever (YF) is a mosquito-borne viral illness characterized by fever, chills, headache, myalgia, and vomiting. The disease can progress to coagulopathy, shock, and multisystem organ failure.¹⁴ YF vaccine is recommended for individuals 9 months or older who are traveling to or living in areas of South America or Africa where YF virus transmission is common (map: http://www.cdc.gov/yellowfever/maps/).

YF vaccine is a live-attenuated virus formulation and, therefore, should not be given to individuals with primary immunodeficiencies, transplant recipients or patients on immunosuppressive and immunomodulatory therapies, or patients with human immunodeficiency virus (HIV) whose CD4 count is below 200/mL. Other contraindications to YF vaccine are age younger than 6 months, allergy to a vaccine component, and thymic disorders. Serious adverse reactions to the vaccine are rare, but include 2 syndromes: YF-associated neurotropic disease and YF vaccine-associated viscerotropic disease.¹⁵

In many YF-endemic countries, vaccination is legally required for entry, and proof of vaccination must be documented on an International Certificate of Vaccination or Prophylaxis (ICVP). Additionally, some countries may require proof of vaccination before allowing travel through an endemic region, to prevent introduction of the disease elsewhere. Travelers with a specific contraindication to YF vaccine should obtain a waiver from a physician before traveling to a country requiring vaccination.¹⁶

The vaccination certificate is valid beginning 10 days after administration of YF vaccine. Immunity after a single dose is long lasting and may provide lifetime protection. Previously, re-vaccination was required every 10 years; however, in February 2015, ACIP approved a new recommendation stating a single dose of YF vaccine is adequate for most travelers.¹⁷

Many countries in which yellow fever is endemic don't allow entry without proof of vaccination on an International Certificate of Vaccination or Prophylaxis.

Although ACIP no longer recommends booster doses of YF vaccine for most travelers, clinicians and travelers should review the entry requirements for destination countries because changes to the International Health Regulations have not yet been fully implemented. Once this change is instituted, a completed ICVP will be valid for the lifetime of the vaccine.^18,19 Country-specific requirements for YF can be found at http://www.cdc.gov/yellowfever/maps/. (Click on the link below the appropriate map.) In the United States, the YF vaccine is distributed only through approved vaccination centers. These designated clinics are listed in a registry on the CDC travel Web site at https://wwwnc.cdc.gov/travel/yellow-fever-vaccination-clinics/search.

Meningococcal disease. ACIP recommends routine vaccination against meningococcal disease for people 11 to 18 years of age and for individuals with persistent complement component deficiency, functional or anatomic asplenia, and HIV. Vaccination is recommended for travelers who visit or reside in areas where meningococcal disease is hyperendemic or epidemic, such as the meningitis belt of sub-Saharan Africa during the dry season of December to June (map: http://wwwnc.cdc.gov/travel/yellowbook/2016/infectious-diseases-related-to-travel/meningococcal-disease). Travelers to Saudi Arabia during the annual Hajj and Umrah pilgrimages are required to have a certificate of vaccination with quadrivalent (serogroups A, C, Y, W-135) meningococcal vaccine issued within 3 years (and not less than 10 days) before entry.

Several meningococcal vaccines are available in the United States. The quadrivalent vaccines are Menactra (MenACWY-D, Sanofi Pasteur) and Menveo (MenACWY-CRM, GSK). A bivalent (serogroups C and Y) conjugate vaccine MenHibrix (Hib-MenCY-TT, GSK) is also licensed for use in the United States, but infants traveling to areas with high endemic rates of meningococcal disease who received this vaccine are not protected against serogroups A and W and should receive quadrivalent meningococcal conjugate vaccine. Serogroup B vaccination is not routinely recommended for travelers. Approximately 7 to 10 days are required after vaccination for the development of protective antibody levels.^7,8,20,21

Polio. Although polio has been nearly eradicated, as of the time this article was written, the disease has not been eliminated in Afghanistan, Guinea, Laos, Nigeria, or Pakistan. Other countries, such as Cameroon, Chad, and Ukraine remain vulnerable to international transmission.²² The CDC recommends that adults who are traveling to areas where wild polio virus (WPV) has circulated in the last 12 months and who are unvaccinated, incompletely vaccinated, or whose vaccination status is unknown should receive a series of 3 doses of IPV to prevent ongoing spread.²³ Adults who completed the polio vaccine series as children and are traveling to areas where WPV has circulated in the last 12 months should receive a one-time booster dose of IPV.²³

Infants and children in the United States should be vaccinated against polio as part of a routine age-appropriate series. If a child cannot complete the routine series before departure and is traveling to an area where WPV has circulated in the last 12 months, an accelerated schedule is recommended. Vaccination should be documented on the ICVP, as countries with active spread of poliovirus may require proof of polio vaccination upon exit. A list of the countries where the polio virus is currently circulating is available at http://polioeradication.org/polio-today/polio-now/wild-poliovirus-list/.

Both routine and accelerated vaccination schedules for children and adults are published annually by the CDC and are available at http://www.cdc.gov/vaccines/schedules/hcp/index.html.

Recommended vaccines

Japanese encephalitis (JE) is endemic throughout most of Asia and parts of the Western Pacific region (map: http://www.cdc.gov/japaneseencephalitis/maps/). JE vaccine is recommended for travelers who plan to spend more than a month in endemic areas during the JE virus transmission season. (In temperate areas of Asia, JE virus transmission is seasonal and usually peaks in the summer and fall. In the subtropics and tropics, transmission can occur year-round, often with a peak during the rainy season.)

Adults who completed the polio vaccine series as children and are traveling where wild polio virus has circulated in the last 12 months should receive a one-time booster dose of IPV.

This recommendation includes recurrent travelers or expatriates who are likely to visit endemic rural or agricultural areas during a high-risk period of JE virus transmission. Risk is low for travelers who spend less than a month in endemic areas and for those who confine their travel to urban centers. Nevertheless, vaccination should be considered if travel is planned for outside an urban area and includes such activities as camping, hiking, trekking, biking, fishing, hunting, or farming. Inactivated Vero cell culture-derived vaccine (Ixiaro) is the only JE vaccine licensed and available in the United States. Ixiaro is given as a 2-dose series, with the doses spaced 28 days apart. The last dose should be given at least one week before travel.²⁴

Typhoid fever. Vaccination against typhoid fever is recommended for travelers to highly endemic areas such as the Indian subcontinent, Africa, and Central and South America. Two typhoid vaccines are available: Vi capsular polysaccharide vaccine (ViCPS) administered intramuscularly (IM), and oral live attenuated vaccine (Ty21a). Ty21a is a live vaccine and should not be given to immunocompromised people or those taking antibiotics, as it may reduce immunogenicity. Ty21a must be kept refrigerated at 35.6° F to 46.4° F (2° C - 8° C) and administered with cool liquid no warmer than 98.6° F (37° C). Both vaccines are only 50% to 80% efficacious, making access to clean food and water essential.^3,5,25

Hepatitis A vaccine should be given to all children older than one year traveling to areas where there is an intermediate or high risk of the disease. Children younger than one year who are traveling to high-risk areas can receive a single dose of immunoglobulin (IG) 0.02 mL/kg IM, which provides protection for up to 3 months. One 0.06 mL/kg-dose IM provides protection for 3 to 5 months.

If travel continues, children should receive a second dose after 5 months. IG does not interfere with the response to YF vaccine, but can interfere with the response to other live injected vaccines (such as MMR and varicella).²⁶

Hepatitis B vaccination should be administered to all unvaccinated travelers who plan to visit an area with intermediate to high prevalence of chronic hepatitis B (HBV surface antigen prevalence ≥2%). Unvaccinated travelers who may engage in high-risk sexual activity or injection drug use should receive hepatitis B vaccine regardless of destination. Additionally, travelers who access medical care for injury or illness while abroad may also be at risk of acquiring hepatitis B via contaminated blood products or medical equipment.²⁷

Serologic testing and booster vaccination are not recommended before travel for immunocompetent adults who have been previously vaccinated. The combined hepatitis A and B vaccine provides effective and convenient dual protection for travelers and can be administered with an accelerated 0-, 7-, and 21-day schedule for last-minute travelers.^7,8

Rabies remains endemic in developing countries of Africa and Asia, where appropriate post-exposure prophylaxis is limited or non-existent.²⁸ Consider pre-exposure rabies prophylaxis for traveling patients based on the availability of rabies vaccine and immunoglobulin in their destination area, planned duration of stay, and the likelihood of animal exposure (eg, veterinarians, animal handlers, cavers, missionaries). Advise travelers who decline vaccination to avoid or minimize animal contact during travel. In the event the traveler sustains an animal bite or scratch, immediate cleansing of the wound substantially reduces the risk of infection, especially when followed by timely administration of post-exposure prophylaxis.

In the event of an animal bite or scratch, immediate cleansing of the wound significantly reduces the risk of rabies infection.

Post-exposure prophylaxis for unvaccinated individuals consists of local infiltration of rabies immunoglobulin at the site of the bite and a series of 4 injections of rabies vaccine over 14 days, or 5 doses over one month for immunosuppressed patients. The first dose of the 4-dose course should be administered as soon as possible after exposure. Two vaccines are licensed for use in the United States: human diploid cell vaccine (HDCV, Imovax Rabies, Sanofi Pasteur) and purified chick embryo cell vaccine (PCECV, RabAvert, Novartis Vaccines and Diagnostics). The vaccine should never be administered in the gluteal area, as this may result in lower antibody titers.²⁹

Additionally, promising new vaccines against malaria and dengue fever are under clinical development and may be available in the near future.

CORRESPONDENCE
Vini Vijayan, MD, Division of Infectious Diseases, Arkansas Children's Hospital, 1 Children's Way, Slot 512-11, Little Rock, AR 72202; [email protected]. 

International travel, whether for business, pleasure, child adoption, medical tourism, or adventure, continues to grow. In 2015, more than 70 million US citizens traveled internationally.¹ Many individuals contact family physicians first about their plans for travel and questions about travel-related health advice. This article provides an overview of the vaccines recommended for travelers headed to international destinations. Because country-specific vaccination recommendations and requirements for entry and departure change over time, check the Centers for Disease Control and Prevention (CDC) Web site for up-to-date requirements and recommendations (www.cdc.gov/travel).

Vaccine schedules vary according to destination and individual risks

There is no single vaccination schedule that applies to all travelers. Each schedule should be individualized based on the traveler’s destination, risk assessment, previous immunizations, health status, and time available before departure.^2,3 Pregnant or immunocompromised travelers should seek advice from an experienced travel medicine consultant on the immunization recommendations specifically meant for them.^4,5

Travel vaccines (TABLE⁶) are generally categorized as routine, required, or recommended.

1. Routine vaccines are the standard child and adult immunizations recommended by the Advisory Committee on Immunization Practices (ACIP). These include such vaccines as diphtheria-tetanus toxoids-acellular pertussis (DTaP), inactivated polio vaccine (IPV), Haemophilus influenzae type b (Hib), hepatitis B, rotavirus and pneumococcal vaccines, and human papillomavirus (HPV).
2. Required vaccines—eg, yellow fever and meningococcal vaccines—must be documented on the International Certificate of Vaccination before entry into certain countries.
3. Recommended vaccines are advised based on the travel destination and anticipated activities. These would include vaccines for typhoid, rabies, Japanese encephalitis, and polio (adult booster).

Routine vaccinations may need to be accelerated

Pre-travel patient encounters are an opportunity to update routine vaccinations.^7,8 Immunization against childhood diseases remains suboptimal in developing countries, where vaccine-preventable illnesses occur more frequently.⁹

Routine vaccines may be administered on an accelerated basis depending on geographic destination, seasonal disease variations, anticipated exposures, and known outbreaks at the time of travel.

MMR vaccine. Measles is still common in many parts of the world, and unvaccinated or incompletely vaccinated travelers are at risk of acquiring the disease and importing it to the United States (see “Measles: Why it’s still a threat,” 2017;66:446-449.) In 2015, a large, widespread measles outbreak occurred in the United States, linked to an amusement park in California, likely originating with an infected traveler who visited the park.¹⁰

Flu vaccine is recommended for all travelers ≥6 months of age, as flu season varies internationally.

All children older than 12 months should receive 2 doses of measles-mumps-rubella (MMR) vaccine separated by at least 28 days before departure (regardless of their destination). Infants between 6 and 11 months are at risk for high morbidity and may therefore receive a single dose of MMR earlier than the routinely recommended age of 12 to 15 months. Adolescents and adults without evidence of immunity against measles should get 2 doses of MMR separated by at least 28 days.¹¹ Acceptable presumptive evidence of immunity against measles includes written documentation of adequate vaccination, laboratory evidence of immunity, laboratory confirmation of measles, or birth before 1957.

Varicella vaccine. Children, adolescents, and young adults who have received only one dose of varicella should get a second dose prior to departure. For children 7 to 12 years, the recommended minimum interval between doses is 3 months. For individuals 13 years or older, the minimum interval is 4 weeks.^7,8

Influenza vaccine is routinely recommended for all travelers 6 months of age or older, as flu season varies geographically. Flu season in the Northern Hemisphere may begin as early as October and can extend until May. In the Southern Hemisphere, it may begin in April and last through September. Travelers should be vaccinated at least 2 weeks before travel in order to develop adequate immunity.^12,13

Required vaccinations: Proof is needed before traveling

Yellow fever (YF) is a mosquito-borne viral illness characterized by fever, chills, headache, myalgia, and vomiting. The disease can progress to coagulopathy, shock, and multisystem organ failure.¹⁴ YF vaccine is recommended for individuals 9 months or older who are traveling to or living in areas of South America or Africa where YF virus transmission is common (map: http://www.cdc.gov/yellowfever/maps/).

YF vaccine is a live-attenuated virus formulation and, therefore, should not be given to individuals with primary immunodeficiencies, transplant recipients or patients on immunosuppressive and immunomodulatory therapies, or patients with human immunodeficiency virus (HIV) whose CD4 count is below 200/mL. Other contraindications to YF vaccine are age younger than 6 months, allergy to a vaccine component, and thymic disorders. Serious adverse reactions to the vaccine are rare, but include 2 syndromes: YF-associated neurotropic disease and YF vaccine-associated viscerotropic disease.¹⁵

In many YF-endemic countries, vaccination is legally required for entry, and proof of vaccination must be documented on an International Certificate of Vaccination or Prophylaxis (ICVP). Additionally, some countries may require proof of vaccination before allowing travel through an endemic region, to prevent introduction of the disease elsewhere. Travelers with a specific contraindication to YF vaccine should obtain a waiver from a physician before traveling to a country requiring vaccination.¹⁶

The vaccination certificate is valid beginning 10 days after administration of YF vaccine. Immunity after a single dose is long lasting and may provide lifetime protection. Previously, re-vaccination was required every 10 years; however, in February 2015, ACIP approved a new recommendation stating a single dose of YF vaccine is adequate for most travelers.¹⁷

Many countries in which yellow fever is endemic don't allow entry without proof of vaccination on an International Certificate of Vaccination or Prophylaxis.

Although ACIP no longer recommends booster doses of YF vaccine for most travelers, clinicians and travelers should review the entry requirements for destination countries because changes to the International Health Regulations have not yet been fully implemented. Once this change is instituted, a completed ICVP will be valid for the lifetime of the vaccine.^18,19 Country-specific requirements for YF can be found at http://www.cdc.gov/yellowfever/maps/. (Click on the link below the appropriate map.) In the United States, the YF vaccine is distributed only through approved vaccination centers. These designated clinics are listed in a registry on the CDC travel Web site at https://wwwnc.cdc.gov/travel/yellow-fever-vaccination-clinics/search.

Meningococcal disease. ACIP recommends routine vaccination against meningococcal disease for people 11 to 18 years of age and for individuals with persistent complement component deficiency, functional or anatomic asplenia, and HIV. Vaccination is recommended for travelers who visit or reside in areas where meningococcal disease is hyperendemic or epidemic, such as the meningitis belt of sub-Saharan Africa during the dry season of December to June (map: http://wwwnc.cdc.gov/travel/yellowbook/2016/infectious-diseases-related-to-travel/meningococcal-disease). Travelers to Saudi Arabia during the annual Hajj and Umrah pilgrimages are required to have a certificate of vaccination with quadrivalent (serogroups A, C, Y, W-135) meningococcal vaccine issued within 3 years (and not less than 10 days) before entry.

Several meningococcal vaccines are available in the United States. The quadrivalent vaccines are Menactra (MenACWY-D, Sanofi Pasteur) and Menveo (MenACWY-CRM, GSK). A bivalent (serogroups C and Y) conjugate vaccine MenHibrix (Hib-MenCY-TT, GSK) is also licensed for use in the United States, but infants traveling to areas with high endemic rates of meningococcal disease who received this vaccine are not protected against serogroups A and W and should receive quadrivalent meningococcal conjugate vaccine. Serogroup B vaccination is not routinely recommended for travelers. Approximately 7 to 10 days are required after vaccination for the development of protective antibody levels.^7,8,20,21

Polio. Although polio has been nearly eradicated, as of the time this article was written, the disease has not been eliminated in Afghanistan, Guinea, Laos, Nigeria, or Pakistan. Other countries, such as Cameroon, Chad, and Ukraine remain vulnerable to international transmission.²² The CDC recommends that adults who are traveling to areas where wild polio virus (WPV) has circulated in the last 12 months and who are unvaccinated, incompletely vaccinated, or whose vaccination status is unknown should receive a series of 3 doses of IPV to prevent ongoing spread.²³ Adults who completed the polio vaccine series as children and are traveling to areas where WPV has circulated in the last 12 months should receive a one-time booster dose of IPV.²³

Infants and children in the United States should be vaccinated against polio as part of a routine age-appropriate series. If a child cannot complete the routine series before departure and is traveling to an area where WPV has circulated in the last 12 months, an accelerated schedule is recommended. Vaccination should be documented on the ICVP, as countries with active spread of poliovirus may require proof of polio vaccination upon exit. A list of the countries where the polio virus is currently circulating is available at http://polioeradication.org/polio-today/polio-now/wild-poliovirus-list/.

Both routine and accelerated vaccination schedules for children and adults are published annually by the CDC and are available at http://www.cdc.gov/vaccines/schedules/hcp/index.html.

Recommended vaccines

Japanese encephalitis (JE) is endemic throughout most of Asia and parts of the Western Pacific region (map: http://www.cdc.gov/japaneseencephalitis/maps/). JE vaccine is recommended for travelers who plan to spend more than a month in endemic areas during the JE virus transmission season. (In temperate areas of Asia, JE virus transmission is seasonal and usually peaks in the summer and fall. In the subtropics and tropics, transmission can occur year-round, often with a peak during the rainy season.)

Adults who completed the polio vaccine series as children and are traveling where wild polio virus has circulated in the last 12 months should receive a one-time booster dose of IPV.

This recommendation includes recurrent travelers or expatriates who are likely to visit endemic rural or agricultural areas during a high-risk period of JE virus transmission. Risk is low for travelers who spend less than a month in endemic areas and for those who confine their travel to urban centers. Nevertheless, vaccination should be considered if travel is planned for outside an urban area and includes such activities as camping, hiking, trekking, biking, fishing, hunting, or farming. Inactivated Vero cell culture-derived vaccine (Ixiaro) is the only JE vaccine licensed and available in the United States. Ixiaro is given as a 2-dose series, with the doses spaced 28 days apart. The last dose should be given at least one week before travel.²⁴

Typhoid fever. Vaccination against typhoid fever is recommended for travelers to highly endemic areas such as the Indian subcontinent, Africa, and Central and South America. Two typhoid vaccines are available: Vi capsular polysaccharide vaccine (ViCPS) administered intramuscularly (IM), and oral live attenuated vaccine (Ty21a). Ty21a is a live vaccine and should not be given to immunocompromised people or those taking antibiotics, as it may reduce immunogenicity. Ty21a must be kept refrigerated at 35.6° F to 46.4° F (2° C - 8° C) and administered with cool liquid no warmer than 98.6° F (37° C). Both vaccines are only 50% to 80% efficacious, making access to clean food and water essential.^3,5,25

Hepatitis A vaccine should be given to all children older than one year traveling to areas where there is an intermediate or high risk of the disease. Children younger than one year who are traveling to high-risk areas can receive a single dose of immunoglobulin (IG) 0.02 mL/kg IM, which provides protection for up to 3 months. One 0.06 mL/kg-dose IM provides protection for 3 to 5 months.

If travel continues, children should receive a second dose after 5 months. IG does not interfere with the response to YF vaccine, but can interfere with the response to other live injected vaccines (such as MMR and varicella).²⁶

Hepatitis B vaccination should be administered to all unvaccinated travelers who plan to visit an area with intermediate to high prevalence of chronic hepatitis B (HBV surface antigen prevalence ≥2%). Unvaccinated travelers who may engage in high-risk sexual activity or injection drug use should receive hepatitis B vaccine regardless of destination. Additionally, travelers who access medical care for injury or illness while abroad may also be at risk of acquiring hepatitis B via contaminated blood products or medical equipment.²⁷

Serologic testing and booster vaccination are not recommended before travel for immunocompetent adults who have been previously vaccinated. The combined hepatitis A and B vaccine provides effective and convenient dual protection for travelers and can be administered with an accelerated 0-, 7-, and 21-day schedule for last-minute travelers.^7,8

Rabies remains endemic in developing countries of Africa and Asia, where appropriate post-exposure prophylaxis is limited or non-existent.²⁸ Consider pre-exposure rabies prophylaxis for traveling patients based on the availability of rabies vaccine and immunoglobulin in their destination area, planned duration of stay, and the likelihood of animal exposure (eg, veterinarians, animal handlers, cavers, missionaries). Advise travelers who decline vaccination to avoid or minimize animal contact during travel. In the event the traveler sustains an animal bite or scratch, immediate cleansing of the wound substantially reduces the risk of infection, especially when followed by timely administration of post-exposure prophylaxis.

In the event of an animal bite or scratch, immediate cleansing of the wound significantly reduces the risk of rabies infection.

Post-exposure prophylaxis for unvaccinated individuals consists of local infiltration of rabies immunoglobulin at the site of the bite and a series of 4 injections of rabies vaccine over 14 days, or 5 doses over one month for immunosuppressed patients. The first dose of the 4-dose course should be administered as soon as possible after exposure. Two vaccines are licensed for use in the United States: human diploid cell vaccine (HDCV, Imovax Rabies, Sanofi Pasteur) and purified chick embryo cell vaccine (PCECV, RabAvert, Novartis Vaccines and Diagnostics). The vaccine should never be administered in the gluteal area, as this may result in lower antibody titers.²⁹

Additionally, promising new vaccines against malaria and dengue fever are under clinical development and may be available in the near future.

