Diabetes

TOPLINE:

The COVID-19 booster vaccine typically causes transient, clinically insignificant elevations in glucose levels in people with type 1 diabetes, but some individuals may develop more pronounced hyperglycemia.

METHODOLOGY:

• In a single-center prospective cohort study of 21 adults with type 1 diabetes, patients were given a blinded Dexcom G6 Pro continuous glucose monitor (CGM) at the first research clinic visit.
• After 3-4 days, participants received a COVID-19 booster vaccine.
• They returned to the clinic 10 days after the initial visit (5-6 days after booster vaccination) to have the CGM removed and glycemia assessed.

TAKEAWAY:

• Compared with baseline, the mean daily glucose level was significantly increased at day 2 (162.9 mg/dL vs. 172.8 mg/dL; P = .04) and day 3 (173.1 mg/dL; P = .02) post vaccination.
• Glucose excursions at day 0 (173.2 mg/dL; P = .058) and day 1 (173.1 mg/dL; P = .078) didn’t quite reach statistical significance.
• One participant experienced increases in glucose of 36%, 69%, 35%, 26%, 22%, and 19% on days 0-5, respectively, compared with baseline.
• Glucose excursions of at least 25% above baseline occurred in four participants on day 0 and day 1 and in three participants on days 2 and 5.
• Insulin resistance, as measured by Total Daily Insulin Resistance (a metric that integrates daily mean glucose concentration with total daily insulin dose), was also significantly increased from baseline to day 2 post vaccination (7,171 mg/dL vs. 8,070 mg/dL units; P = .03).
• No other measures of glycemia differed significantly, compared with baseline.
• Outcomes didn’t differ significantly by sex, age, or vaccine manufacturer.

IN PRACTICE:

• “To our knowledge this is the first study investigating the effect of the COVID-19 booster vaccine on glycemia specifically in people with type 1 diabetes,” say the authors.
• “Clinicians, pharmacists, and other health care providers may need to counsel people with T1D to be more vigilant with glucose testing and insulin dosing for the first 5 days after vaccination. Most importantly, insulin, required to control glycemia, may need to be transiently increased.”
• “Further studies are warranted to investigate whether other vaccines have similar glycemic effects, and which individuals are at highest risk for profound glucose perturbations post vaccination.”

SOURCE:

The study was conducted by Mihail Zilbermint, MD, of the division of hospital medicine, Johns Hopkins Medicine, Bethesda, Md., and colleagues. It was published in Diabetes Research and Clinical Practice.

LIMITATIONS:

• The sample size was small.
• There were no measurements of inflammatory markers, dietary intake, physical activity, or survey patient symptomatology to adjust for variables that may have influenced glycemic control.
• In the study cohort, glycemia was moderately well controlled at baseline.

DISCLOSURES:

The study was supported by an investigator-initiated study grant from DexCom Inc. Dr. Zilbermint has consulted for EMD Serono.

A version of this article first appeared on Medscape.com.

TOPLINE:

The COVID-19 booster vaccine typically causes transient, clinically insignificant elevations in glucose levels in people with type 1 diabetes, but some individuals may develop more pronounced hyperglycemia.

METHODOLOGY:

• In a single-center prospective cohort study of 21 adults with type 1 diabetes, patients were given a blinded Dexcom G6 Pro continuous glucose monitor (CGM) at the first research clinic visit.
• After 3-4 days, participants received a COVID-19 booster vaccine.
• They returned to the clinic 10 days after the initial visit (5-6 days after booster vaccination) to have the CGM removed and glycemia assessed.

TAKEAWAY:

• Compared with baseline, the mean daily glucose level was significantly increased at day 2 (162.9 mg/dL vs. 172.8 mg/dL; P = .04) and day 3 (173.1 mg/dL; P = .02) post vaccination.
• Glucose excursions at day 0 (173.2 mg/dL; P = .058) and day 1 (173.1 mg/dL; P = .078) didn’t quite reach statistical significance.
• One participant experienced increases in glucose of 36%, 69%, 35%, 26%, 22%, and 19% on days 0-5, respectively, compared with baseline.
• Glucose excursions of at least 25% above baseline occurred in four participants on day 0 and day 1 and in three participants on days 2 and 5.
• Insulin resistance, as measured by Total Daily Insulin Resistance (a metric that integrates daily mean glucose concentration with total daily insulin dose), was also significantly increased from baseline to day 2 post vaccination (7,171 mg/dL vs. 8,070 mg/dL units; P = .03).
• No other measures of glycemia differed significantly, compared with baseline.
• Outcomes didn’t differ significantly by sex, age, or vaccine manufacturer.

IN PRACTICE:

• “To our knowledge this is the first study investigating the effect of the COVID-19 booster vaccine on glycemia specifically in people with type 1 diabetes,” say the authors.
• “Clinicians, pharmacists, and other health care providers may need to counsel people with T1D to be more vigilant with glucose testing and insulin dosing for the first 5 days after vaccination. Most importantly, insulin, required to control glycemia, may need to be transiently increased.”
• “Further studies are warranted to investigate whether other vaccines have similar glycemic effects, and which individuals are at highest risk for profound glucose perturbations post vaccination.”

SOURCE:

The study was conducted by Mihail Zilbermint, MD, of the division of hospital medicine, Johns Hopkins Medicine, Bethesda, Md., and colleagues. It was published in Diabetes Research and Clinical Practice.

LIMITATIONS:

• The sample size was small.
• There were no measurements of inflammatory markers, dietary intake, physical activity, or survey patient symptomatology to adjust for variables that may have influenced glycemic control.
• In the study cohort, glycemia was moderately well controlled at baseline.

DISCLOSURES:

The study was supported by an investigator-initiated study grant from DexCom Inc. Dr. Zilbermint has consulted for EMD Serono.

A version of this article first appeared on Medscape.com.

TOPLINE:

The COVID-19 booster vaccine typically causes transient, clinically insignificant elevations in glucose levels in people with type 1 diabetes, but some individuals may develop more pronounced hyperglycemia.

METHODOLOGY:

• In a single-center prospective cohort study of 21 adults with type 1 diabetes, patients were given a blinded Dexcom G6 Pro continuous glucose monitor (CGM) at the first research clinic visit.
• After 3-4 days, participants received a COVID-19 booster vaccine.
• They returned to the clinic 10 days after the initial visit (5-6 days after booster vaccination) to have the CGM removed and glycemia assessed.

TAKEAWAY:

• Compared with baseline, the mean daily glucose level was significantly increased at day 2 (162.9 mg/dL vs. 172.8 mg/dL; P = .04) and day 3 (173.1 mg/dL; P = .02) post vaccination.
• Glucose excursions at day 0 (173.2 mg/dL; P = .058) and day 1 (173.1 mg/dL; P = .078) didn’t quite reach statistical significance.
• One participant experienced increases in glucose of 36%, 69%, 35%, 26%, 22%, and 19% on days 0-5, respectively, compared with baseline.
• Glucose excursions of at least 25% above baseline occurred in four participants on day 0 and day 1 and in three participants on days 2 and 5.
• Insulin resistance, as measured by Total Daily Insulin Resistance (a metric that integrates daily mean glucose concentration with total daily insulin dose), was also significantly increased from baseline to day 2 post vaccination (7,171 mg/dL vs. 8,070 mg/dL units; P = .03).
• No other measures of glycemia differed significantly, compared with baseline.
• Outcomes didn’t differ significantly by sex, age, or vaccine manufacturer.

IN PRACTICE:

• “To our knowledge this is the first study investigating the effect of the COVID-19 booster vaccine on glycemia specifically in people with type 1 diabetes,” say the authors.
• “Clinicians, pharmacists, and other health care providers may need to counsel people with T1D to be more vigilant with glucose testing and insulin dosing for the first 5 days after vaccination. Most importantly, insulin, required to control glycemia, may need to be transiently increased.”
• “Further studies are warranted to investigate whether other vaccines have similar glycemic effects, and which individuals are at highest risk for profound glucose perturbations post vaccination.”

SOURCE:

The study was conducted by Mihail Zilbermint, MD, of the division of hospital medicine, Johns Hopkins Medicine, Bethesda, Md., and colleagues. It was published in Diabetes Research and Clinical Practice.

LIMITATIONS:

• The sample size was small.
• There were no measurements of inflammatory markers, dietary intake, physical activity, or survey patient symptomatology to adjust for variables that may have influenced glycemic control.
• In the study cohort, glycemia was moderately well controlled at baseline.

DISCLOSURES:

The study was supported by an investigator-initiated study grant from DexCom Inc. Dr. Zilbermint has consulted for EMD Serono.

A version of this article first appeared on Medscape.com.

A new meta-analysis has shown that SGLT2 inhibitors do not lead to lower 28-day all-cause mortality, compared with usual care or placebo, in patients hospitalized with COVID-19.

However, no major safety issues were identified with the use of SGLT2 inhibitors in these acutely ill patients, the researchers report.

“While these findings do not support the use of SGLT2-inhibitors as standard of care for patients hospitalized with COVID-19, I think the most important take home message here is that the use of these medications appears to be safe even in really acutely ill hospitalized patients,” lead investigator of the meta-analysis, Mikhail Kosiborod, MD, Saint Luke’s Mid America Heart Institute, Kansas City, Mo., concluded.

He said this was important because the list of indications for SGLT2 inhibitors is rapidly growing.

“These medications are being used in more and more patients. And we know that when we discontinue medications in the hospital they frequently don’t get restarted, which can lead to real risks if SGLT2 inhibitors are stopped in patients with heart failure, chronic kidney disease, or diabetes. So, the bottom line is that there is no compelling reason to stop these medications in the hospital,” he added.

The new meta-analysis was presented at the recent annual congress of the European Society of Cardiology, held in Amsterdam.

Discussant of the presentation at the ESC Hotline session, Muthiah Vaduganathan, MD, MPH, Brigham and Women’s Hospital, Boston, agreed with Dr. Kosiborod’s interpretation.

“Until today we have had very limited information on the safety of SGLT2-inhibitors in acute illness, as the pivotal trials which established the use of these drugs in diabetes and chronic kidney disease largely excluded patients who were hospitalized,” Dr. Vaduganathan said.

“While the overall results of this meta-analysis are neutral and SGLT2 inhibitors will not be added as drugs to be used in the primary care of patients with COVID-19, it certainly sends a strong message of safety in acutely ill patients,” he added.

Dr. Vaduganathan explained that from the beginning of the COVID-19 pandemic, there was great interest in repurposing established therapies for alternative indications for their use in the management of COVID-19.

“Conditions that strongly predispose to adverse COVID outcomes strongly overlap with established indications for SGLT2-inhibitors. So many wondered whether these drugs may be an ideal treatment candidate for the management of COVID-19. However, there have been many safety concerns about the use of SGLT2-inhibitors in this acute setting, with worries that they may induce hemodynamic changes such an excessive lowering of blood pressure, or metabolic changes such as ketoacidosis in acutely ill patients,” he noted.

The initial DARE-19 study investigating SGLT2-inhibitors in COVID-19, with 1,250 participants, found a 20% reduction in the primary outcome of organ dysfunction or death, but this did not reach statistical significance, and no safety issues were seen. This “intriguing” result led to two further larger trials – the ACTIV-4a and RECOVERY trials, Dr. Vaduganathan reported.

“Those early signals of benefit seen in DARE-19 were largely not substantiated in the ACTIV-4A and RECOVERY trials, or in this new meta-analysis, and now we have this much larger body of evidence and more stable estimates about the efficacy of these drugs in acutely ill COVID-19 patients,” he said.

“But the story that we will all take forward is one of safety. This set of trials was arguably conducted in some of the sickest patients we’ve seen who have been exposed to SGLT2-inhibitors, and they strongly affirm that these agents can be safely continued in the setting of acute illness, with very low rates of ketoacidosis and kidney injury, and there was no prolongation of hospital stay,” he commented.

In his presentation, Dr. Kosiborod explained that treatments targeting COVID-19 pathobiology such as dysregulated immune responses, endothelial damage, microvascular thrombosis, and inflammation have been shown to improve the key outcomes in this patient group.

SGLT2 inhibitors, which modulate similar pathobiology, provide cardiovascular protection and prevent the progression of kidney disease in patients at risk for these events, including those with type 2 diabetes, heart failure, and kidney disease, and may also lead to organ protection in a setting of acute illness such as COVID-19, he noted. However, the role of SGLT2 inhibitors in patients hospitalized with COVID-19 remains uncertain.

To address the need for more definitive efficacy data, the World Health Organization Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group conducted a prospective meta-analysis using data from the three randomized controlled trials, DARE-19, RECOVERY, and ACTIV-4a, evaluating SGLT2 inhibitors in patients hospitalized with COVID-19.

Overall, these trials randomized 6,096 participants: 3,025 to SGLT2 inhibitors and 3,071 to usual care or placebo. The average age of participants ranged between 62 and 73 years across the trials, 39% were women, and 25% had type 2 diabetes.

By 28 days after randomization, all-cause mortality, the primary endpoint, had occurred in 11.6% of the SGLT2-inhibitor patients, compared with 12.4% of those randomized to usual care or placebo, giving an odds ratio of 0.93 (95% confidence interval, 0.79-1.08; P = .33) for SGLT2 inhibitors, with consistency across trials.

Data on in-hospital and 90-day all-cause mortality were only available for two out of three trials (DARE-19 and ACTIV-4a), but the results were similar to the primary endpoint showing nonsignificant trends toward a possible benefit in the SGLT2-inhibitor group.

The results were also similar for the secondary outcomes of progression to acute kidney injury or requirement for dialysis or death, and progression to invasive mechanical ventilation, extracorporeal membrane oxygenation, or death, both assessed at 28 days.

The primary safety outcome of ketoacidosis by 28 days was observed in seven and two patients allocated to SGLT2 inhibitors and usual care or placebo, respectively, and overall, the incidence of reported serious adverse events was balanced between treatment groups.

The RECOVERY trial was supported by grants to the University of Oxford from UK Research and Innovation, the National Institute for Health and Care Research, and Wellcome. The ACTIV-4a platform was sponsored by the National Heart, Lung, and Blood Institute. DARE-19 was an investigator-initiated collaborative trial supported by AstraZeneca. Dr. Kosiborod reported numerous conflicts of interest.

A version of this article first appeared on Medscape.com.

A new meta-analysis has shown that SGLT2 inhibitors do not lead to lower 28-day all-cause mortality, compared with usual care or placebo, in patients hospitalized with COVID-19.

However, no major safety issues were identified with the use of SGLT2 inhibitors in these acutely ill patients, the researchers report.

“While these findings do not support the use of SGLT2-inhibitors as standard of care for patients hospitalized with COVID-19, I think the most important take home message here is that the use of these medications appears to be safe even in really acutely ill hospitalized patients,” lead investigator of the meta-analysis, Mikhail Kosiborod, MD, Saint Luke’s Mid America Heart Institute, Kansas City, Mo., concluded.

He said this was important because the list of indications for SGLT2 inhibitors is rapidly growing.

“These medications are being used in more and more patients. And we know that when we discontinue medications in the hospital they frequently don’t get restarted, which can lead to real risks if SGLT2 inhibitors are stopped in patients with heart failure, chronic kidney disease, or diabetes. So, the bottom line is that there is no compelling reason to stop these medications in the hospital,” he added.

The new meta-analysis was presented at the recent annual congress of the European Society of Cardiology, held in Amsterdam.

Discussant of the presentation at the ESC Hotline session, Muthiah Vaduganathan, MD, MPH, Brigham and Women’s Hospital, Boston, agreed with Dr. Kosiborod’s interpretation.

“Until today we have had very limited information on the safety of SGLT2-inhibitors in acute illness, as the pivotal trials which established the use of these drugs in diabetes and chronic kidney disease largely excluded patients who were hospitalized,” Dr. Vaduganathan said.

“While the overall results of this meta-analysis are neutral and SGLT2 inhibitors will not be added as drugs to be used in the primary care of patients with COVID-19, it certainly sends a strong message of safety in acutely ill patients,” he added.

Dr. Vaduganathan explained that from the beginning of the COVID-19 pandemic, there was great interest in repurposing established therapies for alternative indications for their use in the management of COVID-19.

“Conditions that strongly predispose to adverse COVID outcomes strongly overlap with established indications for SGLT2-inhibitors. So many wondered whether these drugs may be an ideal treatment candidate for the management of COVID-19. However, there have been many safety concerns about the use of SGLT2-inhibitors in this acute setting, with worries that they may induce hemodynamic changes such an excessive lowering of blood pressure, or metabolic changes such as ketoacidosis in acutely ill patients,” he noted.

The initial DARE-19 study investigating SGLT2-inhibitors in COVID-19, with 1,250 participants, found a 20% reduction in the primary outcome of organ dysfunction or death, but this did not reach statistical significance, and no safety issues were seen. This “intriguing” result led to two further larger trials – the ACTIV-4a and RECOVERY trials, Dr. Vaduganathan reported.

“Those early signals of benefit seen in DARE-19 were largely not substantiated in the ACTIV-4A and RECOVERY trials, or in this new meta-analysis, and now we have this much larger body of evidence and more stable estimates about the efficacy of these drugs in acutely ill COVID-19 patients,” he said.

“But the story that we will all take forward is one of safety. This set of trials was arguably conducted in some of the sickest patients we’ve seen who have been exposed to SGLT2-inhibitors, and they strongly affirm that these agents can be safely continued in the setting of acute illness, with very low rates of ketoacidosis and kidney injury, and there was no prolongation of hospital stay,” he commented.

In his presentation, Dr. Kosiborod explained that treatments targeting COVID-19 pathobiology such as dysregulated immune responses, endothelial damage, microvascular thrombosis, and inflammation have been shown to improve the key outcomes in this patient group.

