Diabetes

In 2019, 30.3 million US adults were reported to have diabetes—an epidemic according to some public health experts.^1,2 Even more sobering, an estimated 84.1 million (or more than 1 in 3) American adults have prediabetes.¹ Diabetes is associated with multiple complications, including an increased risk for heart disease or stroke.³ In 2015, it was the seventh leading cause of death and a major cause of kidney failure, lower limb amputations, stroke, and blindness.^2,4

As clinicians we often ask ourselves, “How can I help my patients become more effective managers of their diabetes, so that they can maximize their quality of life over both the short and long term?” Unfortunately, management of diabetes is fraught with difficulty, both for the provider and the patient. Medications for glycemic control can be expensive and inconvenient and can have adverse effects—all of which may lead to inconsistent adherence. Lifestyle changes—including diet, regular physical activity, exercise, and weight management—are important low-risk interventions that help patients maintain glycemic values and reduce the risk for diabetic complications. However, some patients may find it difficult to make or are ambivalent to behavioral change.

These patients may benefit from having structured verbal encouragement—such as motivational interviewing (MI)—incorporated into their visits. The following discussion will explain how MI can be an effective communication tool for encouraging patients with diabetes or prediabetes to make important behavioral changes and improve health outcomes.

Q What is MI?

First created by William R. Miller and Stephen Rollnick in the 1980s as a counseling method to help patients with substance use disorders, MI was eventually expanded to address other clinical challenges, including tobacco cessation, weight management, and diabetes care. MI helps patients identify their motivations and goals to improve long-term outcomes and work through any ambivalence to change. It utilizes an empathic approach with open-ended questions.⁵ This helps reduce the resistance frequently encountered during an average “lecture-style” interaction and facilitates a collaborative relationship that empowers the patient to make positive lifestyle changes.

MI affirms the patient’s experience while exploring any discrepancies between goals and actions. Two important components for conducting MI are (1) verbally reflecting the patient’s motivations and thoughts about change and (2) allowing the patient to “voice the arguments for change.”⁶ These components help the patient take ownership of the overarching goal for behavioral change and in the development of an action plan.

MI involves 4 primary processes: engaging, focusing, evoking, and planning (defined in the Table).⁷ MI begins with building rapport and a trusting relationship by engaging with empathic responses that reflect the patient’s concerns and focusing on what is important to him or her. The clinician should evoke the patient’s reasons and motivations for change. During the planning process, the clinician highlights the salient points of the conversation and works with the patient to identify an action he or she could take as a first step toward change.⁷

Table
Motivational Interviewing Processes

Source: Arkowitz H, et al. Motivational Interviewing in the Treatment of Psychological Problems. 2015. ⁷

Continue to: Q How can I use MI with my patients with diabetes?

 

 

Q How can I use MI with my patients with diabetes?

MI can be used in a variety of clinical settings, including primary care and behavioral health, and can be effective when employed even in short periods of time.^8,9 This communication style can be incorporated into regular follow-up appointments to help the clinician and the patient work toward better glycemic control and improved long-term outcomes.

For clinicians who are new users of MI, consider the mnemonic OARS (Open-ended questions, Affirmations, accurate empathic Reflections, Summarizing) to utilize the core components of MI.¹⁰ The OARS techniques are vital MI tools that can help the clinician explore the patient’s motivation for pursuing change, and they help the clinician recognize and appreciate the patient’s perspective on the challenges of initiating change.¹⁰ The following sample conversation illustrates how OARS can be used.

Open-ended question:

Clinician: What do you think are the greatest challenges when it comes to controlling your diabetes?

Patient: It’s just so frustrating, I keep avoiding bad food and trying to eat healthy, but my sugar still goes up.

Affirmations:

Clinician: Thank you for sharing that with me. It sounds like you are persistent and have been working hard to make healthier choices.

Patient: Yes, but I’m so tired of trying. It just doesn’t seem to work.

Accurate empathic reflections:

Clinician: It is important for you to control your diabetes, but you feel discouraged by the results that you’ve seen.

Patient: Yeah, I just don’t know what else to do to make my sugar better.

Continue to: Summarizing

Summarizing:

Clinician: You’ve said that controlling your blood sugar is important to you and that you’ve tried eating healthily, but it just isn’t working well enough. It sounds like you are ready to explore alternatives that might help you gain better control of the situation. Is that right?

Patient: Well, yes, it is.

Here the patient recognizes the need for help in controlling his or her diabetes, and the clinician can then move the conversation to additional treatment options, such as medication changes or support group intervention. Using OARS, the provider can focus on what is important to the patient and evaluate any discrepancies between the patient’s goals and actions.

Q Does the research support MI for patients with diabetes?

Many studies have evaluated the efficacy of MI on behavioral change and health care–related outcomes.^8,11-15 Since its inception, MI has shown great promise in addictive behavior modification.¹⁶ Multiple studies also show support for its beneficial effect on weight management as well as on physical activity level, which are 2 factors strongly associated with improved outcomes in patients with prediabetes and diabetes.^8,11-15,17 In a 2017 meta-analysis of MI for patients with obesity, prediabetes, and type 2 diabetes, Phillips and Guarnaccia found significant support for behavioral change leading to improvements in quantifiable medical measurements.¹⁸

Systematic reviews of MI in health care settings have produced some conflicting findings. While there is evidence for the usefulness of MI in bringing about positive lifestyle changes, data supporting the effective use of MI in specific diabetes-related outcomes (eg, A1C levels) have been less robust.^8,11-15,19 However, this is a particularly challenging area of study due in part to limitations of research designs and the inherent difficulties in assuring high-quality, consistent MI approaches. Despite these limitations, MI has significant positive results in improving patient adherence to treatment regimens.^9,16,20,21

Conclusion

MI is a promising method that empowers patients to make modifications to their lifestyle choices, work through ambivalence, and better align goals with actions. Although the data on patient outcomes is inconclusive, evidence suggests that MI conducted across appointments holds benefit and that it is even more effective when combined with additional nonpharmacologic techniques, such as cognitive behavioral therapy.^17,22 Additionally, research suggests that MI strengthens the clinician-patient relationship, with patients reporting greater empathy from their clinicians and overall satisfaction with interactions.²³ Improved communication and mutual respect in clinician-patient interactions help maintain the therapeutic alliance for the future. For additional guidance and resources on MI, visit the Motivational Interviewing Network of Trainers website at motivationalinterviewing.org.

In 2019, 30.3 million US adults were reported to have diabetes—an epidemic according to some public health experts.^1,2 Even more sobering, an estimated 84.1 million (or more than 1 in 3) American adults have prediabetes.¹ Diabetes is associated with multiple complications, including an increased risk for heart disease or stroke.³ In 2015, it was the seventh leading cause of death and a major cause of kidney failure, lower limb amputations, stroke, and blindness.^2,4

As clinicians we often ask ourselves, “How can I help my patients become more effective managers of their diabetes, so that they can maximize their quality of life over both the short and long term?” Unfortunately, management of diabetes is fraught with difficulty, both for the provider and the patient. Medications for glycemic control can be expensive and inconvenient and can have adverse effects—all of which may lead to inconsistent adherence. Lifestyle changes—including diet, regular physical activity, exercise, and weight management—are important low-risk interventions that help patients maintain glycemic values and reduce the risk for diabetic complications. However, some patients may find it difficult to make or are ambivalent to behavioral change.

These patients may benefit from having structured verbal encouragement—such as motivational interviewing (MI)—incorporated into their visits. The following discussion will explain how MI can be an effective communication tool for encouraging patients with diabetes or prediabetes to make important behavioral changes and improve health outcomes.

Q What is MI?

First created by William R. Miller and Stephen Rollnick in the 1980s as a counseling method to help patients with substance use disorders, MI was eventually expanded to address other clinical challenges, including tobacco cessation, weight management, and diabetes care. MI helps patients identify their motivations and goals to improve long-term outcomes and work through any ambivalence to change. It utilizes an empathic approach with open-ended questions.⁵ This helps reduce the resistance frequently encountered during an average “lecture-style” interaction and facilitates a collaborative relationship that empowers the patient to make positive lifestyle changes.

MI affirms the patient’s experience while exploring any discrepancies between goals and actions. Two important components for conducting MI are (1) verbally reflecting the patient’s motivations and thoughts about change and (2) allowing the patient to “voice the arguments for change.”⁶ These components help the patient take ownership of the overarching goal for behavioral change and in the development of an action plan.

MI involves 4 primary processes: engaging, focusing, evoking, and planning (defined in the Table).⁷ MI begins with building rapport and a trusting relationship by engaging with empathic responses that reflect the patient’s concerns and focusing on what is important to him or her. The clinician should evoke the patient’s reasons and motivations for change. During the planning process, the clinician highlights the salient points of the conversation and works with the patient to identify an action he or she could take as a first step toward change.⁷

Table
Motivational Interviewing Processes

Source: Arkowitz H, et al. Motivational Interviewing in the Treatment of Psychological Problems. 2015. ⁷

Continue to: Q How can I use MI with my patients with diabetes?

 

 

Q How can I use MI with my patients with diabetes?

MI can be used in a variety of clinical settings, including primary care and behavioral health, and can be effective when employed even in short periods of time.^8,9 This communication style can be incorporated into regular follow-up appointments to help the clinician and the patient work toward better glycemic control and improved long-term outcomes.

For clinicians who are new users of MI, consider the mnemonic OARS (Open-ended questions, Affirmations, accurate empathic Reflections, Summarizing) to utilize the core components of MI.¹⁰ The OARS techniques are vital MI tools that can help the clinician explore the patient’s motivation for pursuing change, and they help the clinician recognize and appreciate the patient’s perspective on the challenges of initiating change.¹⁰ The following sample conversation illustrates how OARS can be used.

Open-ended question:

Clinician: What do you think are the greatest challenges when it comes to controlling your diabetes?

Patient: It’s just so frustrating, I keep avoiding bad food and trying to eat healthy, but my sugar still goes up.

Affirmations:

Clinician: Thank you for sharing that with me. It sounds like you are persistent and have been working hard to make healthier choices.

Patient: Yes, but I’m so tired of trying. It just doesn’t seem to work.

Accurate empathic reflections:

Clinician: It is important for you to control your diabetes, but you feel discouraged by the results that you’ve seen.

Patient: Yeah, I just don’t know what else to do to make my sugar better.

Continue to: Summarizing

Summarizing:

Clinician: You’ve said that controlling your blood sugar is important to you and that you’ve tried eating healthily, but it just isn’t working well enough. It sounds like you are ready to explore alternatives that might help you gain better control of the situation. Is that right?

Patient: Well, yes, it is.

Here the patient recognizes the need for help in controlling his or her diabetes, and the clinician can then move the conversation to additional treatment options, such as medication changes or support group intervention. Using OARS, the provider can focus on what is important to the patient and evaluate any discrepancies between the patient’s goals and actions.

Q Does the research support MI for patients with diabetes?

Many studies have evaluated the efficacy of MI on behavioral change and health care–related outcomes.^8,11-15 Since its inception, MI has shown great promise in addictive behavior modification.¹⁶ Multiple studies also show support for its beneficial effect on weight management as well as on physical activity level, which are 2 factors strongly associated with improved outcomes in patients with prediabetes and diabetes.^8,11-15,17 In a 2017 meta-analysis of MI for patients with obesity, prediabetes, and type 2 diabetes, Phillips and Guarnaccia found significant support for behavioral change leading to improvements in quantifiable medical measurements.¹⁸

Systematic reviews of MI in health care settings have produced some conflicting findings. While there is evidence for the usefulness of MI in bringing about positive lifestyle changes, data supporting the effective use of MI in specific diabetes-related outcomes (eg, A1C levels) have been less robust.^8,11-15,19 However, this is a particularly challenging area of study due in part to limitations of research designs and the inherent difficulties in assuring high-quality, consistent MI approaches. Despite these limitations, MI has significant positive results in improving patient adherence to treatment regimens.^9,16,20,21

Conclusion

MI is a promising method that empowers patients to make modifications to their lifestyle choices, work through ambivalence, and better align goals with actions. Although the data on patient outcomes is inconclusive, evidence suggests that MI conducted across appointments holds benefit and that it is even more effective when combined with additional nonpharmacologic techniques, such as cognitive behavioral therapy.^17,22 Additionally, research suggests that MI strengthens the clinician-patient relationship, with patients reporting greater empathy from their clinicians and overall satisfaction with interactions.²³ Improved communication and mutual respect in clinician-patient interactions help maintain the therapeutic alliance for the future. For additional guidance and resources on MI, visit the Motivational Interviewing Network of Trainers website at motivationalinterviewing.org.

In 2019, 30.3 million US adults were reported to have diabetes—an epidemic according to some public health experts.^1,2 Even more sobering, an estimated 84.1 million (or more than 1 in 3) American adults have prediabetes.¹ Diabetes is associated with multiple complications, including an increased risk for heart disease or stroke.³ In 2015, it was the seventh leading cause of death and a major cause of kidney failure, lower limb amputations, stroke, and blindness.^2,4

As clinicians we often ask ourselves, “How can I help my patients become more effective managers of their diabetes, so that they can maximize their quality of life over both the short and long term?” Unfortunately, management of diabetes is fraught with difficulty, both for the provider and the patient. Medications for glycemic control can be expensive and inconvenient and can have adverse effects—all of which may lead to inconsistent adherence. Lifestyle changes—including diet, regular physical activity, exercise, and weight management—are important low-risk interventions that help patients maintain glycemic values and reduce the risk for diabetic complications. However, some patients may find it difficult to make or are ambivalent to behavioral change.