CORRESPONDENCE
Vini Vijayan, MD, Division of Infectious Diseases, Arkansas Children's Hospital, 1 Children's Way, Slot 512-11, Little Rock, AR 72202; [email protected]. 

ABSTRACT

Purpose The purpose of this study was to determine the frequency of patients seen at a single institution who were diagnosed with a cervical vessel dissection related to chiropractic neck manipulation.

Methods We identified cases through a retrospective chart review of patients seen between April 2008 and March 2012 who had a diagnosis of cervical artery dissection following a recent chiropractic manipulation. Relevant imaging studies were reviewed by a board-certified neuroradiologist to confirm the findings of a cervical artery dissection and stroke. We conducted telephone interviews to ascertain the presence of residual symptoms in the affected patients.

Results Of the 141 patients with cervical artery dissection, 12 had documented chiropractic neck manipulation prior to the onset of the symptoms that led to medical presentation. The 12 patients had a total of 16 cervical artery dissections. All 12 patients developed symptoms of acute stroke. All strokes were confirmed with magnetic resonance imaging or computerized tomography. We obtained follow-up information on 9 patients, 8 of whom had residual symptoms and one of whom died as a result of his injury.

Conclusions In this case series, 12 patients with newly diagnosed cervical artery dissection(s) had recent chiropractic neck manipulation. Patients who are considering chiropractic cervical manipulation should be informed of the potential risk and be advised to seek immediate medical attention should they develop symptoms.

A prospective randomized controlled study published in 2012 showed chiropractic manipulation is beneficial in the treatment of neck pain compared with medical treatment, but it showed no significant difference between chiropractic manipulation and physical therapy exercises.¹ Although chiropractic manipulation of the cervical spine may be effective, it may also cause harm.

Cerebellar and spinal cord injuries related to cervical chiropractic manipulation were first reported in 1947.² By 1974, there were 12 reported cases.³ Noninvasive imaging has since greatly improved the diagnosis of cervical artery dissection and of stroke,⁴ and cervical artery dissection is now recognized as pathogenic of strokes occurring in association with chiropractic manipulation.⁵

A prospective series published in 2011 reported that, over 4 years, 13 patients were treated at a single institution for cervical arterial dissection following chiropractic treatment.⁶ That so many patients might be seen for this condition in that time frame at a single institution suggests the risk for such injury may be greater than thought. To explore that possibility, we performed a 4-year retrospective review to determine the experience at OSF Saint Francis Medical Center, which is affiliated with the University of Illinois College of Medicine, Peoria.

METHODS

Data sources. After receiving approval by the local institutional review board, we obtained data from the electronic medical records of OSF Saint Francis Medical Center, Peoria, Ill., using Epic (Epic Systems Corporation, Verona, Wis.) and IDX (General Electric Corporation, Fairfield, Conn.) systems. The records were queried using ICD-9 codes 443.21 and 443.24 to identify patients from April 2008 through March 2012 who had primary or secondary diagnoses of vertebral artery dissection (VAD) or carotid artery dissection (CAD). We reviewed all records of VAD and CAD to identify those that may have been associated with chiropractic manipulation.

Data collection. We abstracted data from 12 patients’ charts. Two patients were unavailable for direct contact: one was involved in ongoing litigation, and one had died (although we were able to speak with his wife). We attempted telephone contact with the 10 remaining patients and reached 8.

Data included the symptoms leading to chiropractic manipulation, symptoms following manipulation, timing of onset of symptoms relative to chiropractic manipulation, identifying information for the treating chiropractor, and residual patient symptoms. We also recorded patients’ ages, sex, locations of dissection, and locations of stroke. All dissections and strokes had been diagnosed during the patient’s initial hospitalization.

A board-certified radiologist (JRD) with a Certificate of Added Qualification in Neuroradiology (American Board of Medical Specialties) reviewed all pertinent imaging to confirm all dissections and strokes.

RESULTS

The medical record query yielded 141 patients with VAD or CAD, 15 of whom had undergone chiropractic manipulation prior to their presentation. The temporal association between chiropractic manipulation and arterial dissection was equivocal for 3 patients. In 12 patients, there was a verifiable temporal association between chiropractic manipulation and the arterial dissection. Three of the 12 patients were men and 9 were women. Ages ranged from 22 to 46 years, with a mean of 35.3 years.

Acute or chronic neck pain was the most common reason for seeking chiropractic care (TABLE 1). Immediately upon performance of cervical manipulation, 10 of the 12 developed acute symptoms different than those that caused them to seek chiropractic care. Two patients developed symptoms 2 to 3 days post-manipulation. Neither of the 2 had a history of neck trauma within the preceding year. Ten of the 12 patients sought immediate medical attention. Two of the 12 patients sought care when their symptoms became more severe, ranging from 2 days to several weeks later (TABLE 2). The treating chiropractor was identified in 7 cases and was different in each of the 7 cases.

A total of 16 cervical artery dissections, 14 VAD and 2 CAD, were confirmed by computed tomography angiography (CTA), magnetic resonance angiography (MRA), or catheter angiography (FIGURE 1). All 12 patients had acute strokes confirmed by MRA or CTA, including 9 in the cerebellum (FIGURE 2), 4 in the cerebrum, 2 in the medulla, and one in the pons.

Long-term outcomes were determined for 9 patients (TABLE 2). One patient’s symptoms resolved. Three patients had dizziness, clumsiness, or balance problems; 3 had persistent headaches; 2 had bilateral visual field abnormalities; and one patient walked with a cane, was no longer driving a car, and was on disability. One patient died as a result of his injury. One of the 12 cases was previously described in a case report.⁷

DISCUSSION

Dissection of the cervical arteries is more common than dissection in other arteries of comparable size. This increased risk in the cervical arteries is believed to be due to their relative mobility and proximity to bony structures.⁴

Sudden neck movement, a feature of chiropractic treatment, is one of several known risk factors for ‘spontaneous’ cervical artery dissection.^8,9 Symptom onset and stroke may be delayed after a spontaneous cervical artery dissection.¹⁰ Spontaneous dissection more commonly involves the carotid arteries;⁴ however, the vertebral arteries appear more prone to dissection as a consequence of chiropractic manipulation,¹¹ likely due to their relation to the cervical spine.

The Canadian Stroke Consortium has shown a 28% incidence of chiropractic manipulation in cases of cervical artery dissection.

The vertebral artery runs through foramina in the transverse processes of vertebral bodies C1 through C6 (FIGURE 3). On exiting the C2 transverse process, the vertebral artery has a tortuous course, making several turns over and through adjacent bony structures.¹² The artery is most prone to injury between the entrance to the transverse foramen of C6 and the foramen magnum (V2 and V3 segments).¹³ (The area of highest vulnerability is the tortuous segment from the transverse foramen of C2 to the foramen magnum.)

Sudden movements of the cervical spine may cause arterial dissection, whether the maneuvers are performed by a physician, a chiropractor, or a physical therapist.¹⁴ Injuries reported in the literature, however, most commonly follow chiropractic manipulation. In our series of 141 dissections, we found no cases associated with manipulation by other health professionals.

A 2003 study revealed cervical spine manipulation to be an independent and strong risk factor for vertebral artery dissection. The authors believed the relationship was likely causal.⁵ Data from the Canadian Stroke Consortium showed a 28% incidence of chiropractic manipulation in cases of cervical artery dissection.¹⁰

A 2008 study showed an association between vertebrobasilar stroke and chiropractic visits within one month of the vascular event.¹⁵ However, the study also showed an association of similar magnitude between vertebrobasilar stroke and visits to primary care physicians within the prior month. This suggests that cervical manipulation by chiropractors poses no more risk for cervical artery dissection than visits to primary care physicians. However, it is hard to reconcile such a conclusion with other studies, including our own, in which 10 patients developed new symptoms immediately with chiropractic manipulation of their cervical spines.

Perhaps the one-month observation period of Cassidy et al was excessive. Many post-manipulation events occur within hours or at most a few days, as would be expected given the hypothesized pathogenic mechanism. Perhaps if they had shortened their interval of study to the preceding 3 days, their findings may have been different.

A recent systematic review and meta-analysis demonstrated a slight association between chiropractic neck manipulation and cervical artery dissection. It stated that the quality of the published literature was very low, and it concluded there was no convincing evidence of causation.¹⁶ The fact that 10 of the 12 patients in our case series demonstrated acute symptoms immediately upon receiving spinal manipulation suggests a possible causal link; however, we agree with the authors of the meta-analysis that the quality of the literature is low.

A recent statement from the American Heart Association/American Stroke Association (and endorsed by the American Association of Neurological Surgeons and the Congress of Neurological Surgeons) has recommended that chiropractors inform patients of the statistical association between cervical artery dissection and cervical manipulation.¹⁷ In addition, it is important for chiropractors to be aware of the signs and symptoms of cervical artery dissection and stroke and to assess for these symptoms before performing neck manipulation, as illustrated in a recent case report.¹⁸ Due to the risk of death, patients who experience symptoms consistent with cervical artery dissection after chiropractic manipulation of the cervical spine should be advised to seek medical care immediately.

Our case series has several limitations. The study was retrospective. Existing documentation of associated chiropractic care was often sparse, necessitating phone calls to supplement the information. We believe it is possible that cases may have been missed because of inaccurate medical record documentation, deficits in the interview process concerning chiropractic care at the time of hospitalization, or because information concerning chiropractic care was not recorded in the chart.

A significant portion of our information came through phone contact with several of the patients. In some cases, we relied heavily on their recollection of events that had occurred anytime from a few days to a few years earlier. The accuracy and completeness of the information supplied by patients was not verified, allowing for potential recall bias.

We do not know whether our experience is consistent with that of other areas of the United States. However, the fact that a similar-size hospital in Phoenix reported similar findings suggests the experience may be more widespread.⁶

IMPLICATIONS OF OUR FINDINGS

Over a 4-year period at our institution, 12 patients experienced cervical vessel dissection related to chiropractic neck manipulation. A similar institution in another part of the country had previously described 13 such cases. The patients at both institutions were relatively young and incurred substantial residual morbidity. A single patient at each institution died. If these findings are representative of other institutions across the United States, the incidence of stroke secondary to chiropractic manipulation may be higher than supposed.

Tell patients considering cervical spine manipulation to seek medical help if symptoms suggestive of dissection or stroke occur during or after manipulation.

To assess this problem further, a randomized prospective cohort study could establish the relative risk of chiropractic manipulation of the cervical spine resulting in a cervical artery dissection. But such a study may be methodologically prohibitive. More feasible would be a case-control study similar to one carried out by Smith et al⁵ in which patients who had experienced cervical artery dissection were matched with subjects who had not incurred such injuries. Comparing the groups’ odds of having received chiropractic manipulation demonstrated that spinal manipulative therapy is an independent risk factor for vertebral artery dissection and is highly suggestive of a causal association. Replicating this study in a different population would be valuable.

Based on our findings, all patients who visit chiropractors for cervical spine manipulation should be informed of the potential risks and of the need to seek immediate medical assistance should symptoms suggestive of dissection or stroke occur during or after manipulation. Until the actual level of risk from chiropractic manipulation is known, patients with neck pain may be better served by equally effective passive physical therapy exercises.¹

CORRESPONDENCE
Raymond E. Bertino, MD, 427 West Crestwood Drive, Peoria, IL 61614; [email protected].

ACKNOWLEDGEMENTS
We thank Deepak Nair, MD, for his assistance in reviewing the stroke neurology aspects of this study; Katie Groesch, MD, for her assistance in drafting portions of the Methods and Results sections; Rita Hermacinski for the generation of 3D images; and Stephanie Arthalony for her assistance in gathering information through patient telephone interviews.

ABSTRACT

Purpose The purpose of this study was to determine the frequency of patients seen at a single institution who were diagnosed with a cervical vessel dissection related to chiropractic neck manipulation.

Methods We identified cases through a retrospective chart review of patients seen between April 2008 and March 2012 who had a diagnosis of cervical artery dissection following a recent chiropractic manipulation. Relevant imaging studies were reviewed by a board-certified neuroradiologist to confirm the findings of a cervical artery dissection and stroke. We conducted telephone interviews to ascertain the presence of residual symptoms in the affected patients.

Results Of the 141 patients with cervical artery dissection, 12 had documented chiropractic neck manipulation prior to the onset of the symptoms that led to medical presentation. The 12 patients had a total of 16 cervical artery dissections. All 12 patients developed symptoms of acute stroke. All strokes were confirmed with magnetic resonance imaging or computerized tomography. We obtained follow-up information on 9 patients, 8 of whom had residual symptoms and one of whom died as a result of his injury.

Conclusions In this case series, 12 patients with newly diagnosed cervical artery dissection(s) had recent chiropractic neck manipulation. Patients who are considering chiropractic cervical manipulation should be informed of the potential risk and be advised to seek immediate medical attention should they develop symptoms.

A prospective randomized controlled study published in 2012 showed chiropractic manipulation is beneficial in the treatment of neck pain compared with medical treatment, but it showed no significant difference between chiropractic manipulation and physical therapy exercises.¹ Although chiropractic manipulation of the cervical spine may be effective, it may also cause harm.

Cerebellar and spinal cord injuries related to cervical chiropractic manipulation were first reported in 1947.² By 1974, there were 12 reported cases.³ Noninvasive imaging has since greatly improved the diagnosis of cervical artery dissection and of stroke,⁴ and cervical artery dissection is now recognized as pathogenic of strokes occurring in association with chiropractic manipulation.⁵

A prospective series published in 2011 reported that, over 4 years, 13 patients were treated at a single institution for cervical arterial dissection following chiropractic treatment.⁶ That so many patients might be seen for this condition in that time frame at a single institution suggests the risk for such injury may be greater than thought. To explore that possibility, we performed a 4-year retrospective review to determine the experience at OSF Saint Francis Medical Center, which is affiliated with the University of Illinois College of Medicine, Peoria.

METHODS

Data sources. After receiving approval by the local institutional review board, we obtained data from the electronic medical records of OSF Saint Francis Medical Center, Peoria, Ill., using Epic (Epic Systems Corporation, Verona, Wis.) and IDX (General Electric Corporation, Fairfield, Conn.) systems. The records were queried using ICD-9 codes 443.21 and 443.24 to identify patients from April 2008 through March 2012 who had primary or secondary diagnoses of vertebral artery dissection (VAD) or carotid artery dissection (CAD). We reviewed all records of VAD and CAD to identify those that may have been associated with chiropractic manipulation.

Data collection. We abstracted data from 12 patients’ charts. Two patients were unavailable for direct contact: one was involved in ongoing litigation, and one had died (although we were able to speak with his wife). We attempted telephone contact with the 10 remaining patients and reached 8.

Data included the symptoms leading to chiropractic manipulation, symptoms following manipulation, timing of onset of symptoms relative to chiropractic manipulation, identifying information for the treating chiropractor, and residual patient symptoms. We also recorded patients’ ages, sex, locations of dissection, and locations of stroke. All dissections and strokes had been diagnosed during the patient’s initial hospitalization.

A board-certified radiologist (JRD) with a Certificate of Added Qualification in Neuroradiology (American Board of Medical Specialties) reviewed all pertinent imaging to confirm all dissections and strokes.

RESULTS

The medical record query yielded 141 patients with VAD or CAD, 15 of whom had undergone chiropractic manipulation prior to their presentation. The temporal association between chiropractic manipulation and arterial dissection was equivocal for 3 patients. In 12 patients, there was a verifiable temporal association between chiropractic manipulation and the arterial dissection. Three of the 12 patients were men and 9 were women. Ages ranged from 22 to 46 years, with a mean of 35.3 years.

Acute or chronic neck pain was the most common reason for seeking chiropractic care (TABLE 1). Immediately upon performance of cervical manipulation, 10 of the 12 developed acute symptoms different than those that caused them to seek chiropractic care. Two patients developed symptoms 2 to 3 days post-manipulation. Neither of the 2 had a history of neck trauma within the preceding year. Ten of the 12 patients sought immediate medical attention. Two of the 12 patients sought care when their symptoms became more severe, ranging from 2 days to several weeks later (TABLE 2). The treating chiropractor was identified in 7 cases and was different in each of the 7 cases.

A total of 16 cervical artery dissections, 14 VAD and 2 CAD, were confirmed by computed tomography angiography (CTA), magnetic resonance angiography (MRA), or catheter angiography (FIGURE 1). All 12 patients had acute strokes confirmed by MRA or CTA, including 9 in the cerebellum (FIGURE 2), 4 in the cerebrum, 2 in the medulla, and one in the pons.

Long-term outcomes were determined for 9 patients (TABLE 2). One patient’s symptoms resolved. Three patients had dizziness, clumsiness, or balance problems; 3 had persistent headaches; 2 had bilateral visual field abnormalities; and one patient walked with a cane, was no longer driving a car, and was on disability. One patient died as a result of his injury. One of the 12 cases was previously described in a case report.⁷

DISCUSSION

Dissection of the cervical arteries is more common than dissection in other arteries of comparable size. This increased risk in the cervical arteries is believed to be due to their relative mobility and proximity to bony structures.⁴

Sudden neck movement, a feature of chiropractic treatment, is one of several known risk factors for ‘spontaneous’ cervical artery dissection.^8,9 Symptom onset and stroke may be delayed after a spontaneous cervical artery dissection.¹⁰ Spontaneous dissection more commonly involves the carotid arteries;⁴ however, the vertebral arteries appear more prone to dissection as a consequence of chiropractic manipulation,¹¹ likely due to their relation to the cervical spine.

The Canadian Stroke Consortium has shown a 28% incidence of chiropractic manipulation in cases of cervical artery dissection.

The vertebral artery runs through foramina in the transverse processes of vertebral bodies C1 through C6 (FIGURE 3). On exiting the C2 transverse process, the vertebral artery has a tortuous course, making several turns over and through adjacent bony structures.¹² The artery is most prone to injury between the entrance to the transverse foramen of C6 and the foramen magnum (V2 and V3 segments).¹³ (The area of highest vulnerability is the tortuous segment from the transverse foramen of C2 to the foramen magnum.)

Sudden movements of the cervical spine may cause arterial dissection, whether the maneuvers are performed by a physician, a chiropractor, or a physical therapist.¹⁴ Injuries reported in the literature, however, most commonly follow chiropractic manipulation. In our series of 141 dissections, we found no cases associated with manipulation by other health professionals.

A 2003 study revealed cervical spine manipulation to be an independent and strong risk factor for vertebral artery dissection. The authors believed the relationship was likely causal.⁵ Data from the Canadian Stroke Consortium showed a 28% incidence of chiropractic manipulation in cases of cervical artery dissection.¹⁰

A 2008 study showed an association between vertebrobasilar stroke and chiropractic visits within one month of the vascular event.¹⁵ However, the study also showed an association of similar magnitude between vertebrobasilar stroke and visits to primary care physicians within the prior month. This suggests that cervical manipulation by chiropractors poses no more risk for cervical artery dissection than visits to primary care physicians. However, it is hard to reconcile such a conclusion with other studies, including our own, in which 10 patients developed new symptoms immediately with chiropractic manipulation of their cervical spines.

Perhaps the one-month observation period of Cassidy et al was excessive. Many post-manipulation events occur within hours or at most a few days, as would be expected given the hypothesized pathogenic mechanism. Perhaps if they had shortened their interval of study to the preceding 3 days, their findings may have been different.

A recent systematic review and meta-analysis demonstrated a slight association between chiropractic neck manipulation and cervical artery dissection. It stated that the quality of the published literature was very low, and it concluded there was no convincing evidence of causation.¹⁶ The fact that 10 of the 12 patients in our case series demonstrated acute symptoms immediately upon receiving spinal manipulation suggests a possible causal link; however, we agree with the authors of the meta-analysis that the quality of the literature is low.

A recent statement from the American Heart Association/American Stroke Association (and endorsed by the American Association of Neurological Surgeons and the Congress of Neurological Surgeons) has recommended that chiropractors inform patients of the statistical association between cervical artery dissection and cervical manipulation.¹⁷ In addition, it is important for chiropractors to be aware of the signs and symptoms of cervical artery dissection and stroke and to assess for these symptoms before performing neck manipulation, as illustrated in a recent case report.¹⁸ Due to the risk of death, patients who experience symptoms consistent with cervical artery dissection after chiropractic manipulation of the cervical spine should be advised to seek medical care immediately.

Our case series has several limitations. The study was retrospective. Existing documentation of associated chiropractic care was often sparse, necessitating phone calls to supplement the information. We believe it is possible that cases may have been missed because of inaccurate medical record documentation, deficits in the interview process concerning chiropractic care at the time of hospitalization, or because information concerning chiropractic care was not recorded in the chart.

A significant portion of our information came through phone contact with several of the patients. In some cases, we relied heavily on their recollection of events that had occurred anytime from a few days to a few years earlier. The accuracy and completeness of the information supplied by patients was not verified, allowing for potential recall bias.

We do not know whether our experience is consistent with that of other areas of the United States. However, the fact that a similar-size hospital in Phoenix reported similar findings suggests the experience may be more widespread.⁶

IMPLICATIONS OF OUR FINDINGS

Over a 4-year period at our institution, 12 patients experienced cervical vessel dissection related to chiropractic neck manipulation. A similar institution in another part of the country had previously described 13 such cases. The patients at both institutions were relatively young and incurred substantial residual morbidity. A single patient at each institution died. If these findings are representative of other institutions across the United States, the incidence of stroke secondary to chiropractic manipulation may be higher than supposed.

Tell patients considering cervical spine manipulation to seek medical help if symptoms suggestive of dissection or stroke occur during or after manipulation.

To assess this problem further, a randomized prospective cohort study could establish the relative risk of chiropractic manipulation of the cervical spine resulting in a cervical artery dissection. But such a study may be methodologically prohibitive. More feasible would be a case-control study similar to one carried out by Smith et al⁵ in which patients who had experienced cervical artery dissection were matched with subjects who had not incurred such injuries. Comparing the groups’ odds of having received chiropractic manipulation demonstrated that spinal manipulative therapy is an independent risk factor for vertebral artery dissection and is highly suggestive of a causal association. Replicating this study in a different population would be valuable.

Based on our findings, all patients who visit chiropractors for cervical spine manipulation should be informed of the potential risks and of the need to seek immediate medical assistance should symptoms suggestive of dissection or stroke occur during or after manipulation. Until the actual level of risk from chiropractic manipulation is known, patients with neck pain may be better served by equally effective passive physical therapy exercises.¹

CORRESPONDENCE
Raymond E. Bertino, MD, 427 West Crestwood Drive, Peoria, IL 61614; [email protected].