SGLT2 inhibitors, which modulate similar pathobiology, provide cardiovascular protection and prevent the progression of kidney disease in patients at risk for these events, including those with type 2 diabetes, heart failure, and kidney disease, and may also lead to organ protection in a setting of acute illness such as COVID-19, he noted. However, the role of SGLT2 inhibitors in patients hospitalized with COVID-19 remains uncertain.

To address the need for more definitive efficacy data, the World Health Organization Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group conducted a prospective meta-analysis using data from the three randomized controlled trials, DARE-19, RECOVERY, and ACTIV-4a, evaluating SGLT2 inhibitors in patients hospitalized with COVID-19.

Overall, these trials randomized 6,096 participants: 3,025 to SGLT2 inhibitors and 3,071 to usual care or placebo. The average age of participants ranged between 62 and 73 years across the trials, 39% were women, and 25% had type 2 diabetes.

By 28 days after randomization, all-cause mortality, the primary endpoint, had occurred in 11.6% of the SGLT2-inhibitor patients, compared with 12.4% of those randomized to usual care or placebo, giving an odds ratio of 0.93 (95% confidence interval, 0.79-1.08; P = .33) for SGLT2 inhibitors, with consistency across trials.

Data on in-hospital and 90-day all-cause mortality were only available for two out of three trials (DARE-19 and ACTIV-4a), but the results were similar to the primary endpoint showing nonsignificant trends toward a possible benefit in the SGLT2-inhibitor group.

The results were also similar for the secondary outcomes of progression to acute kidney injury or requirement for dialysis or death, and progression to invasive mechanical ventilation, extracorporeal membrane oxygenation, or death, both assessed at 28 days.

The primary safety outcome of ketoacidosis by 28 days was observed in seven and two patients allocated to SGLT2 inhibitors and usual care or placebo, respectively, and overall, the incidence of reported serious adverse events was balanced between treatment groups.

The RECOVERY trial was supported by grants to the University of Oxford from UK Research and Innovation, the National Institute for Health and Care Research, and Wellcome. The ACTIV-4a platform was sponsored by the National Heart, Lung, and Blood Institute. DARE-19 was an investigator-initiated collaborative trial supported by AstraZeneca. Dr. Kosiborod reported numerous conflicts of interest.

A version of this article first appeared on Medscape.com.

A new meta-analysis has shown that SGLT2 inhibitors do not lead to lower 28-day all-cause mortality, compared with usual care or placebo, in patients hospitalized with COVID-19.

However, no major safety issues were identified with the use of SGLT2 inhibitors in these acutely ill patients, the researchers report.

“While these findings do not support the use of SGLT2-inhibitors as standard of care for patients hospitalized with COVID-19, I think the most important take home message here is that the use of these medications appears to be safe even in really acutely ill hospitalized patients,” lead investigator of the meta-analysis, Mikhail Kosiborod, MD, Saint Luke’s Mid America Heart Institute, Kansas City, Mo., concluded.

He said this was important because the list of indications for SGLT2 inhibitors is rapidly growing.

“These medications are being used in more and more patients. And we know that when we discontinue medications in the hospital they frequently don’t get restarted, which can lead to real risks if SGLT2 inhibitors are stopped in patients with heart failure, chronic kidney disease, or diabetes. So, the bottom line is that there is no compelling reason to stop these medications in the hospital,” he added.

The new meta-analysis was presented at the recent annual congress of the European Society of Cardiology, held in Amsterdam.

Discussant of the presentation at the ESC Hotline session, Muthiah Vaduganathan, MD, MPH, Brigham and Women’s Hospital, Boston, agreed with Dr. Kosiborod’s interpretation.

“Until today we have had very limited information on the safety of SGLT2-inhibitors in acute illness, as the pivotal trials which established the use of these drugs in diabetes and chronic kidney disease largely excluded patients who were hospitalized,” Dr. Vaduganathan said.

“While the overall results of this meta-analysis are neutral and SGLT2 inhibitors will not be added as drugs to be used in the primary care of patients with COVID-19, it certainly sends a strong message of safety in acutely ill patients,” he added.

Dr. Vaduganathan explained that from the beginning of the COVID-19 pandemic, there was great interest in repurposing established therapies for alternative indications for their use in the management of COVID-19.

“Conditions that strongly predispose to adverse COVID outcomes strongly overlap with established indications for SGLT2-inhibitors. So many wondered whether these drugs may be an ideal treatment candidate for the management of COVID-19. However, there have been many safety concerns about the use of SGLT2-inhibitors in this acute setting, with worries that they may induce hemodynamic changes such an excessive lowering of blood pressure, or metabolic changes such as ketoacidosis in acutely ill patients,” he noted.

The initial DARE-19 study investigating SGLT2-inhibitors in COVID-19, with 1,250 participants, found a 20% reduction in the primary outcome of organ dysfunction or death, but this did not reach statistical significance, and no safety issues were seen. This “intriguing” result led to two further larger trials – the ACTIV-4a and RECOVERY trials, Dr. Vaduganathan reported.

“Those early signals of benefit seen in DARE-19 were largely not substantiated in the ACTIV-4A and RECOVERY trials, or in this new meta-analysis, and now we have this much larger body of evidence and more stable estimates about the efficacy of these drugs in acutely ill COVID-19 patients,” he said.

“But the story that we will all take forward is one of safety. This set of trials was arguably conducted in some of the sickest patients we’ve seen who have been exposed to SGLT2-inhibitors, and they strongly affirm that these agents can be safely continued in the setting of acute illness, with very low rates of ketoacidosis and kidney injury, and there was no prolongation of hospital stay,” he commented.

In his presentation, Dr. Kosiborod explained that treatments targeting COVID-19 pathobiology such as dysregulated immune responses, endothelial damage, microvascular thrombosis, and inflammation have been shown to improve the key outcomes in this patient group.

SGLT2 inhibitors, which modulate similar pathobiology, provide cardiovascular protection and prevent the progression of kidney disease in patients at risk for these events, including those with type 2 diabetes, heart failure, and kidney disease, and may also lead to organ protection in a setting of acute illness such as COVID-19, he noted. However, the role of SGLT2 inhibitors in patients hospitalized with COVID-19 remains uncertain.

To address the need for more definitive efficacy data, the World Health Organization Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group conducted a prospective meta-analysis using data from the three randomized controlled trials, DARE-19, RECOVERY, and ACTIV-4a, evaluating SGLT2 inhibitors in patients hospitalized with COVID-19.

Overall, these trials randomized 6,096 participants: 3,025 to SGLT2 inhibitors and 3,071 to usual care or placebo. The average age of participants ranged between 62 and 73 years across the trials, 39% were women, and 25% had type 2 diabetes.

By 28 days after randomization, all-cause mortality, the primary endpoint, had occurred in 11.6% of the SGLT2-inhibitor patients, compared with 12.4% of those randomized to usual care or placebo, giving an odds ratio of 0.93 (95% confidence interval, 0.79-1.08; P = .33) for SGLT2 inhibitors, with consistency across trials.

Data on in-hospital and 90-day all-cause mortality were only available for two out of three trials (DARE-19 and ACTIV-4a), but the results were similar to the primary endpoint showing nonsignificant trends toward a possible benefit in the SGLT2-inhibitor group.

The results were also similar for the secondary outcomes of progression to acute kidney injury or requirement for dialysis or death, and progression to invasive mechanical ventilation, extracorporeal membrane oxygenation, or death, both assessed at 28 days.

The primary safety outcome of ketoacidosis by 28 days was observed in seven and two patients allocated to SGLT2 inhibitors and usual care or placebo, respectively, and overall, the incidence of reported serious adverse events was balanced between treatment groups.

The RECOVERY trial was supported by grants to the University of Oxford from UK Research and Innovation, the National Institute for Health and Care Research, and Wellcome. The ACTIV-4a platform was sponsored by the National Heart, Lung, and Blood Institute. DARE-19 was an investigator-initiated collaborative trial supported by AstraZeneca. Dr. Kosiborod reported numerous conflicts of interest.

A version of this article first appeared on Medscape.com.

People with type 1 diabetes have not experienced the same improved survival after a heart attack over the past 15 years that has occurred in people with type 2 diabetes and those without diabetes, new research shows.

Between 2006 and 2020, the annual incidences of overall mortality and major adverse cardiovascular events after a first-time myocardial infarction dropped significantly for people with type 2 diabetes and those without diabetes (controls).

However, the same trend was not seen for people with type 1 diabetes.

“There is an urgent need for further studies understanding cardiovascular disease in people with type 1 diabetes. Clinicians have to be aware of the absence of the declined mortality trend in people with type 1 diabetes having a first-time myocardial infarction,” lead author Thomas Nyström, MD, professor of medicine at the Karolinska Institute, Stockholm, said in an interview.

The findings are scheduled to be presented Oct. 5, 2023, at the annual meeting of the European Association for the Study of Diabetes.

Discussing potential reasons for the findings, the authors say that the standard care after a heart attack has improved with more availability of, for example, percutaneous coronary intervention and better overall medical treatment. However, this standard of care should have improved in all three groups.

“Although glycemic control and diabetes duration were much different between diabetes groups, in that those with type 1 had been exposed for a longer period of glycemia, the current study cannot tell whether glucose control is behind the association between mortality trends observed. Whether this is the case must be investigated with further studies,” Nyström said.
 

Data from Swedish health care registry

Among people with a first-time MI recorded in national Swedish health care registries between 2006 and 2020, there were 2,527 individuals with type 1 diabetes, 48,321 with type 2 diabetes, and 243,170 controls with neither form of diabetes.

Those with type 1 diabetes were younger than those with type 2 diabetes and controls (62 years vs. 75 and 73 years, respectively). The type 1 diabetes group also had a higher proportion of females (43.6% vs. 38.1% of both the type 2 diabetes and control groups).

The proportions of people with the most severe type of heart attack, ST-elevation MI (STEMI), versus non-STEMI were 29% versus 71% in the type 1 diabetes group, 30% versus 70% in the type 2 diabetes group, and 39% versus 61% in the control group, respectively.

After adjustment for covariates including age, sex, comorbidities, socioeconomic factors, and medication, there was a significant decreased annual incidence trend for all-cause death among the controls (–1.9%) and persons with type 2 diabetes (–1.3%), but there was no such decrease among those with type 1 diabetes.

For cardiovascular deaths, the annual incidence declines were –2.0% and –1.6% in the control group and the type 2 diabetes group, respectively, versus a nonsignificant –0.5% decline in the type 1 diabetes group. Similarly, for major adverse cardiovascular events, those decreases were –2.0% for controls and –1.6% for those with type 2 diabetes, but –0.6% for those with type 1 diabetes – again, a nonsignificant value.

“During the last 15 years, the risk of death and major cardiovascular events in people without diabetes and with type 2 diabetes after having a first-time heart attack has decreased significantly. In contrast, this decreasing trend was absent in people with type 1 diabetes. Our study highlights the urgent need for understanding the cardiovascular risk in people with type 1 diabetes,” the authors conclude.

Dr. Nyström has received honoraria from AstraZeneca, Merck Sharp & Dohme, Novo Nordisk, Eli Lilly , Boehringer Ingelheim, Abbott, and Amgen. The authors acknowledge the ALF agreement between Stockholm County Council and Karolinska Institutet.

A version of this article appeared on Medscape.com.

People with type 1 diabetes have not experienced the same improved survival after a heart attack over the past 15 years that has occurred in people with type 2 diabetes and those without diabetes, new research shows.

Between 2006 and 2020, the annual incidences of overall mortality and major adverse cardiovascular events after a first-time myocardial infarction dropped significantly for people with type 2 diabetes and those without diabetes (controls).

However, the same trend was not seen for people with type 1 diabetes.

“There is an urgent need for further studies understanding cardiovascular disease in people with type 1 diabetes. Clinicians have to be aware of the absence of the declined mortality trend in people with type 1 diabetes having a first-time myocardial infarction,” lead author Thomas Nyström, MD, professor of medicine at the Karolinska Institute, Stockholm, said in an interview.

The findings are scheduled to be presented Oct. 5, 2023, at the annual meeting of the European Association for the Study of Diabetes.

Discussing potential reasons for the findings, the authors say that the standard care after a heart attack has improved with more availability of, for example, percutaneous coronary intervention and better overall medical treatment. However, this standard of care should have improved in all three groups.

“Although glycemic control and diabetes duration were much different between diabetes groups, in that those with type 1 had been exposed for a longer period of glycemia, the current study cannot tell whether glucose control is behind the association between mortality trends observed. Whether this is the case must be investigated with further studies,” Nyström said.
 

Data from Swedish health care registry

Among people with a first-time MI recorded in national Swedish health care registries between 2006 and 2020, there were 2,527 individuals with type 1 diabetes, 48,321 with type 2 diabetes, and 243,170 controls with neither form of diabetes.

Those with type 1 diabetes were younger than those with type 2 diabetes and controls (62 years vs. 75 and 73 years, respectively). The type 1 diabetes group also had a higher proportion of females (43.6% vs. 38.1% of both the type 2 diabetes and control groups).

The proportions of people with the most severe type of heart attack, ST-elevation MI (STEMI), versus non-STEMI were 29% versus 71% in the type 1 diabetes group, 30% versus 70% in the type 2 diabetes group, and 39% versus 61% in the control group, respectively.

After adjustment for covariates including age, sex, comorbidities, socioeconomic factors, and medication, there was a significant decreased annual incidence trend for all-cause death among the controls (–1.9%) and persons with type 2 diabetes (–1.3%), but there was no such decrease among those with type 1 diabetes.

For cardiovascular deaths, the annual incidence declines were –2.0% and –1.6% in the control group and the type 2 diabetes group, respectively, versus a nonsignificant –0.5% decline in the type 1 diabetes group. Similarly, for major adverse cardiovascular events, those decreases were –2.0% for controls and –1.6% for those with type 2 diabetes, but –0.6% for those with type 1 diabetes – again, a nonsignificant value.

“During the last 15 years, the risk of death and major cardiovascular events in people without diabetes and with type 2 diabetes after having a first-time heart attack has decreased significantly. In contrast, this decreasing trend was absent in people with type 1 diabetes. Our study highlights the urgent need for understanding the cardiovascular risk in people with type 1 diabetes,” the authors conclude.

Dr. Nyström has received honoraria from AstraZeneca, Merck Sharp & Dohme, Novo Nordisk, Eli Lilly , Boehringer Ingelheim, Abbott, and Amgen. The authors acknowledge the ALF agreement between Stockholm County Council and Karolinska Institutet.

A version of this article appeared on Medscape.com.

People with type 1 diabetes have not experienced the same improved survival after a heart attack over the past 15 years that has occurred in people with type 2 diabetes and those without diabetes, new research shows.

Between 2006 and 2020, the annual incidences of overall mortality and major adverse cardiovascular events after a first-time myocardial infarction dropped significantly for people with type 2 diabetes and those without diabetes (controls).

However, the same trend was not seen for people with type 1 diabetes.

“There is an urgent need for further studies understanding cardiovascular disease in people with type 1 diabetes. Clinicians have to be aware of the absence of the declined mortality trend in people with type 1 diabetes having a first-time myocardial infarction,” lead author Thomas Nyström, MD, professor of medicine at the Karolinska Institute, Stockholm, said in an interview.

The findings are scheduled to be presented Oct. 5, 2023, at the annual meeting of the European Association for the Study of Diabetes.

Discussing potential reasons for the findings, the authors say that the standard care after a heart attack has improved with more availability of, for example, percutaneous coronary intervention and better overall medical treatment. However, this standard of care should have improved in all three groups.

“Although glycemic control and diabetes duration were much different between diabetes groups, in that those with type 1 had been exposed for a longer period of glycemia, the current study cannot tell whether glucose control is behind the association between mortality trends observed. Whether this is the case must be investigated with further studies,” Nyström said.
 

Data from Swedish health care registry

Among people with a first-time MI recorded in national Swedish health care registries between 2006 and 2020, there were 2,527 individuals with type 1 diabetes, 48,321 with type 2 diabetes, and 243,170 controls with neither form of diabetes.

Those with type 1 diabetes were younger than those with type 2 diabetes and controls (62 years vs. 75 and 73 years, respectively). The type 1 diabetes group also had a higher proportion of females (43.6% vs. 38.1% of both the type 2 diabetes and control groups).

The proportions of people with the most severe type of heart attack, ST-elevation MI (STEMI), versus non-STEMI were 29% versus 71% in the type 1 diabetes group, 30% versus 70% in the type 2 diabetes group, and 39% versus 61% in the control group, respectively.

After adjustment for covariates including age, sex, comorbidities, socioeconomic factors, and medication, there was a significant decreased annual incidence trend for all-cause death among the controls (–1.9%) and persons with type 2 diabetes (–1.3%), but there was no such decrease among those with type 1 diabetes.

For cardiovascular deaths, the annual incidence declines were –2.0% and –1.6% in the control group and the type 2 diabetes group, respectively, versus a nonsignificant –0.5% decline in the type 1 diabetes group. Similarly, for major adverse cardiovascular events, those decreases were –2.0% for controls and –1.6% for those with type 2 diabetes, but –0.6% for those with type 1 diabetes – again, a nonsignificant value.

“During the last 15 years, the risk of death and major cardiovascular events in people without diabetes and with type 2 diabetes after having a first-time heart attack has decreased significantly. In contrast, this decreasing trend was absent in people with type 1 diabetes. Our study highlights the urgent need for understanding the cardiovascular risk in people with type 1 diabetes,” the authors conclude.

Dr. Nyström has received honoraria from AstraZeneca, Merck Sharp & Dohme, Novo Nordisk, Eli Lilly , Boehringer Ingelheim, Abbott, and Amgen. The authors acknowledge the ALF agreement between Stockholm County Council and Karolinska Institutet.

A version of this article appeared on Medscape.com.

TOPLINE:

In an online survey of 605 people with diabetes who use insulin and continuous glucose monitors (CGMs), a majority expressed satisfaction with many aspects of the devices’ performance. However, significant proportions also reported concerns about accuracy under certain circumstances and about skin problems.