These patients may benefit from having structured verbal encouragement—such as motivational interviewing (MI)—incorporated into their visits. The following discussion will explain how MI can be an effective communication tool for encouraging patients with diabetes or prediabetes to make important behavioral changes and improve health outcomes.

Q What is MI?

First created by William R. Miller and Stephen Rollnick in the 1980s as a counseling method to help patients with substance use disorders, MI was eventually expanded to address other clinical challenges, including tobacco cessation, weight management, and diabetes care. MI helps patients identify their motivations and goals to improve long-term outcomes and work through any ambivalence to change. It utilizes an empathic approach with open-ended questions.⁵ This helps reduce the resistance frequently encountered during an average “lecture-style” interaction and facilitates a collaborative relationship that empowers the patient to make positive lifestyle changes.

MI affirms the patient’s experience while exploring any discrepancies between goals and actions. Two important components for conducting MI are (1) verbally reflecting the patient’s motivations and thoughts about change and (2) allowing the patient to “voice the arguments for change.”⁶ These components help the patient take ownership of the overarching goal for behavioral change and in the development of an action plan.

MI involves 4 primary processes: engaging, focusing, evoking, and planning (defined in the Table).⁷ MI begins with building rapport and a trusting relationship by engaging with empathic responses that reflect the patient’s concerns and focusing on what is important to him or her. The clinician should evoke the patient’s reasons and motivations for change. During the planning process, the clinician highlights the salient points of the conversation and works with the patient to identify an action he or she could take as a first step toward change.⁷

Table
Motivational Interviewing Processes

Source: Arkowitz H, et al. Motivational Interviewing in the Treatment of Psychological Problems. 2015. ⁷

Continue to: Q How can I use MI with my patients with diabetes?

 

 

Q How can I use MI with my patients with diabetes?

MI can be used in a variety of clinical settings, including primary care and behavioral health, and can be effective when employed even in short periods of time.^8,9 This communication style can be incorporated into regular follow-up appointments to help the clinician and the patient work toward better glycemic control and improved long-term outcomes.

For clinicians who are new users of MI, consider the mnemonic OARS (Open-ended questions, Affirmations, accurate empathic Reflections, Summarizing) to utilize the core components of MI.¹⁰ The OARS techniques are vital MI tools that can help the clinician explore the patient’s motivation for pursuing change, and they help the clinician recognize and appreciate the patient’s perspective on the challenges of initiating change.¹⁰ The following sample conversation illustrates how OARS can be used.

Open-ended question:

Clinician: What do you think are the greatest challenges when it comes to controlling your diabetes?

Patient: It’s just so frustrating, I keep avoiding bad food and trying to eat healthy, but my sugar still goes up.

Affirmations:

Clinician: Thank you for sharing that with me. It sounds like you are persistent and have been working hard to make healthier choices.

Patient: Yes, but I’m so tired of trying. It just doesn’t seem to work.

Accurate empathic reflections:

Clinician: It is important for you to control your diabetes, but you feel discouraged by the results that you’ve seen.

Patient: Yeah, I just don’t know what else to do to make my sugar better.

Continue to: Summarizing

Summarizing:

Clinician: You’ve said that controlling your blood sugar is important to you and that you’ve tried eating healthily, but it just isn’t working well enough. It sounds like you are ready to explore alternatives that might help you gain better control of the situation. Is that right?

Patient: Well, yes, it is.

Here the patient recognizes the need for help in controlling his or her diabetes, and the clinician can then move the conversation to additional treatment options, such as medication changes or support group intervention. Using OARS, the provider can focus on what is important to the patient and evaluate any discrepancies between the patient’s goals and actions.

Q Does the research support MI for patients with diabetes?

Many studies have evaluated the efficacy of MI on behavioral change and health care–related outcomes.^8,11-15 Since its inception, MI has shown great promise in addictive behavior modification.¹⁶ Multiple studies also show support for its beneficial effect on weight management as well as on physical activity level, which are 2 factors strongly associated with improved outcomes in patients with prediabetes and diabetes.^8,11-15,17 In a 2017 meta-analysis of MI for patients with obesity, prediabetes, and type 2 diabetes, Phillips and Guarnaccia found significant support for behavioral change leading to improvements in quantifiable medical measurements.¹⁸

Systematic reviews of MI in health care settings have produced some conflicting findings. While there is evidence for the usefulness of MI in bringing about positive lifestyle changes, data supporting the effective use of MI in specific diabetes-related outcomes (eg, A1C levels) have been less robust.^8,11-15,19 However, this is a particularly challenging area of study due in part to limitations of research designs and the inherent difficulties in assuring high-quality, consistent MI approaches. Despite these limitations, MI has significant positive results in improving patient adherence to treatment regimens.^9,16,20,21

Conclusion

MI is a promising method that empowers patients to make modifications to their lifestyle choices, work through ambivalence, and better align goals with actions. Although the data on patient outcomes is inconclusive, evidence suggests that MI conducted across appointments holds benefit and that it is even more effective when combined with additional nonpharmacologic techniques, such as cognitive behavioral therapy.^17,22 Additionally, research suggests that MI strengthens the clinician-patient relationship, with patients reporting greater empathy from their clinicians and overall satisfaction with interactions.²³ Improved communication and mutual respect in clinician-patient interactions help maintain the therapeutic alliance for the future. For additional guidance and resources on MI, visit the Motivational Interviewing Network of Trainers website at motivationalinterviewing.org.

The Food and Drug Administration is investigating whether forms of the type 2 diabetes drug metformin that are available in the United States contain the genotoxic nitrosamine, N-nitrosodimethylamine (NDMA).

This follows reports of low-level NDMA contamination of metformin in other countries and of a few regulatory agencies issuing recalls for the drug, according to a statement from Janet Woodcock, MD, director of the FDA’s Center for Drug Evaluation and Research.

“There are no metformin recalls affecting the U.S. market at this time,” the agency emphasized in the statement. It said NDMA levels in affected medication have been low, at or even below the acceptable intake limit, and there is currently no evidence indicating that metformin drugs within the United States or European Union have been contaminated.

The FDA advised that patients should continue taking metformin alone or in combination with other drugs to control their diabetes and that it would be dangerous for them to stop taking the medication without first discussing it with their providers. It also recommended that providers continue to use metformin when “clinically appropriate” while the investigation is underway as there are no alternative therapies to treat the disease in the same way.

NDMA is a common contaminant that is found in water and some foods and has probable carcinogenic effects when exposure is too high. The acceptable daily intake for NDMA in the United States is 96 ng/day, according to the statement, though people who take in that amount or less every day for 70 years are not expected to have an increased risk of cancer.

Both the FDA and its counterpart, the European Medicines Agency, have recently investigated the presence of NDMA impurities in ranitidine, a drug used to reduce production of stomach acid, which led to several manufacturers issuing recalls for it.

The agencies have also investigated angiotensin II receptor blockers, which are used to treat hypertension, heart failure, and high blood pressure.

Wikimedia Commons/FitzColinGerald/ Creative Commons License

The presence of NDMA “can be related to the drug’s manufacturing process or its chemical structure or even the conditions in which they are stored or packaged. As food and drugs are processed in the body, nitrosamines, including NDMA, can be formed,” Dr. Woodcock noted in the statement.

“We are monitoring this issue closely to assess any potential impact on patients with diabetes,” said Robert W. Lash, MD, chief professional and clinical affairs officer of the Endocrine Society. “We have members around the world and are concerned about the possibility of carcinogenic impurities in medications, both in the United States and elsewhere.”

[email protected]

The Food and Drug Administration is investigating whether forms of the type 2 diabetes drug metformin that are available in the United States contain the genotoxic nitrosamine, N-nitrosodimethylamine (NDMA).

This follows reports of low-level NDMA contamination of metformin in other countries and of a few regulatory agencies issuing recalls for the drug, according to a statement from Janet Woodcock, MD, director of the FDA’s Center for Drug Evaluation and Research.

“There are no metformin recalls affecting the U.S. market at this time,” the agency emphasized in the statement. It said NDMA levels in affected medication have been low, at or even below the acceptable intake limit, and there is currently no evidence indicating that metformin drugs within the United States or European Union have been contaminated.

The FDA advised that patients should continue taking metformin alone or in combination with other drugs to control their diabetes and that it would be dangerous for them to stop taking the medication without first discussing it with their providers. It also recommended that providers continue to use metformin when “clinically appropriate” while the investigation is underway as there are no alternative therapies to treat the disease in the same way.

NDMA is a common contaminant that is found in water and some foods and has probable carcinogenic effects when exposure is too high. The acceptable daily intake for NDMA in the United States is 96 ng/day, according to the statement, though people who take in that amount or less every day for 70 years are not expected to have an increased risk of cancer.

Both the FDA and its counterpart, the European Medicines Agency, have recently investigated the presence of NDMA impurities in ranitidine, a drug used to reduce production of stomach acid, which led to several manufacturers issuing recalls for it.

The agencies have also investigated angiotensin II receptor blockers, which are used to treat hypertension, heart failure, and high blood pressure.

Wikimedia Commons/FitzColinGerald/ Creative Commons License

The presence of NDMA “can be related to the drug’s manufacturing process or its chemical structure or even the conditions in which they are stored or packaged. As food and drugs are processed in the body, nitrosamines, including NDMA, can be formed,” Dr. Woodcock noted in the statement.

“We are monitoring this issue closely to assess any potential impact on patients with diabetes,” said Robert W. Lash, MD, chief professional and clinical affairs officer of the Endocrine Society. “We have members around the world and are concerned about the possibility of carcinogenic impurities in medications, both in the United States and elsewhere.”

[email protected]

The Food and Drug Administration is investigating whether forms of the type 2 diabetes drug metformin that are available in the United States contain the genotoxic nitrosamine, N-nitrosodimethylamine (NDMA).

This follows reports of low-level NDMA contamination of metformin in other countries and of a few regulatory agencies issuing recalls for the drug, according to a statement from Janet Woodcock, MD, director of the FDA’s Center for Drug Evaluation and Research.

“There are no metformin recalls affecting the U.S. market at this time,” the agency emphasized in the statement. It said NDMA levels in affected medication have been low, at or even below the acceptable intake limit, and there is currently no evidence indicating that metformin drugs within the United States or European Union have been contaminated.

The FDA advised that patients should continue taking metformin alone or in combination with other drugs to control their diabetes and that it would be dangerous for them to stop taking the medication without first discussing it with their providers. It also recommended that providers continue to use metformin when “clinically appropriate” while the investigation is underway as there are no alternative therapies to treat the disease in the same way.

NDMA is a common contaminant that is found in water and some foods and has probable carcinogenic effects when exposure is too high. The acceptable daily intake for NDMA in the United States is 96 ng/day, according to the statement, though people who take in that amount or less every day for 70 years are not expected to have an increased risk of cancer.

Both the FDA and its counterpart, the European Medicines Agency, have recently investigated the presence of NDMA impurities in ranitidine, a drug used to reduce production of stomach acid, which led to several manufacturers issuing recalls for it.

The agencies have also investigated angiotensin II receptor blockers, which are used to treat hypertension, heart failure, and high blood pressure.

Wikimedia Commons/FitzColinGerald/ Creative Commons License

The presence of NDMA “can be related to the drug’s manufacturing process or its chemical structure or even the conditions in which they are stored or packaged. As food and drugs are processed in the body, nitrosamines, including NDMA, can be formed,” Dr. Woodcock noted in the statement.

“We are monitoring this issue closely to assess any potential impact on patients with diabetes,” said Robert W. Lash, MD, chief professional and clinical affairs officer of the Endocrine Society. “We have members around the world and are concerned about the possibility of carcinogenic impurities in medications, both in the United States and elsewhere.”

[email protected]

BARCELONA – The investigational oral agent cenicriviroc showed positive effects on liver fibrosis in adults with nonalcoholic steatohepatitis (NASH), many of whom had type 2 diabetes, in a phase 2b trial reported at the annual meeting of the European Association for the Study of Diabetes.

Other data released at the meeting, which showed potential positive effects of novel or existing diabetes treatments on nonalcoholic fatty liver disease (NAFLD), included post hoc analyses of a phase 2b study with tirzepatide and a phase 3 study that combined exenatide and dapagliflozin.

Currently, no medications for NAFLD or NASH have been approved in the United States.

CENTAUR with cenicriviroc

Results of the previously reported CENTAUR trial showed that the antifibrotic effects of cenicriviroc, a dual chemokine receptor antagonist, were greatest in patients with more-severe liver disease (Hepatology. 2018;67[5]:1754-67). At the meeting, Henrik Landgren, PhD, of Allergan, presented data from the 2-year trial overall, and specifically in patients with advanced, stage 3 fibrosis.

CENTAUR was a randomized, double-blind, placebo-controlled, multinational study with 289 adults who had biopsy-confirmed NASH, an NAFLD Activity Score (NAS; range, 0-8; score of 5 or more diagnostic of NASH) of 4 or more, and stages 1-3 liver fibrosis as determined by the NASH clinical research network system (Contemp Clin Trials. 2016;47:356-65). The mean age of the patients enrolled at baseline was 54 years, the mean body mass index was 33.9 kg/m², and just more than half the patients (52%) had type 2 diabetes.

The patients were randomized to three treatment arms: cenicriviroc 150 mg for 2 years; placebo for 1 year, then cenicriviroc 150 mg for 1 year; or placebo for 2 years. The primary endpoint was histologic improvement (reduction of 2 or more points in overall NAS, with reduction of 1 or more points in more than one category of the NAS without worsening of fibrosis at the end of year 1. The key secondary endpoint was complete NASH resolution without worsening of fibrosis at year 2.