ACKNOWLEDGEMENTS
We thank Deepak Nair, MD, for his assistance in reviewing the stroke neurology aspects of this study; Katie Groesch, MD, for her assistance in drafting portions of the Methods and Results sections; Rita Hermacinski for the generation of 3D images; and Stephanie Arthalony for her assistance in gathering information through patient telephone interviews.

ABSTRACT

Purpose The purpose of this study was to determine the frequency of patients seen at a single institution who were diagnosed with a cervical vessel dissection related to chiropractic neck manipulation.

Methods We identified cases through a retrospective chart review of patients seen between April 2008 and March 2012 who had a diagnosis of cervical artery dissection following a recent chiropractic manipulation. Relevant imaging studies were reviewed by a board-certified neuroradiologist to confirm the findings of a cervical artery dissection and stroke. We conducted telephone interviews to ascertain the presence of residual symptoms in the affected patients.

Results Of the 141 patients with cervical artery dissection, 12 had documented chiropractic neck manipulation prior to the onset of the symptoms that led to medical presentation. The 12 patients had a total of 16 cervical artery dissections. All 12 patients developed symptoms of acute stroke. All strokes were confirmed with magnetic resonance imaging or computerized tomography. We obtained follow-up information on 9 patients, 8 of whom had residual symptoms and one of whom died as a result of his injury.

Conclusions In this case series, 12 patients with newly diagnosed cervical artery dissection(s) had recent chiropractic neck manipulation. Patients who are considering chiropractic cervical manipulation should be informed of the potential risk and be advised to seek immediate medical attention should they develop symptoms.

A prospective randomized controlled study published in 2012 showed chiropractic manipulation is beneficial in the treatment of neck pain compared with medical treatment, but it showed no significant difference between chiropractic manipulation and physical therapy exercises.¹ Although chiropractic manipulation of the cervical spine may be effective, it may also cause harm.

Cerebellar and spinal cord injuries related to cervical chiropractic manipulation were first reported in 1947.² By 1974, there were 12 reported cases.³ Noninvasive imaging has since greatly improved the diagnosis of cervical artery dissection and of stroke,⁴ and cervical artery dissection is now recognized as pathogenic of strokes occurring in association with chiropractic manipulation.⁵

A prospective series published in 2011 reported that, over 4 years, 13 patients were treated at a single institution for cervical arterial dissection following chiropractic treatment.⁶ That so many patients might be seen for this condition in that time frame at a single institution suggests the risk for such injury may be greater than thought. To explore that possibility, we performed a 4-year retrospective review to determine the experience at OSF Saint Francis Medical Center, which is affiliated with the University of Illinois College of Medicine, Peoria.

METHODS

Data sources. After receiving approval by the local institutional review board, we obtained data from the electronic medical records of OSF Saint Francis Medical Center, Peoria, Ill., using Epic (Epic Systems Corporation, Verona, Wis.) and IDX (General Electric Corporation, Fairfield, Conn.) systems. The records were queried using ICD-9 codes 443.21 and 443.24 to identify patients from April 2008 through March 2012 who had primary or secondary diagnoses of vertebral artery dissection (VAD) or carotid artery dissection (CAD). We reviewed all records of VAD and CAD to identify those that may have been associated with chiropractic manipulation.

Data collection. We abstracted data from 12 patients’ charts. Two patients were unavailable for direct contact: one was involved in ongoing litigation, and one had died (although we were able to speak with his wife). We attempted telephone contact with the 10 remaining patients and reached 8.

Data included the symptoms leading to chiropractic manipulation, symptoms following manipulation, timing of onset of symptoms relative to chiropractic manipulation, identifying information for the treating chiropractor, and residual patient symptoms. We also recorded patients’ ages, sex, locations of dissection, and locations of stroke. All dissections and strokes had been diagnosed during the patient’s initial hospitalization.

A board-certified radiologist (JRD) with a Certificate of Added Qualification in Neuroradiology (American Board of Medical Specialties) reviewed all pertinent imaging to confirm all dissections and strokes.

RESULTS

The medical record query yielded 141 patients with VAD or CAD, 15 of whom had undergone chiropractic manipulation prior to their presentation. The temporal association between chiropractic manipulation and arterial dissection was equivocal for 3 patients. In 12 patients, there was a verifiable temporal association between chiropractic manipulation and the arterial dissection. Three of the 12 patients were men and 9 were women. Ages ranged from 22 to 46 years, with a mean of 35.3 years.

Acute or chronic neck pain was the most common reason for seeking chiropractic care (TABLE 1). Immediately upon performance of cervical manipulation, 10 of the 12 developed acute symptoms different than those that caused them to seek chiropractic care. Two patients developed symptoms 2 to 3 days post-manipulation. Neither of the 2 had a history of neck trauma within the preceding year. Ten of the 12 patients sought immediate medical attention. Two of the 12 patients sought care when their symptoms became more severe, ranging from 2 days to several weeks later (TABLE 2). The treating chiropractor was identified in 7 cases and was different in each of the 7 cases.

A total of 16 cervical artery dissections, 14 VAD and 2 CAD, were confirmed by computed tomography angiography (CTA), magnetic resonance angiography (MRA), or catheter angiography (FIGURE 1). All 12 patients had acute strokes confirmed by MRA or CTA, including 9 in the cerebellum (FIGURE 2), 4 in the cerebrum, 2 in the medulla, and one in the pons.

Long-term outcomes were determined for 9 patients (TABLE 2). One patient’s symptoms resolved. Three patients had dizziness, clumsiness, or balance problems; 3 had persistent headaches; 2 had bilateral visual field abnormalities; and one patient walked with a cane, was no longer driving a car, and was on disability. One patient died as a result of his injury. One of the 12 cases was previously described in a case report.⁷

DISCUSSION

Dissection of the cervical arteries is more common than dissection in other arteries of comparable size. This increased risk in the cervical arteries is believed to be due to their relative mobility and proximity to bony structures.⁴

Sudden neck movement, a feature of chiropractic treatment, is one of several known risk factors for ‘spontaneous’ cervical artery dissection.^8,9 Symptom onset and stroke may be delayed after a spontaneous cervical artery dissection.¹⁰ Spontaneous dissection more commonly involves the carotid arteries;⁴ however, the vertebral arteries appear more prone to dissection as a consequence of chiropractic manipulation,¹¹ likely due to their relation to the cervical spine.

The Canadian Stroke Consortium has shown a 28% incidence of chiropractic manipulation in cases of cervical artery dissection.

The vertebral artery runs through foramina in the transverse processes of vertebral bodies C1 through C6 (FIGURE 3). On exiting the C2 transverse process, the vertebral artery has a tortuous course, making several turns over and through adjacent bony structures.¹² The artery is most prone to injury between the entrance to the transverse foramen of C6 and the foramen magnum (V2 and V3 segments).¹³ (The area of highest vulnerability is the tortuous segment from the transverse foramen of C2 to the foramen magnum.)

Sudden movements of the cervical spine may cause arterial dissection, whether the maneuvers are performed by a physician, a chiropractor, or a physical therapist.¹⁴ Injuries reported in the literature, however, most commonly follow chiropractic manipulation. In our series of 141 dissections, we found no cases associated with manipulation by other health professionals.

A 2003 study revealed cervical spine manipulation to be an independent and strong risk factor for vertebral artery dissection. The authors believed the relationship was likely causal.⁵ Data from the Canadian Stroke Consortium showed a 28% incidence of chiropractic manipulation in cases of cervical artery dissection.¹⁰

A 2008 study showed an association between vertebrobasilar stroke and chiropractic visits within one month of the vascular event.¹⁵ However, the study also showed an association of similar magnitude between vertebrobasilar stroke and visits to primary care physicians within the prior month. This suggests that cervical manipulation by chiropractors poses no more risk for cervical artery dissection than visits to primary care physicians. However, it is hard to reconcile such a conclusion with other studies, including our own, in which 10 patients developed new symptoms immediately with chiropractic manipulation of their cervical spines.

Perhaps the one-month observation period of Cassidy et al was excessive. Many post-manipulation events occur within hours or at most a few days, as would be expected given the hypothesized pathogenic mechanism. Perhaps if they had shortened their interval of study to the preceding 3 days, their findings may have been different.

A recent systematic review and meta-analysis demonstrated a slight association between chiropractic neck manipulation and cervical artery dissection. It stated that the quality of the published literature was very low, and it concluded there was no convincing evidence of causation.¹⁶ The fact that 10 of the 12 patients in our case series demonstrated acute symptoms immediately upon receiving spinal manipulation suggests a possible causal link; however, we agree with the authors of the meta-analysis that the quality of the literature is low.

A recent statement from the American Heart Association/American Stroke Association (and endorsed by the American Association of Neurological Surgeons and the Congress of Neurological Surgeons) has recommended that chiropractors inform patients of the statistical association between cervical artery dissection and cervical manipulation.¹⁷ In addition, it is important for chiropractors to be aware of the signs and symptoms of cervical artery dissection and stroke and to assess for these symptoms before performing neck manipulation, as illustrated in a recent case report.¹⁸ Due to the risk of death, patients who experience symptoms consistent with cervical artery dissection after chiropractic manipulation of the cervical spine should be advised to seek medical care immediately.

Our case series has several limitations. The study was retrospective. Existing documentation of associated chiropractic care was often sparse, necessitating phone calls to supplement the information. We believe it is possible that cases may have been missed because of inaccurate medical record documentation, deficits in the interview process concerning chiropractic care at the time of hospitalization, or because information concerning chiropractic care was not recorded in the chart.

A significant portion of our information came through phone contact with several of the patients. In some cases, we relied heavily on their recollection of events that had occurred anytime from a few days to a few years earlier. The accuracy and completeness of the information supplied by patients was not verified, allowing for potential recall bias.

We do not know whether our experience is consistent with that of other areas of the United States. However, the fact that a similar-size hospital in Phoenix reported similar findings suggests the experience may be more widespread.⁶

IMPLICATIONS OF OUR FINDINGS

Over a 4-year period at our institution, 12 patients experienced cervical vessel dissection related to chiropractic neck manipulation. A similar institution in another part of the country had previously described 13 such cases. The patients at both institutions were relatively young and incurred substantial residual morbidity. A single patient at each institution died. If these findings are representative of other institutions across the United States, the incidence of stroke secondary to chiropractic manipulation may be higher than supposed.

Tell patients considering cervical spine manipulation to seek medical help if symptoms suggestive of dissection or stroke occur during or after manipulation.

To assess this problem further, a randomized prospective cohort study could establish the relative risk of chiropractic manipulation of the cervical spine resulting in a cervical artery dissection. But such a study may be methodologically prohibitive. More feasible would be a case-control study similar to one carried out by Smith et al⁵ in which patients who had experienced cervical artery dissection were matched with subjects who had not incurred such injuries. Comparing the groups’ odds of having received chiropractic manipulation demonstrated that spinal manipulative therapy is an independent risk factor for vertebral artery dissection and is highly suggestive of a causal association. Replicating this study in a different population would be valuable.

Based on our findings, all patients who visit chiropractors for cervical spine manipulation should be informed of the potential risks and of the need to seek immediate medical assistance should symptoms suggestive of dissection or stroke occur during or after manipulation. Until the actual level of risk from chiropractic manipulation is known, patients with neck pain may be better served by equally effective passive physical therapy exercises.¹

CORRESPONDENCE
Raymond E. Bertino, MD, 427 West Crestwood Drive, Peoria, IL 61614; [email protected].

ACKNOWLEDGEMENTS
We thank Deepak Nair, MD, for his assistance in reviewing the stroke neurology aspects of this study; Katie Groesch, MD, for her assistance in drafting portions of the Methods and Results sections; Rita Hermacinski for the generation of 3D images; and Stephanie Arthalony for her assistance in gathering information through patient telephone interviews.

Signs and symptoms of autonomic dysfunction commonly present in the primary care setting. Potential causes of dysfunction include certain medications and age-related changes in physiology, as well as conditions such as diabetes mellitus, multiple sclerosis, and Parkinson’s disease (TABLE¹). This evidence-based review details common manifestations of autonomic dysfunction, provides a streamlined approach to patients presenting with symptoms, and reviews appropriate step-wise management.

When a delicate balance is disrupted

The autonomic nervous system provides brisk physiologic adjustments necessary to maintain homeostasis. Physiologic functions impacted by the central nervous system include: heart rate, blood pressure (BP), tone of the bladder sphincter and detrusor muscle, bowel motility, bronchodilation and constriction, pupillary dilation and constriction, sweating, catecholamine release, erection, ejaculation and orgasm, tearing, and salivation.¹

Disorders of the autonomic system may result from pathologies of the central or peripheral nervous system or from medications including some antihypertensives, selective serotonin-reuptake inhibitors (SSRIs), and opioids.¹ Such disorders tend to be grouped into one of 3 categories: those involving the brain, those involving the spinal cord, and autonomic neuropathies.¹

The source of dysautonomia can often be determined by clinical context, coexisting neurologic abnormalities, targeted testing of the autonomic nervous system, and neuroimaging.¹

Worrisome symptoms prompt a visit

A thorough history is critical to zeroing in on a patient’s complaints and ultimately providing treatment that will help manage symptoms.

When patient complaints are suggestive of autonomic dysfunction, a review of systems should include inquiry about lightheadedness, abnormal salivation, temperature changes of the extremities, gastrointestinal issues (vomiting, constipation, or diarrhea), and symptoms of presyncope/syncope or urinary or sexual dysfunction.¹ The physical exam should include recordings of BP and heart rate in the supine and standing positions and a complete neurologic examination.¹ Findings will typically point to one or more common complications.

Common complications of autonomic dysfunction

Complications of autonomic dysfunction include impotence, bladder dysfunction, gastrointestinal (GI) dysfunction, and orthostatic hypotension and vasomotor abnormalities. A less common condition—autonomic dysreflexia, which is a distinct type of autonomic dysfunction, and a true medical emergency—is also important to keep in mind.

Impotence

Autonomic neuropathy is a common cause of impotence and retrograde ejaculation. Loss of early morning erections and complete loss of nocturnal erections often have an etiology related to vascular disease and/or autonomic neuropathy. In addition, poor glycemic control and vascular risk factors appear to be associated with the development of diabetic autonomic neuropathy.²

If diabetic autonomic neuropathy is the suspected etiology of impotence, consider prescribing a phosphodiesterase inhibitor.

Development of an erection requires an increase in parasympathetic activity and a decrease in sympathetic output. Nocturnal penile tumescence testing has been used to infer parasympathetic damage to the penis in men with diabetes who do not have vascular disease.³

First- and second-line agents. Phosphodiesterase-5 inhibitors (eg, sildenafil, tadalafil, vardenafil) have demonstrated efficacy in improving the ability to achieve and maintain erections in patients with autonomic dysfunction, including diabetic autonomic neuropathy.^4-6 Second-line therapies with proven efficacy include intraurethral application and intracavernosal injections of alprostadil.^7,8

Bladder dysfunction

Sympathetic activity increases bladder sphincter tone and inhibits detrusor activity, while the parasympathetic nervous system increases detrusor activity and decreases sphincter tone to aid in voiding.¹ Disrupted autonomic activity can lead to urinary frequency, retention, and hesitancy; overactive bladder; and incontinence.¹ Brain and spinal cord disease above the level of the lumbar spine results in urinary frequency and small bladder volumes, whereas diseases involving autonomic nerve fibers to and from the bladder result in large bladder volumes and overflow incontinence.⁹

Botulinum toxin type A, injected directly into the detrusor muscle, can be as effective as medication in patients with urinary urge incontinence.

Patients presenting with lower urinary tract symptoms require a comprehensive evaluation to rule out other pathologies, as the differential for such symptoms is broad and includes infection, malignancies, interstitial cystitis, and bladder stones. The initial evaluation of lower urinary tract symptoms should include a history and physical exam including that of the abdomen, pelvis, and neurologic system. Lab work should assess renal function and blood glucose, and should include urinalysis and culture to rule out infection and/or hematuria. A prostate-specific antigen (PSA) test may be appropriate in men with a life expectancy >10 years, after counseling regarding the risks and benefits of screening.

Anticholinergic drugs with antimuscarinic effects, such as oxybutynin, may be used to treat symptoms of urge incontinence and overactive bladder. They work to suppress involuntary contractions of the bladder’s smooth muscle by blocking the release of acetylcholine. These medications relax the bladder’s outer layer of muscle—the detrusor. Such medications often have a number of anticholinergic adverse effects, such as dry mouth and constipation, sometimes leading to discontinuation. A post-void residual (PVR) test may be helpful in guiding management. For example, caution should be used in patients with elevated PVRs, as anticholinergics can worsen urinary retention.

Beta-3 agonists (eg, mirabegron) are a novel class of medications used to treat overactive bladder. These medications act to increase sympathetic tone in the bladder. Because they have the potential to raise BP, monitor BP in patients taking these agents. In addition, monitor patients taking antimuscarinics or beta-3 agonists for the development of urinary retention.

Other tests, treatments. Urodynamic testing is recommended for patients who fail to respond to treatment. Combining behavioral therapy with medication has been shown to be effective in patients with urge incontinence.¹⁰ Botulinum toxin type A, injected directly into the detrusor muscle, can be as effective as medication in patients with urinary urge incontinence.¹¹

Detrusor underactivity is defined as contraction of reduced strength and/or duration, resulting in prolonged bladder emptying and/or a failure to achieve complete bladder emptying within a normal timespan.¹² This diagnosis is typically made using urodynamic testing.¹³ PVRs ≥150 mL are considered evidence of urinary retention. Overflow incontinence can result from detrusor underactivity.

Consider a trial of a cholinergic agonist, such as bethanechol, in patients with urinary retention. Some patients will require intermittent straight catheterization or chronic indwelling foley or suprapubic catheters to void.

Gastrointestinal dysfunction

In patients with diabetes, GI autonomic neuropathy can result in altered esophageal motility leading to gastroesophageal reflux disease (GERD) or dysphagia, gastroparesis, or diabetic enteropathy.¹⁴ Gastroparesis often presents as nausea, vomiting, and bloating.¹ It may be diagnosed via gastric emptying studies (scintigraphy), and often requires a multidimensional approach to treatment.

Management. Food may be chopped or pureed to aid in digestion. Metoclopramide is the most commonly used prokinetic agent, but avoid its use in patients with parkinsonism. In more severe cases, consider adding domperidone and erythromycin as prokinetic agents. Recommend antiemetics, such as diphenhydramine, ondansetron, and prochlorperazine for management of nausea and vomiting. Severe cases of gastroparesis may merit a venting gastrostomy tube for decompression and/or feeding via a jejunostomy tube.¹⁵ Impaired intestinal mobility may lead to stasis syndrome, causing diarrhea.

Hypermobility caused by decreased sympathetic inhibition can also contribute to diarrhea. Altered anal sphincter function tone may contribute to fecal incontinence. Management should focus on balancing electrolytes, maintaining adequate fluid intake, and relieving symptoms. Consider antidiarrheals such as loperamide, but use them with caution to avoid toxic megacolon.¹⁶

Constipation. Another common manifestation of autonomic dysfunction in the GI tract is severe constipation.¹ This may be managed conservatively with hydration, increased activity, and increased fiber intake. If such measures prove inadequate, consider stool softeners and laxatives.

Patients with constipation due to spinal cord lesions may benefit from a routine bowel regimen. To provide predictable defecation, advise patients to begin by inserting a stimulant rectal suppository. Follow with gentle digital stimulation of the distal rectum for one minute or less. They’ll need to repeat the process every 5 to 10 minutes until stool evacuation is complete. A forward-leaning position may assist with evacuation. It is helpful to perform this routine at the same time each day.¹⁷

Orthostatic (postural) hypotension

The autonomic nervous system plays an important role in maintaining BP during positional changes. The sympathetic nervous system adjusts the tone in arteries, veins, and the heart. Baroreceptors located primarily in the carotid arteries and aorta, are highly sensitive to changes in BP. When the baroreceptors sense the slightest drop in pressure, a coordinated increase in sympathetic outflow occurs. Arteries constrict to increase peripheral resistance and BP, and heart rate and contractility increase, all in an attempt to maintain BP and perfusion.¹⁸

The most common causes of orthostatic hypotension are not neurologic in origin,⁹ but rather involve medications, hypovolemia, and impaired autonomic reflexes. The condition is common in the elderly, with one study demonstrating a prevalence of 18.2% in those ≥65 years.¹⁹

Orthostatic hypotension may present with dimming or loss of vision, lightheadedness, diaphoresis, diminished hearing, pallor, and weakness. As a result, it is a risk factor for falls. Syncope results when the drop in BP impairs cerebral perfusion. Signs of impaired baroreflexes are supine hypertension, a heart rate that is fixed regardless of posture (the heart rate should increase upon standing), postprandial hypotension, and an excessively high nocturnal BP.¹

Orthostatic hypotension is diagnosed when, within 3 minutes of quiet standing after a 5-minute period of supine rest, one or both of the following is present: at least a 20 mm Hg-fall in systolic pressure or at least a 10 mm Hg-fall in diastolic pressure.²⁰ Soysal et al demonstrated that such a drop in BP, measured one minute after standing, is adequate and effective for diagnosing orthostatic hypotension in the elderly.²¹

Nonpharmacologic management. Recognition and removal of medications that can exacerbate orthostatic hypotension is the first step in managing the condition. Such medications include diuretics, beta-blockers, alpha adrenergic blockers, vasodilators, antipsychotics, antidepressants (SSRIs, trazodone, monoamine oxidase inhibitors, and tricyclic antidepressants), phosphodiesterase inhibitors, narcotics, and antiparkinsonian medications.²²

The most common causes of orthostatic hypotension are not neurologic in origin, but rather involve medications, hypovolemia, and impaired autonomic reflexes.

Lifestyle interventions, such as having the patient arise slowly and maintain good hydration, can be helpful. Eating smaller, more frequent meals may also help if the orthostatic hypotension is triggered postprandially. Compressive stockings can help limit venous pooling in the lower extremities and improve venous return. Tensing the legs by crossing them while standing on both feet has been shown to increase cardiac output and BP.²³ An aerobic exercise regimen of walking or stair climbing 30 to 45 minutes/day 3 days/week for 6 months was shown to eliminate symptoms of orthostasis on tilt table testing in elderly patients with cardiac deconditioning, as opposed to chronic autonomic failure.²⁴

The reduction in central blood volume associated with autonomic insufficiency (due to increased urinary sodium and water excretion) can be lessened by increasing sodium and water intake.^25-27

Pharmacotherapy. Fludrocortisone acetate, a synthetic mineralocorticoid, is the medication of first choice for most patients with orthostatic hypotension whose symptoms are not adequately controlled using nonpharmacologic measures,²⁸ but keep in mind that treating orthostatic hypotension with fludrocortisones is an off-label use of the medication.