METHODOLOGY:

Researchers did an online survey of 504 people with type 1 diabetes from the T1D Exchange and 101 with type 2 diabetes from the Dynata database.

TAKEAWAY:

• The Dexcom G6 device was used by 60.7% of all current CGM users, including 69% of those with type 1 diabetes vs. 12% with type 2 diabetes.
• People with type 2 diabetes were more likely to use older Dexcom versions (G4/G5) (32%) or Abbott’s FreeStyle Libre systems (35%).
• Overall, 90% agreed that most sensors were accurate, but just 79% and 78%, respectively, were satisfied with sensor performance on the first and last day of wear.
• Moreover, 42% suspected variations in accuracy from sensor to sensor, and 32% continue to perform finger-stick monitoring more than six times a week.
• Individuals with type 2 diabetes were more likely than those with type 1 diabetes to be concerned about poor sensor performance affecting confidence in making diabetes management decisions (52% vs. 19%).
• Over half reported skin reactions and/or pain with the sensors (53.7% and 55.4%, respectively).
• Concerns about medications affecting sensor accuracy were more common among those with type 2 vs. type 1 diabetes (65% vs. 29%).
• Among overall concerns about substances or situations affecting sensor accuracy, the top choice (47%) was dehydration (despite a lack of supportive published literature), followed by pain medications (43%), cold/flu medications (32%), and coffee (24%).
• Inaccurate/false alarms negatively affected daily life for 36% of participants and diabetes management for 34%.

IN PRACTICE:

“CGM is a game-changing technology and has evolved in the past decade to overcome many technical and usability obstacles. Our survey suggests that there remain areas for further improvement ... Mistrust in CGM performance was more common than expected.”

SOURCE:

The study was done by Elizabeth Holt, of LifeScan, and colleagues. It was published in Clinical Diabetes.

LIMITATIONS:

• The databases used to recruit study participants may not be representative of the entire respective patient populations.
• Exercise wasn’t given as an option for affecting CGM accuracy, which might partly explain the dehydration finding.

DISCLOSURES:

Funding for this study and preparation of the manuscript were provided by LifeScan Inc. Two authors are LifeScan employees, and two others currently work for the T1D Exchange.

A version of this article first appeared on Medscape.com.

TOPLINE:

In an online survey of 605 people with diabetes who use insulin and continuous glucose monitors (CGMs), a majority expressed satisfaction with many aspects of the devices’ performance. However, significant proportions also reported concerns about accuracy under certain circumstances and about skin problems.

METHODOLOGY:

Researchers did an online survey of 504 people with type 1 diabetes from the T1D Exchange and 101 with type 2 diabetes from the Dynata database.

TAKEAWAY:

• The Dexcom G6 device was used by 60.7% of all current CGM users, including 69% of those with type 1 diabetes vs. 12% with type 2 diabetes.
• People with type 2 diabetes were more likely to use older Dexcom versions (G4/G5) (32%) or Abbott’s FreeStyle Libre systems (35%).
• Overall, 90% agreed that most sensors were accurate, but just 79% and 78%, respectively, were satisfied with sensor performance on the first and last day of wear.
• Moreover, 42% suspected variations in accuracy from sensor to sensor, and 32% continue to perform finger-stick monitoring more than six times a week.
• Individuals with type 2 diabetes were more likely than those with type 1 diabetes to be concerned about poor sensor performance affecting confidence in making diabetes management decisions (52% vs. 19%).
• Over half reported skin reactions and/or pain with the sensors (53.7% and 55.4%, respectively).
• Concerns about medications affecting sensor accuracy were more common among those with type 2 vs. type 1 diabetes (65% vs. 29%).
• Among overall concerns about substances or situations affecting sensor accuracy, the top choice (47%) was dehydration (despite a lack of supportive published literature), followed by pain medications (43%), cold/flu medications (32%), and coffee (24%).
• Inaccurate/false alarms negatively affected daily life for 36% of participants and diabetes management for 34%.

IN PRACTICE:

“CGM is a game-changing technology and has evolved in the past decade to overcome many technical and usability obstacles. Our survey suggests that there remain areas for further improvement ... Mistrust in CGM performance was more common than expected.”

SOURCE:

The study was done by Elizabeth Holt, of LifeScan, and colleagues. It was published in Clinical Diabetes.

LIMITATIONS:

• The databases used to recruit study participants may not be representative of the entire respective patient populations.
• Exercise wasn’t given as an option for affecting CGM accuracy, which might partly explain the dehydration finding.

DISCLOSURES:

Funding for this study and preparation of the manuscript were provided by LifeScan Inc. Two authors are LifeScan employees, and two others currently work for the T1D Exchange.

A version of this article first appeared on Medscape.com.

TOPLINE:

In an online survey of 605 people with diabetes who use insulin and continuous glucose monitors (CGMs), a majority expressed satisfaction with many aspects of the devices’ performance. However, significant proportions also reported concerns about accuracy under certain circumstances and about skin problems.

METHODOLOGY:

Researchers did an online survey of 504 people with type 1 diabetes from the T1D Exchange and 101 with type 2 diabetes from the Dynata database.

TAKEAWAY:

• The Dexcom G6 device was used by 60.7% of all current CGM users, including 69% of those with type 1 diabetes vs. 12% with type 2 diabetes.
• People with type 2 diabetes were more likely to use older Dexcom versions (G4/G5) (32%) or Abbott’s FreeStyle Libre systems (35%).
• Overall, 90% agreed that most sensors were accurate, but just 79% and 78%, respectively, were satisfied with sensor performance on the first and last day of wear.
• Moreover, 42% suspected variations in accuracy from sensor to sensor, and 32% continue to perform finger-stick monitoring more than six times a week.
• Individuals with type 2 diabetes were more likely than those with type 1 diabetes to be concerned about poor sensor performance affecting confidence in making diabetes management decisions (52% vs. 19%).
• Over half reported skin reactions and/or pain with the sensors (53.7% and 55.4%, respectively).
• Concerns about medications affecting sensor accuracy were more common among those with type 2 vs. type 1 diabetes (65% vs. 29%).
• Among overall concerns about substances or situations affecting sensor accuracy, the top choice (47%) was dehydration (despite a lack of supportive published literature), followed by pain medications (43%), cold/flu medications (32%), and coffee (24%).
• Inaccurate/false alarms negatively affected daily life for 36% of participants and diabetes management for 34%.

IN PRACTICE:

“CGM is a game-changing technology and has evolved in the past decade to overcome many technical and usability obstacles. Our survey suggests that there remain areas for further improvement ... Mistrust in CGM performance was more common than expected.”

SOURCE:

The study was done by Elizabeth Holt, of LifeScan, and colleagues. It was published in Clinical Diabetes.

LIMITATIONS:

• The databases used to recruit study participants may not be representative of the entire respective patient populations.
• Exercise wasn’t given as an option for affecting CGM accuracy, which might partly explain the dehydration finding.

DISCLOSURES:

Funding for this study and preparation of the manuscript were provided by LifeScan Inc. Two authors are LifeScan employees, and two others currently work for the T1D Exchange.

A version of this article first appeared on Medscape.com.

“Night owls” have an increased risk for developing type 2 diabetes and are more likely to smoke more, exercise less, and have poor sleep habits, compared with their “early bird” counterparts, according to a new study, published in Annals of Internal Medicine.

The work focused on participants’ self-assessed chronotype – an individuals’ circadian preference, or natural preference to sleep and wake up earlier or later, commonly known as being an early bird or a night owl.

Analyzing the self-reported lifestyle behaviors and sleeping habits of more than 60,000 middle-aged female nurses, researchers from Brigham and Women’s Hospital and Harvard Medical School, both in Boston, found that those with a preference for waking up later had a 72% higher risk for diabetes and were 54% more likely to have unhealthy lifestyle behaviors, compared with participants who tended to wake up earlier.

After adjustment for six lifestyle factors – diet, alcohol use, body mass index (BMI), physical activity, smoking status, and sleep duration – the association between diabetes risk and evening chronotype weakened to a 19% higher risk of developing type 2 diabetes.

In a subgroup analysis, this association was stronger among women who either had had no night shifts over the previous 2 years or had worked night shifts for less than 10 years in their careers. For nurses who had worked night shifts recently, the study found no association between evening chronotype and diabetes risk.

The participants, drawn from the Nurses’ Health Study II, were between 45 and 62 years age, with no history of cancer, cardiovascular disease, or diabetes. Researchers followed the group from 2009 until 2017.
 

Is there a mismatch between natural circadian rhythm and work schedule?

The authors, led by Sina Kianersi, DVM, PhD, of Harvard Medical School, Boston, suggest that their results may be linked to a mismatch between a person’s circadian rhythm and their physical and social environment – for example, if someone lives on a schedule opposite to their circadian preference.

In one 2015 study, female nurses who had worked daytime shifts for more than 10 years but had an evening chronotype had the highest diabetes risk, compared with early chronotypes (51% more likely to develop type 2 diabetes).

In a 2022 study, an evening chronotype was associated with a 30% elevated risk for type 2 diabetes. The authors speculated that circadian misalignment could be to blame – for example, being a night owl but working early morning – which can disrupt glycemic and lipid metabolism.

Previous studies have found that shorter or irregular sleep habits are associated with a higher risk of type 2 diabetes. Other studies have also found that people with an evening chronotype are more likely than early birds to have unhealthy eating habits, have lower levels of physical activity, and smoke and drink.

This new study did not find that an evening chronotype was associated with unhealthy drinking, which the authors defined as having one or more drinks per day.

In an accompanying editorial, two physicians from the Harvard T.H. Chan School of Public Health in Boston caution that the statistical design of the study limits its ability to establish causation.

“Chronotype could change later, which might correlate with lifestyle changes,” write Kehuan Lin, MS, Mingyang Song, MBBS, and Edward Giovannucci, MD. “Experimental trials are required to determine whether chronotype is a marker of unhealthy lifestyle or an independent determinant.”

They also suggest that psychological factors and the type of work being performed by the participants could be potential confounders.

The authors of the study note that their findings might not be generalizable to groups other than middle-aged White female nurses. The study population also had a relatively high level of education and were socioeconomically advantaged.

Self-reporting chronotypes with a single question could also result in misclassification and measurement error, the authors acknowledge.

The findings underscore the value of assessing an individuals’ chronotype for scheduling shift work – for example, assigning night owls to night shifts may improve their metabolic health and sleeping habits, according to the authors of the study.

“Given the importance of lifestyle modification in diabetes prevention, future research is warranted to investigate whether improving lifestyle behaviors could effectively reduce diabetes risk in persons with an evening chronotype,” the authors conclude.

The study was supported by grants from the National Institutes of Health and the European Research Council.

A version of this article first appeared on Medscape.com.

“Night owls” have an increased risk for developing type 2 diabetes and are more likely to smoke more, exercise less, and have poor sleep habits, compared with their “early bird” counterparts, according to a new study, published in Annals of Internal Medicine.

The work focused on participants’ self-assessed chronotype – an individuals’ circadian preference, or natural preference to sleep and wake up earlier or later, commonly known as being an early bird or a night owl.

Analyzing the self-reported lifestyle behaviors and sleeping habits of more than 60,000 middle-aged female nurses, researchers from Brigham and Women’s Hospital and Harvard Medical School, both in Boston, found that those with a preference for waking up later had a 72% higher risk for diabetes and were 54% more likely to have unhealthy lifestyle behaviors, compared with participants who tended to wake up earlier.

After adjustment for six lifestyle factors – diet, alcohol use, body mass index (BMI), physical activity, smoking status, and sleep duration – the association between diabetes risk and evening chronotype weakened to a 19% higher risk of developing type 2 diabetes.

In a subgroup analysis, this association was stronger among women who either had had no night shifts over the previous 2 years or had worked night shifts for less than 10 years in their careers. For nurses who had worked night shifts recently, the study found no association between evening chronotype and diabetes risk.

The participants, drawn from the Nurses’ Health Study II, were between 45 and 62 years age, with no history of cancer, cardiovascular disease, or diabetes. Researchers followed the group from 2009 until 2017.
 

Is there a mismatch between natural circadian rhythm and work schedule?

The authors, led by Sina Kianersi, DVM, PhD, of Harvard Medical School, Boston, suggest that their results may be linked to a mismatch between a person’s circadian rhythm and their physical and social environment – for example, if someone lives on a schedule opposite to their circadian preference.

In one 2015 study, female nurses who had worked daytime shifts for more than 10 years but had an evening chronotype had the highest diabetes risk, compared with early chronotypes (51% more likely to develop type 2 diabetes).

In a 2022 study, an evening chronotype was associated with a 30% elevated risk for type 2 diabetes. The authors speculated that circadian misalignment could be to blame – for example, being a night owl but working early morning – which can disrupt glycemic and lipid metabolism.

Previous studies have found that shorter or irregular sleep habits are associated with a higher risk of type 2 diabetes. Other studies have also found that people with an evening chronotype are more likely than early birds to have unhealthy eating habits, have lower levels of physical activity, and smoke and drink.

This new study did not find that an evening chronotype was associated with unhealthy drinking, which the authors defined as having one or more drinks per day.

In an accompanying editorial, two physicians from the Harvard T.H. Chan School of Public Health in Boston caution that the statistical design of the study limits its ability to establish causation.

“Chronotype could change later, which might correlate with lifestyle changes,” write Kehuan Lin, MS, Mingyang Song, MBBS, and Edward Giovannucci, MD. “Experimental trials are required to determine whether chronotype is a marker of unhealthy lifestyle or an independent determinant.”

They also suggest that psychological factors and the type of work being performed by the participants could be potential confounders.

The authors of the study note that their findings might not be generalizable to groups other than middle-aged White female nurses. The study population also had a relatively high level of education and were socioeconomically advantaged.

Self-reporting chronotypes with a single question could also result in misclassification and measurement error, the authors acknowledge.

The findings underscore the value of assessing an individuals’ chronotype for scheduling shift work – for example, assigning night owls to night shifts may improve their metabolic health and sleeping habits, according to the authors of the study.

“Given the importance of lifestyle modification in diabetes prevention, future research is warranted to investigate whether improving lifestyle behaviors could effectively reduce diabetes risk in persons with an evening chronotype,” the authors conclude.

The study was supported by grants from the National Institutes of Health and the European Research Council.

A version of this article first appeared on Medscape.com.

“Night owls” have an increased risk for developing type 2 diabetes and are more likely to smoke more, exercise less, and have poor sleep habits, compared with their “early bird” counterparts, according to a new study, published in Annals of Internal Medicine.

The work focused on participants’ self-assessed chronotype – an individuals’ circadian preference, or natural preference to sleep and wake up earlier or later, commonly known as being an early bird or a night owl.

Analyzing the self-reported lifestyle behaviors and sleeping habits of more than 60,000 middle-aged female nurses, researchers from Brigham and Women’s Hospital and Harvard Medical School, both in Boston, found that those with a preference for waking up later had a 72% higher risk for diabetes and were 54% more likely to have unhealthy lifestyle behaviors, compared with participants who tended to wake up earlier.

After adjustment for six lifestyle factors – diet, alcohol use, body mass index (BMI), physical activity, smoking status, and sleep duration – the association between diabetes risk and evening chronotype weakened to a 19% higher risk of developing type 2 diabetes.

In a subgroup analysis, this association was stronger among women who either had had no night shifts over the previous 2 years or had worked night shifts for less than 10 years in their careers. For nurses who had worked night shifts recently, the study found no association between evening chronotype and diabetes risk.

The participants, drawn from the Nurses’ Health Study II, were between 45 and 62 years age, with no history of cancer, cardiovascular disease, or diabetes. Researchers followed the group from 2009 until 2017.
 

Is there a mismatch between natural circadian rhythm and work schedule?

The authors, led by Sina Kianersi, DVM, PhD, of Harvard Medical School, Boston, suggest that their results may be linked to a mismatch between a person’s circadian rhythm and their physical and social environment – for example, if someone lives on a schedule opposite to their circadian preference.

In one 2015 study, female nurses who had worked daytime shifts for more than 10 years but had an evening chronotype had the highest diabetes risk, compared with early chronotypes (51% more likely to develop type 2 diabetes).

In a 2022 study, an evening chronotype was associated with a 30% elevated risk for type 2 diabetes. The authors speculated that circadian misalignment could be to blame – for example, being a night owl but working early morning – which can disrupt glycemic and lipid metabolism.

Previous studies have found that shorter or irregular sleep habits are associated with a higher risk of type 2 diabetes. Other studies have also found that people with an evening chronotype are more likely than early birds to have unhealthy eating habits, have lower levels of physical activity, and smoke and drink.

This new study did not find that an evening chronotype was associated with unhealthy drinking, which the authors defined as having one or more drinks per day.

In an accompanying editorial, two physicians from the Harvard T.H. Chan School of Public Health in Boston caution that the statistical design of the study limits its ability to establish causation.

“Chronotype could change later, which might correlate with lifestyle changes,” write Kehuan Lin, MS, Mingyang Song, MBBS, and Edward Giovannucci, MD. “Experimental trials are required to determine whether chronotype is a marker of unhealthy lifestyle or an independent determinant.”

They also suggest that psychological factors and the type of work being performed by the participants could be potential confounders.

The authors of the study note that their findings might not be generalizable to groups other than middle-aged White female nurses. The study population also had a relatively high level of education and were socioeconomically advantaged.

Self-reporting chronotypes with a single question could also result in misclassification and measurement error, the authors acknowledge.

The findings underscore the value of assessing an individuals’ chronotype for scheduling shift work – for example, assigning night owls to night shifts may improve their metabolic health and sleeping habits, according to the authors of the study.

“Given the importance of lifestyle modification in diabetes prevention, future research is warranted to investigate whether improving lifestyle behaviors could effectively reduce diabetes risk in persons with an evening chronotype,” the authors conclude.