Dr. Landgren reported that, at year 1, of the total number of patients, 28.6% of those receiving cenicriviroc achieved an improvement in fibrosis of one or more stages, compared with 19.0% of those receiving placebo. Of the 97 patients who had advanced fibrosis at baseline, 38.3% of those on cenicriviroc and 28.0% of those on placebo achieved the same endpoint.

Those effects were sustained at year 2, Dr. Landgren emphasized, with twice as many cenicriviroc- than placebo-treated patients achieving one or more stage improvement in fibrosis and no worsening of NASH at year 2 (60% and 30%, respectively), with more pronounced improvements in those who had advanced fibrosis at baseline (86% and 60%).

In addition, analyses of biomarkers suggested that cenicriviroc had systematic anti-inflammatory activity, with reductions observed in high-sensitivity C-reactive protein; fibrinogen; and levels of interleukin-6, IL-8, and IL-1-beta.

Dr. Landgren and colleagues noted that cenicriviroc provided antifibrotic benefit in patients with NASH and fibrosis. Those benefits were sustained through year 2 and were more pronounced in patients who had advanced fibrosis at baseline.

The safety of cenicriviroc was “comparable with placebo,” he said, suggesting that the data supported the phase 3 AURORA study that is currently recruiting.

Tirzepatide for NASH

Another approach worth exploring for the treatment of NASH, is the use of tirzepatide, a dual agonist of glucose-dependent insulinotropic polypeptide and the glucagonlike peptide–1 (GLP-1) receptor, according to Axel Haupt, MD, PhD, of Eli Lilly.

Tirzepatide (LY3298176) is currently under investigation for the treatment of type 2 diabetes, and Dr. Haupt reported data from a post hoc analysis of a double-blind, placebo-controlled, phase 2b study showing that “exploratory” serum markers of apoptosis and fibrosis – keratin-18 (K-18) and Pro-C3, respectively – were decreased from baseline to a greater extent in patients treated with tirzepatide than with placebo, while total adiponectin was increased. The latter is “thought to protect the liver from inflammation and fibrosis,” Dr. Haupt observed.

The main results of the trial were published last year (Lancet. 2018;392:2180-93) and showed that, after 26 weeks, there was a dose-dependent decrease in both glycated hemoglobin (HbA_1c) and body weight with tirzepatide 10 mg and 15 mg, compared with placebo and an active comparator, dulaglutide 1.5 mg.

The study population was typical of type 2 diabetes: baseline HbA_1c was 8.1%; the average body mass index was 32 kg/m², with a diabetes duration of 5 years; and the main treatment (90%) had been metformin.

The rationale for the NASH-related biomarker analysis was that type 2 diabetes and NAFLD were known to be overlapping conditions, and weight loss had been shown to be an effective means of resolving NASH, Dr. Haupt said. In addition, a small “proof-of-concept” study with the GLP-1 receptor agonist liraglutide had suggested that these drugs may be effective in NASH.

Tirzepatide, at doses of 5, 10, and 15 mg, was associated with significant decreases in K-18 from baseline to week 26 and compared with placebo and the 1-mg tirzepatide dose. Mean baseline concentrations of K-18 were 394.4 U/L in the placebo group and reduced by 22.6 U/L by week 26. Corresponding baseline values for tirzepatide 5 mg were 375.8 U/L (change, –87.6 U/L); for 10 mg, 409.9 U/L (–157.8 U/L); and for 15 mg, 376.2 U/L (–110.6 U/L).

Dr. Haupt noted that a K-18 value of 250 U/L was considered a cutoff for a diagnosis of NASH. “So we really think that we have some NASH patients in this population,” he observed.

At week 26, Pro-C3 levels significantly decreased by 1.2 ng/mL from a baseline of 8.6 ng/mL with tirzepatide 15 mg, compared with an increase of 0.9 ng/mL from a baseline of 9.3 ng/mL for placebo (P less than .05). However, values of between 15-20 ng/mL would be expected for advanced fibrosis, Dr. Haupt said, “so we think we [don’t] have a lot of patients with advanced fibrosis, we have a lower grade of fibrosis or no fibrosis in our patient population.”

By week 26, adiponectin levels significantly increased by 0.9 mg/L from baseline, both with tirzepatide 10 mg (P less than .05) and 15 mg (P less than .05), compared with placebo (–0.1 mg/L; both P less than .05).

“This study was really designed as a type 2 diabetes efficacy study, so the NASH biomarker work is exploratory and only hypothesis generating,” Dr. Haupt noted. “We think there is overlap in type 2 diabetes and NASH, but it is not an ideal population to look into those biomarkers.” There are also other limitations, such as the baseline values across treatment groups not being matched, so there is likely to be some inconsistency in these data, he added.

That said, Dr. Haupt concluded that, “along with the weight-loss findings,” these exploratory biomarker findings supported the further evaluation of tirzepatide in patients with NASH.”

DURATION-8: Exenatide plus dapagliflozin

In another hypothesis-generating post hoc analysis, this time of the phase 3 DURATION-8 clinical trial, a combination of exenatide and dapagliflozin was found to have a beneficial effect on markers of hepatic steatosis and fibrosis in patients with type 2 diabetes.

Sara Freeman/MDedge News

“We have some good evidence that both GLP-1 receptor agonists and SGLT2 [sodium-glucose cotransporter 2] inhibitors may have benefits in reducing steatosis and even steatohepatitis in [patients with] type 2 diabetes. So the association of two diabetes drugs might provide an advantage. However, this had not previously been tested in a randomized, controlled trial,” observed Cristian Guja, MD, PhD, of Carol Davila University of Medicine and Pharmacy in Bucharest, Romania.

The main aims of the DURATION-8 clinical trial, which ran for 104 weeks, was to compare the efficacy and safety of combining exenatide (2 mg, once a week) and dapagliflozin (10 mg, daily) with either exenatide 2 mg with placebo or dapagliflozin 10 mg with placebo. Results showed greater improved glycemic control and reductions in body weight and systolic BP with the exenatide-dapagliflozin combination.

A total of 685 patients were included in the post hoc analysis, of whom 228 had been treated with the combination, 228 with exenatide plus placebo, and 230 with dapagliflozin plus placebo. At baseline, levels of the markers of NAFLD and fibrosis that were assessed were similar between the groups. Between 81% and 93% of study participants had fatty liver or steatosis as defined by a Fatty Liver Index (FLI) of 60 or more or an overall NAFLD Liver Fat Score (NLFS) of –0.64 or higher. Between 9% and 13% of patients had liver fibrosis, as defined as an NAFLD Fibrosis Score (NFS) above 0.676, a Fibrosis-4 score (FIB-4) of 1.46 or more, or both.

At 28 weeks, the proportion of patients with biomarker scores suggestive of fatty liver disease or steatosis was significantly reduced from baseline with the exenatide-dapagliflozin combination (–10.5% for FLI of 60 or more; –6.5% for NLFS of –0.640 or more), Dr. Guja said, and biomarker scores suggestive of advanced fibrosis (NFS greater than 0.676; FIB-4 of 1.46 or more) were reduced by 4.1% and 3.6%, respectively.

At 28 and 52 weeks, the combination therapy showed stronger effects than exenatide and dapagliflozin alone in improving markers of hepatic steatosis (FLI: 28 weeks, –6.81, –3.90, –4.04; and 52 weeks, –6.23, –3.00, –4.58). The combination therapy also showed improvement for advanced fibrosis biomarkers at both time points (FIB-4: 28 weeks, –0.06, –0.03, –0.04; and 52 weeks, –0.05, –0.02, –0,04).

Dr. Guja noted that, although the study was not powered to assess the effect of on fatty liver, making all these data exploratory, this was the first analysis to describe improvements in biomarkers of fatty liver or steatosis and fibrosis from a large trial. “Some specific, dedicated, prospective trials are needed in the future to validate these findings.”

The CENTAUR study was funded by Allergan, of which Dr. Landgren is an employee. The phase 2b study with tirzepatide was supported by Eli Lilly. Dr. Haupt disclosed being an employee and also holding stocks in the company. The DURATION-8 study was sponsored by AstraZeneca. Dr. Guja disclosed that he had participated in scientific advisory boards and received consulting fees from AstraZeneca and other companies.

SOURCES: Landgren H et al. EASD 2019, Oral Presentation 179; Haupt A et al. EASD 2019, Oral Presentation 177; Guja C et al. EASD 2019, Oral Presentation 178.

BARCELONA – The investigational oral agent cenicriviroc showed positive effects on liver fibrosis in adults with nonalcoholic steatohepatitis (NASH), many of whom had type 2 diabetes, in a phase 2b trial reported at the annual meeting of the European Association for the Study of Diabetes.

Other data released at the meeting, which showed potential positive effects of novel or existing diabetes treatments on nonalcoholic fatty liver disease (NAFLD), included post hoc analyses of a phase 2b study with tirzepatide and a phase 3 study that combined exenatide and dapagliflozin.

Currently, no medications for NAFLD or NASH have been approved in the United States.

CENTAUR with cenicriviroc

Results of the previously reported CENTAUR trial showed that the antifibrotic effects of cenicriviroc, a dual chemokine receptor antagonist, were greatest in patients with more-severe liver disease (Hepatology. 2018;67[5]:1754-67). At the meeting, Henrik Landgren, PhD, of Allergan, presented data from the 2-year trial overall, and specifically in patients with advanced, stage 3 fibrosis.

CENTAUR was a randomized, double-blind, placebo-controlled, multinational study with 289 adults who had biopsy-confirmed NASH, an NAFLD Activity Score (NAS; range, 0-8; score of 5 or more diagnostic of NASH) of 4 or more, and stages 1-3 liver fibrosis as determined by the NASH clinical research network system (Contemp Clin Trials. 2016;47:356-65). The mean age of the patients enrolled at baseline was 54 years, the mean body mass index was 33.9 kg/m², and just more than half the patients (52%) had type 2 diabetes.

The patients were randomized to three treatment arms: cenicriviroc 150 mg for 2 years; placebo for 1 year, then cenicriviroc 150 mg for 1 year; or placebo for 2 years. The primary endpoint was histologic improvement (reduction of 2 or more points in overall NAS, with reduction of 1 or more points in more than one category of the NAS without worsening of fibrosis at the end of year 1. The key secondary endpoint was complete NASH resolution without worsening of fibrosis at year 2.

Dr. Landgren reported that, at year 1, of the total number of patients, 28.6% of those receiving cenicriviroc achieved an improvement in fibrosis of one or more stages, compared with 19.0% of those receiving placebo. Of the 97 patients who had advanced fibrosis at baseline, 38.3% of those on cenicriviroc and 28.0% of those on placebo achieved the same endpoint.

Those effects were sustained at year 2, Dr. Landgren emphasized, with twice as many cenicriviroc- than placebo-treated patients achieving one or more stage improvement in fibrosis and no worsening of NASH at year 2 (60% and 30%, respectively), with more pronounced improvements in those who had advanced fibrosis at baseline (86% and 60%).

In addition, analyses of biomarkers suggested that cenicriviroc had systematic anti-inflammatory activity, with reductions observed in high-sensitivity C-reactive protein; fibrinogen; and levels of interleukin-6, IL-8, and IL-1-beta.

Dr. Landgren and colleagues noted that cenicriviroc provided antifibrotic benefit in patients with NASH and fibrosis. Those benefits were sustained through year 2 and were more pronounced in patients who had advanced fibrosis at baseline.

The safety of cenicriviroc was “comparable with placebo,” he said, suggesting that the data supported the phase 3 AURORA study that is currently recruiting.

Tirzepatide for NASH

Another approach worth exploring for the treatment of NASH, is the use of tirzepatide, a dual agonist of glucose-dependent insulinotropic polypeptide and the glucagonlike peptide–1 (GLP-1) receptor, according to Axel Haupt, MD, PhD, of Eli Lilly.

Tirzepatide (LY3298176) is currently under investigation for the treatment of type 2 diabetes, and Dr. Haupt reported data from a post hoc analysis of a double-blind, placebo-controlled, phase 2b study showing that “exploratory” serum markers of apoptosis and fibrosis – keratin-18 (K-18) and Pro-C3, respectively – were decreased from baseline to a greater extent in patients treated with tirzepatide than with placebo, while total adiponectin was increased. The latter is “thought to protect the liver from inflammation and fibrosis,” Dr. Haupt observed.

The main results of the trial were published last year (Lancet. 2018;392:2180-93) and showed that, after 26 weeks, there was a dose-dependent decrease in both glycated hemoglobin (HbA_1c) and body weight with tirzepatide 10 mg and 15 mg, compared with placebo and an active comparator, dulaglutide 1.5 mg.

The study population was typical of type 2 diabetes: baseline HbA_1c was 8.1%; the average body mass index was 32 kg/m², with a diabetes duration of 5 years; and the main treatment (90%) had been metformin.

The rationale for the NASH-related biomarker analysis was that type 2 diabetes and NAFLD were known to be overlapping conditions, and weight loss had been shown to be an effective means of resolving NASH, Dr. Haupt said. In addition, a small “proof-of-concept” study with the GLP-1 receptor agonist liraglutide had suggested that these drugs may be effective in NASH.

Tirzepatide, at doses of 5, 10, and 15 mg, was associated with significant decreases in K-18 from baseline to week 26 and compared with placebo and the 1-mg tirzepatide dose. Mean baseline concentrations of K-18 were 394.4 U/L in the placebo group and reduced by 22.6 U/L by week 26. Corresponding baseline values for tirzepatide 5 mg were 375.8 U/L (change, –87.6 U/L); for 10 mg, 409.9 U/L (–157.8 U/L); and for 15 mg, 376.2 U/L (–110.6 U/L).