Monitor patients taking fludrocortisone for worsened supine hypertension and edema. Also, check their serum potassium levels one to 2 weeks after initiation of therapy and after dose increases. Frequent home monitoring of BP in sitting, standing, and supine positions may be helpful in assessing response to therapy.

If the patient remains symptomatic despite therapy with fludrocortisone, consider adding an alpha-1 adrenergic agonist, such as midodrine. Avoid prescribing midodrine, however, for patients with advanced cardiovascular disease, urinary retention, or uncontrolled hypertension.²⁹

Autonomic dysreflexia: A medical emergency

Autonomic dysreflexia, a medical emergency that must be recognized immediately, is a distinct type of autonomic dysfunction seen in patients with spinal cord injury at or above the T6 level.³⁰ It is a condition of uncontrolled sympathetic response secondary to an underlying condition such as infection, urinary retention, or rectal distention.³⁰

Common symptoms include headache, significant hypertension, flushing of the skin, and diaphoresis above the level of injury.² In addition, a review of systems should screen for fever, visual changes, abnormalities of the cardiovascular system, syncope, bowel and bladder symptoms, and sexual dysfunction.

When nonpharmacologic measures don't control orthostatic hypotension, consider the off-label use of fludrocortisone.

Patients demonstrating autonomic dysreflexia should be placed in the upright position to produce an orthostatic decrease in BP.³⁰ Patients should be evaluated to identify any reversible precipitants, such as urinary retention or fecal impaction. Severe attacks involving hypertensive crisis require prompt transfer to the emergency department. Sublingual nifedipine or an intravenous agent, such as hydralazine, may be used to lower BP.³¹

CORRESPONDENCE
Kristen Thornton, MD, 777 South Clinton Ave., Rochester, NY 14620; [email protected]

Signs and symptoms of autonomic dysfunction commonly present in the primary care setting. Potential causes of dysfunction include certain medications and age-related changes in physiology, as well as conditions such as diabetes mellitus, multiple sclerosis, and Parkinson’s disease (TABLE¹). This evidence-based review details common manifestations of autonomic dysfunction, provides a streamlined approach to patients presenting with symptoms, and reviews appropriate step-wise management.

When a delicate balance is disrupted

The autonomic nervous system provides brisk physiologic adjustments necessary to maintain homeostasis. Physiologic functions impacted by the central nervous system include: heart rate, blood pressure (BP), tone of the bladder sphincter and detrusor muscle, bowel motility, bronchodilation and constriction, pupillary dilation and constriction, sweating, catecholamine release, erection, ejaculation and orgasm, tearing, and salivation.¹

Disorders of the autonomic system may result from pathologies of the central or peripheral nervous system or from medications including some antihypertensives, selective serotonin-reuptake inhibitors (SSRIs), and opioids.¹ Such disorders tend to be grouped into one of 3 categories: those involving the brain, those involving the spinal cord, and autonomic neuropathies.¹

The source of dysautonomia can often be determined by clinical context, coexisting neurologic abnormalities, targeted testing of the autonomic nervous system, and neuroimaging.¹

Worrisome symptoms prompt a visit

A thorough history is critical to zeroing in on a patient’s complaints and ultimately providing treatment that will help manage symptoms.

When patient complaints are suggestive of autonomic dysfunction, a review of systems should include inquiry about lightheadedness, abnormal salivation, temperature changes of the extremities, gastrointestinal issues (vomiting, constipation, or diarrhea), and symptoms of presyncope/syncope or urinary or sexual dysfunction.¹ The physical exam should include recordings of BP and heart rate in the supine and standing positions and a complete neurologic examination.¹ Findings will typically point to one or more common complications.

Common complications of autonomic dysfunction

Complications of autonomic dysfunction include impotence, bladder dysfunction, gastrointestinal (GI) dysfunction, and orthostatic hypotension and vasomotor abnormalities. A less common condition—autonomic dysreflexia, which is a distinct type of autonomic dysfunction, and a true medical emergency—is also important to keep in mind.

Impotence

Autonomic neuropathy is a common cause of impotence and retrograde ejaculation. Loss of early morning erections and complete loss of nocturnal erections often have an etiology related to vascular disease and/or autonomic neuropathy. In addition, poor glycemic control and vascular risk factors appear to be associated with the development of diabetic autonomic neuropathy.²

If diabetic autonomic neuropathy is the suspected etiology of impotence, consider prescribing a phosphodiesterase inhibitor.

Development of an erection requires an increase in parasympathetic activity and a decrease in sympathetic output. Nocturnal penile tumescence testing has been used to infer parasympathetic damage to the penis in men with diabetes who do not have vascular disease.³

First- and second-line agents. Phosphodiesterase-5 inhibitors (eg, sildenafil, tadalafil, vardenafil) have demonstrated efficacy in improving the ability to achieve and maintain erections in patients with autonomic dysfunction, including diabetic autonomic neuropathy.^4-6 Second-line therapies with proven efficacy include intraurethral application and intracavernosal injections of alprostadil.^7,8

Bladder dysfunction

Sympathetic activity increases bladder sphincter tone and inhibits detrusor activity, while the parasympathetic nervous system increases detrusor activity and decreases sphincter tone to aid in voiding.¹ Disrupted autonomic activity can lead to urinary frequency, retention, and hesitancy; overactive bladder; and incontinence.¹ Brain and spinal cord disease above the level of the lumbar spine results in urinary frequency and small bladder volumes, whereas diseases involving autonomic nerve fibers to and from the bladder result in large bladder volumes and overflow incontinence.⁹

Botulinum toxin type A, injected directly into the detrusor muscle, can be as effective as medication in patients with urinary urge incontinence.

Patients presenting with lower urinary tract symptoms require a comprehensive evaluation to rule out other pathologies, as the differential for such symptoms is broad and includes infection, malignancies, interstitial cystitis, and bladder stones. The initial evaluation of lower urinary tract symptoms should include a history and physical exam including that of the abdomen, pelvis, and neurologic system. Lab work should assess renal function and blood glucose, and should include urinalysis and culture to rule out infection and/or hematuria. A prostate-specific antigen (PSA) test may be appropriate in men with a life expectancy >10 years, after counseling regarding the risks and benefits of screening.

Anticholinergic drugs with antimuscarinic effects, such as oxybutynin, may be used to treat symptoms of urge incontinence and overactive bladder. They work to suppress involuntary contractions of the bladder’s smooth muscle by blocking the release of acetylcholine. These medications relax the bladder’s outer layer of muscle—the detrusor. Such medications often have a number of anticholinergic adverse effects, such as dry mouth and constipation, sometimes leading to discontinuation. A post-void residual (PVR) test may be helpful in guiding management. For example, caution should be used in patients with elevated PVRs, as anticholinergics can worsen urinary retention.

Beta-3 agonists (eg, mirabegron) are a novel class of medications used to treat overactive bladder. These medications act to increase sympathetic tone in the bladder. Because they have the potential to raise BP, monitor BP in patients taking these agents. In addition, monitor patients taking antimuscarinics or beta-3 agonists for the development of urinary retention.

Other tests, treatments. Urodynamic testing is recommended for patients who fail to respond to treatment. Combining behavioral therapy with medication has been shown to be effective in patients with urge incontinence.¹⁰ Botulinum toxin type A, injected directly into the detrusor muscle, can be as effective as medication in patients with urinary urge incontinence.¹¹

Detrusor underactivity is defined as contraction of reduced strength and/or duration, resulting in prolonged bladder emptying and/or a failure to achieve complete bladder emptying within a normal timespan.¹² This diagnosis is typically made using urodynamic testing.¹³ PVRs ≥150 mL are considered evidence of urinary retention. Overflow incontinence can result from detrusor underactivity.

Consider a trial of a cholinergic agonist, such as bethanechol, in patients with urinary retention. Some patients will require intermittent straight catheterization or chronic indwelling foley or suprapubic catheters to void.

Gastrointestinal dysfunction

In patients with diabetes, GI autonomic neuropathy can result in altered esophageal motility leading to gastroesophageal reflux disease (GERD) or dysphagia, gastroparesis, or diabetic enteropathy.¹⁴ Gastroparesis often presents as nausea, vomiting, and bloating.¹ It may be diagnosed via gastric emptying studies (scintigraphy), and often requires a multidimensional approach to treatment.

Management. Food may be chopped or pureed to aid in digestion. Metoclopramide is the most commonly used prokinetic agent, but avoid its use in patients with parkinsonism. In more severe cases, consider adding domperidone and erythromycin as prokinetic agents. Recommend antiemetics, such as diphenhydramine, ondansetron, and prochlorperazine for management of nausea and vomiting. Severe cases of gastroparesis may merit a venting gastrostomy tube for decompression and/or feeding via a jejunostomy tube.¹⁵ Impaired intestinal mobility may lead to stasis syndrome, causing diarrhea.

Hypermobility caused by decreased sympathetic inhibition can also contribute to diarrhea. Altered anal sphincter function tone may contribute to fecal incontinence. Management should focus on balancing electrolytes, maintaining adequate fluid intake, and relieving symptoms. Consider antidiarrheals such as loperamide, but use them with caution to avoid toxic megacolon.¹⁶

Constipation. Another common manifestation of autonomic dysfunction in the GI tract is severe constipation.¹ This may be managed conservatively with hydration, increased activity, and increased fiber intake. If such measures prove inadequate, consider stool softeners and laxatives.

Patients with constipation due to spinal cord lesions may benefit from a routine bowel regimen. To provide predictable defecation, advise patients to begin by inserting a stimulant rectal suppository. Follow with gentle digital stimulation of the distal rectum for one minute or less. They’ll need to repeat the process every 5 to 10 minutes until stool evacuation is complete. A forward-leaning position may assist with evacuation. It is helpful to perform this routine at the same time each day.¹⁷

Orthostatic (postural) hypotension

The autonomic nervous system plays an important role in maintaining BP during positional changes. The sympathetic nervous system adjusts the tone in arteries, veins, and the heart. Baroreceptors located primarily in the carotid arteries and aorta, are highly sensitive to changes in BP. When the baroreceptors sense the slightest drop in pressure, a coordinated increase in sympathetic outflow occurs. Arteries constrict to increase peripheral resistance and BP, and heart rate and contractility increase, all in an attempt to maintain BP and perfusion.¹⁸

The most common causes of orthostatic hypotension are not neurologic in origin,⁹ but rather involve medications, hypovolemia, and impaired autonomic reflexes. The condition is common in the elderly, with one study demonstrating a prevalence of 18.2% in those ≥65 years.¹⁹

Orthostatic hypotension may present with dimming or loss of vision, lightheadedness, diaphoresis, diminished hearing, pallor, and weakness. As a result, it is a risk factor for falls. Syncope results when the drop in BP impairs cerebral perfusion. Signs of impaired baroreflexes are supine hypertension, a heart rate that is fixed regardless of posture (the heart rate should increase upon standing), postprandial hypotension, and an excessively high nocturnal BP.¹

Orthostatic hypotension is diagnosed when, within 3 minutes of quiet standing after a 5-minute period of supine rest, one or both of the following is present: at least a 20 mm Hg-fall in systolic pressure or at least a 10 mm Hg-fall in diastolic pressure.²⁰ Soysal et al demonstrated that such a drop in BP, measured one minute after standing, is adequate and effective for diagnosing orthostatic hypotension in the elderly.²¹

Nonpharmacologic management. Recognition and removal of medications that can exacerbate orthostatic hypotension is the first step in managing the condition. Such medications include diuretics, beta-blockers, alpha adrenergic blockers, vasodilators, antipsychotics, antidepressants (SSRIs, trazodone, monoamine oxidase inhibitors, and tricyclic antidepressants), phosphodiesterase inhibitors, narcotics, and antiparkinsonian medications.²²

The most common causes of orthostatic hypotension are not neurologic in origin, but rather involve medications, hypovolemia, and impaired autonomic reflexes.

Lifestyle interventions, such as having the patient arise slowly and maintain good hydration, can be helpful. Eating smaller, more frequent meals may also help if the orthostatic hypotension is triggered postprandially. Compressive stockings can help limit venous pooling in the lower extremities and improve venous return. Tensing the legs by crossing them while standing on both feet has been shown to increase cardiac output and BP.²³ An aerobic exercise regimen of walking or stair climbing 30 to 45 minutes/day 3 days/week for 6 months was shown to eliminate symptoms of orthostasis on tilt table testing in elderly patients with cardiac deconditioning, as opposed to chronic autonomic failure.²⁴

The reduction in central blood volume associated with autonomic insufficiency (due to increased urinary sodium and water excretion) can be lessened by increasing sodium and water intake.^25-27

Pharmacotherapy. Fludrocortisone acetate, a synthetic mineralocorticoid, is the medication of first choice for most patients with orthostatic hypotension whose symptoms are not adequately controlled using nonpharmacologic measures,²⁸ but keep in mind that treating orthostatic hypotension with fludrocortisones is an off-label use of the medication.

Monitor patients taking fludrocortisone for worsened supine hypertension and edema. Also, check their serum potassium levels one to 2 weeks after initiation of therapy and after dose increases. Frequent home monitoring of BP in sitting, standing, and supine positions may be helpful in assessing response to therapy.

If the patient remains symptomatic despite therapy with fludrocortisone, consider adding an alpha-1 adrenergic agonist, such as midodrine. Avoid prescribing midodrine, however, for patients with advanced cardiovascular disease, urinary retention, or uncontrolled hypertension.²⁹

Autonomic dysreflexia: A medical emergency

Autonomic dysreflexia, a medical emergency that must be recognized immediately, is a distinct type of autonomic dysfunction seen in patients with spinal cord injury at or above the T6 level.³⁰ It is a condition of uncontrolled sympathetic response secondary to an underlying condition such as infection, urinary retention, or rectal distention.³⁰

Common symptoms include headache, significant hypertension, flushing of the skin, and diaphoresis above the level of injury.² In addition, a review of systems should screen for fever, visual changes, abnormalities of the cardiovascular system, syncope, bowel and bladder symptoms, and sexual dysfunction.

When nonpharmacologic measures don't control orthostatic hypotension, consider the off-label use of fludrocortisone.

Patients demonstrating autonomic dysreflexia should be placed in the upright position to produce an orthostatic decrease in BP.³⁰ Patients should be evaluated to identify any reversible precipitants, such as urinary retention or fecal impaction. Severe attacks involving hypertensive crisis require prompt transfer to the emergency department. Sublingual nifedipine or an intravenous agent, such as hydralazine, may be used to lower BP.³¹

CORRESPONDENCE
Kristen Thornton, MD, 777 South Clinton Ave., Rochester, NY 14620; [email protected]

Signs and symptoms of autonomic dysfunction commonly present in the primary care setting. Potential causes of dysfunction include certain medications and age-related changes in physiology, as well as conditions such as diabetes mellitus, multiple sclerosis, and Parkinson’s disease (TABLE¹). This evidence-based review details common manifestations of autonomic dysfunction, provides a streamlined approach to patients presenting with symptoms, and reviews appropriate step-wise management.

When a delicate balance is disrupted

The autonomic nervous system provides brisk physiologic adjustments necessary to maintain homeostasis. Physiologic functions impacted by the central nervous system include: heart rate, blood pressure (BP), tone of the bladder sphincter and detrusor muscle, bowel motility, bronchodilation and constriction, pupillary dilation and constriction, sweating, catecholamine release, erection, ejaculation and orgasm, tearing, and salivation.¹

Disorders of the autonomic system may result from pathologies of the central or peripheral nervous system or from medications including some antihypertensives, selective serotonin-reuptake inhibitors (SSRIs), and opioids.¹ Such disorders tend to be grouped into one of 3 categories: those involving the brain, those involving the spinal cord, and autonomic neuropathies.¹

The source of dysautonomia can often be determined by clinical context, coexisting neurologic abnormalities, targeted testing of the autonomic nervous system, and neuroimaging.¹

Worrisome symptoms prompt a visit

A thorough history is critical to zeroing in on a patient’s complaints and ultimately providing treatment that will help manage symptoms.

When patient complaints are suggestive of autonomic dysfunction, a review of systems should include inquiry about lightheadedness, abnormal salivation, temperature changes of the extremities, gastrointestinal issues (vomiting, constipation, or diarrhea), and symptoms of presyncope/syncope or urinary or sexual dysfunction.¹ The physical exam should include recordings of BP and heart rate in the supine and standing positions and a complete neurologic examination.¹ Findings will typically point to one or more common complications.

Common complications of autonomic dysfunction

Complications of autonomic dysfunction include impotence, bladder dysfunction, gastrointestinal (GI) dysfunction, and orthostatic hypotension and vasomotor abnormalities. A less common condition—autonomic dysreflexia, which is a distinct type of autonomic dysfunction, and a true medical emergency—is also important to keep in mind.

Impotence

Autonomic neuropathy is a common cause of impotence and retrograde ejaculation. Loss of early morning erections and complete loss of nocturnal erections often have an etiology related to vascular disease and/or autonomic neuropathy. In addition, poor glycemic control and vascular risk factors appear to be associated with the development of diabetic autonomic neuropathy.²

If diabetic autonomic neuropathy is the suspected etiology of impotence, consider prescribing a phosphodiesterase inhibitor.

Development of an erection requires an increase in parasympathetic activity and a decrease in sympathetic output. Nocturnal penile tumescence testing has been used to infer parasympathetic damage to the penis in men with diabetes who do not have vascular disease.³

First- and second-line agents. Phosphodiesterase-5 inhibitors (eg, sildenafil, tadalafil, vardenafil) have demonstrated efficacy in improving the ability to achieve and maintain erections in patients with autonomic dysfunction, including diabetic autonomic neuropathy.^4-6 Second-line therapies with proven efficacy include intraurethral application and intracavernosal injections of alprostadil.^7,8

Bladder dysfunction

Sympathetic activity increases bladder sphincter tone and inhibits detrusor activity, while the parasympathetic nervous system increases detrusor activity and decreases sphincter tone to aid in voiding.¹ Disrupted autonomic activity can lead to urinary frequency, retention, and hesitancy; overactive bladder; and incontinence.¹ Brain and spinal cord disease above the level of the lumbar spine results in urinary frequency and small bladder volumes, whereas diseases involving autonomic nerve fibers to and from the bladder result in large bladder volumes and overflow incontinence.⁹

Botulinum toxin type A, injected directly into the detrusor muscle, can be as effective as medication in patients with urinary urge incontinence.

Patients presenting with lower urinary tract symptoms require a comprehensive evaluation to rule out other pathologies, as the differential for such symptoms is broad and includes infection, malignancies, interstitial cystitis, and bladder stones. The initial evaluation of lower urinary tract symptoms should include a history and physical exam including that of the abdomen, pelvis, and neurologic system. Lab work should assess renal function and blood glucose, and should include urinalysis and culture to rule out infection and/or hematuria. A prostate-specific antigen (PSA) test may be appropriate in men with a life expectancy >10 years, after counseling regarding the risks and benefits of screening.

Anticholinergic drugs with antimuscarinic effects, such as oxybutynin, may be used to treat symptoms of urge incontinence and overactive bladder. They work to suppress involuntary contractions of the bladder’s smooth muscle by blocking the release of acetylcholine. These medications relax the bladder’s outer layer of muscle—the detrusor. Such medications often have a number of anticholinergic adverse effects, such as dry mouth and constipation, sometimes leading to discontinuation. A post-void residual (PVR) test may be helpful in guiding management. For example, caution should be used in patients with elevated PVRs, as anticholinergics can worsen urinary retention.

Beta-3 agonists (eg, mirabegron) are a novel class of medications used to treat overactive bladder. These medications act to increase sympathetic tone in the bladder. Because they have the potential to raise BP, monitor BP in patients taking these agents. In addition, monitor patients taking antimuscarinics or beta-3 agonists for the development of urinary retention.

Other tests, treatments. Urodynamic testing is recommended for patients who fail to respond to treatment. Combining behavioral therapy with medication has been shown to be effective in patients with urge incontinence.¹⁰ Botulinum toxin type A, injected directly into the detrusor muscle, can be as effective as medication in patients with urinary urge incontinence.¹¹

Detrusor underactivity is defined as contraction of reduced strength and/or duration, resulting in prolonged bladder emptying and/or a failure to achieve complete bladder emptying within a normal timespan.¹² This diagnosis is typically made using urodynamic testing.¹³ PVRs ≥150 mL are considered evidence of urinary retention. Overflow incontinence can result from detrusor underactivity.

Consider a trial of a cholinergic agonist, such as bethanechol, in patients with urinary retention. Some patients will require intermittent straight catheterization or chronic indwelling foley or suprapubic catheters to void.

Gastrointestinal dysfunction

In patients with diabetes, GI autonomic neuropathy can result in altered esophageal motility leading to gastroesophageal reflux disease (GERD) or dysphagia, gastroparesis, or diabetic enteropathy.¹⁴ Gastroparesis often presents as nausea, vomiting, and bloating.¹ It may be diagnosed via gastric emptying studies (scintigraphy), and often requires a multidimensional approach to treatment.

Management. Food may be chopped or pureed to aid in digestion. Metoclopramide is the most commonly used prokinetic agent, but avoid its use in patients with parkinsonism. In more severe cases, consider adding domperidone and erythromycin as prokinetic agents. Recommend antiemetics, such as diphenhydramine, ondansetron, and prochlorperazine for management of nausea and vomiting. Severe cases of gastroparesis may merit a venting gastrostomy tube for decompression and/or feeding via a jejunostomy tube.¹⁵ Impaired intestinal mobility may lead to stasis syndrome, causing diarrhea.

Hypermobility caused by decreased sympathetic inhibition can also contribute to diarrhea. Altered anal sphincter function tone may contribute to fecal incontinence. Management should focus on balancing electrolytes, maintaining adequate fluid intake, and relieving symptoms. Consider antidiarrheals such as loperamide, but use them with caution to avoid toxic megacolon.¹⁶

Constipation. Another common manifestation of autonomic dysfunction in the GI tract is severe constipation.¹ This may be managed conservatively with hydration, increased activity, and increased fiber intake. If such measures prove inadequate, consider stool softeners and laxatives.