The study was supported by grants from the National Institutes of Health and the European Research Council.

A version of this article first appeared on Medscape.com.

ILLUSTRATIVE CASE

A 51-year-old woman with a history of elevated cholesterol and a body mass index (BMI) of 31 presents to your clinic for a scheduled follow-up visit to review recent blood test results. Her A1C was elevated at 5.9%. She wants to know if she should start medication now.

Prediabetes is a high-risk state that ­confers increased risk for type 2 ­diabetes (T2D). It is identified by impaired fasting glucose (fasting plasma glucose [FPG], 100-125 mg/dL), impaired glucose tolerance (2-hour oral glucose tolerance test, 140-199 mg/dL), or an elevated A1C (between 5.7% and 6.4%).²

An estimated 96 million ­Americans—38% of the US adult population—have prediabetes, according to the Centers for Disease Control and Prevention.³ Family physicians frequently encounter this condition when screening for T2D in asymptomatic adults (ages 35 to 70 years) with overweight or obesity, as recommended by the US Preventive Services Task Force (grade “B”).⁴

To treat, or not? Studies have shown that interventions such as lifestyle modification and use of metformin by patients with prediabetes can decrease their risk for T2D.^5,6 In the Diabetes Prevention Program (DPP) study, progression from prediabetes to T2D was reduced to 14% with lifestyle modification and 22% with metformin use, vs 29% with placebo.⁷

However, there is disagreement about whether to treat prediabetes, particularly with medication. Some argue that metformin is a safe, effective, and cost-saving treatment to prevent T2D and its associated health consequences.⁸ The current American Diabetes Association (ADA) guidelines suggest that metformin be considered in certain patients with prediabetes and high-risk factors, especially younger age, obesity or hyperglycemia, or a history of gestational diabetes.⁹ However, only an estimated 1% to 4% of adults with prediabetes are prescribed metformin.¹⁰

Others argue that treating a preclinical condition is not a patient-centered approach, especially since not all patients with prediabetes progress to T2D and the risk for development or progression of retinopathy and microalbuminuria is extremely low if A1C levels remain < 7.0%.¹¹ By this standard, pharmacologic treatment should be initiated only if, or when, a patient develops T2D, with a focus on intensive lifestyle intervention for high-risk patients in the interim.¹¹

Given the conflicting viewpoints, ongoing long-term studies on T2D prevention will help guide treatment decisions for patients with prediabetes. The study by Lee et al¹ was the first to evaluate the effect of metformin or intensive lifestyle modification on all-cause and cause-specific mortality in patients at high risk for T2D.

Continue to: STUDY SUMMARY

No mortality benefit from metformin or lifestyle modification

This secondary analysis evaluated mortality outcomes for patients at risk for T2D who were part of the DPP trial and then were ­followed long term in the Diabetes Prevention Program Outcomes Study (DPPOS).¹ The initial DPP trial included 3234 adult patients at high risk for T2D (defined as having a BMI ≥ 24; an FPG of 95-125 mg/dL; and a 2-hour glucose level of 140-199 mg/dL). Participants were randomized into groups receiving either intensive lifestyle intervention (which focused on achieving ≥ 150 min/wk of exercise and ≥ 7% body weight loss), metformin 850 mg twice daily, or placebo twice daily; the latter 2 groups also received standard exercise and diet recommendations. Mean age was 51 years, mean BMI was 34, and 68% of participants were female.

Both the metformin and lifestyle intervention groups experienced decreases in weight and cardiovascular risk factors but not in mortality.

At the conclusion of the initial 5-year trial, treatment was unmasked and 86% of the patients continued to be followed for long-term outcomes. Patients in the lifestyle group were offered semiannual lifestyle reinforcement, while the metformin group continued to receive the twice-daily 850-mg dose unless a contraindication developed. If FPG levels increased to ≥ 140 mg/dL in the DPP study, or A1C increased to ≥ 7% in the DPPOS, study metformin was discontinued and management of the patient’s diabetes was transferred to their health care provider. By the end of the DPPOS, 53% of patients in the lifestyle group and 55% in the metformin group had progressed to T2D, compared with 60% in the placebo group (P = 0.003).

After a median 21-year follow-up interval, the investigators collected data on cause of death for patients and evaluated hazard ratios (HRs) for overall and cause-specific mortality. In total, 14% of the participants died, with no statistically significant difference in rates between the 3 groups. Cancer (37%) was the leading cause of death in all groups, followed by cardiovascular disease (CVD; 29%).

Compared with the placebo group, patients taking metformin did not have a decreased rate of overall mortality (HR = 0.99; 95% CI, 0.79-1.25), mortality from cancer (HR = 1.04; 95% CI, 0.72-1.52), or mortality due to CVD (HR = 1.08; 95% CI, 0.70-1.66). Similarly, compared with the placebo group, lifestyle intervention did not decrease overall mortality (HR = 1.02; 95% CI, 0.81-1.28), mortality from cancer (HR = 1.07; 95% CI, 0.74-1.55), or mortality due to CVD (HR = 1.18; 95% CI, 0.77-1.81). Results were similar when adjusted for other factors, including out-of-study metformin use, T2D status and duration, BMI change, and other cardiovascular risk factors.

WHAT’S NEW

Long-term data clarifylimits to interventions’ utility

This study looked at long-term follow-up data on mortality outcomes for patients with prediabetes treated with metformin or lifestyle intervention. Although these interventions did support weight loss, reduce the incidence of T2D, and lower cardiovascular risk factors (eg, hypertension, dyslipidemia), the comorbidity benefits did not affect risk for all-cause or cause-specific mortality, which were similar between the treatment and placebo groups.

Continue to: CAVEATS

Exclusion criteria, residual confounding may limit the findings

Patients with significant cardiovascular or renal disease were excluded, so results may not apply to patients with these comorbidities. Additionally, there was a high amount of “drop-in” use of metformin prescribed by physicians once patients developed T2D, which may not have been controlled for completely. And while the intensive lifestyle intervention group had specific goals, the metformin and placebo groups also were encouraged to follow standard diet and lifestyle recommendations—and during a bridge period, all participants were offered a modified group lifestyle intervention. However, multivariable adjustment did not change the study conclusion.

CHALLENGES TO IMPLEMENTATION

Physicians may be unwilling to change their current prescribing habits

Physicians may not be willing to change their practice of prescribing metformin in prediabetes based on a singular study (with residual confounding) that showed no long-term mortality differences between the study groups. However, there may be long-term morbidity differences of interest to patients that were not specifically evaluated in this study—such as quality-of-life benefits from weight loss that may outweigh the risks (eg, gastrointestinal adverse effects such as diarrhea, nausea, and abdominal pain) of metformin for some patients. Therefore, a discussion of the risks and benefits of treatment for prediabetes should be had with patients at high risk who would prefer a pharmacologic intervention.

ILLUSTRATIVE CASE

A 51-year-old woman with a history of elevated cholesterol and a body mass index (BMI) of 31 presents to your clinic for a scheduled follow-up visit to review recent blood test results. Her A1C was elevated at 5.9%. She wants to know if she should start medication now.

Prediabetes is a high-risk state that ­confers increased risk for type 2 ­diabetes (T2D). It is identified by impaired fasting glucose (fasting plasma glucose [FPG], 100-125 mg/dL), impaired glucose tolerance (2-hour oral glucose tolerance test, 140-199 mg/dL), or an elevated A1C (between 5.7% and 6.4%).²

An estimated 96 million ­Americans—38% of the US adult population—have prediabetes, according to the Centers for Disease Control and Prevention.³ Family physicians frequently encounter this condition when screening for T2D in asymptomatic adults (ages 35 to 70 years) with overweight or obesity, as recommended by the US Preventive Services Task Force (grade “B”).⁴

To treat, or not? Studies have shown that interventions such as lifestyle modification and use of metformin by patients with prediabetes can decrease their risk for T2D.^5,6 In the Diabetes Prevention Program (DPP) study, progression from prediabetes to T2D was reduced to 14% with lifestyle modification and 22% with metformin use, vs 29% with placebo.⁷

However, there is disagreement about whether to treat prediabetes, particularly with medication. Some argue that metformin is a safe, effective, and cost-saving treatment to prevent T2D and its associated health consequences.⁸ The current American Diabetes Association (ADA) guidelines suggest that metformin be considered in certain patients with prediabetes and high-risk factors, especially younger age, obesity or hyperglycemia, or a history of gestational diabetes.⁹ However, only an estimated 1% to 4% of adults with prediabetes are prescribed metformin.¹⁰

Others argue that treating a preclinical condition is not a patient-centered approach, especially since not all patients with prediabetes progress to T2D and the risk for development or progression of retinopathy and microalbuminuria is extremely low if A1C levels remain < 7.0%.¹¹ By this standard, pharmacologic treatment should be initiated only if, or when, a patient develops T2D, with a focus on intensive lifestyle intervention for high-risk patients in the interim.¹¹

Given the conflicting viewpoints, ongoing long-term studies on T2D prevention will help guide treatment decisions for patients with prediabetes. The study by Lee et al¹ was the first to evaluate the effect of metformin or intensive lifestyle modification on all-cause and cause-specific mortality in patients at high risk for T2D.

Continue to: STUDY SUMMARY

No mortality benefit from metformin or lifestyle modification

This secondary analysis evaluated mortality outcomes for patients at risk for T2D who were part of the DPP trial and then were ­followed long term in the Diabetes Prevention Program Outcomes Study (DPPOS).¹ The initial DPP trial included 3234 adult patients at high risk for T2D (defined as having a BMI ≥ 24; an FPG of 95-125 mg/dL; and a 2-hour glucose level of 140-199 mg/dL). Participants were randomized into groups receiving either intensive lifestyle intervention (which focused on achieving ≥ 150 min/wk of exercise and ≥ 7% body weight loss), metformin 850 mg twice daily, or placebo twice daily; the latter 2 groups also received standard exercise and diet recommendations. Mean age was 51 years, mean BMI was 34, and 68% of participants were female.

Both the metformin and lifestyle intervention groups experienced decreases in weight and cardiovascular risk factors but not in mortality.

At the conclusion of the initial 5-year trial, treatment was unmasked and 86% of the patients continued to be followed for long-term outcomes. Patients in the lifestyle group were offered semiannual lifestyle reinforcement, while the metformin group continued to receive the twice-daily 850-mg dose unless a contraindication developed. If FPG levels increased to ≥ 140 mg/dL in the DPP study, or A1C increased to ≥ 7% in the DPPOS, study metformin was discontinued and management of the patient’s diabetes was transferred to their health care provider. By the end of the DPPOS, 53% of patients in the lifestyle group and 55% in the metformin group had progressed to T2D, compared with 60% in the placebo group (P = 0.003).

After a median 21-year follow-up interval, the investigators collected data on cause of death for patients and evaluated hazard ratios (HRs) for overall and cause-specific mortality. In total, 14% of the participants died, with no statistically significant difference in rates between the 3 groups. Cancer (37%) was the leading cause of death in all groups, followed by cardiovascular disease (CVD; 29%).

Compared with the placebo group, patients taking metformin did not have a decreased rate of overall mortality (HR = 0.99; 95% CI, 0.79-1.25), mortality from cancer (HR = 1.04; 95% CI, 0.72-1.52), or mortality due to CVD (HR = 1.08; 95% CI, 0.70-1.66). Similarly, compared with the placebo group, lifestyle intervention did not decrease overall mortality (HR = 1.02; 95% CI, 0.81-1.28), mortality from cancer (HR = 1.07; 95% CI, 0.74-1.55), or mortality due to CVD (HR = 1.18; 95% CI, 0.77-1.81). Results were similar when adjusted for other factors, including out-of-study metformin use, T2D status and duration, BMI change, and other cardiovascular risk factors.

WHAT’S NEW

Long-term data clarifylimits to interventions’ utility

This study looked at long-term follow-up data on mortality outcomes for patients with prediabetes treated with metformin or lifestyle intervention. Although these interventions did support weight loss, reduce the incidence of T2D, and lower cardiovascular risk factors (eg, hypertension, dyslipidemia), the comorbidity benefits did not affect risk for all-cause or cause-specific mortality, which were similar between the treatment and placebo groups.

Continue to: CAVEATS

Exclusion criteria, residual confounding may limit the findings

Patients with significant cardiovascular or renal disease were excluded, so results may not apply to patients with these comorbidities. Additionally, there was a high amount of “drop-in” use of metformin prescribed by physicians once patients developed T2D, which may not have been controlled for completely. And while the intensive lifestyle intervention group had specific goals, the metformin and placebo groups also were encouraged to follow standard diet and lifestyle recommendations—and during a bridge period, all participants were offered a modified group lifestyle intervention. However, multivariable adjustment did not change the study conclusion.

CHALLENGES TO IMPLEMENTATION

Physicians may be unwilling to change their current prescribing habits

Physicians may not be willing to change their practice of prescribing metformin in prediabetes based on a singular study (with residual confounding) that showed no long-term mortality differences between the study groups. However, there may be long-term morbidity differences of interest to patients that were not specifically evaluated in this study—such as quality-of-life benefits from weight loss that may outweigh the risks (eg, gastrointestinal adverse effects such as diarrhea, nausea, and abdominal pain) of metformin for some patients. Therefore, a discussion of the risks and benefits of treatment for prediabetes should be had with patients at high risk who would prefer a pharmacologic intervention.

ILLUSTRATIVE CASE

A 51-year-old woman with a history of elevated cholesterol and a body mass index (BMI) of 31 presents to your clinic for a scheduled follow-up visit to review recent blood test results. Her A1C was elevated at 5.9%. She wants to know if she should start medication now.

Prediabetes is a high-risk state that ­confers increased risk for type 2 ­diabetes (T2D). It is identified by impaired fasting glucose (fasting plasma glucose [FPG], 100-125 mg/dL), impaired glucose tolerance (2-hour oral glucose tolerance test, 140-199 mg/dL), or an elevated A1C (between 5.7% and 6.4%).²

An estimated 96 million ­Americans—38% of the US adult population—have prediabetes, according to the Centers for Disease Control and Prevention.³ Family physicians frequently encounter this condition when screening for T2D in asymptomatic adults (ages 35 to 70 years) with overweight or obesity, as recommended by the US Preventive Services Task Force (grade “B”).⁴

To treat, or not? Studies have shown that interventions such as lifestyle modification and use of metformin by patients with prediabetes can decrease their risk for T2D.^5,6 In the Diabetes Prevention Program (DPP) study, progression from prediabetes to T2D was reduced to 14% with lifestyle modification and 22% with metformin use, vs 29% with placebo.⁷

However, there is disagreement about whether to treat prediabetes, particularly with medication. Some argue that metformin is a safe, effective, and cost-saving treatment to prevent T2D and its associated health consequences.⁸ The current American Diabetes Association (ADA) guidelines suggest that metformin be considered in certain patients with prediabetes and high-risk factors, especially younger age, obesity or hyperglycemia, or a history of gestational diabetes.⁹ However, only an estimated 1% to 4% of adults with prediabetes are prescribed metformin.¹⁰

Others argue that treating a preclinical condition is not a patient-centered approach, especially since not all patients with prediabetes progress to T2D and the risk for development or progression of retinopathy and microalbuminuria is extremely low if A1C levels remain < 7.0%.¹¹ By this standard, pharmacologic treatment should be initiated only if, or when, a patient develops T2D, with a focus on intensive lifestyle intervention for high-risk patients in the interim.¹¹

Given the conflicting viewpoints, ongoing long-term studies on T2D prevention will help guide treatment decisions for patients with prediabetes. The study by Lee et al¹ was the first to evaluate the effect of metformin or intensive lifestyle modification on all-cause and cause-specific mortality in patients at high risk for T2D.

Continue to: STUDY SUMMARY

No mortality benefit from metformin or lifestyle modification

This secondary analysis evaluated mortality outcomes for patients at risk for T2D who were part of the DPP trial and then were ­followed long term in the Diabetes Prevention Program Outcomes Study (DPPOS).¹ The initial DPP trial included 3234 adult patients at high risk for T2D (defined as having a BMI ≥ 24; an FPG of 95-125 mg/dL; and a 2-hour glucose level of 140-199 mg/dL). Participants were randomized into groups receiving either intensive lifestyle intervention (which focused on achieving ≥ 150 min/wk of exercise and ≥ 7% body weight loss), metformin 850 mg twice daily, or placebo twice daily; the latter 2 groups also received standard exercise and diet recommendations. Mean age was 51 years, mean BMI was 34, and 68% of participants were female.

Both the metformin and lifestyle intervention groups experienced decreases in weight and cardiovascular risk factors but not in mortality.

At the conclusion of the initial 5-year trial, treatment was unmasked and 86% of the patients continued to be followed for long-term outcomes. Patients in the lifestyle group were offered semiannual lifestyle reinforcement, while the metformin group continued to receive the twice-daily 850-mg dose unless a contraindication developed. If FPG levels increased to ≥ 140 mg/dL in the DPP study, or A1C increased to ≥ 7% in the DPPOS, study metformin was discontinued and management of the patient’s diabetes was transferred to their health care provider. By the end of the DPPOS, 53% of patients in the lifestyle group and 55% in the metformin group had progressed to T2D, compared with 60% in the placebo group (P = 0.003).

After a median 21-year follow-up interval, the investigators collected data on cause of death for patients and evaluated hazard ratios (HRs) for overall and cause-specific mortality. In total, 14% of the participants died, with no statistically significant difference in rates between the 3 groups. Cancer (37%) was the leading cause of death in all groups, followed by cardiovascular disease (CVD; 29%).