Dr. Haupt noted that a K-18 value of 250 U/L was considered a cutoff for a diagnosis of NASH. “So we really think that we have some NASH patients in this population,” he observed.

At week 26, Pro-C3 levels significantly decreased by 1.2 ng/mL from a baseline of 8.6 ng/mL with tirzepatide 15 mg, compared with an increase of 0.9 ng/mL from a baseline of 9.3 ng/mL for placebo (P less than .05). However, values of between 15-20 ng/mL would be expected for advanced fibrosis, Dr. Haupt said, “so we think we [don’t] have a lot of patients with advanced fibrosis, we have a lower grade of fibrosis or no fibrosis in our patient population.”

By week 26, adiponectin levels significantly increased by 0.9 mg/L from baseline, both with tirzepatide 10 mg (P less than .05) and 15 mg (P less than .05), compared with placebo (–0.1 mg/L; both P less than .05).

“This study was really designed as a type 2 diabetes efficacy study, so the NASH biomarker work is exploratory and only hypothesis generating,” Dr. Haupt noted. “We think there is overlap in type 2 diabetes and NASH, but it is not an ideal population to look into those biomarkers.” There are also other limitations, such as the baseline values across treatment groups not being matched, so there is likely to be some inconsistency in these data, he added.

That said, Dr. Haupt concluded that, “along with the weight-loss findings,” these exploratory biomarker findings supported the further evaluation of tirzepatide in patients with NASH.”

DURATION-8: Exenatide plus dapagliflozin

In another hypothesis-generating post hoc analysis, this time of the phase 3 DURATION-8 clinical trial, a combination of exenatide and dapagliflozin was found to have a beneficial effect on markers of hepatic steatosis and fibrosis in patients with type 2 diabetes.

Sara Freeman/MDedge News

“We have some good evidence that both GLP-1 receptor agonists and SGLT2 [sodium-glucose cotransporter 2] inhibitors may have benefits in reducing steatosis and even steatohepatitis in [patients with] type 2 diabetes. So the association of two diabetes drugs might provide an advantage. However, this had not previously been tested in a randomized, controlled trial,” observed Cristian Guja, MD, PhD, of Carol Davila University of Medicine and Pharmacy in Bucharest, Romania.

The main aims of the DURATION-8 clinical trial, which ran for 104 weeks, was to compare the efficacy and safety of combining exenatide (2 mg, once a week) and dapagliflozin (10 mg, daily) with either exenatide 2 mg with placebo or dapagliflozin 10 mg with placebo. Results showed greater improved glycemic control and reductions in body weight and systolic BP with the exenatide-dapagliflozin combination.

A total of 685 patients were included in the post hoc analysis, of whom 228 had been treated with the combination, 228 with exenatide plus placebo, and 230 with dapagliflozin plus placebo. At baseline, levels of the markers of NAFLD and fibrosis that were assessed were similar between the groups. Between 81% and 93% of study participants had fatty liver or steatosis as defined by a Fatty Liver Index (FLI) of 60 or more or an overall NAFLD Liver Fat Score (NLFS) of –0.64 or higher. Between 9% and 13% of patients had liver fibrosis, as defined as an NAFLD Fibrosis Score (NFS) above 0.676, a Fibrosis-4 score (FIB-4) of 1.46 or more, or both.

At 28 weeks, the proportion of patients with biomarker scores suggestive of fatty liver disease or steatosis was significantly reduced from baseline with the exenatide-dapagliflozin combination (–10.5% for FLI of 60 or more; –6.5% for NLFS of –0.640 or more), Dr. Guja said, and biomarker scores suggestive of advanced fibrosis (NFS greater than 0.676; FIB-4 of 1.46 or more) were reduced by 4.1% and 3.6%, respectively.

At 28 and 52 weeks, the combination therapy showed stronger effects than exenatide and dapagliflozin alone in improving markers of hepatic steatosis (FLI: 28 weeks, –6.81, –3.90, –4.04; and 52 weeks, –6.23, –3.00, –4.58). The combination therapy also showed improvement for advanced fibrosis biomarkers at both time points (FIB-4: 28 weeks, –0.06, –0.03, –0.04; and 52 weeks, –0.05, –0.02, –0,04).

Dr. Guja noted that, although the study was not powered to assess the effect of on fatty liver, making all these data exploratory, this was the first analysis to describe improvements in biomarkers of fatty liver or steatosis and fibrosis from a large trial. “Some specific, dedicated, prospective trials are needed in the future to validate these findings.”

The CENTAUR study was funded by Allergan, of which Dr. Landgren is an employee. The phase 2b study with tirzepatide was supported by Eli Lilly. Dr. Haupt disclosed being an employee and also holding stocks in the company. The DURATION-8 study was sponsored by AstraZeneca. Dr. Guja disclosed that he had participated in scientific advisory boards and received consulting fees from AstraZeneca and other companies.

SOURCES: Landgren H et al. EASD 2019, Oral Presentation 179; Haupt A et al. EASD 2019, Oral Presentation 177; Guja C et al. EASD 2019, Oral Presentation 178.

BARCELONA – The investigational oral agent cenicriviroc showed positive effects on liver fibrosis in adults with nonalcoholic steatohepatitis (NASH), many of whom had type 2 diabetes, in a phase 2b trial reported at the annual meeting of the European Association for the Study of Diabetes.

Other data released at the meeting, which showed potential positive effects of novel or existing diabetes treatments on nonalcoholic fatty liver disease (NAFLD), included post hoc analyses of a phase 2b study with tirzepatide and a phase 3 study that combined exenatide and dapagliflozin.

Currently, no medications for NAFLD or NASH have been approved in the United States.

CENTAUR with cenicriviroc

Results of the previously reported CENTAUR trial showed that the antifibrotic effects of cenicriviroc, a dual chemokine receptor antagonist, were greatest in patients with more-severe liver disease (Hepatology. 2018;67[5]:1754-67). At the meeting, Henrik Landgren, PhD, of Allergan, presented data from the 2-year trial overall, and specifically in patients with advanced, stage 3 fibrosis.

CENTAUR was a randomized, double-blind, placebo-controlled, multinational study with 289 adults who had biopsy-confirmed NASH, an NAFLD Activity Score (NAS; range, 0-8; score of 5 or more diagnostic of NASH) of 4 or more, and stages 1-3 liver fibrosis as determined by the NASH clinical research network system (Contemp Clin Trials. 2016;47:356-65). The mean age of the patients enrolled at baseline was 54 years, the mean body mass index was 33.9 kg/m², and just more than half the patients (52%) had type 2 diabetes.

The patients were randomized to three treatment arms: cenicriviroc 150 mg for 2 years; placebo for 1 year, then cenicriviroc 150 mg for 1 year; or placebo for 2 years. The primary endpoint was histologic improvement (reduction of 2 or more points in overall NAS, with reduction of 1 or more points in more than one category of the NAS without worsening of fibrosis at the end of year 1. The key secondary endpoint was complete NASH resolution without worsening of fibrosis at year 2.

Dr. Landgren reported that, at year 1, of the total number of patients, 28.6% of those receiving cenicriviroc achieved an improvement in fibrosis of one or more stages, compared with 19.0% of those receiving placebo. Of the 97 patients who had advanced fibrosis at baseline, 38.3% of those on cenicriviroc and 28.0% of those on placebo achieved the same endpoint.

Those effects were sustained at year 2, Dr. Landgren emphasized, with twice as many cenicriviroc- than placebo-treated patients achieving one or more stage improvement in fibrosis and no worsening of NASH at year 2 (60% and 30%, respectively), with more pronounced improvements in those who had advanced fibrosis at baseline (86% and 60%).

In addition, analyses of biomarkers suggested that cenicriviroc had systematic anti-inflammatory activity, with reductions observed in high-sensitivity C-reactive protein; fibrinogen; and levels of interleukin-6, IL-8, and IL-1-beta.

Dr. Landgren and colleagues noted that cenicriviroc provided antifibrotic benefit in patients with NASH and fibrosis. Those benefits were sustained through year 2 and were more pronounced in patients who had advanced fibrosis at baseline.

The safety of cenicriviroc was “comparable with placebo,” he said, suggesting that the data supported the phase 3 AURORA study that is currently recruiting.

Tirzepatide for NASH

Another approach worth exploring for the treatment of NASH, is the use of tirzepatide, a dual agonist of glucose-dependent insulinotropic polypeptide and the glucagonlike peptide–1 (GLP-1) receptor, according to Axel Haupt, MD, PhD, of Eli Lilly.

Tirzepatide (LY3298176) is currently under investigation for the treatment of type 2 diabetes, and Dr. Haupt reported data from a post hoc analysis of a double-blind, placebo-controlled, phase 2b study showing that “exploratory” serum markers of apoptosis and fibrosis – keratin-18 (K-18) and Pro-C3, respectively – were decreased from baseline to a greater extent in patients treated with tirzepatide than with placebo, while total adiponectin was increased. The latter is “thought to protect the liver from inflammation and fibrosis,” Dr. Haupt observed.

The main results of the trial were published last year (Lancet. 2018;392:2180-93) and showed that, after 26 weeks, there was a dose-dependent decrease in both glycated hemoglobin (HbA_1c) and body weight with tirzepatide 10 mg and 15 mg, compared with placebo and an active comparator, dulaglutide 1.5 mg.

The study population was typical of type 2 diabetes: baseline HbA_1c was 8.1%; the average body mass index was 32 kg/m², with a diabetes duration of 5 years; and the main treatment (90%) had been metformin.

The rationale for the NASH-related biomarker analysis was that type 2 diabetes and NAFLD were known to be overlapping conditions, and weight loss had been shown to be an effective means of resolving NASH, Dr. Haupt said. In addition, a small “proof-of-concept” study with the GLP-1 receptor agonist liraglutide had suggested that these drugs may be effective in NASH.

Tirzepatide, at doses of 5, 10, and 15 mg, was associated with significant decreases in K-18 from baseline to week 26 and compared with placebo and the 1-mg tirzepatide dose. Mean baseline concentrations of K-18 were 394.4 U/L in the placebo group and reduced by 22.6 U/L by week 26. Corresponding baseline values for tirzepatide 5 mg were 375.8 U/L (change, –87.6 U/L); for 10 mg, 409.9 U/L (–157.8 U/L); and for 15 mg, 376.2 U/L (–110.6 U/L).

Dr. Haupt noted that a K-18 value of 250 U/L was considered a cutoff for a diagnosis of NASH. “So we really think that we have some NASH patients in this population,” he observed.

At week 26, Pro-C3 levels significantly decreased by 1.2 ng/mL from a baseline of 8.6 ng/mL with tirzepatide 15 mg, compared with an increase of 0.9 ng/mL from a baseline of 9.3 ng/mL for placebo (P less than .05). However, values of between 15-20 ng/mL would be expected for advanced fibrosis, Dr. Haupt said, “so we think we [don’t] have a lot of patients with advanced fibrosis, we have a lower grade of fibrosis or no fibrosis in our patient population.”

By week 26, adiponectin levels significantly increased by 0.9 mg/L from baseline, both with tirzepatide 10 mg (P less than .05) and 15 mg (P less than .05), compared with placebo (–0.1 mg/L; both P less than .05).

“This study was really designed as a type 2 diabetes efficacy study, so the NASH biomarker work is exploratory and only hypothesis generating,” Dr. Haupt noted. “We think there is overlap in type 2 diabetes and NASH, but it is not an ideal population to look into those biomarkers.” There are also other limitations, such as the baseline values across treatment groups not being matched, so there is likely to be some inconsistency in these data, he added.

That said, Dr. Haupt concluded that, “along with the weight-loss findings,” these exploratory biomarker findings supported the further evaluation of tirzepatide in patients with NASH.”

DURATION-8: Exenatide plus dapagliflozin

In another hypothesis-generating post hoc analysis, this time of the phase 3 DURATION-8 clinical trial, a combination of exenatide and dapagliflozin was found to have a beneficial effect on markers of hepatic steatosis and fibrosis in patients with type 2 diabetes.

Sara Freeman/MDedge News

“We have some good evidence that both GLP-1 receptor agonists and SGLT2 [sodium-glucose cotransporter 2] inhibitors may have benefits in reducing steatosis and even steatohepatitis in [patients with] type 2 diabetes. So the association of two diabetes drugs might provide an advantage. However, this had not previously been tested in a randomized, controlled trial,” observed Cristian Guja, MD, PhD, of Carol Davila University of Medicine and Pharmacy in Bucharest, Romania.

The main aims of the DURATION-8 clinical trial, which ran for 104 weeks, was to compare the efficacy and safety of combining exenatide (2 mg, once a week) and dapagliflozin (10 mg, daily) with either exenatide 2 mg with placebo or dapagliflozin 10 mg with placebo. Results showed greater improved glycemic control and reductions in body weight and systolic BP with the exenatide-dapagliflozin combination.

A total of 685 patients were included in the post hoc analysis, of whom 228 had been treated with the combination, 228 with exenatide plus placebo, and 230 with dapagliflozin plus placebo. At baseline, levels of the markers of NAFLD and fibrosis that were assessed were similar between the groups. Between 81% and 93% of study participants had fatty liver or steatosis as defined by a Fatty Liver Index (FLI) of 60 or more or an overall NAFLD Liver Fat Score (NLFS) of –0.64 or higher. Between 9% and 13% of patients had liver fibrosis, as defined as an NAFLD Fibrosis Score (NFS) above 0.676, a Fibrosis-4 score (FIB-4) of 1.46 or more, or both.