Patients with constipation due to spinal cord lesions may benefit from a routine bowel regimen. To provide predictable defecation, advise patients to begin by inserting a stimulant rectal suppository. Follow with gentle digital stimulation of the distal rectum for one minute or less. They’ll need to repeat the process every 5 to 10 minutes until stool evacuation is complete. A forward-leaning position may assist with evacuation. It is helpful to perform this routine at the same time each day.¹⁷

Orthostatic (postural) hypotension

The autonomic nervous system plays an important role in maintaining BP during positional changes. The sympathetic nervous system adjusts the tone in arteries, veins, and the heart. Baroreceptors located primarily in the carotid arteries and aorta, are highly sensitive to changes in BP. When the baroreceptors sense the slightest drop in pressure, a coordinated increase in sympathetic outflow occurs. Arteries constrict to increase peripheral resistance and BP, and heart rate and contractility increase, all in an attempt to maintain BP and perfusion.¹⁸

The most common causes of orthostatic hypotension are not neurologic in origin,⁹ but rather involve medications, hypovolemia, and impaired autonomic reflexes. The condition is common in the elderly, with one study demonstrating a prevalence of 18.2% in those ≥65 years.¹⁹

Orthostatic hypotension may present with dimming or loss of vision, lightheadedness, diaphoresis, diminished hearing, pallor, and weakness. As a result, it is a risk factor for falls. Syncope results when the drop in BP impairs cerebral perfusion. Signs of impaired baroreflexes are supine hypertension, a heart rate that is fixed regardless of posture (the heart rate should increase upon standing), postprandial hypotension, and an excessively high nocturnal BP.¹

Orthostatic hypotension is diagnosed when, within 3 minutes of quiet standing after a 5-minute period of supine rest, one or both of the following is present: at least a 20 mm Hg-fall in systolic pressure or at least a 10 mm Hg-fall in diastolic pressure.²⁰ Soysal et al demonstrated that such a drop in BP, measured one minute after standing, is adequate and effective for diagnosing orthostatic hypotension in the elderly.²¹

Nonpharmacologic management. Recognition and removal of medications that can exacerbate orthostatic hypotension is the first step in managing the condition. Such medications include diuretics, beta-blockers, alpha adrenergic blockers, vasodilators, antipsychotics, antidepressants (SSRIs, trazodone, monoamine oxidase inhibitors, and tricyclic antidepressants), phosphodiesterase inhibitors, narcotics, and antiparkinsonian medications.²²

The most common causes of orthostatic hypotension are not neurologic in origin, but rather involve medications, hypovolemia, and impaired autonomic reflexes.

Lifestyle interventions, such as having the patient arise slowly and maintain good hydration, can be helpful. Eating smaller, more frequent meals may also help if the orthostatic hypotension is triggered postprandially. Compressive stockings can help limit venous pooling in the lower extremities and improve venous return. Tensing the legs by crossing them while standing on both feet has been shown to increase cardiac output and BP.²³ An aerobic exercise regimen of walking or stair climbing 30 to 45 minutes/day 3 days/week for 6 months was shown to eliminate symptoms of orthostasis on tilt table testing in elderly patients with cardiac deconditioning, as opposed to chronic autonomic failure.²⁴

The reduction in central blood volume associated with autonomic insufficiency (due to increased urinary sodium and water excretion) can be lessened by increasing sodium and water intake.^25-27

Pharmacotherapy. Fludrocortisone acetate, a synthetic mineralocorticoid, is the medication of first choice for most patients with orthostatic hypotension whose symptoms are not adequately controlled using nonpharmacologic measures,²⁸ but keep in mind that treating orthostatic hypotension with fludrocortisones is an off-label use of the medication.

Monitor patients taking fludrocortisone for worsened supine hypertension and edema. Also, check their serum potassium levels one to 2 weeks after initiation of therapy and after dose increases. Frequent home monitoring of BP in sitting, standing, and supine positions may be helpful in assessing response to therapy.

If the patient remains symptomatic despite therapy with fludrocortisone, consider adding an alpha-1 adrenergic agonist, such as midodrine. Avoid prescribing midodrine, however, for patients with advanced cardiovascular disease, urinary retention, or uncontrolled hypertension.²⁹

Autonomic dysreflexia: A medical emergency

Autonomic dysreflexia, a medical emergency that must be recognized immediately, is a distinct type of autonomic dysfunction seen in patients with spinal cord injury at or above the T6 level.³⁰ It is a condition of uncontrolled sympathetic response secondary to an underlying condition such as infection, urinary retention, or rectal distention.³⁰

Common symptoms include headache, significant hypertension, flushing of the skin, and diaphoresis above the level of injury.² In addition, a review of systems should screen for fever, visual changes, abnormalities of the cardiovascular system, syncope, bowel and bladder symptoms, and sexual dysfunction.

When nonpharmacologic measures don't control orthostatic hypotension, consider the off-label use of fludrocortisone.

Patients demonstrating autonomic dysreflexia should be placed in the upright position to produce an orthostatic decrease in BP.³⁰ Patients should be evaluated to identify any reversible precipitants, such as urinary retention or fecal impaction. Severe attacks involving hypertensive crisis require prompt transfer to the emergency department. Sublingual nifedipine or an intravenous agent, such as hydralazine, may be used to lower BP.³¹

CORRESPONDENCE
Kristen Thornton, MD, 777 South Clinton Ave., Rochester, NY 14620; [email protected]

BARCELONA – Aggressive treatment of known risk factors for atrial fibrillation resulted in improved 1-year maintenance of sinus rhythm in patients with recent-onset atrial fibrillation and heart failure in the randomized multicenter RACE 3 trial, Isabelle C. van Gelder, MD, reported at the annual congress of the European Society of Cardiology.

“We now screen for AF, making it possible to catch patients early. That’s what we’ve learned from this trial: if we start treating patients after their first episode of AF and aggressively reduce risk factors for AF, it may help the sinus rhythm. I think that’s an important message: do not wait too long, start treatment early,” said Dr. van Gelder, professor of cardiology at the University of Groningen, the Netherlands.

She calls the interventional strategy tested in RACE 3 “risk factor-driven upstream therapy.” The four-pronged strategy consisted of statin therapy, a mineralcorticoid receptor antagonist, an ACE inhibitor and/or an angiotensin receptor blocker, and a 9- to 11-week supervised cardiac rehabilitation program emphasizing lifestyle modification through physical training and dietary changes supported by professional counseling to promote adherence.

“These are interventions designed to improve the atrial substrate,” Dr. van Gelder explained.

RACE 3 (Routine versus Aggressive Upstream Rhythm Control for Prevention of Early Atrial Fibrillation in Heart Failure 3) was a multicenter, randomized, nonblinded clinical trial including 245 patients with, on average, a 3-month history of AF, a 2-month history of persistent AF, and a 2-month history of mild to moderate heart failure, either with preserved or reduced ejection fraction. All participants received guideline-directed rhythm control and heart failure therapies. In addition, half of participants were randomized to the upstream intervention. Three weeks after enrollment, all patients underwent electrical cardioversion.

The primary outcome was maintenance of sinus rhythm at 1 year as determined by 7-day Holter monitoring analyzed in blinded fashion at a central laboratory. The rate was 75% in the upstream intervention group, significantly better than the 63% in controls. This represented a 76% greater likelihood of sinus rhythm at 1 year in the upstream intervention group. They also showed significant reductions in systolic and diastolic blood pressure, N-terminal pro-brain natriuretic peptide, and LDL cholesterol, compared with controls. However, at 1 year, the two groups didn’t differ significantly in body mass index or left atrial volume. The lack of impact on left atrial volume was disappointing, Dr. van Gelder said.

“The remodeling process starts long before the first episode of AF, although we don’t know exactly when. Although we intended to intervene early in the remodeling process, I think we weren’t that early,” according to the cardiologist.

Discussant Josep Brugada, MD, applauded the Dutch investigators for opening the door to evidence-based preventive upstream therapy for AF, which he declared is vital given the worsening AF epidemic.

[email protected]

BARCELONA – Aggressive treatment of known risk factors for atrial fibrillation resulted in improved 1-year maintenance of sinus rhythm in patients with recent-onset atrial fibrillation and heart failure in the randomized multicenter RACE 3 trial, Isabelle C. van Gelder, MD, reported at the annual congress of the European Society of Cardiology.

“We now screen for AF, making it possible to catch patients early. That’s what we’ve learned from this trial: if we start treating patients after their first episode of AF and aggressively reduce risk factors for AF, it may help the sinus rhythm. I think that’s an important message: do not wait too long, start treatment early,” said Dr. van Gelder, professor of cardiology at the University of Groningen, the Netherlands.

She calls the interventional strategy tested in RACE 3 “risk factor-driven upstream therapy.” The four-pronged strategy consisted of statin therapy, a mineralcorticoid receptor antagonist, an ACE inhibitor and/or an angiotensin receptor blocker, and a 9- to 11-week supervised cardiac rehabilitation program emphasizing lifestyle modification through physical training and dietary changes supported by professional counseling to promote adherence.

“These are interventions designed to improve the atrial substrate,” Dr. van Gelder explained.

RACE 3 (Routine versus Aggressive Upstream Rhythm Control for Prevention of Early Atrial Fibrillation in Heart Failure 3) was a multicenter, randomized, nonblinded clinical trial including 245 patients with, on average, a 3-month history of AF, a 2-month history of persistent AF, and a 2-month history of mild to moderate heart failure, either with preserved or reduced ejection fraction. All participants received guideline-directed rhythm control and heart failure therapies. In addition, half of participants were randomized to the upstream intervention. Three weeks after enrollment, all patients underwent electrical cardioversion.

The primary outcome was maintenance of sinus rhythm at 1 year as determined by 7-day Holter monitoring analyzed in blinded fashion at a central laboratory. The rate was 75% in the upstream intervention group, significantly better than the 63% in controls. This represented a 76% greater likelihood of sinus rhythm at 1 year in the upstream intervention group. They also showed significant reductions in systolic and diastolic blood pressure, N-terminal pro-brain natriuretic peptide, and LDL cholesterol, compared with controls. However, at 1 year, the two groups didn’t differ significantly in body mass index or left atrial volume. The lack of impact on left atrial volume was disappointing, Dr. van Gelder said.

“The remodeling process starts long before the first episode of AF, although we don’t know exactly when. Although we intended to intervene early in the remodeling process, I think we weren’t that early,” according to the cardiologist.

Discussant Josep Brugada, MD, applauded the Dutch investigators for opening the door to evidence-based preventive upstream therapy for AF, which he declared is vital given the worsening AF epidemic.

[email protected]

BARCELONA – Aggressive treatment of known risk factors for atrial fibrillation resulted in improved 1-year maintenance of sinus rhythm in patients with recent-onset atrial fibrillation and heart failure in the randomized multicenter RACE 3 trial, Isabelle C. van Gelder, MD, reported at the annual congress of the European Society of Cardiology.

“We now screen for AF, making it possible to catch patients early. That’s what we’ve learned from this trial: if we start treating patients after their first episode of AF and aggressively reduce risk factors for AF, it may help the sinus rhythm. I think that’s an important message: do not wait too long, start treatment early,” said Dr. van Gelder, professor of cardiology at the University of Groningen, the Netherlands.

She calls the interventional strategy tested in RACE 3 “risk factor-driven upstream therapy.” The four-pronged strategy consisted of statin therapy, a mineralcorticoid receptor antagonist, an ACE inhibitor and/or an angiotensin receptor blocker, and a 9- to 11-week supervised cardiac rehabilitation program emphasizing lifestyle modification through physical training and dietary changes supported by professional counseling to promote adherence.

“These are interventions designed to improve the atrial substrate,” Dr. van Gelder explained.

RACE 3 (Routine versus Aggressive Upstream Rhythm Control for Prevention of Early Atrial Fibrillation in Heart Failure 3) was a multicenter, randomized, nonblinded clinical trial including 245 patients with, on average, a 3-month history of AF, a 2-month history of persistent AF, and a 2-month history of mild to moderate heart failure, either with preserved or reduced ejection fraction. All participants received guideline-directed rhythm control and heart failure therapies. In addition, half of participants were randomized to the upstream intervention. Three weeks after enrollment, all patients underwent electrical cardioversion.

The primary outcome was maintenance of sinus rhythm at 1 year as determined by 7-day Holter monitoring analyzed in blinded fashion at a central laboratory. The rate was 75% in the upstream intervention group, significantly better than the 63% in controls. This represented a 76% greater likelihood of sinus rhythm at 1 year in the upstream intervention group. They also showed significant reductions in systolic and diastolic blood pressure, N-terminal pro-brain natriuretic peptide, and LDL cholesterol, compared with controls. However, at 1 year, the two groups didn’t differ significantly in body mass index or left atrial volume. The lack of impact on left atrial volume was disappointing, Dr. van Gelder said.

“The remodeling process starts long before the first episode of AF, although we don’t know exactly when. Although we intended to intervene early in the remodeling process, I think we weren’t that early,” according to the cardiologist.

Discussant Josep Brugada, MD, applauded the Dutch investigators for opening the door to evidence-based preventive upstream therapy for AF, which he declared is vital given the worsening AF epidemic.

[email protected]

From the University of Arizona College of Pharmacy and the University of Arizona College of Medicine-Tucson, Tucson, AZ.

Abstract

• Objective: To summarize key issues relevant to managing hyperglycemia in patients with type 2 diabetes mellitus (T2DM) and review a strategy for initiating and intensifying therapy.
• Methods: Review of the literature.
• Results: The 6 most widely used pharmacologic treatment options for hyperglycemia in T2DM are metformin, sulfonylureas, dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists, sodium-glucose cotransporter-2 inhibitors, and insulin. Recent guidelines stress the importance of an individualized, patient-centered approach to managing hyperglycemia in T2DM, although sufficient guidance for nonspecialists on how to individualize treatment is often lacking. For patients with no contraindications, metformin should be recommended concurrent with lifestyle intervention at the time of diabetes diagnosis. Due to the progressive nature of T2DM, glycemic control on metformin monotherapy is likely to deteriorate over time, and there is no consensus as to what the second-line agent should be. A second agent should be selected based on glycemic goal and potential advantages and disadvantages of each agent for any given patient. If the patient progresses to the point where dual therapy does not provide adequate control, either a third non-insulin agent or insulin can be added.
• Conclusion: Although research is increasingly focusing on what the ideal number and sequence of drugs should be when managing T2DM, investigating all possible combinations in diverse patient populations is not feasible. Physicians therefore must continue to rely on clinical judgment to determine how to apply trial data to the treatment of individual patients.

Key words: type 2 diabetes; patient-centered care; antihyper-glycemic drugs; insulin; therapeutic decision-making.

Diabetes mellitus affects approximately 29.1 million people, or 9.3% of the U.S. population [1,2]. The high prevalence of diabetes and its associated multiple complications, including cardiovascular disease (CVD), blindness, renal failure, lower extremity amputations, and premature death, lead to a tremendous overall burden of disease. The financial cost is staggering as well, with more than 1 in 5 health care dollars spent on treating diabetes or its complications [3]. The goal of diabetes treatment is to prevent acute complications and reduce the risk of long-term complications. Interventions that have been shown to improve diabetes outcomes include medications for glycemic control and treatment of cardiovascular risk factors, nutrition and physical activity counseling, smoking cessation, immunizations, psychosocial care, and ongoing surveillance and early treatment for eye, kidney, and foot problems [4].

Glycemic management in type 2 diabetes mellitus (T2DM), the focus of this review, is growing increasingly complex and has been the subject of numerous extensive reviews [5,6] and published guidelines [4,7]. In the context of an increasing array of available pharmacologic options, there are mounting uncertainties regarding the benefits of intensive glycemic control as well as increasing concerns about potential adverse treatment effects, hypoglycemia in particular. While previous guidelines encouraged specific approaches for most patients, more recent guidelines stress the importance of a patient-centered approach with shared decision-making [4]. Less prescriptive guidelines are more appropriate, given the current state of science, but they also may be viewed as providing insufficient guidance to some providers. It can be overwhelming for a non-specialist to try to match the nuances of antihyperglycemic medications to the nuances of each patient’s preferences and medical characteristics.

This article examines key issues faced by primary care providers when managing hyperglycemia in patients with T2DM and outlines a stepwise approach to determining the optimal antihyperglycemic agent(s) (Table 1). 

Confirm Diagnosis of T2DM

It can be difficult to distinguish between type 1 diabetes mellitus and T2DM in some individuals due to overlapping characteristics. However, correctly classifying a patient’s diabetes at the outset is essential, as the classification helps determine the best treatment regimen and is rarely reconsidered [4,8]. Considerable evidence suggests that misclassification of diabetes occurs frequently [9,10], resulting in patients receiving inappropriate treatment. Clinical characteristics suggestive of T2DM include older age and features of insulin resistance such as obesity, hyper-tension, hypertriglyceridemia, and low high-density lipoprotein cholesterol. When these features are not present, an alternate diagnosis should be entertained.

Establish Glycemic Goal

Research over the past decade has led to a growing appreciation of the enormous complexity of hyperglycemia management. During the 1990s, landmark trials such as the Diabetes Control and Complications Trial (DCCT) [11] and UK Prospective Diabetes Study (UKPDS) [12] demonstrated that improving glucose control could reduce the incidence of microvascular complications [11,12], prompting a lower-is-better philosophy regarding glucose targets. Despite limited evidence to support such thinking, this viewpoint was adopted by the developers of many guidelines. During the following decade more research was devoted to determining whether aggressively lowering a patient’s glucose could also improve macrovascular outcomes. Table 2 summarizes microvascular and macrovascular effects of intensive glycemic control seen in major trials [11–23]. After several major trials [20,22] found only mild cardiovascular benefits and even suggested harm [18], experts and policy makers began to reconsider the value of tightly controlling glucose levels [24]. Since then, other studies have demonstrated that the potential benefits and risks of glucose control are strongly related to individual patient factors, such as age and duration of diabetes, and associated comorbidities, such as CVD and impaired renal function [6].

A one-size-fits-all glycemic goal is no longer recommended. Personalization is necessary, balancing the potential benefits and risks of treatments required to achieve that goal. Whereas an A1C of < 7% is an appropriate target for some individuals with diabetes, glycemic targets may be more or less stringent based on patient features including life expectancy, duration of diabetes, comorbidities, and patient attitude and support system (Table 3) [4].

A particular group in which less stringent goals should be considered is older patients, especially those with complex or poor health status [4,25]. The risk of intensive glycemic control may exceed the benefits in these patients, as they are at higher risk of hypoglycemia and polypharmacy [26]. A goal A1C of 7% to 7.5% is now recommended for healthy older adults, and less stringent A1C goals of 7.5% to 8% and 8% to 8.5% should be considered based on the presence and severity of multiple coexisting chronic illnesses, decreased self-care ability, or cognitive impairment [4,25]. Unfortunately, overtreatment is frequently seen in this group. In a recent study of patients over age 65 years, about 40% of those with complex or poor health status had tight glycemic control with A1C below 6.5% [26]. An analysis of U.S. Veterans Affairs administration data showed that only 27% of 12,917 patients older than 65 with very low A1C (< 6%) and about 21% of those with A1C of 6% to 6.5% underwent treatment deintensification [27].

Initiate Treatment with Metformin

There is strong consensus that metformin is the preferred drug for monotherapy due to its long proven safety record, low cost, weight-reduction benefit, and potential cardiovascular advantages [4,16]. As long as there are no contraindications, metformin should be recommended concurrent with lifestyle intervention at the time of diabetes diagnosis. The recommendation is based on the fact that adherence to diet, weight reduction, and regular exercise is not sustained in most patients, and most patients ultimately will require treatment. Since metformin is usually well-tolerated, does not cause hypoglycemia, has a favorable effect on body weight, and is relatively inexpensive, potential benefits of early initiation of medication appear to outweigh potential risks.

The U.S. Food and Drug Administration (FDA) recently relaxed prescribing polices to extend the use of this important medication to patients who have mild–moderate, but stable, chronic kidney disease (CKD) [28]. Metformin is recommended as first-line therapy and should be used unless it is contraindicated (ie, estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73 m²)[4,7,29].

Add Additional Agent(s) as Needed to Achieve Goal

Other than metformin, evidence is limited for the optimal use of the burgeoning array of available agents, especially in dual or triple combinations [6,30]. Research is now starting to focus more on what the ideal number and sequence of drugs should be. The Glycemic Reduction Approach in Diabetes (GRADE) study, which will compare long-term benefits and risks of the 4 most widely used antihyperglycemic medications in combination with metformin, is now underway [31,32]. The 4 classes being studied are sulfonylurea, dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and a basal, 

Eleven classes of non-insulin medications are currently approved for treating hyperglycemia in T2DM [4]. Within each class, numerous agents are available. Six of these classes (ie, α-glucosidase inhibitors, colesevelam, bromocriptine, pramlintide, meglitinides, and thiazolidinediones) are not used frequently 

Consider Effects on A1C

There is a paucity of high-quality, head-to-head comparison trials evaluating the ability of available agents to achieve recommended glycemic targets. This is important because the glucose-lowering effectiveness of individual medications is strongly influenced by baseline characteristics such as A1C, duration of diabetes, and previous therapy. With these limitations in mind, the relative glucose-lowering effectiveness of commonly used agents is shown in Table 4. When used as monotherapy, A1C reductions of approximately 1% to 1.5% are achieved with metformin, sulfonylureas, and GLP-1 receptor agonists [6,30,34,35,39]. DPP-4 inhibitors and SGLT-2 inhibitors have more modest glucose-lowering efficacy, with A1C reductions of approximately 0.5% to 1% [6,30,34,35,39]. Larger effects may be seen in individuals with higher baseline A1C and those who are drug naïve. Insulin is the most effective glucose-lowering agent—it can reduce virtually any level of A1C down to the normal range, with hypoglycemia being the only limiting factor. When a patient has uncontrolled hyperglycemia on metformin monotherapy, or if there is a contraindication or intolerance to metformin, clinicians should consider the potential glucose-lowering effects of other available options and should choose an agent that conceivably could bring a patient close to meeting their treatment goal.