Compared with the placebo group, patients taking metformin did not have a decreased rate of overall mortality (HR = 0.99; 95% CI, 0.79-1.25), mortality from cancer (HR = 1.04; 95% CI, 0.72-1.52), or mortality due to CVD (HR = 1.08; 95% CI, 0.70-1.66). Similarly, compared with the placebo group, lifestyle intervention did not decrease overall mortality (HR = 1.02; 95% CI, 0.81-1.28), mortality from cancer (HR = 1.07; 95% CI, 0.74-1.55), or mortality due to CVD (HR = 1.18; 95% CI, 0.77-1.81). Results were similar when adjusted for other factors, including out-of-study metformin use, T2D status and duration, BMI change, and other cardiovascular risk factors.

WHAT’S NEW

Long-term data clarifylimits to interventions’ utility

This study looked at long-term follow-up data on mortality outcomes for patients with prediabetes treated with metformin or lifestyle intervention. Although these interventions did support weight loss, reduce the incidence of T2D, and lower cardiovascular risk factors (eg, hypertension, dyslipidemia), the comorbidity benefits did not affect risk for all-cause or cause-specific mortality, which were similar between the treatment and placebo groups.

Continue to: CAVEATS

Exclusion criteria, residual confounding may limit the findings

Patients with significant cardiovascular or renal disease were excluded, so results may not apply to patients with these comorbidities. Additionally, there was a high amount of “drop-in” use of metformin prescribed by physicians once patients developed T2D, which may not have been controlled for completely. And while the intensive lifestyle intervention group had specific goals, the metformin and placebo groups also were encouraged to follow standard diet and lifestyle recommendations—and during a bridge period, all participants were offered a modified group lifestyle intervention. However, multivariable adjustment did not change the study conclusion.

CHALLENGES TO IMPLEMENTATION

Physicians may be unwilling to change their current prescribing habits

Physicians may not be willing to change their practice of prescribing metformin in prediabetes based on a singular study (with residual confounding) that showed no long-term mortality differences between the study groups. However, there may be long-term morbidity differences of interest to patients that were not specifically evaluated in this study—such as quality-of-life benefits from weight loss that may outweigh the risks (eg, gastrointestinal adverse effects such as diarrhea, nausea, and abdominal pain) of metformin for some patients. Therefore, a discussion of the risks and benefits of treatment for prediabetes should be had with patients at high risk who would prefer a pharmacologic intervention.

Evidence summary

Naltrexone is comparable to amitriptyline for diabetic neuropathy pain

A 2021 randomized, double-blind, active-comparator, crossover clinical trial conducted in India examined the efficacy of low-dose naltrexone vs standard-of-care amitriptyline in patients (N = 67) with painful diabetic neuropathy. Participants were adults (ages 18 to 75 years) with painful diabetic neuropathy who had been on a stable dose of nonopioid pain medication for at least 1 month.¹

Patients were randomly assigned to start receiving naltrexone 2 mg (n = 33) or amitriptyline 10 mg (n = 34). They received their starting medication for 6 weeks (with follow-up every 2 weeks), then completed a 2-week washout period, and then switched to the other study medication for 6 weeks (same follow-up schedule). If patients reported < 20% pain reduction on the Visual Analog Scale (VAS; 0-100 scoring system with 0 = no pain and 100 = worst pain) at a follow-up visit, their medication dose was titrated up, to a maximum of 4 mg of naltrexone or 25 to 50 mg of amitriptyline.¹

The primary outcome of interest was the mean change in VAS pain score following 6 weeks of treatment. There was no statistically different change from baseline VAS pain score between the amitriptyline and nal­trexone groups (mean difference [MD] = 1.6; 95% CI, –0.9 to 4.2; P = 0.21). These findings were consistent across the secondary endpoints (Likert 5-point pain scale and McGill Pain Questionnaire scores). There was no statistically significant difference in Hamilton Depression Rating Scale scores (13 in the naltrexone group vs 11 in the amitriptyline group; P = .81), no reports of decreased sleep quality in either group, and no significant difference in Patients’ Global Impression of Change scores at 6-week evaluation.¹

The naltrexone cohort experienced 8 adverse events (most commonly, mild diarrhea), while the amitriptyline cohort experienced 52 adverse events (most commonly, somnolence) (P < .001). The limitations of the study include the lack of a placebo arm and a relatively small sample size.¹

Greater reduction in pain scores with naltrexone

A 2022 retrospective cohort study evaluated the effectiveness of naltrexone for patients treated at a single outpatient integrative pain management practice in Alaska between 2014 and 2019. The exposure group (n = 36) included patients who had completed at least a 2-month continuous regimen of oral naltrexone 4.5 mg. Controls (n = 42) were selected from the remaining practice population receiving standard care and were primarily matched by diagnosis code, followed by gender, then age +/– 5 years. Patients were divided into subgroups for inflammatory and neuropathic pain.²

The primary outcome measured was the mean change in VAS score or numeric rating score (NRS; both used a 1-10 rating system), which was assessed during a patient’s appointment from initiation of treatment to the most recent visit or at the termination of therapy (intervention interquartile range, 12-14 months). There was no statistically significant difference in VAS/NRS between the low-dose naltrexone and control groups at baseline (6.09 vs 6.38; P = .454). The low-dose naltrexone group experienced a greater reduction in VAS/NRS pain scores compared to the control group (–37.8% vs –4.3%; P < .001).²

Compared with control patients in each group, patients in the inflammatory pain subgroup and the neuropathic pain subgroup who received low-dose naltrexone reported reductions in pain scores of 32% (P < .001) and 44% (P = .048), respectively. There was no statistically significant difference in mean change in VAS/NRS scores between the inflammatory and neuropathic subgroups (P = .763). A multivariate linear regression analysis did not identify significant variables other than low-dose naltrexone that correlated with pain improvement. The number needed to treat to observe a ≥ 50% reduction in pain scores was 3.2.²

Continue to: Limitations for this study...

Limitations for this study include its small sample size and open-label design.²

Low-dose naltrexone is effective for fibromyalgia pain

A 2020 single-blind prospective dose-­response study utilized the up-and-down method to identify effective naltrexone dose for patients in a Danish university hospital pain clinic. Patients were White women ages 18 to 60 years (N = 25) who had a diagnosis of fibromyalgia unresponsive to traditional pharmacologic treatment. All patients received treatment with low-dose naltrexone (ranging from 0.75 mg to 6.0 mg) but were blinded to dose.³

Studies show that low-dose naltrexone has some effectiveness in a variety of pain conditions—including diabetic neuropathy and fibromyalgia—with few adverse effects.

Patients were evaluated for improvement in fibromyalgia symptoms using the Patient Global Impression of Improvement (PGI-I) scale—which ranges from 1 (very much improved) to 7 (very much worse), with 4 being “no change”—at baseline and after 2 to 3 weeks of treatment with low-dose naltrexone. A patient was considered a responder if they scored 1 to 3 on the follow-up PGI-I scale or if they experienced a > 30% pain reduction on the VAS. If a patient did not respond to their dose, the next patient began treatment at a dose 0.75 mg higher than the previous patient’s ending dose. If a patient did respond to low-dose naltrexone treatment, the next patient’s starting dose was 0.75 mg less than the previous patient’s. Eleven of 25 patients were considered responders.³

The primary outcomes were effective dose for 50% of fibromyalgia patients (3.88 mg; 95% CI, 3.39-4.35) and effective dose for 95% of fibromyalgia patients (5.4 mg; 95% CI, 4.66-6.13). Secondary outcomes were fibromyalgia symptoms as evaluated on the Fibromyalgia Impact Questionnaire Revised. Five of the 11 responders reported a > 30% improvement in tenderness and 8 of the 11 responders reported a > 30% decrease in waking unrefreshed.³

Limitations of the study include the short time period of treatment before response was assessed and the decision to use low test ­doses, which may have hindered detection of effective doses > 6 mg in fibromyalgia.³

Editor’s takeaway

Low-dose naltrexone, a less-often-used form of pain management, is a welcome option. Studies show some effectiveness in a variety of pain conditions with few adverse effects. The small number of studies, the small sample sizes, and the limited follow-up duration should encourage more investigation into how to best use this intervention.

Evidence summary

Naltrexone is comparable to amitriptyline for diabetic neuropathy pain

A 2021 randomized, double-blind, active-comparator, crossover clinical trial conducted in India examined the efficacy of low-dose naltrexone vs standard-of-care amitriptyline in patients (N = 67) with painful diabetic neuropathy. Participants were adults (ages 18 to 75 years) with painful diabetic neuropathy who had been on a stable dose of nonopioid pain medication for at least 1 month.¹

Patients were randomly assigned to start receiving naltrexone 2 mg (n = 33) or amitriptyline 10 mg (n = 34). They received their starting medication for 6 weeks (with follow-up every 2 weeks), then completed a 2-week washout period, and then switched to the other study medication for 6 weeks (same follow-up schedule). If patients reported < 20% pain reduction on the Visual Analog Scale (VAS; 0-100 scoring system with 0 = no pain and 100 = worst pain) at a follow-up visit, their medication dose was titrated up, to a maximum of 4 mg of naltrexone or 25 to 50 mg of amitriptyline.¹

The primary outcome of interest was the mean change in VAS pain score following 6 weeks of treatment. There was no statistically different change from baseline VAS pain score between the amitriptyline and nal­trexone groups (mean difference [MD] = 1.6; 95% CI, –0.9 to 4.2; P = 0.21). These findings were consistent across the secondary endpoints (Likert 5-point pain scale and McGill Pain Questionnaire scores). There was no statistically significant difference in Hamilton Depression Rating Scale scores (13 in the naltrexone group vs 11 in the amitriptyline group; P = .81), no reports of decreased sleep quality in either group, and no significant difference in Patients’ Global Impression of Change scores at 6-week evaluation.¹

The naltrexone cohort experienced 8 adverse events (most commonly, mild diarrhea), while the amitriptyline cohort experienced 52 adverse events (most commonly, somnolence) (P < .001). The limitations of the study include the lack of a placebo arm and a relatively small sample size.¹

Greater reduction in pain scores with naltrexone

A 2022 retrospective cohort study evaluated the effectiveness of naltrexone for patients treated at a single outpatient integrative pain management practice in Alaska between 2014 and 2019. The exposure group (n = 36) included patients who had completed at least a 2-month continuous regimen of oral naltrexone 4.5 mg. Controls (n = 42) were selected from the remaining practice population receiving standard care and were primarily matched by diagnosis code, followed by gender, then age +/– 5 years. Patients were divided into subgroups for inflammatory and neuropathic pain.²

The primary outcome measured was the mean change in VAS score or numeric rating score (NRS; both used a 1-10 rating system), which was assessed during a patient’s appointment from initiation of treatment to the most recent visit or at the termination of therapy (intervention interquartile range, 12-14 months). There was no statistically significant difference in VAS/NRS between the low-dose naltrexone and control groups at baseline (6.09 vs 6.38; P = .454). The low-dose naltrexone group experienced a greater reduction in VAS/NRS pain scores compared to the control group (–37.8% vs –4.3%; P < .001).²

Compared with control patients in each group, patients in the inflammatory pain subgroup and the neuropathic pain subgroup who received low-dose naltrexone reported reductions in pain scores of 32% (P < .001) and 44% (P = .048), respectively. There was no statistically significant difference in mean change in VAS/NRS scores between the inflammatory and neuropathic subgroups (P = .763). A multivariate linear regression analysis did not identify significant variables other than low-dose naltrexone that correlated with pain improvement. The number needed to treat to observe a ≥ 50% reduction in pain scores was 3.2.²

Continue to: Limitations for this study...

Limitations for this study include its small sample size and open-label design.²

Low-dose naltrexone is effective for fibromyalgia pain

A 2020 single-blind prospective dose-­response study utilized the up-and-down method to identify effective naltrexone dose for patients in a Danish university hospital pain clinic. Patients were White women ages 18 to 60 years (N = 25) who had a diagnosis of fibromyalgia unresponsive to traditional pharmacologic treatment. All patients received treatment with low-dose naltrexone (ranging from 0.75 mg to 6.0 mg) but were blinded to dose.³

Studies show that low-dose naltrexone has some effectiveness in a variety of pain conditions—including diabetic neuropathy and fibromyalgia—with few adverse effects.

Patients were evaluated for improvement in fibromyalgia symptoms using the Patient Global Impression of Improvement (PGI-I) scale—which ranges from 1 (very much improved) to 7 (very much worse), with 4 being “no change”—at baseline and after 2 to 3 weeks of treatment with low-dose naltrexone. A patient was considered a responder if they scored 1 to 3 on the follow-up PGI-I scale or if they experienced a > 30% pain reduction on the VAS. If a patient did not respond to their dose, the next patient began treatment at a dose 0.75 mg higher than the previous patient’s ending dose. If a patient did respond to low-dose naltrexone treatment, the next patient’s starting dose was 0.75 mg less than the previous patient’s. Eleven of 25 patients were considered responders.³

The primary outcomes were effective dose for 50% of fibromyalgia patients (3.88 mg; 95% CI, 3.39-4.35) and effective dose for 95% of fibromyalgia patients (5.4 mg; 95% CI, 4.66-6.13). Secondary outcomes were fibromyalgia symptoms as evaluated on the Fibromyalgia Impact Questionnaire Revised. Five of the 11 responders reported a > 30% improvement in tenderness and 8 of the 11 responders reported a > 30% decrease in waking unrefreshed.³

Limitations of the study include the short time period of treatment before response was assessed and the decision to use low test ­doses, which may have hindered detection of effective doses > 6 mg in fibromyalgia.³

Editor’s takeaway

Low-dose naltrexone, a less-often-used form of pain management, is a welcome option. Studies show some effectiveness in a variety of pain conditions with few adverse effects. The small number of studies, the small sample sizes, and the limited follow-up duration should encourage more investigation into how to best use this intervention.

Evidence summary

Naltrexone is comparable to amitriptyline for diabetic neuropathy pain

A 2021 randomized, double-blind, active-comparator, crossover clinical trial conducted in India examined the efficacy of low-dose naltrexone vs standard-of-care amitriptyline in patients (N = 67) with painful diabetic neuropathy. Participants were adults (ages 18 to 75 years) with painful diabetic neuropathy who had been on a stable dose of nonopioid pain medication for at least 1 month.¹

Patients were randomly assigned to start receiving naltrexone 2 mg (n = 33) or amitriptyline 10 mg (n = 34). They received their starting medication for 6 weeks (with follow-up every 2 weeks), then completed a 2-week washout period, and then switched to the other study medication for 6 weeks (same follow-up schedule). If patients reported < 20% pain reduction on the Visual Analog Scale (VAS; 0-100 scoring system with 0 = no pain and 100 = worst pain) at a follow-up visit, their medication dose was titrated up, to a maximum of 4 mg of naltrexone or 25 to 50 mg of amitriptyline.¹

The primary outcome of interest was the mean change in VAS pain score following 6 weeks of treatment. There was no statistically different change from baseline VAS pain score between the amitriptyline and nal­trexone groups (mean difference [MD] = 1.6; 95% CI, –0.9 to 4.2; P = 0.21). These findings were consistent across the secondary endpoints (Likert 5-point pain scale and McGill Pain Questionnaire scores). There was no statistically significant difference in Hamilton Depression Rating Scale scores (13 in the naltrexone group vs 11 in the amitriptyline group; P = .81), no reports of decreased sleep quality in either group, and no significant difference in Patients’ Global Impression of Change scores at 6-week evaluation.¹

The naltrexone cohort experienced 8 adverse events (most commonly, mild diarrhea), while the amitriptyline cohort experienced 52 adverse events (most commonly, somnolence) (P < .001). The limitations of the study include the lack of a placebo arm and a relatively small sample size.¹

Greater reduction in pain scores with naltrexone

A 2022 retrospective cohort study evaluated the effectiveness of naltrexone for patients treated at a single outpatient integrative pain management practice in Alaska between 2014 and 2019. The exposure group (n = 36) included patients who had completed at least a 2-month continuous regimen of oral naltrexone 4.5 mg. Controls (n = 42) were selected from the remaining practice population receiving standard care and were primarily matched by diagnosis code, followed by gender, then age +/– 5 years. Patients were divided into subgroups for inflammatory and neuropathic pain.²

The primary outcome measured was the mean change in VAS score or numeric rating score (NRS; both used a 1-10 rating system), which was assessed during a patient’s appointment from initiation of treatment to the most recent visit or at the termination of therapy (intervention interquartile range, 12-14 months). There was no statistically significant difference in VAS/NRS between the low-dose naltrexone and control groups at baseline (6.09 vs 6.38; P = .454). The low-dose naltrexone group experienced a greater reduction in VAS/NRS pain scores compared to the control group (–37.8% vs –4.3%; P < .001).²

Compared with control patients in each group, patients in the inflammatory pain subgroup and the neuropathic pain subgroup who received low-dose naltrexone reported reductions in pain scores of 32% (P < .001) and 44% (P = .048), respectively. There was no statistically significant difference in mean change in VAS/NRS scores between the inflammatory and neuropathic subgroups (P = .763). A multivariate linear regression analysis did not identify significant variables other than low-dose naltrexone that correlated with pain improvement. The number needed to treat to observe a ≥ 50% reduction in pain scores was 3.2.²

Continue to: Limitations for this study...

Limitations for this study include its small sample size and open-label design.²

Low-dose naltrexone is effective for fibromyalgia pain

A 2020 single-blind prospective dose-­response study utilized the up-and-down method to identify effective naltrexone dose for patients in a Danish university hospital pain clinic. Patients were White women ages 18 to 60 years (N = 25) who had a diagnosis of fibromyalgia unresponsive to traditional pharmacologic treatment. All patients received treatment with low-dose naltrexone (ranging from 0.75 mg to 6.0 mg) but were blinded to dose.³

Studies show that low-dose naltrexone has some effectiveness in a variety of pain conditions—including diabetic neuropathy and fibromyalgia—with few adverse effects.