At 28 weeks, the proportion of patients with biomarker scores suggestive of fatty liver disease or steatosis was significantly reduced from baseline with the exenatide-dapagliflozin combination (–10.5% for FLI of 60 or more; –6.5% for NLFS of –0.640 or more), Dr. Guja said, and biomarker scores suggestive of advanced fibrosis (NFS greater than 0.676; FIB-4 of 1.46 or more) were reduced by 4.1% and 3.6%, respectively.

At 28 and 52 weeks, the combination therapy showed stronger effects than exenatide and dapagliflozin alone in improving markers of hepatic steatosis (FLI: 28 weeks, –6.81, –3.90, –4.04; and 52 weeks, –6.23, –3.00, –4.58). The combination therapy also showed improvement for advanced fibrosis biomarkers at both time points (FIB-4: 28 weeks, –0.06, –0.03, –0.04; and 52 weeks, –0.05, –0.02, –0,04).

Dr. Guja noted that, although the study was not powered to assess the effect of on fatty liver, making all these data exploratory, this was the first analysis to describe improvements in biomarkers of fatty liver or steatosis and fibrosis from a large trial. “Some specific, dedicated, prospective trials are needed in the future to validate these findings.”

The CENTAUR study was funded by Allergan, of which Dr. Landgren is an employee. The phase 2b study with tirzepatide was supported by Eli Lilly. Dr. Haupt disclosed being an employee and also holding stocks in the company. The DURATION-8 study was sponsored by AstraZeneca. Dr. Guja disclosed that he had participated in scientific advisory boards and received consulting fees from AstraZeneca and other companies.

SOURCES: Landgren H et al. EASD 2019, Oral Presentation 179; Haupt A et al. EASD 2019, Oral Presentation 177; Guja C et al. EASD 2019, Oral Presentation 178.

PHILADELPHIA – The definition and treatment of heart failure with reduced ejection fraction should change based on recent findings and analyses from major trials, said a key heart failure leader at the American Heart Association scientific sessions.

Mitchel L. Zoler/MDedge News

The people charged with writing U.S. guidelines for heart failure management already have enough evidence to change the recommended way of using sacubitril/valsartan (Entresto) in patients with heart failure with reduced ejection fraction (HFrEF), said Clyde W. Yancy, MD, professor of medicine and chief of cardiology at Northwestern University, Chicago. Accumulated evidence from studies and more than 5 years of experience in routine practice with the angiotensin receptor neprilysin inhibitor (ARNI) combination sacubitril/valsartan for treating HFrEF patients justifies striking the existing recommendation to first start patients on an ACE inhibitor or angiotensin receptor blocker and only after that switching to sacubitril/valsartan, a sequence that has rankled some clinicians as an unnecessary delay and barrier to starting patients on the ARNI regimen.

U.S. guidelines should now suggest that ARNI treatment start immediately, suggested Dr. Yancy, who chaired the AHA/American College of Cardiology panel that updated U.S. guidelines for heart failure management in 2013 (Circulation. 2013 Oct 15;128[16]:e240-327), 2016 (J Am Coll Cardiol. 2016 Sep;68[13]:1476-88), and 2017 (Circulation. 2017 Aug 8; 136[6]:e137-61).

Expanding the heart failure group for sacubitril/valsartan

Dr. Yancy also proposed a second major and immediate change to the existing heart failure guideline based on a new appreciation of a heart failure population that could benefit from ARNI treatment: patients with “mid-range” heart failure, defined by a left ventricular ejection fraction (LVEF) of 41%-49% that places them between patients with HFrEF with an ejection fraction of 40% or less, and those with heart failure with preserved ejection fraction (HFpEF) of 50% or more. As yet unchanged in the 2013 AHA/ACC heart failure guideline is the proposition that patients with heart failure and an ejection fraction of 41%-49% have “borderline” heart failure with characteristics, treatment patterns, and outcomes “similar to patients with HFpEF.”

That premise should now go out the window, urged Dr. Yancy, based on a new analysis of data collected from both the recent PARAGON-HF trial of sacubitril/valsartan in patients with HFpEF and ejection fractions of 45% or higher (N Engl J Med. 2019 Oct 24;381[17]:1609-20) and the landmark PARADIGM-HF trial that established sacubitril/valsartan as a treatment for patients with HFrEF (N Engl J Med. 2014 Sep 11;371[11]:993-1004). A combined analysis of the more than 13,000 total patients in both studies suggested that “patients with ejection fraction lower than normal, which includes those with so-called heart failure with mid-range ejection fraction or borderline ejection fraction, would likely benefit from sacubitril/valsartan, compared with RAS inhibition,” concluded the authors of the new analysis (Circulation. 2019 Nov 17. doi: 10.1161/CIRCULATIONAHA.119.044586).

Dr. Yancy argued that, based on this new analysis, a further revision to the 2013 guideline should say that patients with heart failure with a LVEF of 41%-49% have characteristics, treatment responses, and outcomes that “appear similar to those of patient with HFrEF,” a sharp departure from the existing text that lumps these patients with the HFpEF subgroup. “There appears to be a signal that extends the benefit of ARNI to patients with ejection fractions above the current threshold for HFrEF but below what is typically HFpEF,” he said.

Bringing SGLT2 inhibitors into heart failure management

Dr. Yancy also cited recently reported data from another landmark trial, DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure), as an impetus for both another immediate change to the guideline and for a potential second change pending a report of confirmatory evidence that may arrive in 2020.

The DAPA-HF results showed that the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin (Farxiga) was just as effective for preventing all-cause death and heart failure hospitalizations and urgent visits in patients without type 2 diabetes as it is in patients with type 2 diabetes (N Engl J Med. 2019 Nov 21;381[21]:1995-2008), a remarkable finding for an agent that came onto the U.S. market as a diabetes drug specifically aimed at reducing levels of glycosylated hemoglobin.

Dr. Yancy proposed an immediate guideline change to acknowledge the proven protection against incident heart failure that treatment with a SGLT2 inhibitor gives patients with type 2 diabetes. There is now “a strong opportunity to use an SGLT2 inhibitor in patients with type 2 diabetes to reduce the incidence of heart failure,” he said.

And he added that, if results from EMPEROR REDUCED (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction), studying the SGLT2 inhibitor empagliflozin (Jardiance) in HFrEF patients with and without type 2 diabetes, can confirm the efficacy of a second drug from this class in preventing heart failure events in patients with HFrEF but without diabetes, then the time will have arrived for another guideline change to establish the SGLT2 inhibitors as a new “foundational” drug for the management of all HFrEF patients, regardless of their level of glycemic control. The SGLT2 inhibitors are a particularly attractive additional drug because they are taken once daily orally with no need for dosage adjustment, so far they have shown excellent safety in patients without diabetes with no episodes of hypoglycemia or ketoacidosis, and they have even shown evidence for heart failure benefit in patients older than 75 years, Dr. Yancy noted.

Dr. Yancy had no relevant disclosures.

[email protected]

PHILADELPHIA – The definition and treatment of heart failure with reduced ejection fraction should change based on recent findings and analyses from major trials, said a key heart failure leader at the American Heart Association scientific sessions.

Mitchel L. Zoler/MDedge News

The people charged with writing U.S. guidelines for heart failure management already have enough evidence to change the recommended way of using sacubitril/valsartan (Entresto) in patients with heart failure with reduced ejection fraction (HFrEF), said Clyde W. Yancy, MD, professor of medicine and chief of cardiology at Northwestern University, Chicago. Accumulated evidence from studies and more than 5 years of experience in routine practice with the angiotensin receptor neprilysin inhibitor (ARNI) combination sacubitril/valsartan for treating HFrEF patients justifies striking the existing recommendation to first start patients on an ACE inhibitor or angiotensin receptor blocker and only after that switching to sacubitril/valsartan, a sequence that has rankled some clinicians as an unnecessary delay and barrier to starting patients on the ARNI regimen.

U.S. guidelines should now suggest that ARNI treatment start immediately, suggested Dr. Yancy, who chaired the AHA/American College of Cardiology panel that updated U.S. guidelines for heart failure management in 2013 (Circulation. 2013 Oct 15;128[16]:e240-327), 2016 (J Am Coll Cardiol. 2016 Sep;68[13]:1476-88), and 2017 (Circulation. 2017 Aug 8; 136[6]:e137-61).

Expanding the heart failure group for sacubitril/valsartan

Dr. Yancy also proposed a second major and immediate change to the existing heart failure guideline based on a new appreciation of a heart failure population that could benefit from ARNI treatment: patients with “mid-range” heart failure, defined by a left ventricular ejection fraction (LVEF) of 41%-49% that places them between patients with HFrEF with an ejection fraction of 40% or less, and those with heart failure with preserved ejection fraction (HFpEF) of 50% or more. As yet unchanged in the 2013 AHA/ACC heart failure guideline is the proposition that patients with heart failure and an ejection fraction of 41%-49% have “borderline” heart failure with characteristics, treatment patterns, and outcomes “similar to patients with HFpEF.”

That premise should now go out the window, urged Dr. Yancy, based on a new analysis of data collected from both the recent PARAGON-HF trial of sacubitril/valsartan in patients with HFpEF and ejection fractions of 45% or higher (N Engl J Med. 2019 Oct 24;381[17]:1609-20) and the landmark PARADIGM-HF trial that established sacubitril/valsartan as a treatment for patients with HFrEF (N Engl J Med. 2014 Sep 11;371[11]:993-1004). A combined analysis of the more than 13,000 total patients in both studies suggested that “patients with ejection fraction lower than normal, which includes those with so-called heart failure with mid-range ejection fraction or borderline ejection fraction, would likely benefit from sacubitril/valsartan, compared with RAS inhibition,” concluded the authors of the new analysis (Circulation. 2019 Nov 17. doi: 10.1161/CIRCULATIONAHA.119.044586).

Dr. Yancy argued that, based on this new analysis, a further revision to the 2013 guideline should say that patients with heart failure with a LVEF of 41%-49% have characteristics, treatment responses, and outcomes that “appear similar to those of patient with HFrEF,” a sharp departure from the existing text that lumps these patients with the HFpEF subgroup. “There appears to be a signal that extends the benefit of ARNI to patients with ejection fractions above the current threshold for HFrEF but below what is typically HFpEF,” he said.

Bringing SGLT2 inhibitors into heart failure management

Dr. Yancy also cited recently reported data from another landmark trial, DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure), as an impetus for both another immediate change to the guideline and for a potential second change pending a report of confirmatory evidence that may arrive in 2020.

The DAPA-HF results showed that the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin (Farxiga) was just as effective for preventing all-cause death and heart failure hospitalizations and urgent visits in patients without type 2 diabetes as it is in patients with type 2 diabetes (N Engl J Med. 2019 Nov 21;381[21]:1995-2008), a remarkable finding for an agent that came onto the U.S. market as a diabetes drug specifically aimed at reducing levels of glycosylated hemoglobin.

Dr. Yancy proposed an immediate guideline change to acknowledge the proven protection against incident heart failure that treatment with a SGLT2 inhibitor gives patients with type 2 diabetes. There is now “a strong opportunity to use an SGLT2 inhibitor in patients with type 2 diabetes to reduce the incidence of heart failure,” he said.

And he added that, if results from EMPEROR REDUCED (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction), studying the SGLT2 inhibitor empagliflozin (Jardiance) in HFrEF patients with and without type 2 diabetes, can confirm the efficacy of a second drug from this class in preventing heart failure events in patients with HFrEF but without diabetes, then the time will have arrived for another guideline change to establish the SGLT2 inhibitors as a new “foundational” drug for the management of all HFrEF patients, regardless of their level of glycemic control. The SGLT2 inhibitors are a particularly attractive additional drug because they are taken once daily orally with no need for dosage adjustment, so far they have shown excellent safety in patients without diabetes with no episodes of hypoglycemia or ketoacidosis, and they have even shown evidence for heart failure benefit in patients older than 75 years, Dr. Yancy noted.

Dr. Yancy had no relevant disclosures.

[email protected]

PHILADELPHIA – The definition and treatment of heart failure with reduced ejection fraction should change based on recent findings and analyses from major trials, said a key heart failure leader at the American Heart Association scientific sessions.

Mitchel L. Zoler/MDedge News

The people charged with writing U.S. guidelines for heart failure management already have enough evidence to change the recommended way of using sacubitril/valsartan (Entresto) in patients with heart failure with reduced ejection fraction (HFrEF), said Clyde W. Yancy, MD, professor of medicine and chief of cardiology at Northwestern University, Chicago. Accumulated evidence from studies and more than 5 years of experience in routine practice with the angiotensin receptor neprilysin inhibitor (ARNI) combination sacubitril/valsartan for treating HFrEF patients justifies striking the existing recommendation to first start patients on an ACE inhibitor or angiotensin receptor blocker and only after that switching to sacubitril/valsartan, a sequence that has rankled some clinicians as an unnecessary delay and barrier to starting patients on the ARNI regimen.

U.S. guidelines should now suggest that ARNI treatment start immediately, suggested Dr. Yancy, who chaired the AHA/American College of Cardiology panel that updated U.S. guidelines for heart failure management in 2013 (Circulation. 2013 Oct 15;128[16]:e240-327), 2016 (J Am Coll Cardiol. 2016 Sep;68[13]:1476-88), and 2017 (Circulation. 2017 Aug 8; 136[6]:e137-61).