Eliminate Options with Unacceptable Adverse Effects

When the pharmacologic options with acceptable A1C-lowering potential have been identified, the ones with contraindications and potential serious adverse effects for the individual patient can immediately be eliminated (Table 4). For example, if a patient has an eGFR < 30 mL/min/1.73 m², metformin, sulfonylureas, GLP-1 receptor agonists, most DPP-4 inhibitors, and SGLT-2 inhibitors are either contraindicated or should be used with caution. In patients with severe osteoporosis, SGLT-2 inhibitors may not be the best option. In patients with a history of diabetic ketoacidosis (DKA), caution should be used with metformin and SGLT-2 inhibitors. There have been concerns of possible acute pancreatitis and neoplasia with the incretin-based agents, the DPP-4 inhibitors and GLP-1 receptor agonists [40,41], although other clinical trials and observational data have not found increased risk [42–45]. Nevertheless, these agents potentially should be avoided in patients with a history of pancreatitis or neoplasm. SGLT-2 inhibitors may be associated with genitourinary infections and volume depletion [46–48] and probably should be avoided in patients at high risk for these conditions.

If the adverse effects are not serious, changing the way the medication is administered may allow the patient to tolerate agents with high potential benefits. For example, metformin is commonly associated with gastrointestinal (GI) adverse effects, which can be reduced or avoided with slow titration of the dose [6] or by switching to an extended-release formulation [49]. GLP-1 receptor agonists are associated with GI adverse effects [6] and in most cases slow titration is recommended.

Evaluate Potential Risks/Benefits of Remaining Options

Hypoglycemia. The barrier of hypoglycemia generally precludes maintenance of euglycemia and full realization of the long-term benefits of good glucose control over a lifetime. Once considered a trivial issue, concerns about hypoglycemia in T2DM are increasingly being raised [19,50–55]. Clearly, hypoglycemia occurs more often as glycemic targets are lowered to near-normal values, especially in those with advanced age and multiple comorbidities [55]. Various comorbidities frequently encountered particularly as patients age also are associated with increasing propensity for experiencing hypoglycemia and untoward outcomes from it. These include coronary artery disease, heart failure, renal and liver disease, and dementia. Hypoglycemia, when it occurs, may lead to dysrhythmias, dizziness, accidents and falls, work disability, and decreased quality of life. In addition to relaxing blood glucose targets in high-risk patients, drug selection should favor agents that do not precipitate such events (Table 4).

Fortunately, the commonly used non-insulin agents are not associated with hypoglycemia unless they are used in combination with sulfonylureas or insulin. Sulfonylureas should be used with caution and other options considered in patients with high risk for hypoglycemia. When insulin is required, regimens which minimize risk of hypoglycemia should be used. For example, adding a GLP-1 receptor agonist to basal insulin as an alternative to mealtime insulin has been shown to be equally effective with a lower risk of hypoglycemia [4,6]. Also, premixed insulin preparations should be avoided or used cautiously in individuals who miss meals frequently. Additionally, newer basal insulins that exhibit longer duration of action are now available in the United States. Preliminary studies have shown that the newly FDA-approved longer-acting basal insulins, insulin degludec and glargine U-300, may be associated with a reduced risk for hypoglycemia [56,57]. However, it remains unclear how and when these newer agents will best be incorporated into a treatment regimen.

Body weight. Nearly 90% of people living with T2DM are overweight or obese. Given the close tie between obesity and T2DM, treating obesity is an obvious consideration in diabetes treatment. Major trials have shown the effectiveness of lifestyle modifications and weight reduction in delaying, prevention, and management of T2DM [4,58,59].With this in mind, clinicians should consider preferentially using antihyperglycemic agents with weight-lowering or weight-neutral effects. Among commonly used antihyperglycemic agents, metformin, GLP-1 receptor agonists, and SGLT-2 inhibitors have been shown to have weight-reduction benefits, and DPP-4 inhibitors are weight neutral. On the other hand, sulfonylureas and insulin are associated with weight gain. A systematic review and meta-analysis including 204 studies with study durations ranging from 3 months to 8 years showed comparative effects of diabetes medications with a differential effect on weight of up to 5 kg (Table 4) [60].

Metformin is associated with an average weight loss of 1.9 to 3.1 kg that was sustained with long-term use for at least 10 years in the Diabetes Prevention Program Outcomes Study [61].A systematic review of 7 randomized trials showed that in patients with T2DM, the SGLT-2 inhibitors dapagliflozin and canagliflozin were associated with weight loss (mean weighted difference of –1.81 kg and –2.3 kg, respectively) [62]. A systematic review and meta-analysis of 25 randomized controlled trials showed greater weight loss (mean weighted difference of –2.9 kg) in overweight or obese patients with or without T2DM using GLP-1 receptor agonists when compared to placebo, insulin, or oral antihyperglycemic agents [63]. Of note, the GLP-1 receptor agonist liraglutide is now approved for weight loss in patients with or without diabetes [64]. The maximum doses approved for diabetes and obesity treatment are 1.8 and 3.0 mg/day, respectively.

Since weight loss is associated with improved glycemic control, an area of emerging interest is the use of antiobesity medications for managing diabetes. Although most older weight-loss medications were only approved for short-term use, some newer agents are approved for longer-term use. Lorcaserin and the combination drugs topiramate/phentermine and naltrexone/bupropion are approved for chronic therapy, provided certain conditions are met. Patients on weight reduction agents should be monitored regularly. 

An even more radical departure from conventional therapy for diabetes is the consideration of metabolic, or weight-loss, surgery, which has been found to be associated with rapid and dramatic improvements in blood glucose control. Metabolic surgery has been shown to improve glucose control more effectively than any known pharmaceutical or behavioral approach. For example, in an observational study of obese patients with T2DM, bariatric surgery led to diabetes remission rates of 72.3% 2 years after surgery and 30.4% 15 years after surgery compared to 16.4% and 6.5%, respectively, in control patients [69]. With long-term follow-up, significant decreases in microvascular and macrovascular complications were seen in the surgical group [69]. Compared with medical therapy alone, bariatric surgery plus medical therapy has been associated with more weight loss, better glycemic control, less need for diabetes medications, and improved quality of life [70]. A 2016 joint statement by numerous international diabetes organizations recommends considering metabolic surgery as a treatment for T2DM and obesity [71]. American Diabetes Association guidelines recommend consideration of bariatric surgery in individuals with T2DM who have a body mass index greater than 35 kg/m²,especially if achieving disease control is difficult by means of lifestyle modifications and medications [4].

Cardiovascular outcomes. Cardiovascular risk is about 2 to 4 times higher in patients with diabetes, and about half of patients with this condition develop heart failure [4,72]. CVD is responsible for most of the mortality in T2DM [72]. Therefore, prevention of cardiovascular morbidity and mortality is an important goal for diabetes treatment. Due to concerns about potential cardiovascular risks associated with glucose-lowering medications [73–76], the FDA has issued regulatory requirements for manufacturers to monitor the cardiovascular risk profile for these drugs [77]. Recent trials have led to a better understanding of potential cardiovascular benefits or harms of antihyperglycemic medications.

Metformin, the widely recommended first-line therapy for T2DM, carries a large body of evidence supporting its cardiovascular benefits. For example, the UKPDS found that compared to conventional therapy (mostly diet), metformin reduced cardiovascular events and mortality in obese patients with T2DM [15]. This result was supported in Hyperinsulinemia: the Outcome of its Metabolic Effect (HOME) study where, as an add-on to insulin, metformin decreased macrovascular complications when compared to placebo [78]. Research over the past decade also has assuaged concerns about metformin safety in heart failure [60]. A systematic review of observational studies involving 34,000 patients conducted in 2013 showed that metformin is as safe as other glucose-lowering medications in patients with diabetes and heart failure even in the presence of CKD [4,79]. Furthermore, numerous investigations have found metformin is not associated with increased hospitalizations or risk of lactic acidosis [80]. Metformin can be used safely in patients with diabetes and heart failure [60].

Although sulfonylureas have long been a mainstay of diabetes therapy, concerns about their potential adverse cardiovascular effects have been raised by numerous studies [81]. Tolbutamide, a first-generation sulfonylurea, was removed from the market after the University Group Diabetes Program study found increased CVD deaths with this agent versus placebo. Subsequently, the FDA issued a warning for all sulfonylureas [74]. The increased cardiovascular risk associated with sulfonylureas is thought to be due to their effect on cardiac mitochondrial potassium ATP channels. Sulfonylureas bind to these channels, preventing a protective phenomenon called ischemic preconditioning and resulting in a weakened defense against myocardial injury [76]. A recent study showed an increased risk of coronary heart disease associated with long-term use of sulfonylureas in women with diabetes [81].

GLP-1 receptor agonists have recently received much attention for their potential beneficial effects on cardiovascular outcomes. In a recent trial, lixisenatide was shown to be safe in patients with T2DM and acute coronary syndrome when compared to placebo [82]. More recently, the Liraglutide Effect and Action in Diabetes: Evaluation of cardiovascular outcome Results (LEADER) trial demonstrated significant cardiovascular benefits with liraglutide in patients with T2DM and established or high CVD risk [83]. The composite outcome of the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction (MI), or nonfatal stroke, occurred less frequently in the liraglutide group compared to placebo (13% versus 14.9%, respectively), and there were fewer deaths from cardiovascular causes in the liraglutide group compared to placebo (4.7% and 6.0%, respectively) [83]. Other trials investigating the cardiovascular outcomes of this class [84,85] are in progress.

Another class with potential cardiovascular benefits is the SGLT-2 inhibitors. In a recent cardiovascular outcome study, empagliflozin significantly lowered the composite of cardiovascular death, nonfatal MI, or nonfatal stroke in T2DM patients with high cardiovascular risk compared to placebo (10.5% and 12.1%, respectively) [86]. There are several large ongoing studies evaluating the cardiovascular effects of other SGLT-2 inhibitors [87–89].

DPP-4 inhibitors were examined in recent studies and have shown no cardiovascular benefits [42,44,90].The studies showed mixed results regarding an association between DPP-4 inhibitors and heart failure. In one study, saxagliptin was associated with increased hospitalization for heart failure compared to placebo [44], while 2 noninferiority trials did not show a significant increase in heart failure hospitalizations associated with alogliptin and sitagliptin when compared to placebo [42,90].

Administration Considerations

Many patients with T2DM require multiple agents for glycemic control. Additional medications used for comorbid conditions add to this burden. When choosing antihyperglycemic agents, the route and frequency of administration, as well as the patients’ preferences and ability, should be considered. Either once or twice daily dosing is available for most agents, and once weekly dosing is available for some of the GLP-1 receptor agonists. Once daily or once weekly formulations may improve adherence and be more desirable than preparations that are dosed twice daily. Most of the commonly used medications are dosed orally. Although many patients find this route of administration preferable to insulin or GLP-1 receptor agonists, which require injections, some patients may prefer the risk/benefit of injectable agents. All GLP-1 receptor agonists come in a pen delivery system, which eliminates mixing and provides more convenient administration. Extended-release exenatide also is available as a single-dose tray that requires mixing and may be more cumbersome to inject.

Insulin requires special consideration. There has been an enormous increase in the number of insulin products on the market in the past 2 decades. These products include insulin analogs, concentrated insulins (U-200, U-300, and U-500), premixed insulin preparations, and ultra-long-acting insulin [91]. The availability of insulin options with different concentrations, onsets, and durations of actions has made decision making on which insulin to use difficult. Clinicians need to consider patient preference, dosing frequency, and timing with regard to meals, insulin dose, administration, as well as cost. For example, concentrated insulin is preferred for a patient on high doses of insulin requiring injecting a large volume of insulin. Rapid-acting insulin analogs would be more appropriate for patients who have difficulty administering their regular insulin 20 to 30 minutes before eating. Premixed insulin preparations make it impossible to independently adjust short- and long-acting components. However, these may be good choices in patients who have consistent meal schedules and who want to simplify administration. Despite a prevailing misconception that NPH must be given twice a day, it has long been recognized that in T2DM, a single daily injection of NPH yields improvements in control similar to those achieved with 2 daily injections [92].

Cost Considerations

Treating T2DM imposes a great financial burden on individuals living with diabetes and their families due to the high cost of the medications. Table 4 and Table 5 provide information on the cost of non-insulin and insulin diabetes medications for patients who do not have prescription insurance coverage. From a practical standpoint, choice of diabetes agents is largely influenced by insurance formularies.

The older agents, metformin and the sulfonylureas, are available for a cash (no insurance) price of as little as $4 per month. This is in stark contrast to the SGLT-2 inhibitors, GLP-1 receptor agonists, and DPP-4 inhibitors, which range in cost between $400 and $600 per month. Of recent concern, the cost of insulin has been skyrocketing, with a more than 500% increase in the cost of certain insulins from 2001 to 2015 [93]. According to the Medical Expenditure Panel Survey (MEPS) from 2002 to 2013, the mean price of insulin increased by about 200% (from $4.34/mL to $12.92/mL) during this period, which was significantly higher than increases in the price of non-insulin comparators [94]. The introduction of biosimilar insulins to the market is expected to offer treatment options with lower cost. This will be tested when the biosimilar glargine, the first FDA-approved biosimilar insulin, becomes available in the U.S. market. However, a significant reduction in insulin prices is not expected soon [95].

When insulin is required, most patients with T2DM can be treated with older human insulins, which have similar efficacy and lower costs than the more expensive newer insulin analogs. A Cochrane review comparing basal insulin analogs to NPH showed similar efficacy in glycemic control with minimal clinical benefit in the form of less nocturnal hypoglycemia in the insulin analog arm [96]. Furthermore, similar glycemic control and risk of hypoglycemia was seen when regular insulin was compared with the rapid-acting insulin analogs [97]. The cost of human NPH insulin for a patient on a total daily dose of 60 units is approximately $52 per month. This contrasts with the most widely used insulin, insulin glargine, which has a cash price of about $500 per month for the same amount (Table 5). Insulin pens, which are convenient, are more expensive. Interestingly, human insulins do not require prescriptions, allowing underinsured, underfunded patients ongoing access to them.

Incorporating Patient Preferences

Research evidence is necessary but insufficient for making patient care decisions. Along with the potential benefits, harms, costs, and inconveniences of the management options, patient perspectives, beliefs, expectations, and health-related goals must be considered. Patients will undoubtedly have preferences regarding defining goals and ranking options. Clinicians should discuss therapeutic goals and treatment options and work collaboratively with patients in determining management strategies [98].

Summary

Potential treatment approaches for treating hyperglycemia in T2DM are summarized in Figure 1 and Figure 2 [4,7]. As long as there are no contraindications, metformin should be recommended concurrent with lifestyle intervention at the time of diabetes diagnosis. Even if metformin monotherapy is initially effective, glycemic control is likely to deteriorate over time due to progressive loss of β-cell function in T2DM.

There is no consensus as to what the second-line agent should be. Selection of a second agent should be made based on potential advantages and disadvantages of each agent for any given patient. A patient-centered approach is preferred over a fixed algorithm. If the patient progresses to the point where dual therapy does not provide adequate control, either a third non-insulin agent or insulin can be added. In patients with modestly elevated A1C (below ~8%), addition of a third non-insulin agent may be equally effective as (but more expensive than) addition of insulin.

Patients with significantly elevated A1C levels on non-insulin agents usually should have insulin added to their regimen. When insulin is added, metformin should be continued. DPP-4 inhibitors and sulfonylureas are typically stopped. If SGLT-2 inhibitors and/or GLP-1 receptor agonists are continued, this may aid with weight maintenance. However, continuing these agents is likely to be expensive and associated with problems associated with polypharmacy.

The most widely recommended strategy for initiating insulin in T2DM is to add a single bedtime injection of basal insulin (ie, NPH, glargine, detemir, or degludec) to the patient’s regimen. This regimen has been found to be effective in numerous studies and controls hyperglycemia in up to 60% of patients [99]. If the patient is treated with a single bedtime injection of insulin and the fasting glucose level is within the target range but the A1C level remains above goal, addition of mealtime insulin injections is likely to be beneficial. Alternatively, addition of a GLP-1 receptor agonist to basal insulin has been shown to be equally beneficial [4,6]. When adding mealtime insulin, a common strategy is to add a single injection of a rapid-acting insulin (eg, lispro, aspart, glulisine) before the patient’s largest meal of the day. Additional premeal injections of rapid-acting insulin may be added as needed, based on self-monitoring blood glucose results. If glycemia remains significantly uncontrolled on more than 200 units of insulin per day, switching to a concentrated form of insulin (eg, U-200, U-300, or U-500) should be considered.

Corresponding author: Maryam Fazel, PharmD, BCPS, BCACP, CDE, 1295 N. Martin Ave. (Room B211B), Tucson, Arizona 85721-0202, [email protected].

Financial disclosures: None.

From the University of Arizona College of Pharmacy and the University of Arizona College of Medicine-Tucson, Tucson, AZ.

Abstract

• Objective: To summarize key issues relevant to managing hyperglycemia in patients with type 2 diabetes mellitus (T2DM) and review a strategy for initiating and intensifying therapy.
• Methods: Review of the literature.
• Results: The 6 most widely used pharmacologic treatment options for hyperglycemia in T2DM are metformin, sulfonylureas, dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists, sodium-glucose cotransporter-2 inhibitors, and insulin. Recent guidelines stress the importance of an individualized, patient-centered approach to managing hyperglycemia in T2DM, although sufficient guidance for nonspecialists on how to individualize treatment is often lacking. For patients with no contraindications, metformin should be recommended concurrent with lifestyle intervention at the time of diabetes diagnosis. Due to the progressive nature of T2DM, glycemic control on metformin monotherapy is likely to deteriorate over time, and there is no consensus as to what the second-line agent should be. A second agent should be selected based on glycemic goal and potential advantages and disadvantages of each agent for any given patient. If the patient progresses to the point where dual therapy does not provide adequate control, either a third non-insulin agent or insulin can be added.
• Conclusion: Although research is increasingly focusing on what the ideal number and sequence of drugs should be when managing T2DM, investigating all possible combinations in diverse patient populations is not feasible. Physicians therefore must continue to rely on clinical judgment to determine how to apply trial data to the treatment of individual patients.

Key words: type 2 diabetes; patient-centered care; antihyper-glycemic drugs; insulin; therapeutic decision-making.

Diabetes mellitus affects approximately 29.1 million people, or 9.3% of the U.S. population [1,2]. The high prevalence of diabetes and its associated multiple complications, including cardiovascular disease (CVD), blindness, renal failure, lower extremity amputations, and premature death, lead to a tremendous overall burden of disease. The financial cost is staggering as well, with more than 1 in 5 health care dollars spent on treating diabetes or its complications [3]. The goal of diabetes treatment is to prevent acute complications and reduce the risk of long-term complications. Interventions that have been shown to improve diabetes outcomes include medications for glycemic control and treatment of cardiovascular risk factors, nutrition and physical activity counseling, smoking cessation, immunizations, psychosocial care, and ongoing surveillance and early treatment for eye, kidney, and foot problems [4].

Glycemic management in type 2 diabetes mellitus (T2DM), the focus of this review, is growing increasingly complex and has been the subject of numerous extensive reviews [5,6] and published guidelines [4,7]. In the context of an increasing array of available pharmacologic options, there are mounting uncertainties regarding the benefits of intensive glycemic control as well as increasing concerns about potential adverse treatment effects, hypoglycemia in particular. While previous guidelines encouraged specific approaches for most patients, more recent guidelines stress the importance of a patient-centered approach with shared decision-making [4]. Less prescriptive guidelines are more appropriate, given the current state of science, but they also may be viewed as providing insufficient guidance to some providers. It can be overwhelming for a non-specialist to try to match the nuances of antihyperglycemic medications to the nuances of each patient’s preferences and medical characteristics.

This article examines key issues faced by primary care providers when managing hyperglycemia in patients with T2DM and outlines a stepwise approach to determining the optimal antihyperglycemic agent(s) (Table 1). 

Confirm Diagnosis of T2DM

It can be difficult to distinguish between type 1 diabetes mellitus and T2DM in some individuals due to overlapping characteristics. However, correctly classifying a patient’s diabetes at the outset is essential, as the classification helps determine the best treatment regimen and is rarely reconsidered [4,8]. Considerable evidence suggests that misclassification of diabetes occurs frequently [9,10], resulting in patients receiving inappropriate treatment. Clinical characteristics suggestive of T2DM include older age and features of insulin resistance such as obesity, hyper-tension, hypertriglyceridemia, and low high-density lipoprotein cholesterol. When these features are not present, an alternate diagnosis should be entertained.

Establish Glycemic Goal

Research over the past decade has led to a growing appreciation of the enormous complexity of hyperglycemia management. During the 1990s, landmark trials such as the Diabetes Control and Complications Trial (DCCT) [11] and UK Prospective Diabetes Study (UKPDS) [12] demonstrated that improving glucose control could reduce the incidence of microvascular complications [11,12], prompting a lower-is-better philosophy regarding glucose targets. Despite limited evidence to support such thinking, this viewpoint was adopted by the developers of many guidelines. During the following decade more research was devoted to determining whether aggressively lowering a patient’s glucose could also improve macrovascular outcomes. Table 2 summarizes microvascular and macrovascular effects of intensive glycemic control seen in major trials [11–23]. After several major trials [20,22] found only mild cardiovascular benefits and even suggested harm [18], experts and policy makers began to reconsider the value of tightly controlling glucose levels [24]. Since then, other studies have demonstrated that the potential benefits and risks of glucose control are strongly related to individual patient factors, such as age and duration of diabetes, and associated comorbidities, such as CVD and impaired renal function [6].

A one-size-fits-all glycemic goal is no longer recommended. Personalization is necessary, balancing the potential benefits and risks of treatments required to achieve that goal. Whereas an A1C of < 7% is an appropriate target for some individuals with diabetes, glycemic targets may be more or less stringent based on patient features including life expectancy, duration of diabetes, comorbidities, and patient attitude and support system (Table 3) [4].

A particular group in which less stringent goals should be considered is older patients, especially those with complex or poor health status [4,25]. The risk of intensive glycemic control may exceed the benefits in these patients, as they are at higher risk of hypoglycemia and polypharmacy [26]. A goal A1C of 7% to 7.5% is now recommended for healthy older adults, and less stringent A1C goals of 7.5% to 8% and 8% to 8.5% should be considered based on the presence and severity of multiple coexisting chronic illnesses, decreased self-care ability, or cognitive impairment [4,25]. Unfortunately, overtreatment is frequently seen in this group. In a recent study of patients over age 65 years, about 40% of those with complex or poor health status had tight glycemic control with A1C below 6.5% [26]. An analysis of U.S. Veterans Affairs administration data showed that only 27% of 12,917 patients older than 65 with very low A1C (< 6%) and about 21% of those with A1C of 6% to 6.5% underwent treatment deintensification [27].