Patients were evaluated for improvement in fibromyalgia symptoms using the Patient Global Impression of Improvement (PGI-I) scale—which ranges from 1 (very much improved) to 7 (very much worse), with 4 being “no change”—at baseline and after 2 to 3 weeks of treatment with low-dose naltrexone. A patient was considered a responder if they scored 1 to 3 on the follow-up PGI-I scale or if they experienced a > 30% pain reduction on the VAS. If a patient did not respond to their dose, the next patient began treatment at a dose 0.75 mg higher than the previous patient’s ending dose. If a patient did respond to low-dose naltrexone treatment, the next patient’s starting dose was 0.75 mg less than the previous patient’s. Eleven of 25 patients were considered responders.³

The primary outcomes were effective dose for 50% of fibromyalgia patients (3.88 mg; 95% CI, 3.39-4.35) and effective dose for 95% of fibromyalgia patients (5.4 mg; 95% CI, 4.66-6.13). Secondary outcomes were fibromyalgia symptoms as evaluated on the Fibromyalgia Impact Questionnaire Revised. Five of the 11 responders reported a > 30% improvement in tenderness and 8 of the 11 responders reported a > 30% decrease in waking unrefreshed.³

Limitations of the study include the short time period of treatment before response was assessed and the decision to use low test ­doses, which may have hindered detection of effective doses > 6 mg in fibromyalgia.³

Editor’s takeaway

Low-dose naltrexone, a less-often-used form of pain management, is a welcome option. Studies show some effectiveness in a variety of pain conditions with few adverse effects. The small number of studies, the small sample sizes, and the limited follow-up duration should encourage more investigation into how to best use this intervention.

Low-dose aspirin reduces the risk for type 2 diabetes among older adults and slows the increase in fasting glucose levels over time, new research finds.

The data come from a secondary analysis of ASPREE, a double-blind, placebo-controlled trial of healthy adults aged 65 years or older, showing that 100 mg of aspirin taken daily for about 5 years did not provide a cardiovascular benefit but did significantly raise the risk for bleeding.

This new analysis shows that individuals taking aspirin had a 15% lower risk for developing type 2 diabetes and that the medication slowed the rate of increase in fasting plasma glucose, compared with placebo, during follow-up.

However, lead author Sophia Zoungas, MBBS, PhD, head of the School of Public Health and Preventive Medicine, Monash University, Melbourne, said: “Major prescribing guidelines now recommend older adults take daily aspirin only when there is a medical reason to do so, such as after a heart attack. ... Although these new findings are of interest, they do not change the clinical advice about aspirin use in older people at this time.”

Nonetheless, she said in an interview, “at this time, our findings are exploratory but ignite the debate of the important role that anti-inflammatory approaches may play in preventing diabetes. Further work is currently underway to understand which subpopulations may be better targeted and to understand the balance of risk versus benefit.”

The results are scheduled to be presented at the upcoming meeting of the European Association for the Study of Diabetes, taking place Oct. 2-6 in Hamburg, Germany.
 

New findings not robust enough to change current practice

Asked to comment, Debabrata Mukherjee, MD, said: “Given the post hoc secondary nature of the analysis, the findings should be considered hypothesis generating and not definitive… At this time, based on prospective randomized studies, the risks of aspirin outweigh the benefits for aspirin in older adults.”

Among those studies was an ASPREE substudy showing failure of low-dose aspirin to reduce fracture risk while increasing the risk for serious falls, and two other trials, ARRIVE and ASCEND, also showing that harms of aspirin outweigh the benefits in people with cardiovascular risk but not diabetes, and in those with diabetes, respectively, said Dr. Mukherjee, professor and chair of the department of internal medicine at Texas Tech University Health Sciences Center at El Paso.

And, Mukherjee noted, in 2019 the American College of Cardiology updated its practice guidelines to say that low-dose aspirin should not be administered on a routine basis for the primary prevention of atherosclerotic cardiovascular disease in adults over age 70. In 2021, the American Diabetes Association seconded that recommendation.

Asked whether these newest findings might change current practice for any higher-risk subgroup, such as people with prediabetes, Dr. Mukherjee replied: “Unless there is a prospective randomized trial that validates these findings in those with prediabetes, the findings should not change practice. There are also no data [showing] that another antiplatelet agent would be indicated or would be beneficial. Instead, I would recommend lifestyle changes including regular exercise and a healthy diet to minimize risk of diabetes.”

The 16,209 ASPREE participants were community dwelling and did not have diabetes, cardiovascular disease, or dementia at baseline. They were randomized in a 1:1 ratio to receive 100 mg/d of enteric-coated aspirin or placebo. Over a median follow-up of 4.7 years, the proportions developing type 2 diabetes were 5.7% with aspirin versus 6.6% with placebo (hazard ratio, 0.85; P = .01).

The annual rate of increase in fasting plasma glucose over the follow-up period was slowed by 0.006 mmol/L with aspirin, compared with placebo, also a significant difference (P = .004).

According to Dr. Zoungas, “the potential for anti-inflammatory agents like aspirin to prevent type 2 diabetes or improve glucose levels needs further study.”

The ASPREE trial was supported by the U.S. National Institutes of Health, the National Health and Medical Research Council of Australia, Monash University, and the Victorian Cancer Agency. Dr. Zoungas and Dr. Mukherjee have no disclosures.

A version of this article first appeared on Medscape.com.

Low-dose aspirin reduces the risk for type 2 diabetes among older adults and slows the increase in fasting glucose levels over time, new research finds.

The data come from a secondary analysis of ASPREE, a double-blind, placebo-controlled trial of healthy adults aged 65 years or older, showing that 100 mg of aspirin taken daily for about 5 years did not provide a cardiovascular benefit but did significantly raise the risk for bleeding.

This new analysis shows that individuals taking aspirin had a 15% lower risk for developing type 2 diabetes and that the medication slowed the rate of increase in fasting plasma glucose, compared with placebo, during follow-up.

However, lead author Sophia Zoungas, MBBS, PhD, head of the School of Public Health and Preventive Medicine, Monash University, Melbourne, said: “Major prescribing guidelines now recommend older adults take daily aspirin only when there is a medical reason to do so, such as after a heart attack. ... Although these new findings are of interest, they do not change the clinical advice about aspirin use in older people at this time.”

Nonetheless, she said in an interview, “at this time, our findings are exploratory but ignite the debate of the important role that anti-inflammatory approaches may play in preventing diabetes. Further work is currently underway to understand which subpopulations may be better targeted and to understand the balance of risk versus benefit.”

The results are scheduled to be presented at the upcoming meeting of the European Association for the Study of Diabetes, taking place Oct. 2-6 in Hamburg, Germany.
 

New findings not robust enough to change current practice

Asked to comment, Debabrata Mukherjee, MD, said: “Given the post hoc secondary nature of the analysis, the findings should be considered hypothesis generating and not definitive… At this time, based on prospective randomized studies, the risks of aspirin outweigh the benefits for aspirin in older adults.”

Among those studies was an ASPREE substudy showing failure of low-dose aspirin to reduce fracture risk while increasing the risk for serious falls, and two other trials, ARRIVE and ASCEND, also showing that harms of aspirin outweigh the benefits in people with cardiovascular risk but not diabetes, and in those with diabetes, respectively, said Dr. Mukherjee, professor and chair of the department of internal medicine at Texas Tech University Health Sciences Center at El Paso.

And, Mukherjee noted, in 2019 the American College of Cardiology updated its practice guidelines to say that low-dose aspirin should not be administered on a routine basis for the primary prevention of atherosclerotic cardiovascular disease in adults over age 70. In 2021, the American Diabetes Association seconded that recommendation.

Asked whether these newest findings might change current practice for any higher-risk subgroup, such as people with prediabetes, Dr. Mukherjee replied: “Unless there is a prospective randomized trial that validates these findings in those with prediabetes, the findings should not change practice. There are also no data [showing] that another antiplatelet agent would be indicated or would be beneficial. Instead, I would recommend lifestyle changes including regular exercise and a healthy diet to minimize risk of diabetes.”

The 16,209 ASPREE participants were community dwelling and did not have diabetes, cardiovascular disease, or dementia at baseline. They were randomized in a 1:1 ratio to receive 100 mg/d of enteric-coated aspirin or placebo. Over a median follow-up of 4.7 years, the proportions developing type 2 diabetes were 5.7% with aspirin versus 6.6% with placebo (hazard ratio, 0.85; P = .01).

The annual rate of increase in fasting plasma glucose over the follow-up period was slowed by 0.006 mmol/L with aspirin, compared with placebo, also a significant difference (P = .004).

According to Dr. Zoungas, “the potential for anti-inflammatory agents like aspirin to prevent type 2 diabetes or improve glucose levels needs further study.”

The ASPREE trial was supported by the U.S. National Institutes of Health, the National Health and Medical Research Council of Australia, Monash University, and the Victorian Cancer Agency. Dr. Zoungas and Dr. Mukherjee have no disclosures.

A version of this article first appeared on Medscape.com.

Low-dose aspirin reduces the risk for type 2 diabetes among older adults and slows the increase in fasting glucose levels over time, new research finds.

The data come from a secondary analysis of ASPREE, a double-blind, placebo-controlled trial of healthy adults aged 65 years or older, showing that 100 mg of aspirin taken daily for about 5 years did not provide a cardiovascular benefit but did significantly raise the risk for bleeding.

This new analysis shows that individuals taking aspirin had a 15% lower risk for developing type 2 diabetes and that the medication slowed the rate of increase in fasting plasma glucose, compared with placebo, during follow-up.

However, lead author Sophia Zoungas, MBBS, PhD, head of the School of Public Health and Preventive Medicine, Monash University, Melbourne, said: “Major prescribing guidelines now recommend older adults take daily aspirin only when there is a medical reason to do so, such as after a heart attack. ... Although these new findings are of interest, they do not change the clinical advice about aspirin use in older people at this time.”

Nonetheless, she said in an interview, “at this time, our findings are exploratory but ignite the debate of the important role that anti-inflammatory approaches may play in preventing diabetes. Further work is currently underway to understand which subpopulations may be better targeted and to understand the balance of risk versus benefit.”

The results are scheduled to be presented at the upcoming meeting of the European Association for the Study of Diabetes, taking place Oct. 2-6 in Hamburg, Germany.
 

New findings not robust enough to change current practice

Asked to comment, Debabrata Mukherjee, MD, said: “Given the post hoc secondary nature of the analysis, the findings should be considered hypothesis generating and not definitive… At this time, based on prospective randomized studies, the risks of aspirin outweigh the benefits for aspirin in older adults.”

Among those studies was an ASPREE substudy showing failure of low-dose aspirin to reduce fracture risk while increasing the risk for serious falls, and two other trials, ARRIVE and ASCEND, also showing that harms of aspirin outweigh the benefits in people with cardiovascular risk but not diabetes, and in those with diabetes, respectively, said Dr. Mukherjee, professor and chair of the department of internal medicine at Texas Tech University Health Sciences Center at El Paso.

And, Mukherjee noted, in 2019 the American College of Cardiology updated its practice guidelines to say that low-dose aspirin should not be administered on a routine basis for the primary prevention of atherosclerotic cardiovascular disease in adults over age 70. In 2021, the American Diabetes Association seconded that recommendation.

Asked whether these newest findings might change current practice for any higher-risk subgroup, such as people with prediabetes, Dr. Mukherjee replied: “Unless there is a prospective randomized trial that validates these findings in those with prediabetes, the findings should not change practice. There are also no data [showing] that another antiplatelet agent would be indicated or would be beneficial. Instead, I would recommend lifestyle changes including regular exercise and a healthy diet to minimize risk of diabetes.”

The 16,209 ASPREE participants were community dwelling and did not have diabetes, cardiovascular disease, or dementia at baseline. They were randomized in a 1:1 ratio to receive 100 mg/d of enteric-coated aspirin or placebo. Over a median follow-up of 4.7 years, the proportions developing type 2 diabetes were 5.7% with aspirin versus 6.6% with placebo (hazard ratio, 0.85; P = .01).

The annual rate of increase in fasting plasma glucose over the follow-up period was slowed by 0.006 mmol/L with aspirin, compared with placebo, also a significant difference (P = .004).

According to Dr. Zoungas, “the potential for anti-inflammatory agents like aspirin to prevent type 2 diabetes or improve glucose levels needs further study.”

The ASPREE trial was supported by the U.S. National Institutes of Health, the National Health and Medical Research Council of Australia, Monash University, and the Victorian Cancer Agency. Dr. Zoungas and Dr. Mukherjee have no disclosures.

A version of this article first appeared on Medscape.com.

It’s an ongoing debate in the diabetes world: Is it ideal to consume a very-low-carbohydrate diet, or is it better to go with moderate amounts of healthful carbs?

At the annual scientific sessions of the American Diabetes Association, Carol F. Kirkpatrick, PhD, RDN, spoke first, arguing in favor of diets consisting of moderate, high-quality carbohydrates.

Dina Hafez Griauzde, MD, countered that very-low-carbohydrate diets are more beneficial for people with diabetes, primarily type 2 diabetes.

Both speakers based their arguments on published evidence but agreed in the end that discussion with patients about individual dietary preferences should play a major role in the ultimate decision.
 

Moderate-carbohydrate eating is best

Dr. Kirkpatrick began by explaining that definitions of “low carb” vary in the literature, which makes comparisons between studies difficult. On the basis of a 2019 review that she coauthored, “moderate” carbohydrate consumption was defined as a diet in which 26%-44% of total daily calories are from carbohydrates. “Low” carbohydrate consumption was defined as a diet in which 10%-25% of calories were from carbohydrates. Consuming less than 10% was defined as a very-low-carbohydrate diet (i.e., a ketogenic diet).

Across studies, she noted, the literature shows that within the first 6 months weight loss is typically greater with carbohydrate-restricted diets than with higher-carbohydrate diets, but that by 1 year and beyond weight loss is similar.

“That can be partly due to the difficulty in people maintaining that very severe dietary restriction, although ... we can all acknowledge that it’s difficult for patients to adhere to any dietary pattern, so for sure by 12 months, the difference in the weight loss is gone between the two,” said Dr. Kirkpatrick, of Midwest Biomedical Research, Pocatello, Idaho.

In a recent meta-analysis of 35 trials that examined the dose-dependent effects of carbohydrate restriction for patients with type 2 diabetes, there was a significant decrease in weight as carbohydrates were reduced. But by 12 months (17 trials), the greatest weight reduction was seen at 35% carbohydrate intake.

“It may just be that people were able to adhere to that moderate intake better,” she explained.

Regarding lipids, in her 2019 review and in several meta-analyses since, the effects on low-density lipoprotein cholesterol (LDL-C) varied. For some patients, adhering to a low-carb diet led to reductions in LDL-C, especially if the participants also lost weight, whereas in other patients, a low-carb diet led to an increase in LDL-C.

Either way, a high intake of saturated fatty acids is key to an increase in LDL-C, Dr. Kirkpatrick noted. “So, it’s important that, if a patient chooses to follow a very low carbohydrate diet or any kind of dietary pattern that restricts carbohydrate, that they replace the carbohydrate with unsaturated fat and not saturated fatty acid foods to avoid that increase in LDL-C.”

Generally, the evidence also shows that carbohydrate restriction typically leads to lower triglyceride levels and higher high-density lipoprotein (HDL) cholesterol levels. However, the same meta-analysis showed that the greatest reduction in LDL-C occurred at about 40% carbohydrate consumption.

Another recent meta-analysis showed that LDL-C rose significantly by an average 12.4 mg/dL with very-low-carb (3%-30%) diets, but only slightly, by 0.4 mg/dL, with moderate carb (40%-45%) intake.

Consuming very-low-carb diets did lead to greater reductions in triglycerides, compared with consuming moderate carb diets (23.9 mg/dL vs. 8.9 mg/dL).

“However, in terms of cardiovascular health, we are not entirely sure what that means. ... We have to look at the overall results in the presence of both triglyceride lowering as well as LDL cholesterol,” Dr. Kirkpatrick noted.

Carbohydrate restriction did consistently lead to lower hemoglobin A1c levels by an average of 0.4, 0.6, and 1.0 percentage points at 6 months for diets of 40%, 30%, and 15% carbohydrate, respectively. However, by 12 months, the effect had waned to 0.15, 0.2, and 0.4 A1c percentage points.

“Again, carbohydrate restriction, especially severe, is difficult for people to adhere to, and moderate carbohydrate intake would allow our patients to consume an appropriate amount of carbohydrate and still achieve improved glycemic control,” Dr. Kirkpatrick said.

Two large randomized controlled trials – PREDIMED and CORDIOPREV – examined the effects of the Mediterranean diet on cardiovascular disease prevention. Both showed a decrease in cardiovascular events with the Mediterranean diet, which involves consuming moderate amounts of carbohydrates.

“The Mediterranean dietary pattern has the strongest evidence for benefit, and it’s moderate in carbohydrates,” she concluded.
 

Very-low-carbohydrate eating is best

Dr. Griauzde was a last-minute replacement speaker for William S. Yancy Jr, MD, of Duke University, Durham, N.C., and presented his slides. She argued that consuming a very low carb diet improves glycemia and that it does not increase but possibly lowers cardiovascular risk.

She began by noting that prior to the discovery of insulin very-low-carb diets had been consumed for over a century to prolong life for people with type 1 diabetes.

“We have long recognized the deleterious role of carbohydrate in type 1 diabetes management, and we have increasingly recognized that role in the management of type 2 diabetes,” said Dr. Griauzde of the University of Michigan in Ann Arbor.

In a small study that compared maintaining a very-low-carb diet for 2 weeks with maintaining a high-carb diet for 2 weeks, total glucose areas under the curve were substantially lower (P < .05) during the low-carb phase, while A1c levels dropped from 7.3% to 6.8% (P = .006).

“We don’t see those outcomes with meds,” Dr. Griauzde noted, adding, “A diet very low in carbohydrates is one of the most potent tools we have to help our patients achieve glycemic control.”