Expanding the heart failure group for sacubitril/valsartan

Dr. Yancy also proposed a second major and immediate change to the existing heart failure guideline based on a new appreciation of a heart failure population that could benefit from ARNI treatment: patients with “mid-range” heart failure, defined by a left ventricular ejection fraction (LVEF) of 41%-49% that places them between patients with HFrEF with an ejection fraction of 40% or less, and those with heart failure with preserved ejection fraction (HFpEF) of 50% or more. As yet unchanged in the 2013 AHA/ACC heart failure guideline is the proposition that patients with heart failure and an ejection fraction of 41%-49% have “borderline” heart failure with characteristics, treatment patterns, and outcomes “similar to patients with HFpEF.”

That premise should now go out the window, urged Dr. Yancy, based on a new analysis of data collected from both the recent PARAGON-HF trial of sacubitril/valsartan in patients with HFpEF and ejection fractions of 45% or higher (N Engl J Med. 2019 Oct 24;381[17]:1609-20) and the landmark PARADIGM-HF trial that established sacubitril/valsartan as a treatment for patients with HFrEF (N Engl J Med. 2014 Sep 11;371[11]:993-1004). A combined analysis of the more than 13,000 total patients in both studies suggested that “patients with ejection fraction lower than normal, which includes those with so-called heart failure with mid-range ejection fraction or borderline ejection fraction, would likely benefit from sacubitril/valsartan, compared with RAS inhibition,” concluded the authors of the new analysis (Circulation. 2019 Nov 17. doi: 10.1161/CIRCULATIONAHA.119.044586).

Dr. Yancy argued that, based on this new analysis, a further revision to the 2013 guideline should say that patients with heart failure with a LVEF of 41%-49% have characteristics, treatment responses, and outcomes that “appear similar to those of patient with HFrEF,” a sharp departure from the existing text that lumps these patients with the HFpEF subgroup. “There appears to be a signal that extends the benefit of ARNI to patients with ejection fractions above the current threshold for HFrEF but below what is typically HFpEF,” he said.

Bringing SGLT2 inhibitors into heart failure management

Dr. Yancy also cited recently reported data from another landmark trial, DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure), as an impetus for both another immediate change to the guideline and for a potential second change pending a report of confirmatory evidence that may arrive in 2020.

The DAPA-HF results showed that the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin (Farxiga) was just as effective for preventing all-cause death and heart failure hospitalizations and urgent visits in patients without type 2 diabetes as it is in patients with type 2 diabetes (N Engl J Med. 2019 Nov 21;381[21]:1995-2008), a remarkable finding for an agent that came onto the U.S. market as a diabetes drug specifically aimed at reducing levels of glycosylated hemoglobin.

Dr. Yancy proposed an immediate guideline change to acknowledge the proven protection against incident heart failure that treatment with a SGLT2 inhibitor gives patients with type 2 diabetes. There is now “a strong opportunity to use an SGLT2 inhibitor in patients with type 2 diabetes to reduce the incidence of heart failure,” he said.

And he added that, if results from EMPEROR REDUCED (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction), studying the SGLT2 inhibitor empagliflozin (Jardiance) in HFrEF patients with and without type 2 diabetes, can confirm the efficacy of a second drug from this class in preventing heart failure events in patients with HFrEF but without diabetes, then the time will have arrived for another guideline change to establish the SGLT2 inhibitors as a new “foundational” drug for the management of all HFrEF patients, regardless of their level of glycemic control. The SGLT2 inhibitors are a particularly attractive additional drug because they are taken once daily orally with no need for dosage adjustment, so far they have shown excellent safety in patients without diabetes with no episodes of hypoglycemia or ketoacidosis, and they have even shown evidence for heart failure benefit in patients older than 75 years, Dr. Yancy noted.

Dr. Yancy had no relevant disclosures.

[email protected]

AT THE IDF CONGRESS 2019

BUSAN, SOUTH KOREA – The question of whether or not strict glycemic control is appropriate for older adults was the subject of a debate between two experts at the 2019 congress of the International Diabetes Federation.

Current guidelines from the Endocrine Society addressing diabetes management in older adults call for shared decision making and individualized approaches, taking into account comorbidities, complications, and special situations.

Medha Munshi, MD, and Ryo Suzuki, MD, PhD, took differing approaches to the risk-versus-benefit equation for older patients.
 

The case against ...

Dr. Munshi, director of the Joslin geriatric diabetes program at Beth Israel Deaconess Medical Center, Boston, started the debate by stating, “Yes, strict glycemic control in the elderly is meaningless.”

She based this on two main points: The benefits of strict glycemic control in older adults are not clear, and the risks are “catastrophic and well documented.”

The first problem, said Dr. Munshi, is that there is a dearth of data in older adults. In a 2013 review of 2,484 diabetes-focused studies registered on clinicaltrials.gov, just 0.6% included participants who were older than 65 years, whereas 30.8% specifically excluded that age group, and 54.9% excluded people older than 70 years.

Another analysis of 440 studies that investigated treatments for type 2 diabetes showed that, of trials that did include older adults, more than three-quarters (76.8%) excluded those with comorbidities, nearly a third (29.5%) excluded people with polypharmacy or specific drugs, and 18.4% excluded those with cognitive impairment.

“So, the trials are not targeted toward older adults, and those that are, exclude people with multiple comorbidities, so the [participants] who are left in the trials are not [representative of the patients] we see in the clinic,” Dr. Munshi emphasized.

Among the major trials that evaluated intensive treatment versus usual care in type 2 diabetes – including the UK Prospective Diabetes Study (UKPDS), the Veterans Administration Diabetes Trial (VADT), and the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial – no macrovascular benefits were found except in UKPDS, and evidence of harm was found in ACCORD.

What those trials suggested, said Dr. Munshi, is that the patients who do better with intensive glycemic control are younger, have a shorter duration of disease, fewer complications and comorbidities at baseline, better overall health, and longer life expectancy.

Control in healthy adults

A valid question, Dr. Munshi said, is whether strict glycemic control might be appropriate for older adults who are still healthy.

She responded to that by explaining that there is a phenomenon of aging called homeostenosis, a physical limit beyond which homeostasis cannot be restored in the presence of stressors, such as hypoglycemia leading to a fall, hospitalization, delirium, and poor outcome.

Another reasonable question, she added, was whether strict glycemic control in older adults could be achieved more safely and with greater benefit by using newer agents with lower risks for hypoglycemia that have been found to have cardiovascular and renal benefits.

To that, she noted that it’s not clear whether those benefits are a result of glycemic control, that the duration of the trials has been short (2-3 years), and drug interactions and side effects in populations with multiple morbidities have not been studied. Moreover, “cost and availability need consideration,” she said.

And so, she concluded, “Is strict glycemic control in the elderly really worth the risk? My answer would be no.”
 

The case for ...

Dr. Suzuki, a professor in the division of diabetes, metabolism, endocrinology, rheumatology, and collagen diseases at Tokyo Medical University, argued that strict glycemic control in the elderly is not “meaningless.”

He began by pointing out that his country, Japan, is “one of the most highly aging societies in the world.”

His arguments were based on three points: The elderly population is “full of diversity;” HbA_1c is “not a perfect marker of glycemic control;” and new glucose-lowering drug classes may have benefits beyond reduction of blood glucose levels.

He also noted that there is no consensus on the definition of “elderly.”

Most developed countries use age 65 years and older as the cut-off, but the United Nations defines being elderly as 60 years and older, whereas the International Diabetes Federation’s guideline for managing older people with type 2 diabetes, uses 70 and older. These differences, he asserted, emphasize “the difficulty to generalize the gap between calendar age and biological age.”

Glycemic variability

Another point is that HbA_1c does not reflect glycemic variability, so it’s impossible to tell just from that measure the extent to which an individual is experiencing hypoglycemia – that is, two people can have the same A_1c level, yet one experiences frequent hypoglycemia whereas the other never does.

“So, determining treatment based solely on A_1c may be risky,” Dr. Suzuki noted.

And recently, the availability of continuous glucose monitoring is shifting the definition of “strict” glycemic control from “average” glucose to “time in range,” which also allows for a determination of the key metric “time below range.”

Recent international guidelines advise that, for older adults, fewer than 1% of readings should be below 70 mg/dL (3.9 mmol/L), compared with fewer than 4% for most other individuals with diabetes.

Thus, “in terms of avoiding hypoglycemia, older adults have a ‘stricter’ range. In other words, less stringency for high-risk people does not always mean broader allowance range in any glycemic profiles,” Dr. Suzuki noted.

However, newer drugs that don’t increase the risk for hypoglycemia are available for patients with type 2 diabetes.

Dr. Suzuki pointed to his own 2018 study demonstrating that the dipeptidyl peptidase‐4 (DPP-4) inhibitor sitagliptin had a greater ability to reduce daily glucose fluctuations in drug-naive Japanese patients with type 2 diabetes, compared with the sulfonylurea glibenclamide.

A version of this story originally appeared on Medscape.com.

AT THE IDF CONGRESS 2019

BUSAN, SOUTH KOREA – The question of whether or not strict glycemic control is appropriate for older adults was the subject of a debate between two experts at the 2019 congress of the International Diabetes Federation.

Current guidelines from the Endocrine Society addressing diabetes management in older adults call for shared decision making and individualized approaches, taking into account comorbidities, complications, and special situations.

Medha Munshi, MD, and Ryo Suzuki, MD, PhD, took differing approaches to the risk-versus-benefit equation for older patients.
 

The case against ...

Dr. Munshi, director of the Joslin geriatric diabetes program at Beth Israel Deaconess Medical Center, Boston, started the debate by stating, “Yes, strict glycemic control in the elderly is meaningless.”

She based this on two main points: The benefits of strict glycemic control in older adults are not clear, and the risks are “catastrophic and well documented.”

The first problem, said Dr. Munshi, is that there is a dearth of data in older adults. In a 2013 review of 2,484 diabetes-focused studies registered on clinicaltrials.gov, just 0.6% included participants who were older than 65 years, whereas 30.8% specifically excluded that age group, and 54.9% excluded people older than 70 years.

Another analysis of 440 studies that investigated treatments for type 2 diabetes showed that, of trials that did include older adults, more than three-quarters (76.8%) excluded those with comorbidities, nearly a third (29.5%) excluded people with polypharmacy or specific drugs, and 18.4% excluded those with cognitive impairment.

“So, the trials are not targeted toward older adults, and those that are, exclude people with multiple comorbidities, so the [participants] who are left in the trials are not [representative of the patients] we see in the clinic,” Dr. Munshi emphasized.

Among the major trials that evaluated intensive treatment versus usual care in type 2 diabetes – including the UK Prospective Diabetes Study (UKPDS), the Veterans Administration Diabetes Trial (VADT), and the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial – no macrovascular benefits were found except in UKPDS, and evidence of harm was found in ACCORD.

What those trials suggested, said Dr. Munshi, is that the patients who do better with intensive glycemic control are younger, have a shorter duration of disease, fewer complications and comorbidities at baseline, better overall health, and longer life expectancy.

Control in healthy adults

A valid question, Dr. Munshi said, is whether strict glycemic control might be appropriate for older adults who are still healthy.

She responded to that by explaining that there is a phenomenon of aging called homeostenosis, a physical limit beyond which homeostasis cannot be restored in the presence of stressors, such as hypoglycemia leading to a fall, hospitalization, delirium, and poor outcome.

Another reasonable question, she added, was whether strict glycemic control in older adults could be achieved more safely and with greater benefit by using newer agents with lower risks for hypoglycemia that have been found to have cardiovascular and renal benefits.

To that, she noted that it’s not clear whether those benefits are a result of glycemic control, that the duration of the trials has been short (2-3 years), and drug interactions and side effects in populations with multiple morbidities have not been studied. Moreover, “cost and availability need consideration,” she said.

And so, she concluded, “Is strict glycemic control in the elderly really worth the risk? My answer would be no.”
 

The case for ...

Dr. Suzuki, a professor in the division of diabetes, metabolism, endocrinology, rheumatology, and collagen diseases at Tokyo Medical University, argued that strict glycemic control in the elderly is not “meaningless.”

He began by pointing out that his country, Japan, is “one of the most highly aging societies in the world.”

His arguments were based on three points: The elderly population is “full of diversity;” HbA_1c is “not a perfect marker of glycemic control;” and new glucose-lowering drug classes may have benefits beyond reduction of blood glucose levels.

He also noted that there is no consensus on the definition of “elderly.”

Most developed countries use age 65 years and older as the cut-off, but the United Nations defines being elderly as 60 years and older, whereas the International Diabetes Federation’s guideline for managing older people with type 2 diabetes, uses 70 and older. These differences, he asserted, emphasize “the difficulty to generalize the gap between calendar age and biological age.”

Glycemic variability

Another point is that HbA_1c does not reflect glycemic variability, so it’s impossible to tell just from that measure the extent to which an individual is experiencing hypoglycemia – that is, two people can have the same A_1c level, yet one experiences frequent hypoglycemia whereas the other never does.

“So, determining treatment based solely on A_1c may be risky,” Dr. Suzuki noted.

And recently, the availability of continuous glucose monitoring is shifting the definition of “strict” glycemic control from “average” glucose to “time in range,” which also allows for a determination of the key metric “time below range.”

Recent international guidelines advise that, for older adults, fewer than 1% of readings should be below 70 mg/dL (3.9 mmol/L), compared with fewer than 4% for most other individuals with diabetes.

Thus, “in terms of avoiding hypoglycemia, older adults have a ‘stricter’ range. In other words, less stringency for high-risk people does not always mean broader allowance range in any glycemic profiles,” Dr. Suzuki noted.

However, newer drugs that don’t increase the risk for hypoglycemia are available for patients with type 2 diabetes.