Initiate Treatment with Metformin

There is strong consensus that metformin is the preferred drug for monotherapy due to its long proven safety record, low cost, weight-reduction benefit, and potential cardiovascular advantages [4,16]. As long as there are no contraindications, metformin should be recommended concurrent with lifestyle intervention at the time of diabetes diagnosis. The recommendation is based on the fact that adherence to diet, weight reduction, and regular exercise is not sustained in most patients, and most patients ultimately will require treatment. Since metformin is usually well-tolerated, does not cause hypoglycemia, has a favorable effect on body weight, and is relatively inexpensive, potential benefits of early initiation of medication appear to outweigh potential risks.

The U.S. Food and Drug Administration (FDA) recently relaxed prescribing polices to extend the use of this important medication to patients who have mild–moderate, but stable, chronic kidney disease (CKD) [28]. Metformin is recommended as first-line therapy and should be used unless it is contraindicated (ie, estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73 m²)[4,7,29].

Add Additional Agent(s) as Needed to Achieve Goal

Other than metformin, evidence is limited for the optimal use of the burgeoning array of available agents, especially in dual or triple combinations [6,30]. Research is now starting to focus more on what the ideal number and sequence of drugs should be. The Glycemic Reduction Approach in Diabetes (GRADE) study, which will compare long-term benefits and risks of the 4 most widely used antihyperglycemic medications in combination with metformin, is now underway [31,32]. The 4 classes being studied are sulfonylurea, dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and a basal, 

Eleven classes of non-insulin medications are currently approved for treating hyperglycemia in T2DM [4]. Within each class, numerous agents are available. Six of these classes (ie, α-glucosidase inhibitors, colesevelam, bromocriptine, pramlintide, meglitinides, and thiazolidinediones) are not used frequently 

Consider Effects on A1C

There is a paucity of high-quality, head-to-head comparison trials evaluating the ability of available agents to achieve recommended glycemic targets. This is important because the glucose-lowering effectiveness of individual medications is strongly influenced by baseline characteristics such as A1C, duration of diabetes, and previous therapy. With these limitations in mind, the relative glucose-lowering effectiveness of commonly used agents is shown in Table 4. When used as monotherapy, A1C reductions of approximately 1% to 1.5% are achieved with metformin, sulfonylureas, and GLP-1 receptor agonists [6,30,34,35,39]. DPP-4 inhibitors and SGLT-2 inhibitors have more modest glucose-lowering efficacy, with A1C reductions of approximately 0.5% to 1% [6,30,34,35,39]. Larger effects may be seen in individuals with higher baseline A1C and those who are drug naïve. Insulin is the most effective glucose-lowering agent—it can reduce virtually any level of A1C down to the normal range, with hypoglycemia being the only limiting factor. When a patient has uncontrolled hyperglycemia on metformin monotherapy, or if there is a contraindication or intolerance to metformin, clinicians should consider the potential glucose-lowering effects of other available options and should choose an agent that conceivably could bring a patient close to meeting their treatment goal.

Eliminate Options with Unacceptable Adverse Effects

When the pharmacologic options with acceptable A1C-lowering potential have been identified, the ones with contraindications and potential serious adverse effects for the individual patient can immediately be eliminated (Table 4). For example, if a patient has an eGFR < 30 mL/min/1.73 m², metformin, sulfonylureas, GLP-1 receptor agonists, most DPP-4 inhibitors, and SGLT-2 inhibitors are either contraindicated or should be used with caution. In patients with severe osteoporosis, SGLT-2 inhibitors may not be the best option. In patients with a history of diabetic ketoacidosis (DKA), caution should be used with metformin and SGLT-2 inhibitors. There have been concerns of possible acute pancreatitis and neoplasia with the incretin-based agents, the DPP-4 inhibitors and GLP-1 receptor agonists [40,41], although other clinical trials and observational data have not found increased risk [42–45]. Nevertheless, these agents potentially should be avoided in patients with a history of pancreatitis or neoplasm. SGLT-2 inhibitors may be associated with genitourinary infections and volume depletion [46–48] and probably should be avoided in patients at high risk for these conditions.

If the adverse effects are not serious, changing the way the medication is administered may allow the patient to tolerate agents with high potential benefits. For example, metformin is commonly associated with gastrointestinal (GI) adverse effects, which can be reduced or avoided with slow titration of the dose [6] or by switching to an extended-release formulation [49]. GLP-1 receptor agonists are associated with GI adverse effects [6] and in most cases slow titration is recommended.

Evaluate Potential Risks/Benefits of Remaining Options

Hypoglycemia. The barrier of hypoglycemia generally precludes maintenance of euglycemia and full realization of the long-term benefits of good glucose control over a lifetime. Once considered a trivial issue, concerns about hypoglycemia in T2DM are increasingly being raised [19,50–55]. Clearly, hypoglycemia occurs more often as glycemic targets are lowered to near-normal values, especially in those with advanced age and multiple comorbidities [55]. Various comorbidities frequently encountered particularly as patients age also are associated with increasing propensity for experiencing hypoglycemia and untoward outcomes from it. These include coronary artery disease, heart failure, renal and liver disease, and dementia. Hypoglycemia, when it occurs, may lead to dysrhythmias, dizziness, accidents and falls, work disability, and decreased quality of life. In addition to relaxing blood glucose targets in high-risk patients, drug selection should favor agents that do not precipitate such events (Table 4).

Fortunately, the commonly used non-insulin agents are not associated with hypoglycemia unless they are used in combination with sulfonylureas or insulin. Sulfonylureas should be used with caution and other options considered in patients with high risk for hypoglycemia. When insulin is required, regimens which minimize risk of hypoglycemia should be used. For example, adding a GLP-1 receptor agonist to basal insulin as an alternative to mealtime insulin has been shown to be equally effective with a lower risk of hypoglycemia [4,6]. Also, premixed insulin preparations should be avoided or used cautiously in individuals who miss meals frequently. Additionally, newer basal insulins that exhibit longer duration of action are now available in the United States. Preliminary studies have shown that the newly FDA-approved longer-acting basal insulins, insulin degludec and glargine U-300, may be associated with a reduced risk for hypoglycemia [56,57]. However, it remains unclear how and when these newer agents will best be incorporated into a treatment regimen.

Body weight. Nearly 90% of people living with T2DM are overweight or obese. Given the close tie between obesity and T2DM, treating obesity is an obvious consideration in diabetes treatment. Major trials have shown the effectiveness of lifestyle modifications and weight reduction in delaying, prevention, and management of T2DM [4,58,59].With this in mind, clinicians should consider preferentially using antihyperglycemic agents with weight-lowering or weight-neutral effects. Among commonly used antihyperglycemic agents, metformin, GLP-1 receptor agonists, and SGLT-2 inhibitors have been shown to have weight-reduction benefits, and DPP-4 inhibitors are weight neutral. On the other hand, sulfonylureas and insulin are associated with weight gain. A systematic review and meta-analysis including 204 studies with study durations ranging from 3 months to 8 years showed comparative effects of diabetes medications with a differential effect on weight of up to 5 kg (Table 4) [60].

Metformin is associated with an average weight loss of 1.9 to 3.1 kg that was sustained with long-term use for at least 10 years in the Diabetes Prevention Program Outcomes Study [61].A systematic review of 7 randomized trials showed that in patients with T2DM, the SGLT-2 inhibitors dapagliflozin and canagliflozin were associated with weight loss (mean weighted difference of –1.81 kg and –2.3 kg, respectively) [62]. A systematic review and meta-analysis of 25 randomized controlled trials showed greater weight loss (mean weighted difference of –2.9 kg) in overweight or obese patients with or without T2DM using GLP-1 receptor agonists when compared to placebo, insulin, or oral antihyperglycemic agents [63]. Of note, the GLP-1 receptor agonist liraglutide is now approved for weight loss in patients with or without diabetes [64]. The maximum doses approved for diabetes and obesity treatment are 1.8 and 3.0 mg/day, respectively.

Since weight loss is associated with improved glycemic control, an area of emerging interest is the use of antiobesity medications for managing diabetes. Although most older weight-loss medications were only approved for short-term use, some newer agents are approved for longer-term use. Lorcaserin and the combination drugs topiramate/phentermine and naltrexone/bupropion are approved for chronic therapy, provided certain conditions are met. Patients on weight reduction agents should be monitored regularly. 

An even more radical departure from conventional therapy for diabetes is the consideration of metabolic, or weight-loss, surgery, which has been found to be associated with rapid and dramatic improvements in blood glucose control. Metabolic surgery has been shown to improve glucose control more effectively than any known pharmaceutical or behavioral approach. For example, in an observational study of obese patients with T2DM, bariatric surgery led to diabetes remission rates of 72.3% 2 years after surgery and 30.4% 15 years after surgery compared to 16.4% and 6.5%, respectively, in control patients [69]. With long-term follow-up, significant decreases in microvascular and macrovascular complications were seen in the surgical group [69]. Compared with medical therapy alone, bariatric surgery plus medical therapy has been associated with more weight loss, better glycemic control, less need for diabetes medications, and improved quality of life [70]. A 2016 joint statement by numerous international diabetes organizations recommends considering metabolic surgery as a treatment for T2DM and obesity [71]. American Diabetes Association guidelines recommend consideration of bariatric surgery in individuals with T2DM who have a body mass index greater than 35 kg/m²,especially if achieving disease control is difficult by means of lifestyle modifications and medications [4].

Cardiovascular outcomes. Cardiovascular risk is about 2 to 4 times higher in patients with diabetes, and about half of patients with this condition develop heart failure [4,72]. CVD is responsible for most of the mortality in T2DM [72]. Therefore, prevention of cardiovascular morbidity and mortality is an important goal for diabetes treatment. Due to concerns about potential cardiovascular risks associated with glucose-lowering medications [73–76], the FDA has issued regulatory requirements for manufacturers to monitor the cardiovascular risk profile for these drugs [77]. Recent trials have led to a better understanding of potential cardiovascular benefits or harms of antihyperglycemic medications.

Metformin, the widely recommended first-line therapy for T2DM, carries a large body of evidence supporting its cardiovascular benefits. For example, the UKPDS found that compared to conventional therapy (mostly diet), metformin reduced cardiovascular events and mortality in obese patients with T2DM [15]. This result was supported in Hyperinsulinemia: the Outcome of its Metabolic Effect (HOME) study where, as an add-on to insulin, metformin decreased macrovascular complications when compared to placebo [78]. Research over the past decade also has assuaged concerns about metformin safety in heart failure [60]. A systematic review of observational studies involving 34,000 patients conducted in 2013 showed that metformin is as safe as other glucose-lowering medications in patients with diabetes and heart failure even in the presence of CKD [4,79]. Furthermore, numerous investigations have found metformin is not associated with increased hospitalizations or risk of lactic acidosis [80]. Metformin can be used safely in patients with diabetes and heart failure [60].

Although sulfonylureas have long been a mainstay of diabetes therapy, concerns about their potential adverse cardiovascular effects have been raised by numerous studies [81]. Tolbutamide, a first-generation sulfonylurea, was removed from the market after the University Group Diabetes Program study found increased CVD deaths with this agent versus placebo. Subsequently, the FDA issued a warning for all sulfonylureas [74]. The increased cardiovascular risk associated with sulfonylureas is thought to be due to their effect on cardiac mitochondrial potassium ATP channels. Sulfonylureas bind to these channels, preventing a protective phenomenon called ischemic preconditioning and resulting in a weakened defense against myocardial injury [76]. A recent study showed an increased risk of coronary heart disease associated with long-term use of sulfonylureas in women with diabetes [81].

GLP-1 receptor agonists have recently received much attention for their potential beneficial effects on cardiovascular outcomes. In a recent trial, lixisenatide was shown to be safe in patients with T2DM and acute coronary syndrome when compared to placebo [82]. More recently, the Liraglutide Effect and Action in Diabetes: Evaluation of cardiovascular outcome Results (LEADER) trial demonstrated significant cardiovascular benefits with liraglutide in patients with T2DM and established or high CVD risk [83]. The composite outcome of the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction (MI), or nonfatal stroke, occurred less frequently in the liraglutide group compared to placebo (13% versus 14.9%, respectively), and there were fewer deaths from cardiovascular causes in the liraglutide group compared to placebo (4.7% and 6.0%, respectively) [83]. Other trials investigating the cardiovascular outcomes of this class [84,85] are in progress.

Another class with potential cardiovascular benefits is the SGLT-2 inhibitors. In a recent cardiovascular outcome study, empagliflozin significantly lowered the composite of cardiovascular death, nonfatal MI, or nonfatal stroke in T2DM patients with high cardiovascular risk compared to placebo (10.5% and 12.1%, respectively) [86]. There are several large ongoing studies evaluating the cardiovascular effects of other SGLT-2 inhibitors [87–89].

DPP-4 inhibitors were examined in recent studies and have shown no cardiovascular benefits [42,44,90].The studies showed mixed results regarding an association between DPP-4 inhibitors and heart failure. In one study, saxagliptin was associated with increased hospitalization for heart failure compared to placebo [44], while 2 noninferiority trials did not show a significant increase in heart failure hospitalizations associated with alogliptin and sitagliptin when compared to placebo [42,90].

Administration Considerations

Many patients with T2DM require multiple agents for glycemic control. Additional medications used for comorbid conditions add to this burden. When choosing antihyperglycemic agents, the route and frequency of administration, as well as the patients’ preferences and ability, should be considered. Either once or twice daily dosing is available for most agents, and once weekly dosing is available for some of the GLP-1 receptor agonists. Once daily or once weekly formulations may improve adherence and be more desirable than preparations that are dosed twice daily. Most of the commonly used medications are dosed orally. Although many patients find this route of administration preferable to insulin or GLP-1 receptor agonists, which require injections, some patients may prefer the risk/benefit of injectable agents. All GLP-1 receptor agonists come in a pen delivery system, which eliminates mixing and provides more convenient administration. Extended-release exenatide also is available as a single-dose tray that requires mixing and may be more cumbersome to inject.

Insulin requires special consideration. There has been an enormous increase in the number of insulin products on the market in the past 2 decades. These products include insulin analogs, concentrated insulins (U-200, U-300, and U-500), premixed insulin preparations, and ultra-long-acting insulin [91]. The availability of insulin options with different concentrations, onsets, and durations of actions has made decision making on which insulin to use difficult. Clinicians need to consider patient preference, dosing frequency, and timing with regard to meals, insulin dose, administration, as well as cost. For example, concentrated insulin is preferred for a patient on high doses of insulin requiring injecting a large volume of insulin. Rapid-acting insulin analogs would be more appropriate for patients who have difficulty administering their regular insulin 20 to 30 minutes before eating. Premixed insulin preparations make it impossible to independently adjust short- and long-acting components. However, these may be good choices in patients who have consistent meal schedules and who want to simplify administration. Despite a prevailing misconception that NPH must be given twice a day, it has long been recognized that in T2DM, a single daily injection of NPH yields improvements in control similar to those achieved with 2 daily injections [92].

Cost Considerations

Treating T2DM imposes a great financial burden on individuals living with diabetes and their families due to the high cost of the medications. Table 4 and Table 5 provide information on the cost of non-insulin and insulin diabetes medications for patients who do not have prescription insurance coverage. From a practical standpoint, choice of diabetes agents is largely influenced by insurance formularies.

The older agents, metformin and the sulfonylureas, are available for a cash (no insurance) price of as little as $4 per month. This is in stark contrast to the SGLT-2 inhibitors, GLP-1 receptor agonists, and DPP-4 inhibitors, which range in cost between $400 and $600 per month. Of recent concern, the cost of insulin has been skyrocketing, with a more than 500% increase in the cost of certain insulins from 2001 to 2015 [93]. According to the Medical Expenditure Panel Survey (MEPS) from 2002 to 2013, the mean price of insulin increased by about 200% (from $4.34/mL to $12.92/mL) during this period, which was significantly higher than increases in the price of non-insulin comparators [94]. The introduction of biosimilar insulins to the market is expected to offer treatment options with lower cost. This will be tested when the biosimilar glargine, the first FDA-approved biosimilar insulin, becomes available in the U.S. market. However, a significant reduction in insulin prices is not expected soon [95].

When insulin is required, most patients with T2DM can be treated with older human insulins, which have similar efficacy and lower costs than the more expensive newer insulin analogs. A Cochrane review comparing basal insulin analogs to NPH showed similar efficacy in glycemic control with minimal clinical benefit in the form of less nocturnal hypoglycemia in the insulin analog arm [96]. Furthermore, similar glycemic control and risk of hypoglycemia was seen when regular insulin was compared with the rapid-acting insulin analogs [97]. The cost of human NPH insulin for a patient on a total daily dose of 60 units is approximately $52 per month. This contrasts with the most widely used insulin, insulin glargine, which has a cash price of about $500 per month for the same amount (Table 5). Insulin pens, which are convenient, are more expensive. Interestingly, human insulins do not require prescriptions, allowing underinsured, underfunded patients ongoing access to them.

Incorporating Patient Preferences

Research evidence is necessary but insufficient for making patient care decisions. Along with the potential benefits, harms, costs, and inconveniences of the management options, patient perspectives, beliefs, expectations, and health-related goals must be considered. Patients will undoubtedly have preferences regarding defining goals and ranking options. Clinicians should discuss therapeutic goals and treatment options and work collaboratively with patients in determining management strategies [98].

Summary

Potential treatment approaches for treating hyperglycemia in T2DM are summarized in Figure 1 and Figure 2 [4,7]. As long as there are no contraindications, metformin should be recommended concurrent with lifestyle intervention at the time of diabetes diagnosis. Even if metformin monotherapy is initially effective, glycemic control is likely to deteriorate over time due to progressive loss of β-cell function in T2DM.

There is no consensus as to what the second-line agent should be. Selection of a second agent should be made based on potential advantages and disadvantages of each agent for any given patient. A patient-centered approach is preferred over a fixed algorithm. If the patient progresses to the point where dual therapy does not provide adequate control, either a third non-insulin agent or insulin can be added. In patients with modestly elevated A1C (below ~8%), addition of a third non-insulin agent may be equally effective as (but more expensive than) addition of insulin.

Patients with significantly elevated A1C levels on non-insulin agents usually should have insulin added to their regimen. When insulin is added, metformin should be continued. DPP-4 inhibitors and sulfonylureas are typically stopped. If SGLT-2 inhibitors and/or GLP-1 receptor agonists are continued, this may aid with weight maintenance. However, continuing these agents is likely to be expensive and associated with problems associated with polypharmacy.

The most widely recommended strategy for initiating insulin in T2DM is to add a single bedtime injection of basal insulin (ie, NPH, glargine, detemir, or degludec) to the patient’s regimen. This regimen has been found to be effective in numerous studies and controls hyperglycemia in up to 60% of patients [99]. If the patient is treated with a single bedtime injection of insulin and the fasting glucose level is within the target range but the A1C level remains above goal, addition of mealtime insulin injections is likely to be beneficial. Alternatively, addition of a GLP-1 receptor agonist to basal insulin has been shown to be equally beneficial [4,6]. When adding mealtime insulin, a common strategy is to add a single injection of a rapid-acting insulin (eg, lispro, aspart, glulisine) before the patient’s largest meal of the day. Additional premeal injections of rapid-acting insulin may be added as needed, based on self-monitoring blood glucose results. If glycemia remains significantly uncontrolled on more than 200 units of insulin per day, switching to a concentrated form of insulin (eg, U-200, U-300, or U-500) should be considered.

Corresponding author: Maryam Fazel, PharmD, BCPS, BCACP, CDE, 1295 N. Martin Ave. (Room B211B), Tucson, Arizona 85721-0202, [email protected].

Financial disclosures: None.

From the University of Arizona College of Pharmacy and the University of Arizona College of Medicine-Tucson, Tucson, AZ.

Abstract

• Objective: To summarize key issues relevant to managing hyperglycemia in patients with type 2 diabetes mellitus (T2DM) and review a strategy for initiating and intensifying therapy.
• Methods: Review of the literature.
• Results: The 6 most widely used pharmacologic treatment options for hyperglycemia in T2DM are metformin, sulfonylureas, dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists, sodium-glucose cotransporter-2 inhibitors, and insulin. Recent guidelines stress the importance of an individualized, patient-centered approach to managing hyperglycemia in T2DM, although sufficient guidance for nonspecialists on how to individualize treatment is often lacking. For patients with no contraindications, metformin should be recommended concurrent with lifestyle intervention at the time of diabetes diagnosis. Due to the progressive nature of T2DM, glycemic control on metformin monotherapy is likely to deteriorate over time, and there is no consensus as to what the second-line agent should be. A second agent should be selected based on glycemic goal and potential advantages and disadvantages of each agent for any given patient. If the patient progresses to the point where dual therapy does not provide adequate control, either a third non-insulin agent or insulin can be added.
• Conclusion: Although research is increasingly focusing on what the ideal number and sequence of drugs should be when managing T2DM, investigating all possible combinations in diverse patient populations is not feasible. Physicians therefore must continue to rely on clinical judgment to determine how to apply trial data to the treatment of individual patients.

Key words: type 2 diabetes; patient-centered care; antihyper-glycemic drugs; insulin; therapeutic decision-making.

Diabetes mellitus affects approximately 29.1 million people, or 9.3% of the U.S. population [1,2]. The high prevalence of diabetes and its associated multiple complications, including cardiovascular disease (CVD), blindness, renal failure, lower extremity amputations, and premature death, lead to a tremendous overall burden of disease. The financial cost is staggering as well, with more than 1 in 5 health care dollars spent on treating diabetes or its complications [3]. The goal of diabetes treatment is to prevent acute complications and reduce the risk of long-term complications. Interventions that have been shown to improve diabetes outcomes include medications for glycemic control and treatment of cardiovascular risk factors, nutrition and physical activity counseling, smoking cessation, immunizations, psychosocial care, and ongoing surveillance and early treatment for eye, kidney, and foot problems [4].

Glycemic management in type 2 diabetes mellitus (T2DM), the focus of this review, is growing increasingly complex and has been the subject of numerous extensive reviews [5,6] and published guidelines [4,7]. In the context of an increasing array of available pharmacologic options, there are mounting uncertainties regarding the benefits of intensive glycemic control as well as increasing concerns about potential adverse treatment effects, hypoglycemia in particular. While previous guidelines encouraged specific approaches for most patients, more recent guidelines stress the importance of a patient-centered approach with shared decision-making [4]. Less prescriptive guidelines are more appropriate, given the current state of science, but they also may be viewed as providing insufficient guidance to some providers. It can be overwhelming for a non-specialist to try to match the nuances of antihyperglycemic medications to the nuances of each patient’s preferences and medical characteristics.

This article examines key issues faced by primary care providers when managing hyperglycemia in patients with T2DM and outlines a stepwise approach to determining the optimal antihyperglycemic agent(s) (Table 1). 