Dr. Griauzde said that the carbohydrate-insulin model provides an explanation for why dietary carbohydrates are particularly obesogenic and metabolically harmful. That model contrasts with the energy balance model, which suggests that all calories are equal.

The rationale of the carbohydrate-insulin model is that dietary carbohydrate – either sugar or starch – raises serum glucose and insulin levels. A carbohydrate-restricted diet therefore reduces the dietary contribution to serum glucose, which then results in lower insulin levels. Insulin is a potent stimulator of lipogenesis (fat storage), and it is a potent inhibitor of lipolysis (the burning of fat). By lowering insulin levels, stored body fat is burned, serum ketone levels increase, and body weight is lowered.

This model suggests that, when insulin levels are chronically high because of excess carbohydrate consumption, circulating fuels are lowered, which leads to an increase in hunger and to overeating. This was demonstrated in a study that compared different levels of isocaloric glycemic index diets in 12 teenage boys with overweight or obesity. The higher-carbohydrate meals led to higher glucose and insulin levels and more food consumption.

In a systematic review of 13 trials of restricted-carbohydrate diets (< 45% carbohydrates) for adults with diabetes, the degree of improvement in A1c level correlated with the degree of carbohydrate restriction over 2-26 weeks (P = .013).

And in a network meta-analysis of 56 trials that compared nine diets among a total of 4,937 participants with type 2 diabetes, one conclusion was that “for reducing A1c, the low-carbohydrate diet was ranked as the best dietary approach (SUCRA: 84%), followed by the Mediterranean diet (80%), and Paleolithic diet (76%), compared with a control diet.”

Regarding the criticism that very-low-carbohydrate diets are high in saturated fat and therefore raise the risk of cardiovascular disease, Dr. Griauzde pointed to another meta-analysis of 21 prospective studies with more than 300,000 participants with 5-25 years of follow-up. In that analysis, the intake of saturated fat was not associated with an increased risk of cardiovascular disease or stroke.

Furthermore, a 12-week randomized controlled trial that involved 40 adults with overweight also suggested that a very-low-carb diet may be superior to a low-fat diet in improving aspects of the metabolic syndrome, including body mass index, lipid levels, and insulin sensitivity. Small LDL particles, which are more atherogenic than larger LDL particles, also decreased despite a threefold increase in saturated fat intake.
 

Rebuttals: Overall diet, patient preference matter

During the rebuttals, Dr. Kirkpatrick pointed out that large LDL particles are also atherogenic. In addition, she noted that the studies that showed that saturated fat isn’t associated with cardiovascular disease didn’t consider the macronutrients that replaced the saturated fat.

“It really is about increasing consumption of foods that we know are associated with cardiovascular benefit, including plant-based foods that are high quality and not refined carbohydrates ... and healthy protein sources. ... Hopefully we can step away from just looking at macronutrients and look at the total amount of food that people are choosing to eat.”

Importantly, Dr. Kirkpatrick said, patients need to be asked about their current dietary patterns and preferences. “Interventions should be patient centered and sensitive to cultural differences. Personalized lifestyle interventions increase the likelihood of success.”

Dr. Griauzde pointed out that newer antiobesity drugs can be added to any diet to decrease appetite and enhance adherence.

Dr. Griauzde also observed, “We can label a very-low-carbohydrate diet ‘extreme,’ but maybe, from the patient’s perspective, it’s extreme to take 200 units of insulin a day. If you can give them the opportunity to discontinue use of the insulin by following a very-low-carbohydrate dietary pattern, that is the opportunity that our patients deserve to have.”

But overall, she agreed with Dr. Kirkpatrick about individualizing any dietary approach: “We will never know from any of the trials that have been done or that will be done in the future what diet is best for an individual patient. ... Our job is to help our patients find the dietary approach that works best for them.”

Dr. Kirkpatrick is a clinical scientist with Midwest Biomedical Research, which has received funding from various food and pharmaceutical companies. She has not received any direct funding. Dr. Yancy is a consultant for The Simply Good Foods Co. Dr. Griauzde has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

It’s an ongoing debate in the diabetes world: Is it ideal to consume a very-low-carbohydrate diet, or is it better to go with moderate amounts of healthful carbs?

At the annual scientific sessions of the American Diabetes Association, Carol F. Kirkpatrick, PhD, RDN, spoke first, arguing in favor of diets consisting of moderate, high-quality carbohydrates.

Dina Hafez Griauzde, MD, countered that very-low-carbohydrate diets are more beneficial for people with diabetes, primarily type 2 diabetes.

Both speakers based their arguments on published evidence but agreed in the end that discussion with patients about individual dietary preferences should play a major role in the ultimate decision.
 

Moderate-carbohydrate eating is best

Dr. Kirkpatrick began by explaining that definitions of “low carb” vary in the literature, which makes comparisons between studies difficult. On the basis of a 2019 review that she coauthored, “moderate” carbohydrate consumption was defined as a diet in which 26%-44% of total daily calories are from carbohydrates. “Low” carbohydrate consumption was defined as a diet in which 10%-25% of calories were from carbohydrates. Consuming less than 10% was defined as a very-low-carbohydrate diet (i.e., a ketogenic diet).

Across studies, she noted, the literature shows that within the first 6 months weight loss is typically greater with carbohydrate-restricted diets than with higher-carbohydrate diets, but that by 1 year and beyond weight loss is similar.

“That can be partly due to the difficulty in people maintaining that very severe dietary restriction, although ... we can all acknowledge that it’s difficult for patients to adhere to any dietary pattern, so for sure by 12 months, the difference in the weight loss is gone between the two,” said Dr. Kirkpatrick, of Midwest Biomedical Research, Pocatello, Idaho.

In a recent meta-analysis of 35 trials that examined the dose-dependent effects of carbohydrate restriction for patients with type 2 diabetes, there was a significant decrease in weight as carbohydrates were reduced. But by 12 months (17 trials), the greatest weight reduction was seen at 35% carbohydrate intake.

“It may just be that people were able to adhere to that moderate intake better,” she explained.

Regarding lipids, in her 2019 review and in several meta-analyses since, the effects on low-density lipoprotein cholesterol (LDL-C) varied. For some patients, adhering to a low-carb diet led to reductions in LDL-C, especially if the participants also lost weight, whereas in other patients, a low-carb diet led to an increase in LDL-C.

Either way, a high intake of saturated fatty acids is key to an increase in LDL-C, Dr. Kirkpatrick noted. “So, it’s important that, if a patient chooses to follow a very low carbohydrate diet or any kind of dietary pattern that restricts carbohydrate, that they replace the carbohydrate with unsaturated fat and not saturated fatty acid foods to avoid that increase in LDL-C.”

Generally, the evidence also shows that carbohydrate restriction typically leads to lower triglyceride levels and higher high-density lipoprotein (HDL) cholesterol levels. However, the same meta-analysis showed that the greatest reduction in LDL-C occurred at about 40% carbohydrate consumption.

Another recent meta-analysis showed that LDL-C rose significantly by an average 12.4 mg/dL with very-low-carb (3%-30%) diets, but only slightly, by 0.4 mg/dL, with moderate carb (40%-45%) intake.

Consuming very-low-carb diets did lead to greater reductions in triglycerides, compared with consuming moderate carb diets (23.9 mg/dL vs. 8.9 mg/dL).

“However, in terms of cardiovascular health, we are not entirely sure what that means. ... We have to look at the overall results in the presence of both triglyceride lowering as well as LDL cholesterol,” Dr. Kirkpatrick noted.

Carbohydrate restriction did consistently lead to lower hemoglobin A1c levels by an average of 0.4, 0.6, and 1.0 percentage points at 6 months for diets of 40%, 30%, and 15% carbohydrate, respectively. However, by 12 months, the effect had waned to 0.15, 0.2, and 0.4 A1c percentage points.

“Again, carbohydrate restriction, especially severe, is difficult for people to adhere to, and moderate carbohydrate intake would allow our patients to consume an appropriate amount of carbohydrate and still achieve improved glycemic control,” Dr. Kirkpatrick said.

Two large randomized controlled trials – PREDIMED and CORDIOPREV – examined the effects of the Mediterranean diet on cardiovascular disease prevention. Both showed a decrease in cardiovascular events with the Mediterranean diet, which involves consuming moderate amounts of carbohydrates.

“The Mediterranean dietary pattern has the strongest evidence for benefit, and it’s moderate in carbohydrates,” she concluded.
 

Very-low-carbohydrate eating is best

Dr. Griauzde was a last-minute replacement speaker for William S. Yancy Jr, MD, of Duke University, Durham, N.C., and presented his slides. She argued that consuming a very low carb diet improves glycemia and that it does not increase but possibly lowers cardiovascular risk.

She began by noting that prior to the discovery of insulin very-low-carb diets had been consumed for over a century to prolong life for people with type 1 diabetes.

“We have long recognized the deleterious role of carbohydrate in type 1 diabetes management, and we have increasingly recognized that role in the management of type 2 diabetes,” said Dr. Griauzde of the University of Michigan in Ann Arbor.

In a small study that compared maintaining a very-low-carb diet for 2 weeks with maintaining a high-carb diet for 2 weeks, total glucose areas under the curve were substantially lower (P < .05) during the low-carb phase, while A1c levels dropped from 7.3% to 6.8% (P = .006).

“We don’t see those outcomes with meds,” Dr. Griauzde noted, adding, “A diet very low in carbohydrates is one of the most potent tools we have to help our patients achieve glycemic control.”

Dr. Griauzde said that the carbohydrate-insulin model provides an explanation for why dietary carbohydrates are particularly obesogenic and metabolically harmful. That model contrasts with the energy balance model, which suggests that all calories are equal.

The rationale of the carbohydrate-insulin model is that dietary carbohydrate – either sugar or starch – raises serum glucose and insulin levels. A carbohydrate-restricted diet therefore reduces the dietary contribution to serum glucose, which then results in lower insulin levels. Insulin is a potent stimulator of lipogenesis (fat storage), and it is a potent inhibitor of lipolysis (the burning of fat). By lowering insulin levels, stored body fat is burned, serum ketone levels increase, and body weight is lowered.

This model suggests that, when insulin levels are chronically high because of excess carbohydrate consumption, circulating fuels are lowered, which leads to an increase in hunger and to overeating. This was demonstrated in a study that compared different levels of isocaloric glycemic index diets in 12 teenage boys with overweight or obesity. The higher-carbohydrate meals led to higher glucose and insulin levels and more food consumption.

In a systematic review of 13 trials of restricted-carbohydrate diets (< 45% carbohydrates) for adults with diabetes, the degree of improvement in A1c level correlated with the degree of carbohydrate restriction over 2-26 weeks (P = .013).

And in a network meta-analysis of 56 trials that compared nine diets among a total of 4,937 participants with type 2 diabetes, one conclusion was that “for reducing A1c, the low-carbohydrate diet was ranked as the best dietary approach (SUCRA: 84%), followed by the Mediterranean diet (80%), and Paleolithic diet (76%), compared with a control diet.”

Regarding the criticism that very-low-carbohydrate diets are high in saturated fat and therefore raise the risk of cardiovascular disease, Dr. Griauzde pointed to another meta-analysis of 21 prospective studies with more than 300,000 participants with 5-25 years of follow-up. In that analysis, the intake of saturated fat was not associated with an increased risk of cardiovascular disease or stroke.

Furthermore, a 12-week randomized controlled trial that involved 40 adults with overweight also suggested that a very-low-carb diet may be superior to a low-fat diet in improving aspects of the metabolic syndrome, including body mass index, lipid levels, and insulin sensitivity. Small LDL particles, which are more atherogenic than larger LDL particles, also decreased despite a threefold increase in saturated fat intake.
 

Rebuttals: Overall diet, patient preference matter

During the rebuttals, Dr. Kirkpatrick pointed out that large LDL particles are also atherogenic. In addition, she noted that the studies that showed that saturated fat isn’t associated with cardiovascular disease didn’t consider the macronutrients that replaced the saturated fat.

“It really is about increasing consumption of foods that we know are associated with cardiovascular benefit, including plant-based foods that are high quality and not refined carbohydrates ... and healthy protein sources. ... Hopefully we can step away from just looking at macronutrients and look at the total amount of food that people are choosing to eat.”

Importantly, Dr. Kirkpatrick said, patients need to be asked about their current dietary patterns and preferences. “Interventions should be patient centered and sensitive to cultural differences. Personalized lifestyle interventions increase the likelihood of success.”

Dr. Griauzde pointed out that newer antiobesity drugs can be added to any diet to decrease appetite and enhance adherence.

Dr. Griauzde also observed, “We can label a very-low-carbohydrate diet ‘extreme,’ but maybe, from the patient’s perspective, it’s extreme to take 200 units of insulin a day. If you can give them the opportunity to discontinue use of the insulin by following a very-low-carbohydrate dietary pattern, that is the opportunity that our patients deserve to have.”

But overall, she agreed with Dr. Kirkpatrick about individualizing any dietary approach: “We will never know from any of the trials that have been done or that will be done in the future what diet is best for an individual patient. ... Our job is to help our patients find the dietary approach that works best for them.”

Dr. Kirkpatrick is a clinical scientist with Midwest Biomedical Research, which has received funding from various food and pharmaceutical companies. She has not received any direct funding. Dr. Yancy is a consultant for The Simply Good Foods Co. Dr. Griauzde has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

It’s an ongoing debate in the diabetes world: Is it ideal to consume a very-low-carbohydrate diet, or is it better to go with moderate amounts of healthful carbs?

At the annual scientific sessions of the American Diabetes Association, Carol F. Kirkpatrick, PhD, RDN, spoke first, arguing in favor of diets consisting of moderate, high-quality carbohydrates.

Dina Hafez Griauzde, MD, countered that very-low-carbohydrate diets are more beneficial for people with diabetes, primarily type 2 diabetes.

Both speakers based their arguments on published evidence but agreed in the end that discussion with patients about individual dietary preferences should play a major role in the ultimate decision.
 

Moderate-carbohydrate eating is best

Dr. Kirkpatrick began by explaining that definitions of “low carb” vary in the literature, which makes comparisons between studies difficult. On the basis of a 2019 review that she coauthored, “moderate” carbohydrate consumption was defined as a diet in which 26%-44% of total daily calories are from carbohydrates. “Low” carbohydrate consumption was defined as a diet in which 10%-25% of calories were from carbohydrates. Consuming less than 10% was defined as a very-low-carbohydrate diet (i.e., a ketogenic diet).

Across studies, she noted, the literature shows that within the first 6 months weight loss is typically greater with carbohydrate-restricted diets than with higher-carbohydrate diets, but that by 1 year and beyond weight loss is similar.

“That can be partly due to the difficulty in people maintaining that very severe dietary restriction, although ... we can all acknowledge that it’s difficult for patients to adhere to any dietary pattern, so for sure by 12 months, the difference in the weight loss is gone between the two,” said Dr. Kirkpatrick, of Midwest Biomedical Research, Pocatello, Idaho.

In a recent meta-analysis of 35 trials that examined the dose-dependent effects of carbohydrate restriction for patients with type 2 diabetes, there was a significant decrease in weight as carbohydrates were reduced. But by 12 months (17 trials), the greatest weight reduction was seen at 35% carbohydrate intake.

“It may just be that people were able to adhere to that moderate intake better,” she explained.

Regarding lipids, in her 2019 review and in several meta-analyses since, the effects on low-density lipoprotein cholesterol (LDL-C) varied. For some patients, adhering to a low-carb diet led to reductions in LDL-C, especially if the participants also lost weight, whereas in other patients, a low-carb diet led to an increase in LDL-C.

Either way, a high intake of saturated fatty acids is key to an increase in LDL-C, Dr. Kirkpatrick noted. “So, it’s important that, if a patient chooses to follow a very low carbohydrate diet or any kind of dietary pattern that restricts carbohydrate, that they replace the carbohydrate with unsaturated fat and not saturated fatty acid foods to avoid that increase in LDL-C.”

Generally, the evidence also shows that carbohydrate restriction typically leads to lower triglyceride levels and higher high-density lipoprotein (HDL) cholesterol levels. However, the same meta-analysis showed that the greatest reduction in LDL-C occurred at about 40% carbohydrate consumption.

Another recent meta-analysis showed that LDL-C rose significantly by an average 12.4 mg/dL with very-low-carb (3%-30%) diets, but only slightly, by 0.4 mg/dL, with moderate carb (40%-45%) intake.

Consuming very-low-carb diets did lead to greater reductions in triglycerides, compared with consuming moderate carb diets (23.9 mg/dL vs. 8.9 mg/dL).

“However, in terms of cardiovascular health, we are not entirely sure what that means. ... We have to look at the overall results in the presence of both triglyceride lowering as well as LDL cholesterol,” Dr. Kirkpatrick noted.

Carbohydrate restriction did consistently lead to lower hemoglobin A1c levels by an average of 0.4, 0.6, and 1.0 percentage points at 6 months for diets of 40%, 30%, and 15% carbohydrate, respectively. However, by 12 months, the effect had waned to 0.15, 0.2, and 0.4 A1c percentage points.

“Again, carbohydrate restriction, especially severe, is difficult for people to adhere to, and moderate carbohydrate intake would allow our patients to consume an appropriate amount of carbohydrate and still achieve improved glycemic control,” Dr. Kirkpatrick said.

Two large randomized controlled trials – PREDIMED and CORDIOPREV – examined the effects of the Mediterranean diet on cardiovascular disease prevention. Both showed a decrease in cardiovascular events with the Mediterranean diet, which involves consuming moderate amounts of carbohydrates.

“The Mediterranean dietary pattern has the strongest evidence for benefit, and it’s moderate in carbohydrates,” she concluded.
 