Dr. Suzuki pointed to his own 2018 study demonstrating that the dipeptidyl peptidase‐4 (DPP-4) inhibitor sitagliptin had a greater ability to reduce daily glucose fluctuations in drug-naive Japanese patients with type 2 diabetes, compared with the sulfonylurea glibenclamide.

A version of this story originally appeared on Medscape.com.

AT THE IDF CONGRESS 2019

BUSAN, SOUTH KOREA – The question of whether or not strict glycemic control is appropriate for older adults was the subject of a debate between two experts at the 2019 congress of the International Diabetes Federation.

Current guidelines from the Endocrine Society addressing diabetes management in older adults call for shared decision making and individualized approaches, taking into account comorbidities, complications, and special situations.

Medha Munshi, MD, and Ryo Suzuki, MD, PhD, took differing approaches to the risk-versus-benefit equation for older patients.
 

The case against ...

Dr. Munshi, director of the Joslin geriatric diabetes program at Beth Israel Deaconess Medical Center, Boston, started the debate by stating, “Yes, strict glycemic control in the elderly is meaningless.”

She based this on two main points: The benefits of strict glycemic control in older adults are not clear, and the risks are “catastrophic and well documented.”

The first problem, said Dr. Munshi, is that there is a dearth of data in older adults. In a 2013 review of 2,484 diabetes-focused studies registered on clinicaltrials.gov, just 0.6% included participants who were older than 65 years, whereas 30.8% specifically excluded that age group, and 54.9% excluded people older than 70 years.

Another analysis of 440 studies that investigated treatments for type 2 diabetes showed that, of trials that did include older adults, more than three-quarters (76.8%) excluded those with comorbidities, nearly a third (29.5%) excluded people with polypharmacy or specific drugs, and 18.4% excluded those with cognitive impairment.

“So, the trials are not targeted toward older adults, and those that are, exclude people with multiple comorbidities, so the [participants] who are left in the trials are not [representative of the patients] we see in the clinic,” Dr. Munshi emphasized.

Among the major trials that evaluated intensive treatment versus usual care in type 2 diabetes – including the UK Prospective Diabetes Study (UKPDS), the Veterans Administration Diabetes Trial (VADT), and the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial – no macrovascular benefits were found except in UKPDS, and evidence of harm was found in ACCORD.

What those trials suggested, said Dr. Munshi, is that the patients who do better with intensive glycemic control are younger, have a shorter duration of disease, fewer complications and comorbidities at baseline, better overall health, and longer life expectancy.

Control in healthy adults

A valid question, Dr. Munshi said, is whether strict glycemic control might be appropriate for older adults who are still healthy.

She responded to that by explaining that there is a phenomenon of aging called homeostenosis, a physical limit beyond which homeostasis cannot be restored in the presence of stressors, such as hypoglycemia leading to a fall, hospitalization, delirium, and poor outcome.

Another reasonable question, she added, was whether strict glycemic control in older adults could be achieved more safely and with greater benefit by using newer agents with lower risks for hypoglycemia that have been found to have cardiovascular and renal benefits.

To that, she noted that it’s not clear whether those benefits are a result of glycemic control, that the duration of the trials has been short (2-3 years), and drug interactions and side effects in populations with multiple morbidities have not been studied. Moreover, “cost and availability need consideration,” she said.

And so, she concluded, “Is strict glycemic control in the elderly really worth the risk? My answer would be no.”
 

The case for ...

Dr. Suzuki, a professor in the division of diabetes, metabolism, endocrinology, rheumatology, and collagen diseases at Tokyo Medical University, argued that strict glycemic control in the elderly is not “meaningless.”

He began by pointing out that his country, Japan, is “one of the most highly aging societies in the world.”

His arguments were based on three points: The elderly population is “full of diversity;” HbA_1c is “not a perfect marker of glycemic control;” and new glucose-lowering drug classes may have benefits beyond reduction of blood glucose levels.

He also noted that there is no consensus on the definition of “elderly.”

Most developed countries use age 65 years and older as the cut-off, but the United Nations defines being elderly as 60 years and older, whereas the International Diabetes Federation’s guideline for managing older people with type 2 diabetes, uses 70 and older. These differences, he asserted, emphasize “the difficulty to generalize the gap between calendar age and biological age.”

Glycemic variability

Another point is that HbA_1c does not reflect glycemic variability, so it’s impossible to tell just from that measure the extent to which an individual is experiencing hypoglycemia – that is, two people can have the same A_1c level, yet one experiences frequent hypoglycemia whereas the other never does.

“So, determining treatment based solely on A_1c may be risky,” Dr. Suzuki noted.

And recently, the availability of continuous glucose monitoring is shifting the definition of “strict” glycemic control from “average” glucose to “time in range,” which also allows for a determination of the key metric “time below range.”

Recent international guidelines advise that, for older adults, fewer than 1% of readings should be below 70 mg/dL (3.9 mmol/L), compared with fewer than 4% for most other individuals with diabetes.

Thus, “in terms of avoiding hypoglycemia, older adults have a ‘stricter’ range. In other words, less stringency for high-risk people does not always mean broader allowance range in any glycemic profiles,” Dr. Suzuki noted.

However, newer drugs that don’t increase the risk for hypoglycemia are available for patients with type 2 diabetes.

Dr. Suzuki pointed to his own 2018 study demonstrating that the dipeptidyl peptidase‐4 (DPP-4) inhibitor sitagliptin had a greater ability to reduce daily glucose fluctuations in drug-naive Japanese patients with type 2 diabetes, compared with the sulfonylurea glibenclamide.

A version of this story originally appeared on Medscape.com.

Mitchel L. Zoler’s article on Abstract A105, presented at Obesity Week 2019, addresses an important health concern and is timely.

Over the past 4 decades we have seen a rise in the prevalence of obesity and associated health complications, not just in the United States but across the world. The incidence of obesity (having a BMI greater than 30) was 35% for women and 31% for men in the United States, and associated deaths and disability were primarily attributed to diabetes and cardiovascular disease resulting from obesity.

This article references the benefits of bariatric/metabolic surgery in individuals with class 1 obesity. In the United States, more than half of those who meet the criteria for obesity come under the class 1 category (BMI, 30-34.9). Those in this class of obesity are at increased risk of developing diabetes, hypertension, hyperlipidemia, coronary artery disease, cerebrovascular disease, obstructive sleep apnea, polycystic ovarian syndrome, and bone and joint disorders.

There are several studies that document the significant reduction in incidence of the above cardiometabolic risks with sustained weight loss. Nonsurgical interventions in individuals with class 1 obesity through lifestyle modifications and pharmacotherapy have not demonstrated success in providing persistent weight loss or metabolic benefits. The data presented in this article are of great significance to patients and physicians alike as they highlight the long-term benefits and reversal of metabolic disorders.

Current guidelines for bariatric surgery for individuals with a BMI greater than 35 were published in 1991. Since then several safe surgical options including laparoscopic procedures, sleeve gastrectomy, and adjustable gastric banding have been developed with decreased surgical risks, morbidity, and mortality.

The International Federation for the Surgery of Obesity and Metabolic Disorders, the International Diabetes Federation, and the National Institute for Health and Care Excellence of the United Kingdom, have supported the option of bariatric surgery in class 1 obese individuals with metabolic disorders.

While lifestyle modifications with medications should be the first-line treatment for class 1 obesity, as a primary care physician I believe that, given the major changes in the surgical options, the proven long-term benefits, and the rising incidences of obesity and metabolic syndrome, it is time for the health care community, insurers, patients, and all other stakeholders to consider bariatric surgery in class 1 obese individuals as a potential and viable option.

Noel N. Deep, MD, is a general internist in a multispecialty group practice with Aspirus Antigo (Wis.) Clinic and the chief medical officer and a staff physician at Aspirus Langlade Hospital in Antigo. He is also assistant clinical professor at the Medical College of Wisconsin, Central Wisconsin Campus, Wausau, and the governor of the Wisconsin chapter of the American College of Physicians. Dr. Deep serves on the editorial advisory board of Internal Medicine News.

He made these comments in response to questions from MDedge and had no relevant disclosures.

Mitchel L. Zoler’s article on Abstract A105, presented at Obesity Week 2019, addresses an important health concern and is timely.

Over the past 4 decades we have seen a rise in the prevalence of obesity and associated health complications, not just in the United States but across the world. The incidence of obesity (having a BMI greater than 30) was 35% for women and 31% for men in the United States, and associated deaths and disability were primarily attributed to diabetes and cardiovascular disease resulting from obesity.

This article references the benefits of bariatric/metabolic surgery in individuals with class 1 obesity. In the United States, more than half of those who meet the criteria for obesity come under the class 1 category (BMI, 30-34.9). Those in this class of obesity are at increased risk of developing diabetes, hypertension, hyperlipidemia, coronary artery disease, cerebrovascular disease, obstructive sleep apnea, polycystic ovarian syndrome, and bone and joint disorders.

There are several studies that document the significant reduction in incidence of the above cardiometabolic risks with sustained weight loss. Nonsurgical interventions in individuals with class 1 obesity through lifestyle modifications and pharmacotherapy have not demonstrated success in providing persistent weight loss or metabolic benefits. The data presented in this article are of great significance to patients and physicians alike as they highlight the long-term benefits and reversal of metabolic disorders.

Current guidelines for bariatric surgery for individuals with a BMI greater than 35 were published in 1991. Since then several safe surgical options including laparoscopic procedures, sleeve gastrectomy, and adjustable gastric banding have been developed with decreased surgical risks, morbidity, and mortality.

The International Federation for the Surgery of Obesity and Metabolic Disorders, the International Diabetes Federation, and the National Institute for Health and Care Excellence of the United Kingdom, have supported the option of bariatric surgery in class 1 obese individuals with metabolic disorders.

While lifestyle modifications with medications should be the first-line treatment for class 1 obesity, as a primary care physician I believe that, given the major changes in the surgical options, the proven long-term benefits, and the rising incidences of obesity and metabolic syndrome, it is time for the health care community, insurers, patients, and all other stakeholders to consider bariatric surgery in class 1 obese individuals as a potential and viable option.

Noel N. Deep, MD, is a general internist in a multispecialty group practice with Aspirus Antigo (Wis.) Clinic and the chief medical officer and a staff physician at Aspirus Langlade Hospital in Antigo. He is also assistant clinical professor at the Medical College of Wisconsin, Central Wisconsin Campus, Wausau, and the governor of the Wisconsin chapter of the American College of Physicians. Dr. Deep serves on the editorial advisory board of Internal Medicine News.

He made these comments in response to questions from MDedge and had no relevant disclosures.

Mitchel L. Zoler’s article on Abstract A105, presented at Obesity Week 2019, addresses an important health concern and is timely.

Over the past 4 decades we have seen a rise in the prevalence of obesity and associated health complications, not just in the United States but across the world. The incidence of obesity (having a BMI greater than 30) was 35% for women and 31% for men in the United States, and associated deaths and disability were primarily attributed to diabetes and cardiovascular disease resulting from obesity.

This article references the benefits of bariatric/metabolic surgery in individuals with class 1 obesity. In the United States, more than half of those who meet the criteria for obesity come under the class 1 category (BMI, 30-34.9). Those in this class of obesity are at increased risk of developing diabetes, hypertension, hyperlipidemia, coronary artery disease, cerebrovascular disease, obstructive sleep apnea, polycystic ovarian syndrome, and bone and joint disorders.

There are several studies that document the significant reduction in incidence of the above cardiometabolic risks with sustained weight loss. Nonsurgical interventions in individuals with class 1 obesity through lifestyle modifications and pharmacotherapy have not demonstrated success in providing persistent weight loss or metabolic benefits. The data presented in this article are of great significance to patients and physicians alike as they highlight the long-term benefits and reversal of metabolic disorders.

Current guidelines for bariatric surgery for individuals with a BMI greater than 35 were published in 1991. Since then several safe surgical options including laparoscopic procedures, sleeve gastrectomy, and adjustable gastric banding have been developed with decreased surgical risks, morbidity, and mortality.

The International Federation for the Surgery of Obesity and Metabolic Disorders, the International Diabetes Federation, and the National Institute for Health and Care Excellence of the United Kingdom, have supported the option of bariatric surgery in class 1 obese individuals with metabolic disorders.

While lifestyle modifications with medications should be the first-line treatment for class 1 obesity, as a primary care physician I believe that, given the major changes in the surgical options, the proven long-term benefits, and the rising incidences of obesity and metabolic syndrome, it is time for the health care community, insurers, patients, and all other stakeholders to consider bariatric surgery in class 1 obese individuals as a potential and viable option.

Noel N. Deep, MD, is a general internist in a multispecialty group practice with Aspirus Antigo (Wis.) Clinic and the chief medical officer and a staff physician at Aspirus Langlade Hospital in Antigo. He is also assistant clinical professor at the Medical College of Wisconsin, Central Wisconsin Campus, Wausau, and the governor of the Wisconsin chapter of the American College of Physicians. Dr. Deep serves on the editorial advisory board of Internal Medicine News.

He made these comments in response to questions from MDedge and had no relevant disclosures.

The Food and Drug Administration has expanded the indication for Toujeo (insulin glargine 300 units/mL injection; Sanofi) to include children as young as 6 years of age with type 1 diabetes.

The FDA first approved Toujeo in 2015 for adults with type 1 and type 2 diabetes, designed as a more potent follow-up to Sanofi’s top-selling insulin glargine (Lantus).

Last month, Sanofi reported positive results from the phase 3 EDITION JUNIOR trial of Toujeo in children and adolescents with type 1 diabetes. These were presented at the International Society for Pediatric and Adolescent Diabetes 45th Annual Conference in Boston.