Confirm Diagnosis of T2DM

It can be difficult to distinguish between type 1 diabetes mellitus and T2DM in some individuals due to overlapping characteristics. However, correctly classifying a patient’s diabetes at the outset is essential, as the classification helps determine the best treatment regimen and is rarely reconsidered [4,8]. Considerable evidence suggests that misclassification of diabetes occurs frequently [9,10], resulting in patients receiving inappropriate treatment. Clinical characteristics suggestive of T2DM include older age and features of insulin resistance such as obesity, hyper-tension, hypertriglyceridemia, and low high-density lipoprotein cholesterol. When these features are not present, an alternate diagnosis should be entertained.

Establish Glycemic Goal

Research over the past decade has led to a growing appreciation of the enormous complexity of hyperglycemia management. During the 1990s, landmark trials such as the Diabetes Control and Complications Trial (DCCT) [11] and UK Prospective Diabetes Study (UKPDS) [12] demonstrated that improving glucose control could reduce the incidence of microvascular complications [11,12], prompting a lower-is-better philosophy regarding glucose targets. Despite limited evidence to support such thinking, this viewpoint was adopted by the developers of many guidelines. During the following decade more research was devoted to determining whether aggressively lowering a patient’s glucose could also improve macrovascular outcomes. Table 2 summarizes microvascular and macrovascular effects of intensive glycemic control seen in major trials [11–23]. After several major trials [20,22] found only mild cardiovascular benefits and even suggested harm [18], experts and policy makers began to reconsider the value of tightly controlling glucose levels [24]. Since then, other studies have demonstrated that the potential benefits and risks of glucose control are strongly related to individual patient factors, such as age and duration of diabetes, and associated comorbidities, such as CVD and impaired renal function [6].

A one-size-fits-all glycemic goal is no longer recommended. Personalization is necessary, balancing the potential benefits and risks of treatments required to achieve that goal. Whereas an A1C of < 7% is an appropriate target for some individuals with diabetes, glycemic targets may be more or less stringent based on patient features including life expectancy, duration of diabetes, comorbidities, and patient attitude and support system (Table 3) [4].

A particular group in which less stringent goals should be considered is older patients, especially those with complex or poor health status [4,25]. The risk of intensive glycemic control may exceed the benefits in these patients, as they are at higher risk of hypoglycemia and polypharmacy [26]. A goal A1C of 7% to 7.5% is now recommended for healthy older adults, and less stringent A1C goals of 7.5% to 8% and 8% to 8.5% should be considered based on the presence and severity of multiple coexisting chronic illnesses, decreased self-care ability, or cognitive impairment [4,25]. Unfortunately, overtreatment is frequently seen in this group. In a recent study of patients over age 65 years, about 40% of those with complex or poor health status had tight glycemic control with A1C below 6.5% [26]. An analysis of U.S. Veterans Affairs administration data showed that only 27% of 12,917 patients older than 65 with very low A1C (< 6%) and about 21% of those with A1C of 6% to 6.5% underwent treatment deintensification [27].

Initiate Treatment with Metformin

There is strong consensus that metformin is the preferred drug for monotherapy due to its long proven safety record, low cost, weight-reduction benefit, and potential cardiovascular advantages [4,16]. As long as there are no contraindications, metformin should be recommended concurrent with lifestyle intervention at the time of diabetes diagnosis. The recommendation is based on the fact that adherence to diet, weight reduction, and regular exercise is not sustained in most patients, and most patients ultimately will require treatment. Since metformin is usually well-tolerated, does not cause hypoglycemia, has a favorable effect on body weight, and is relatively inexpensive, potential benefits of early initiation of medication appear to outweigh potential risks.

The U.S. Food and Drug Administration (FDA) recently relaxed prescribing polices to extend the use of this important medication to patients who have mild–moderate, but stable, chronic kidney disease (CKD) [28]. Metformin is recommended as first-line therapy and should be used unless it is contraindicated (ie, estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73 m²)[4,7,29].

Add Additional Agent(s) as Needed to Achieve Goal

Other than metformin, evidence is limited for the optimal use of the burgeoning array of available agents, especially in dual or triple combinations [6,30]. Research is now starting to focus more on what the ideal number and sequence of drugs should be. The Glycemic Reduction Approach in Diabetes (GRADE) study, which will compare long-term benefits and risks of the 4 most widely used antihyperglycemic medications in combination with metformin, is now underway [31,32]. The 4 classes being studied are sulfonylurea, dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and a basal, 

Eleven classes of non-insulin medications are currently approved for treating hyperglycemia in T2DM [4]. Within each class, numerous agents are available. Six of these classes (ie, α-glucosidase inhibitors, colesevelam, bromocriptine, pramlintide, meglitinides, and thiazolidinediones) are not used frequently 

Consider Effects on A1C

There is a paucity of high-quality, head-to-head comparison trials evaluating the ability of available agents to achieve recommended glycemic targets. This is important because the glucose-lowering effectiveness of individual medications is strongly influenced by baseline characteristics such as A1C, duration of diabetes, and previous therapy. With these limitations in mind, the relative glucose-lowering effectiveness of commonly used agents is shown in Table 4. When used as monotherapy, A1C reductions of approximately 1% to 1.5% are achieved with metformin, sulfonylureas, and GLP-1 receptor agonists [6,30,34,35,39]. DPP-4 inhibitors and SGLT-2 inhibitors have more modest glucose-lowering efficacy, with A1C reductions of approximately 0.5% to 1% [6,30,34,35,39]. Larger effects may be seen in individuals with higher baseline A1C and those who are drug naïve. Insulin is the most effective glucose-lowering agent—it can reduce virtually any level of A1C down to the normal range, with hypoglycemia being the only limiting factor. When a patient has uncontrolled hyperglycemia on metformin monotherapy, or if there is a contraindication or intolerance to metformin, clinicians should consider the potential glucose-lowering effects of other available options and should choose an agent that conceivably could bring a patient close to meeting their treatment goal.

Eliminate Options with Unacceptable Adverse Effects

When the pharmacologic options with acceptable A1C-lowering potential have been identified, the ones with contraindications and potential serious adverse effects for the individual patient can immediately be eliminated (Table 4). For example, if a patient has an eGFR < 30 mL/min/1.73 m², metformin, sulfonylureas, GLP-1 receptor agonists, most DPP-4 inhibitors, and SGLT-2 inhibitors are either contraindicated or should be used with caution. In patients with severe osteoporosis, SGLT-2 inhibitors may not be the best option. In patients with a history of diabetic ketoacidosis (DKA), caution should be used with metformin and SGLT-2 inhibitors. There have been concerns of possible acute pancreatitis and neoplasia with the incretin-based agents, the DPP-4 inhibitors and GLP-1 receptor agonists [40,41], although other clinical trials and observational data have not found increased risk [42–45]. Nevertheless, these agents potentially should be avoided in patients with a history of pancreatitis or neoplasm. SGLT-2 inhibitors may be associated with genitourinary infections and volume depletion [46–48] and probably should be avoided in patients at high risk for these conditions.

If the adverse effects are not serious, changing the way the medication is administered may allow the patient to tolerate agents with high potential benefits. For example, metformin is commonly associated with gastrointestinal (GI) adverse effects, which can be reduced or avoided with slow titration of the dose [6] or by switching to an extended-release formulation [49]. GLP-1 receptor agonists are associated with GI adverse effects [6] and in most cases slow titration is recommended.

Evaluate Potential Risks/Benefits of Remaining Options

Hypoglycemia. The barrier of hypoglycemia generally precludes maintenance of euglycemia and full realization of the long-term benefits of good glucose control over a lifetime. Once considered a trivial issue, concerns about hypoglycemia in T2DM are increasingly being raised [19,50–55]. Clearly, hypoglycemia occurs more often as glycemic targets are lowered to near-normal values, especially in those with advanced age and multiple comorbidities [55]. Various comorbidities frequently encountered particularly as patients age also are associated with increasing propensity for experiencing hypoglycemia and untoward outcomes from it. These include coronary artery disease, heart failure, renal and liver disease, and dementia. Hypoglycemia, when it occurs, may lead to dysrhythmias, dizziness, accidents and falls, work disability, and decreased quality of life. In addition to relaxing blood glucose targets in high-risk patients, drug selection should favor agents that do not precipitate such events (Table 4).

Fortunately, the commonly used non-insulin agents are not associated with hypoglycemia unless they are used in combination with sulfonylureas or insulin. Sulfonylureas should be used with caution and other options considered in patients with high risk for hypoglycemia. When insulin is required, regimens which minimize risk of hypoglycemia should be used. For example, adding a GLP-1 receptor agonist to basal insulin as an alternative to mealtime insulin has been shown to be equally effective with a lower risk of hypoglycemia [4,6]. Also, premixed insulin preparations should be avoided or used cautiously in individuals who miss meals frequently. Additionally, newer basal insulins that exhibit longer duration of action are now available in the United States. Preliminary studies have shown that the newly FDA-approved longer-acting basal insulins, insulin degludec and glargine U-300, may be associated with a reduced risk for hypoglycemia [56,57]. However, it remains unclear how and when these newer agents will best be incorporated into a treatment regimen.

Body weight. Nearly 90% of people living with T2DM are overweight or obese. Given the close tie between obesity and T2DM, treating obesity is an obvious consideration in diabetes treatment. Major trials have shown the effectiveness of lifestyle modifications and weight reduction in delaying, prevention, and management of T2DM [4,58,59].With this in mind, clinicians should consider preferentially using antihyperglycemic agents with weight-lowering or weight-neutral effects. Among commonly used antihyperglycemic agents, metformin, GLP-1 receptor agonists, and SGLT-2 inhibitors have been shown to have weight-reduction benefits, and DPP-4 inhibitors are weight neutral. On the other hand, sulfonylureas and insulin are associated with weight gain. A systematic review and meta-analysis including 204 studies with study durations ranging from 3 months to 8 years showed comparative effects of diabetes medications with a differential effect on weight of up to 5 kg (Table 4) [60].

Metformin is associated with an average weight loss of 1.9 to 3.1 kg that was sustained with long-term use for at least 10 years in the Diabetes Prevention Program Outcomes Study [61].A systematic review of 7 randomized trials showed that in patients with T2DM, the SGLT-2 inhibitors dapagliflozin and canagliflozin were associated with weight loss (mean weighted difference of –1.81 kg and –2.3 kg, respectively) [62]. A systematic review and meta-analysis of 25 randomized controlled trials showed greater weight loss (mean weighted difference of –2.9 kg) in overweight or obese patients with or without T2DM using GLP-1 receptor agonists when compared to placebo, insulin, or oral antihyperglycemic agents [63]. Of note, the GLP-1 receptor agonist liraglutide is now approved for weight loss in patients with or without diabetes [64]. The maximum doses approved for diabetes and obesity treatment are 1.8 and 3.0 mg/day, respectively.

Since weight loss is associated with improved glycemic control, an area of emerging interest is the use of antiobesity medications for managing diabetes. Although most older weight-loss medications were only approved for short-term use, some newer agents are approved for longer-term use. Lorcaserin and the combination drugs topiramate/phentermine and naltrexone/bupropion are approved for chronic therapy, provided certain conditions are met. Patients on weight reduction agents should be monitored regularly. 

An even more radical departure from conventional therapy for diabetes is the consideration of metabolic, or weight-loss, surgery, which has been found to be associated with rapid and dramatic improvements in blood glucose control. Metabolic surgery has been shown to improve glucose control more effectively than any known pharmaceutical or behavioral approach. For example, in an observational study of obese patients with T2DM, bariatric surgery led to diabetes remission rates of 72.3% 2 years after surgery and 30.4% 15 years after surgery compared to 16.4% and 6.5%, respectively, in control patients [69]. With long-term follow-up, significant decreases in microvascular and macrovascular complications were seen in the surgical group [69]. Compared with medical therapy alone, bariatric surgery plus medical therapy has been associated with more weight loss, better glycemic control, less need for diabetes medications, and improved quality of life [70]. A 2016 joint statement by numerous international diabetes organizations recommends considering metabolic surgery as a treatment for T2DM and obesity [71]. American Diabetes Association guidelines recommend consideration of bariatric surgery in individuals with T2DM who have a body mass index greater than 35 kg/m²,especially if achieving disease control is difficult by means of lifestyle modifications and medications [4].

Cardiovascular outcomes. Cardiovascular risk is about 2 to 4 times higher in patients with diabetes, and about half of patients with this condition develop heart failure [4,72]. CVD is responsible for most of the mortality in T2DM [72]. Therefore, prevention of cardiovascular morbidity and mortality is an important goal for diabetes treatment. Due to concerns about potential cardiovascular risks associated with glucose-lowering medications [73–76], the FDA has issued regulatory requirements for manufacturers to monitor the cardiovascular risk profile for these drugs [77]. Recent trials have led to a better understanding of potential cardiovascular benefits or harms of antihyperglycemic medications.

Metformin, the widely recommended first-line therapy for T2DM, carries a large body of evidence supporting its cardiovascular benefits. For example, the UKPDS found that compared to conventional therapy (mostly diet), metformin reduced cardiovascular events and mortality in obese patients with T2DM [15]. This result was supported in Hyperinsulinemia: the Outcome of its Metabolic Effect (HOME) study where, as an add-on to insulin, metformin decreased macrovascular complications when compared to placebo [78]. Research over the past decade also has assuaged concerns about metformin safety in heart failure [60]. A systematic review of observational studies involving 34,000 patients conducted in 2013 showed that metformin is as safe as other glucose-lowering medications in patients with diabetes and heart failure even in the presence of CKD [4,79]. Furthermore, numerous investigations have found metformin is not associated with increased hospitalizations or risk of lactic acidosis [80]. Metformin can be used safely in patients with diabetes and heart failure [60].

Although sulfonylureas have long been a mainstay of diabetes therapy, concerns about their potential adverse cardiovascular effects have been raised by numerous studies [81]. Tolbutamide, a first-generation sulfonylurea, was removed from the market after the University Group Diabetes Program study found increased CVD deaths with this agent versus placebo. Subsequently, the FDA issued a warning for all sulfonylureas [74]. The increased cardiovascular risk associated with sulfonylureas is thought to be due to their effect on cardiac mitochondrial potassium ATP channels. Sulfonylureas bind to these channels, preventing a protective phenomenon called ischemic preconditioning and resulting in a weakened defense against myocardial injury [76]. A recent study showed an increased risk of coronary heart disease associated with long-term use of sulfonylureas in women with diabetes [81].

GLP-1 receptor agonists have recently received much attention for their potential beneficial effects on cardiovascular outcomes. In a recent trial, lixisenatide was shown to be safe in patients with T2DM and acute coronary syndrome when compared to placebo [82]. More recently, the Liraglutide Effect and Action in Diabetes: Evaluation of cardiovascular outcome Results (LEADER) trial demonstrated significant cardiovascular benefits with liraglutide in patients with T2DM and established or high CVD risk [83]. The composite outcome of the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction (MI), or nonfatal stroke, occurred less frequently in the liraglutide group compared to placebo (13% versus 14.9%, respectively), and there were fewer deaths from cardiovascular causes in the liraglutide group compared to placebo (4.7% and 6.0%, respectively) [83]. Other trials investigating the cardiovascular outcomes of this class [84,85] are in progress.

Another class with potential cardiovascular benefits is the SGLT-2 inhibitors. In a recent cardiovascular outcome study, empagliflozin significantly lowered the composite of cardiovascular death, nonfatal MI, or nonfatal stroke in T2DM patients with high cardiovascular risk compared to placebo (10.5% and 12.1%, respectively) [86]. There are several large ongoing studies evaluating the cardiovascular effects of other SGLT-2 inhibitors [87–89].

DPP-4 inhibitors were examined in recent studies and have shown no cardiovascular benefits [42,44,90].The studies showed mixed results regarding an association between DPP-4 inhibitors and heart failure. In one study, saxagliptin was associated with increased hospitalization for heart failure compared to placebo [44], while 2 noninferiority trials did not show a significant increase in heart failure hospitalizations associated with alogliptin and sitagliptin when compared to placebo [42,90].

Administration Considerations

Many patients with T2DM require multiple agents for glycemic control. Additional medications used for comorbid conditions add to this burden. When choosing antihyperglycemic agents, the route and frequency of administration, as well as the patients’ preferences and ability, should be considered. Either once or twice daily dosing is available for most agents, and once weekly dosing is available for some of the GLP-1 receptor agonists. Once daily or once weekly formulations may improve adherence and be more desirable than preparations that are dosed twice daily. Most of the commonly used medications are dosed orally. Although many patients find this route of administration preferable to insulin or GLP-1 receptor agonists, which require injections, some patients may prefer the risk/benefit of injectable agents. All GLP-1 receptor agonists come in a pen delivery system, which eliminates mixing and provides more convenient administration. Extended-release exenatide also is available as a single-dose tray that requires mixing and may be more cumbersome to inject.

Insulin requires special consideration. There has been an enormous increase in the number of insulin products on the market in the past 2 decades. These products include insulin analogs, concentrated insulins (U-200, U-300, and U-500), premixed insulin preparations, and ultra-long-acting insulin [91]. The availability of insulin options with different concentrations, onsets, and durations of actions has made decision making on which insulin to use difficult. Clinicians need to consider patient preference, dosing frequency, and timing with regard to meals, insulin dose, administration, as well as cost. For example, concentrated insulin is preferred for a patient on high doses of insulin requiring injecting a large volume of insulin. Rapid-acting insulin analogs would be more appropriate for patients who have difficulty administering their regular insulin 20 to 30 minutes before eating. Premixed insulin preparations make it impossible to independently adjust short- and long-acting components. However, these may be good choices in patients who have consistent meal schedules and who want to simplify administration. Despite a prevailing misconception that NPH must be given twice a day, it has long been recognized that in T2DM, a single daily injection of NPH yields improvements in control similar to those achieved with 2 daily injections [92].

Cost Considerations

Treating T2DM imposes a great financial burden on individuals living with diabetes and their families due to the high cost of the medications. Table 4 and Table 5 provide information on the cost of non-insulin and insulin diabetes medications for patients who do not have prescription insurance coverage. From a practical standpoint, choice of diabetes agents is largely influenced by insurance formularies.

The older agents, metformin and the sulfonylureas, are available for a cash (no insurance) price of as little as $4 per month. This is in stark contrast to the SGLT-2 inhibitors, GLP-1 receptor agonists, and DPP-4 inhibitors, which range in cost between $400 and $600 per month. Of recent concern, the cost of insulin has been skyrocketing, with a more than 500% increase in the cost of certain insulins from 2001 to 2015 [93]. According to the Medical Expenditure Panel Survey (MEPS) from 2002 to 2013, the mean price of insulin increased by about 200% (from $4.34/mL to $12.92/mL) during this period, which was significantly higher than increases in the price of non-insulin comparators [94]. The introduction of biosimilar insulins to the market is expected to offer treatment options with lower cost. This will be tested when the biosimilar glargine, the first FDA-approved biosimilar insulin, becomes available in the U.S. market. However, a significant reduction in insulin prices is not expected soon [95].

When insulin is required, most patients with T2DM can be treated with older human insulins, which have similar efficacy and lower costs than the more expensive newer insulin analogs. A Cochrane review comparing basal insulin analogs to NPH showed similar efficacy in glycemic control with minimal clinical benefit in the form of less nocturnal hypoglycemia in the insulin analog arm [96]. Furthermore, similar glycemic control and risk of hypoglycemia was seen when regular insulin was compared with the rapid-acting insulin analogs [97]. The cost of human NPH insulin for a patient on a total daily dose of 60 units is approximately $52 per month. This contrasts with the most widely used insulin, insulin glargine, which has a cash price of about $500 per month for the same amount (Table 5). Insulin pens, which are convenient, are more expensive. Interestingly, human insulins do not require prescriptions, allowing underinsured, underfunded patients ongoing access to them.

Incorporating Patient Preferences

Research evidence is necessary but insufficient for making patient care decisions. Along with the potential benefits, harms, costs, and inconveniences of the management options, patient perspectives, beliefs, expectations, and health-related goals must be considered. Patients will undoubtedly have preferences regarding defining goals and ranking options. Clinicians should discuss therapeutic goals and treatment options and work collaboratively with patients in determining management strategies [98].

Summary

Potential treatment approaches for treating hyperglycemia in T2DM are summarized in Figure 1 and Figure 2 [4,7]. As long as there are no contraindications, metformin should be recommended concurrent with lifestyle intervention at the time of diabetes diagnosis. Even if metformin monotherapy is initially effective, glycemic control is likely to deteriorate over time due to progressive loss of β-cell function in T2DM.

There is no consensus as to what the second-line agent should be. Selection of a second agent should be made based on potential advantages and disadvantages of each agent for any given patient. A patient-centered approach is preferred over a fixed algorithm. If the patient progresses to the point where dual therapy does not provide adequate control, either a third non-insulin agent or insulin can be added. In patients with modestly elevated A1C (below ~8%), addition of a third non-insulin agent may be equally effective as (but more expensive than) addition of insulin.

Patients with significantly elevated A1C levels on non-insulin agents usually should have insulin added to their regimen. When insulin is added, metformin should be continued. DPP-4 inhibitors and sulfonylureas are typically stopped. If SGLT-2 inhibitors and/or GLP-1 receptor agonists are continued, this may aid with weight maintenance. However, continuing these agents is likely to be expensive and associated with problems associated with polypharmacy.

The most widely recommended strategy for initiating insulin in T2DM is to add a single bedtime injection of basal insulin (ie, NPH, glargine, detemir, or degludec) to the patient’s regimen. This regimen has been found to be effective in numerous studies and controls hyperglycemia in up to 60% of patients [99]. If the patient is treated with a single bedtime injection of insulin and the fasting glucose level is within the target range but the A1C level remains above goal, addition of mealtime insulin injections is likely to be beneficial. Alternatively, addition of a GLP-1 receptor agonist to basal insulin has been shown to be equally beneficial [4,6]. When adding mealtime insulin, a common strategy is to add a single injection of a rapid-acting insulin (eg, lispro, aspart, glulisine) before the patient’s largest meal of the day. Additional premeal injections of rapid-acting insulin may be added as needed, based on self-monitoring blood glucose results. If glycemia remains significantly uncontrolled on more than 200 units of insulin per day, switching to a concentrated form of insulin (eg, U-200, U-300, or U-500) should be considered.

Corresponding author: Maryam Fazel, PharmD, BCPS, BCACP, CDE, 1295 N. Martin Ave. (Room B211B), Tucson, Arizona 85721-0202, [email protected].

Financial disclosures: None.