Very-low-carbohydrate eating is best

Dr. Griauzde was a last-minute replacement speaker for William S. Yancy Jr, MD, of Duke University, Durham, N.C., and presented his slides. She argued that consuming a very low carb diet improves glycemia and that it does not increase but possibly lowers cardiovascular risk.

She began by noting that prior to the discovery of insulin very-low-carb diets had been consumed for over a century to prolong life for people with type 1 diabetes.

“We have long recognized the deleterious role of carbohydrate in type 1 diabetes management, and we have increasingly recognized that role in the management of type 2 diabetes,” said Dr. Griauzde of the University of Michigan in Ann Arbor.

In a small study that compared maintaining a very-low-carb diet for 2 weeks with maintaining a high-carb diet for 2 weeks, total glucose areas under the curve were substantially lower (P < .05) during the low-carb phase, while A1c levels dropped from 7.3% to 6.8% (P = .006).

“We don’t see those outcomes with meds,” Dr. Griauzde noted, adding, “A diet very low in carbohydrates is one of the most potent tools we have to help our patients achieve glycemic control.”

Dr. Griauzde said that the carbohydrate-insulin model provides an explanation for why dietary carbohydrates are particularly obesogenic and metabolically harmful. That model contrasts with the energy balance model, which suggests that all calories are equal.

The rationale of the carbohydrate-insulin model is that dietary carbohydrate – either sugar or starch – raises serum glucose and insulin levels. A carbohydrate-restricted diet therefore reduces the dietary contribution to serum glucose, which then results in lower insulin levels. Insulin is a potent stimulator of lipogenesis (fat storage), and it is a potent inhibitor of lipolysis (the burning of fat). By lowering insulin levels, stored body fat is burned, serum ketone levels increase, and body weight is lowered.

This model suggests that, when insulin levels are chronically high because of excess carbohydrate consumption, circulating fuels are lowered, which leads to an increase in hunger and to overeating. This was demonstrated in a study that compared different levels of isocaloric glycemic index diets in 12 teenage boys with overweight or obesity. The higher-carbohydrate meals led to higher glucose and insulin levels and more food consumption.

In a systematic review of 13 trials of restricted-carbohydrate diets (< 45% carbohydrates) for adults with diabetes, the degree of improvement in A1c level correlated with the degree of carbohydrate restriction over 2-26 weeks (P = .013).

And in a network meta-analysis of 56 trials that compared nine diets among a total of 4,937 participants with type 2 diabetes, one conclusion was that “for reducing A1c, the low-carbohydrate diet was ranked as the best dietary approach (SUCRA: 84%), followed by the Mediterranean diet (80%), and Paleolithic diet (76%), compared with a control diet.”

Regarding the criticism that very-low-carbohydrate diets are high in saturated fat and therefore raise the risk of cardiovascular disease, Dr. Griauzde pointed to another meta-analysis of 21 prospective studies with more than 300,000 participants with 5-25 years of follow-up. In that analysis, the intake of saturated fat was not associated with an increased risk of cardiovascular disease or stroke.

Furthermore, a 12-week randomized controlled trial that involved 40 adults with overweight also suggested that a very-low-carb diet may be superior to a low-fat diet in improving aspects of the metabolic syndrome, including body mass index, lipid levels, and insulin sensitivity. Small LDL particles, which are more atherogenic than larger LDL particles, also decreased despite a threefold increase in saturated fat intake.
 

Rebuttals: Overall diet, patient preference matter

During the rebuttals, Dr. Kirkpatrick pointed out that large LDL particles are also atherogenic. In addition, she noted that the studies that showed that saturated fat isn’t associated with cardiovascular disease didn’t consider the macronutrients that replaced the saturated fat.

“It really is about increasing consumption of foods that we know are associated with cardiovascular benefit, including plant-based foods that are high quality and not refined carbohydrates ... and healthy protein sources. ... Hopefully we can step away from just looking at macronutrients and look at the total amount of food that people are choosing to eat.”

Importantly, Dr. Kirkpatrick said, patients need to be asked about their current dietary patterns and preferences. “Interventions should be patient centered and sensitive to cultural differences. Personalized lifestyle interventions increase the likelihood of success.”

Dr. Griauzde pointed out that newer antiobesity drugs can be added to any diet to decrease appetite and enhance adherence.

Dr. Griauzde also observed, “We can label a very-low-carbohydrate diet ‘extreme,’ but maybe, from the patient’s perspective, it’s extreme to take 200 units of insulin a day. If you can give them the opportunity to discontinue use of the insulin by following a very-low-carbohydrate dietary pattern, that is the opportunity that our patients deserve to have.”

But overall, she agreed with Dr. Kirkpatrick about individualizing any dietary approach: “We will never know from any of the trials that have been done or that will be done in the future what diet is best for an individual patient. ... Our job is to help our patients find the dietary approach that works best for them.”

Dr. Kirkpatrick is a clinical scientist with Midwest Biomedical Research, which has received funding from various food and pharmaceutical companies. She has not received any direct funding. Dr. Yancy is a consultant for The Simply Good Foods Co. Dr. Griauzde has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

The glucose-lowering drug class sodium-glucose cotransporter 2 (SGLT2) inhibitors appear to reduce the risk for recurrent gout flares in people with gout and type 2 diabetes, and to lessen excess mortality in those individuals, compared with those who initiated other types of glucose-lowering medications, new data suggest.

Among nearly 6,000 adults with both type 2 diabetes and gout from a U.K. primary care database, initiation of SGLT2 inhibitor treatment was associated with 19% fewer recurrent gout flares and 29% lower mortality.

Moreover, unlike other urate-lowering therapies, there were no apparent transient increases in the risk of gout flares after initiating therapy, Jie Wei, PhD, of Health Management Center, Xiangya Hospital, Central South University, Changsha, China, and colleagues reported in JAMA Network Open.

These results are important because current management of gout is suboptimal. Many patients either don’t receive adequate urate-lowering therapies such as allopurinol or stop taking them, Dr. Wei and colleagues said.

In addition to lowering glucose, SGLT2 inhibitors also reduce the risk for major adverse cardiovascular events and all-cause mortality in people regardless of their diabetes status. Previous studies have also found that SGLT2 inhibitors reduce the risk for developing gout and of gout flares.

Asked to comment, gout specialist John D. FitzGerald, MD, PhD, clinical chief of rheumatology at the University of California, Los Angeles, said in an interview: “I think it’s a well-done paper, with a large dataset. I think it just reinforces the findings from the other papers. Mostly anything that lowers uric acid levels is going to lower recurrent gout attacks, so it all makes sense.”

However, while Dr. FitzGerald thinks the drug class is a good option for people with diabetes or cardiorenal indications for them who also have gout, he doesn’t envision it as first-line for most other patients with gout. “The current treatments are very effective. Allopurinol brings down uric acid levels by 5-7 points. There are patients who fail allopurinol, but those are less than 5%.”

The most common reason patients stop taking allopurinol is the frequent initial gout flare. But that’s preventable, Dr. FitzGerald said, either by titrating up slowly, or by adding colchicine along with it. “By going slowly, you can avoid that flare risk. I think that’s what’s going on with the SGLT2 inhibitor. It’s not a dramatic urate-lowering drug, but it is clinically meaningful. I think that’s what this paper is showing.”

But, he noted, “I think there are so many reasons to start the SGLT2 inhibitors that if somebody also has gout, all the better. And, if somebody is on the margin with diabetes and gout control and can’t go with allopurinol, it would be great to add for both conditions.”

Less gout recurrence, lower mortality

The retrospective study was conducted from Jan. 1, 2013, to March 31, 2022. Among 5,931 patients with both type 2 diabetes and gout, 1,548 (26.1%) initiated an SGLT2 inhibitor (dapagliflozin, empagliflozin, or canagliflozin), while 4,383 (73.9%) initiated treatment with other active comparators, mostly (92.6%) dipeptidyl peptidase–4 inhibitors.

Gout flares were identified in the charts for a total of 86% of the participants. The weighted incidence rates for the first recurrent flare were 32.4 versus 41.2 per 1,000 person-years in the SGLT2 inhibitor versus comparator groups, with a weighted absolute rate difference of –8.8/1,000 and weighted hazard ratio of 0.81, a significant difference.

All-cause mortality was 18.8 versus 24.9 per 1,000 person-years, respectively, giving an HR of 0.71 at 5-year follow-up.

Dr. FitzGerald, who chaired the American College of Rheumatology’s 2020 gout guidelines, said he anticipates that the SGLT2 inhibitors will be mentioned in the next update to the ACR’s now “living” guidelines, although he was not speaking on the organization’s behalf.

“We talk about losartan in the current [ACR guidelines], about its specific uric acid–lowering effect. Drugs can make uric acid worse or better. For example, thiazides make it higher. I think the SGLT2 [inhibitors] are important, but I don’t think they’re huge. The study is great, and I think the drugs are great, but I don’t think they will change the way gout is managed.”

This work was supported by grants from the National Key Research and Development Plan, the National Natural Science Foundation of China, the Project Program of National Clinical Research Center for Geriatric Disorders, and from the Natural Science Foundation of Hunan Province. Dr. Wei reported receiving grant funding from Xiangya Hospital Central South University Project Program of National Clinical Research Center for Geriatric Disorders and the Science and Technology Department of Hunan Province, the Natural Science Foundation of Hunan Province, during the conduct of the study. Dr. FitzGerald reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

The glucose-lowering drug class sodium-glucose cotransporter 2 (SGLT2) inhibitors appear to reduce the risk for recurrent gout flares in people with gout and type 2 diabetes, and to lessen excess mortality in those individuals, compared with those who initiated other types of glucose-lowering medications, new data suggest.

Among nearly 6,000 adults with both type 2 diabetes and gout from a U.K. primary care database, initiation of SGLT2 inhibitor treatment was associated with 19% fewer recurrent gout flares and 29% lower mortality.

Moreover, unlike other urate-lowering therapies, there were no apparent transient increases in the risk of gout flares after initiating therapy, Jie Wei, PhD, of Health Management Center, Xiangya Hospital, Central South University, Changsha, China, and colleagues reported in JAMA Network Open.

These results are important because current management of gout is suboptimal. Many patients either don’t receive adequate urate-lowering therapies such as allopurinol or stop taking them, Dr. Wei and colleagues said.

In addition to lowering glucose, SGLT2 inhibitors also reduce the risk for major adverse cardiovascular events and all-cause mortality in people regardless of their diabetes status. Previous studies have also found that SGLT2 inhibitors reduce the risk for developing gout and of gout flares.

Asked to comment, gout specialist John D. FitzGerald, MD, PhD, clinical chief of rheumatology at the University of California, Los Angeles, said in an interview: “I think it’s a well-done paper, with a large dataset. I think it just reinforces the findings from the other papers. Mostly anything that lowers uric acid levels is going to lower recurrent gout attacks, so it all makes sense.”

However, while Dr. FitzGerald thinks the drug class is a good option for people with diabetes or cardiorenal indications for them who also have gout, he doesn’t envision it as first-line for most other patients with gout. “The current treatments are very effective. Allopurinol brings down uric acid levels by 5-7 points. There are patients who fail allopurinol, but those are less than 5%.”

The most common reason patients stop taking allopurinol is the frequent initial gout flare. But that’s preventable, Dr. FitzGerald said, either by titrating up slowly, or by adding colchicine along with it. “By going slowly, you can avoid that flare risk. I think that’s what’s going on with the SGLT2 inhibitor. It’s not a dramatic urate-lowering drug, but it is clinically meaningful. I think that’s what this paper is showing.”

But, he noted, “I think there are so many reasons to start the SGLT2 inhibitors that if somebody also has gout, all the better. And, if somebody is on the margin with diabetes and gout control and can’t go with allopurinol, it would be great to add for both conditions.”

Less gout recurrence, lower mortality

The retrospective study was conducted from Jan. 1, 2013, to March 31, 2022. Among 5,931 patients with both type 2 diabetes and gout, 1,548 (26.1%) initiated an SGLT2 inhibitor (dapagliflozin, empagliflozin, or canagliflozin), while 4,383 (73.9%) initiated treatment with other active comparators, mostly (92.6%) dipeptidyl peptidase–4 inhibitors.

Gout flares were identified in the charts for a total of 86% of the participants. The weighted incidence rates for the first recurrent flare were 32.4 versus 41.2 per 1,000 person-years in the SGLT2 inhibitor versus comparator groups, with a weighted absolute rate difference of –8.8/1,000 and weighted hazard ratio of 0.81, a significant difference.

All-cause mortality was 18.8 versus 24.9 per 1,000 person-years, respectively, giving an HR of 0.71 at 5-year follow-up.

Dr. FitzGerald, who chaired the American College of Rheumatology’s 2020 gout guidelines, said he anticipates that the SGLT2 inhibitors will be mentioned in the next update to the ACR’s now “living” guidelines, although he was not speaking on the organization’s behalf.

“We talk about losartan in the current [ACR guidelines], about its specific uric acid–lowering effect. Drugs can make uric acid worse or better. For example, thiazides make it higher. I think the SGLT2 [inhibitors] are important, but I don’t think they’re huge. The study is great, and I think the drugs are great, but I don’t think they will change the way gout is managed.”

This work was supported by grants from the National Key Research and Development Plan, the National Natural Science Foundation of China, the Project Program of National Clinical Research Center for Geriatric Disorders, and from the Natural Science Foundation of Hunan Province. Dr. Wei reported receiving grant funding from Xiangya Hospital Central South University Project Program of National Clinical Research Center for Geriatric Disorders and the Science and Technology Department of Hunan Province, the Natural Science Foundation of Hunan Province, during the conduct of the study. Dr. FitzGerald reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

The glucose-lowering drug class sodium-glucose cotransporter 2 (SGLT2) inhibitors appear to reduce the risk for recurrent gout flares in people with gout and type 2 diabetes, and to lessen excess mortality in those individuals, compared with those who initiated other types of glucose-lowering medications, new data suggest.

Among nearly 6,000 adults with both type 2 diabetes and gout from a U.K. primary care database, initiation of SGLT2 inhibitor treatment was associated with 19% fewer recurrent gout flares and 29% lower mortality.

Moreover, unlike other urate-lowering therapies, there were no apparent transient increases in the risk of gout flares after initiating therapy, Jie Wei, PhD, of Health Management Center, Xiangya Hospital, Central South University, Changsha, China, and colleagues reported in JAMA Network Open.

These results are important because current management of gout is suboptimal. Many patients either don’t receive adequate urate-lowering therapies such as allopurinol or stop taking them, Dr. Wei and colleagues said.

In addition to lowering glucose, SGLT2 inhibitors also reduce the risk for major adverse cardiovascular events and all-cause mortality in people regardless of their diabetes status. Previous studies have also found that SGLT2 inhibitors reduce the risk for developing gout and of gout flares.

Asked to comment, gout specialist John D. FitzGerald, MD, PhD, clinical chief of rheumatology at the University of California, Los Angeles, said in an interview: “I think it’s a well-done paper, with a large dataset. I think it just reinforces the findings from the other papers. Mostly anything that lowers uric acid levels is going to lower recurrent gout attacks, so it all makes sense.”

However, while Dr. FitzGerald thinks the drug class is a good option for people with diabetes or cardiorenal indications for them who also have gout, he doesn’t envision it as first-line for most other patients with gout. “The current treatments are very effective. Allopurinol brings down uric acid levels by 5-7 points. There are patients who fail allopurinol, but those are less than 5%.”

The most common reason patients stop taking allopurinol is the frequent initial gout flare. But that’s preventable, Dr. FitzGerald said, either by titrating up slowly, or by adding colchicine along with it. “By going slowly, you can avoid that flare risk. I think that’s what’s going on with the SGLT2 inhibitor. It’s not a dramatic urate-lowering drug, but it is clinically meaningful. I think that’s what this paper is showing.”

But, he noted, “I think there are so many reasons to start the SGLT2 inhibitors that if somebody also has gout, all the better. And, if somebody is on the margin with diabetes and gout control and can’t go with allopurinol, it would be great to add for both conditions.”

Less gout recurrence, lower mortality

The retrospective study was conducted from Jan. 1, 2013, to March 31, 2022. Among 5,931 patients with both type 2 diabetes and gout, 1,548 (26.1%) initiated an SGLT2 inhibitor (dapagliflozin, empagliflozin, or canagliflozin), while 4,383 (73.9%) initiated treatment with other active comparators, mostly (92.6%) dipeptidyl peptidase–4 inhibitors.

Gout flares were identified in the charts for a total of 86% of the participants. The weighted incidence rates for the first recurrent flare were 32.4 versus 41.2 per 1,000 person-years in the SGLT2 inhibitor versus comparator groups, with a weighted absolute rate difference of –8.8/1,000 and weighted hazard ratio of 0.81, a significant difference.

All-cause mortality was 18.8 versus 24.9 per 1,000 person-years, respectively, giving an HR of 0.71 at 5-year follow-up.

Dr. FitzGerald, who chaired the American College of Rheumatology’s 2020 gout guidelines, said he anticipates that the SGLT2 inhibitors will be mentioned in the next update to the ACR’s now “living” guidelines, although he was not speaking on the organization’s behalf.

“We talk about losartan in the current [ACR guidelines], about its specific uric acid–lowering effect. Drugs can make uric acid worse or better. For example, thiazides make it higher. I think the SGLT2 [inhibitors] are important, but I don’t think they’re huge. The study is great, and I think the drugs are great, but I don’t think they will change the way gout is managed.”

This work was supported by grants from the National Key Research and Development Plan, the National Natural Science Foundation of China, the Project Program of National Clinical Research Center for Geriatric Disorders, and from the Natural Science Foundation of Hunan Province. Dr. Wei reported receiving grant funding from Xiangya Hospital Central South University Project Program of National Clinical Research Center for Geriatric Disorders and the Science and Technology Department of Hunan Province, the Natural Science Foundation of Hunan Province, during the conduct of the study. Dr. FitzGerald reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.