In the trial, 463 children and adolescents (aged 6-17 years) treated for type 1 diabetes for at least 1 year and with A1c between 7.5% and 11.0% at screening were randomized to Toujeo or insulin glargine 100 units/mL (Gla-100); participants continued to take their existing mealtime insulin.

The primary endpoint was noninferior reduction in A_1c after 26 weeks.

The study met its primary endpoint, confirming a noninferior reduction in A_1c with Toujeo versus Gla-100 after 26 weeks (mean reduction, 0.4% vs. 0.4%; difference, 0.004%; 95% confidence interval, –0.17 to 0.18; upper bound was below the prespecified noninferiority margin of 0.3%).

Over 26 weeks, a comparable number of patients in each group experienced one or more hypoglycemic events documented at anytime over 24 hours. Numerically fewer patients taking Toujeo experienced severe hypoglycemia or experienced one or more episodes of hyperglycemia with ketosis compared with those taking Gla-100.

No unexpected safety concerns were reported based on the established profiles of both products, the company said.

In October 2019, the European Medicines Agency Committee for Medicinal Products for Human Use recommended approval of Toujeo for children age 6 years and older with diabetes.

For more diabetes and endocrinology news, follow us on Twitter and Facebook.
 

This story first appeared on Medscape.com.

The Food and Drug Administration has expanded the indication for Toujeo (insulin glargine 300 units/mL injection; Sanofi) to include children as young as 6 years of age with type 1 diabetes.

The FDA first approved Toujeo in 2015 for adults with type 1 and type 2 diabetes, designed as a more potent follow-up to Sanofi’s top-selling insulin glargine (Lantus).

Last month, Sanofi reported positive results from the phase 3 EDITION JUNIOR trial of Toujeo in children and adolescents with type 1 diabetes. These were presented at the International Society for Pediatric and Adolescent Diabetes 45th Annual Conference in Boston.

In the trial, 463 children and adolescents (aged 6-17 years) treated for type 1 diabetes for at least 1 year and with A1c between 7.5% and 11.0% at screening were randomized to Toujeo or insulin glargine 100 units/mL (Gla-100); participants continued to take their existing mealtime insulin.

The primary endpoint was noninferior reduction in A_1c after 26 weeks.

The study met its primary endpoint, confirming a noninferior reduction in A_1c with Toujeo versus Gla-100 after 26 weeks (mean reduction, 0.4% vs. 0.4%; difference, 0.004%; 95% confidence interval, –0.17 to 0.18; upper bound was below the prespecified noninferiority margin of 0.3%).

Over 26 weeks, a comparable number of patients in each group experienced one or more hypoglycemic events documented at anytime over 24 hours. Numerically fewer patients taking Toujeo experienced severe hypoglycemia or experienced one or more episodes of hyperglycemia with ketosis compared with those taking Gla-100.

No unexpected safety concerns were reported based on the established profiles of both products, the company said.

In October 2019, the European Medicines Agency Committee for Medicinal Products for Human Use recommended approval of Toujeo for children age 6 years and older with diabetes.

For more diabetes and endocrinology news, follow us on Twitter and Facebook.
 

This story first appeared on Medscape.com.

The Food and Drug Administration has expanded the indication for Toujeo (insulin glargine 300 units/mL injection; Sanofi) to include children as young as 6 years of age with type 1 diabetes.

The FDA first approved Toujeo in 2015 for adults with type 1 and type 2 diabetes, designed as a more potent follow-up to Sanofi’s top-selling insulin glargine (Lantus).

Last month, Sanofi reported positive results from the phase 3 EDITION JUNIOR trial of Toujeo in children and adolescents with type 1 diabetes. These were presented at the International Society for Pediatric and Adolescent Diabetes 45th Annual Conference in Boston.

In the trial, 463 children and adolescents (aged 6-17 years) treated for type 1 diabetes for at least 1 year and with A1c between 7.5% and 11.0% at screening were randomized to Toujeo or insulin glargine 100 units/mL (Gla-100); participants continued to take their existing mealtime insulin.

The primary endpoint was noninferior reduction in A_1c after 26 weeks.

The study met its primary endpoint, confirming a noninferior reduction in A_1c with Toujeo versus Gla-100 after 26 weeks (mean reduction, 0.4% vs. 0.4%; difference, 0.004%; 95% confidence interval, –0.17 to 0.18; upper bound was below the prespecified noninferiority margin of 0.3%).

Over 26 weeks, a comparable number of patients in each group experienced one or more hypoglycemic events documented at anytime over 24 hours. Numerically fewer patients taking Toujeo experienced severe hypoglycemia or experienced one or more episodes of hyperglycemia with ketosis compared with those taking Gla-100.

No unexpected safety concerns were reported based on the established profiles of both products, the company said.

In October 2019, the European Medicines Agency Committee for Medicinal Products for Human Use recommended approval of Toujeo for children age 6 years and older with diabetes.

For more diabetes and endocrinology news, follow us on Twitter and Facebook.
 

This story first appeared on Medscape.com.

BUSAN, SOUTH KOREA – The practice of insulin rationing because of cost by people with type 1 diabetes is considerably more common in the United States than in other high-income countries, and is even higher than in some low- and middle-income countries, new data suggest.

Findings from the latest survey conducted by the nonprofit advocacy organization T1International were presented at the International Diabetes Federation Congress 2019 by organization trustee James Elliott, MMSc, of Toronto.

The data were also simultaneously posted on the organization’s website.

The 2018 online survey is an update of T1International’s 2016 survey. It was disseminated through the organization’s website, partner organizations, and social media. The survey questions were developed by people living with type 1 diabetes to ensure they made sense to patients.

A total of 1,478 respondents from 90 countries completed the online survey in 2018.

Overall, 18% reported rationing insulin in the previous year because of cost. About 26% of 627 respondents from the United States reported the practice, compared with 6.5% of 525 respondents from other high-income countries, and 10.9% of 256 respondents from low- and middle-income countries. Rates of rationing suplies for blood glucose testing were even higher.

“The take-home point is that insulin rationing and blood glucose testing rationing is a reality for far more people with diabetes than I think is acknowledged,” said Mr. Elliott.

“One of the key findings is that many people are actually better off living in lower- and middle-income countries than in the United States, which is quite shameful,” Mr. Elliott told Medscape Medical News in an interview.

He advised clinicians to ask patients if they’re insulin rationing, but to be mindful that “not everyone is going to be upfront. There’re a lot of associated stigmas.”

Endocrinologist Irl B. Hirsch, MD, noted that the rationing rate reported for the United States in the survey is similar to that found in a recently published study from Yale University, New Haven, Conn., as reported by Medscape Medical News.

Dr. Hirsch, who is chair of Diabetes Treatment and Teaching at the University of Washington, Seattle, agreed wholeheartedly with Mr. Elliott.

“It is shameful and embarrassing sitting here with colleagues from around the world at IDF. It is time for our elected officials [in the United States] to do something instead of simply talking about it,” Dr. Hirsch said.

Many have no coverage, blood glucose test rationing also common

Overall, 66.2% of survey respondents reported having no financial coverage for diabetes expenses, many instead relying on support from family and friends, charities and nonprofit organizations, donations including online programs such as GoFundMe, and/or assistance from government or pharmaceutical company programs.

By region, the proportions reporting no coverage for diabetes supplies were 79.2% in the United States, 54.0% in other high-income countries, and 59.8% in low- and middle-income countries.

“Many countries still lack any kind of support system to help people with type 1 diabetes survive,” Mr. Elliott noted.

Also asked to comment, Edward W. Gregg, PhD, a professor in the department of epidemiology and biostatistics at Imperial College, London, said: “It’s pretty astounding to me that two thirds of people with type 1 diabetes have no coverage whatsoever for out-of-pocket costs.”

“For as much concern as we have [for the US], it’s really staggering to think about how it must be in the low- and middle-income countries where having to pay for insulin takes away a large proportion of income,” he added.

Rationing of blood glucose testing was considerably more common than insulin rationing, with 33.5% overall reporting having done so in the last year.

The proportion was higher in the United States and in low- and middle-income countries, at 38.6% and 55.5%, respectively, compared with just 17.2% of high-income countries other than the United States.

Mr. Elliott told Medscape Medical News that the recent World Health Organization’s launch of its first-ever insulin prequalification program to expand access to treatment is a “start” and that T1International is pushing to expand that beyond human insulins to also include analogues.

“It’s a tough disease to survive in lower- and middle-income countries. Oftentimes, it’s a death sentence,” Mr. Elliott said.
 

This story first appeared on Medscape.com.

BUSAN, SOUTH KOREA – The practice of insulin rationing because of cost by people with type 1 diabetes is considerably more common in the United States than in other high-income countries, and is even higher than in some low- and middle-income countries, new data suggest.

Findings from the latest survey conducted by the nonprofit advocacy organization T1International were presented at the International Diabetes Federation Congress 2019 by organization trustee James Elliott, MMSc, of Toronto.

The data were also simultaneously posted on the organization’s website.

The 2018 online survey is an update of T1International’s 2016 survey. It was disseminated through the organization’s website, partner organizations, and social media. The survey questions were developed by people living with type 1 diabetes to ensure they made sense to patients.

A total of 1,478 respondents from 90 countries completed the online survey in 2018.

Overall, 18% reported rationing insulin in the previous year because of cost. About 26% of 627 respondents from the United States reported the practice, compared with 6.5% of 525 respondents from other high-income countries, and 10.9% of 256 respondents from low- and middle-income countries. Rates of rationing suplies for blood glucose testing were even higher.

“The take-home point is that insulin rationing and blood glucose testing rationing is a reality for far more people with diabetes than I think is acknowledged,” said Mr. Elliott.

“One of the key findings is that many people are actually better off living in lower- and middle-income countries than in the United States, which is quite shameful,” Mr. Elliott told Medscape Medical News in an interview.

He advised clinicians to ask patients if they’re insulin rationing, but to be mindful that “not everyone is going to be upfront. There’re a lot of associated stigmas.”

Endocrinologist Irl B. Hirsch, MD, noted that the rationing rate reported for the United States in the survey is similar to that found in a recently published study from Yale University, New Haven, Conn., as reported by Medscape Medical News.

Dr. Hirsch, who is chair of Diabetes Treatment and Teaching at the University of Washington, Seattle, agreed wholeheartedly with Mr. Elliott.

“It is shameful and embarrassing sitting here with colleagues from around the world at IDF. It is time for our elected officials [in the United States] to do something instead of simply talking about it,” Dr. Hirsch said.

Many have no coverage, blood glucose test rationing also common

Overall, 66.2% of survey respondents reported having no financial coverage for diabetes expenses, many instead relying on support from family and friends, charities and nonprofit organizations, donations including online programs such as GoFundMe, and/or assistance from government or pharmaceutical company programs.

By region, the proportions reporting no coverage for diabetes supplies were 79.2% in the United States, 54.0% in other high-income countries, and 59.8% in low- and middle-income countries.

“Many countries still lack any kind of support system to help people with type 1 diabetes survive,” Mr. Elliott noted.

Also asked to comment, Edward W. Gregg, PhD, a professor in the department of epidemiology and biostatistics at Imperial College, London, said: “It’s pretty astounding to me that two thirds of people with type 1 diabetes have no coverage whatsoever for out-of-pocket costs.”

“For as much concern as we have [for the US], it’s really staggering to think about how it must be in the low- and middle-income countries where having to pay for insulin takes away a large proportion of income,” he added.

Rationing of blood glucose testing was considerably more common than insulin rationing, with 33.5% overall reporting having done so in the last year.

The proportion was higher in the United States and in low- and middle-income countries, at 38.6% and 55.5%, respectively, compared with just 17.2% of high-income countries other than the United States.

Mr. Elliott told Medscape Medical News that the recent World Health Organization’s launch of its first-ever insulin prequalification program to expand access to treatment is a “start” and that T1International is pushing to expand that beyond human insulins to also include analogues.

“It’s a tough disease to survive in lower- and middle-income countries. Oftentimes, it’s a death sentence,” Mr. Elliott said.
 

This story first appeared on Medscape.com.

BUSAN, SOUTH KOREA – The practice of insulin rationing because of cost by people with type 1 diabetes is considerably more common in the United States than in other high-income countries, and is even higher than in some low- and middle-income countries, new data suggest.

Findings from the latest survey conducted by the nonprofit advocacy organization T1International were presented at the International Diabetes Federation Congress 2019 by organization trustee James Elliott, MMSc, of Toronto.

The data were also simultaneously posted on the organization’s website.

The 2018 online survey is an update of T1International’s 2016 survey. It was disseminated through the organization’s website, partner organizations, and social media. The survey questions were developed by people living with type 1 diabetes to ensure they made sense to patients.

A total of 1,478 respondents from 90 countries completed the online survey in 2018.

Overall, 18% reported rationing insulin in the previous year because of cost. About 26% of 627 respondents from the United States reported the practice, compared with 6.5% of 525 respondents from other high-income countries, and 10.9% of 256 respondents from low- and middle-income countries. Rates of rationing suplies for blood glucose testing were even higher.

“The take-home point is that insulin rationing and blood glucose testing rationing is a reality for far more people with diabetes than I think is acknowledged,” said Mr. Elliott.

“One of the key findings is that many people are actually better off living in lower- and middle-income countries than in the United States, which is quite shameful,” Mr. Elliott told Medscape Medical News in an interview.

He advised clinicians to ask patients if they’re insulin rationing, but to be mindful that “not everyone is going to be upfront. There’re a lot of associated stigmas.”

Endocrinologist Irl B. Hirsch, MD, noted that the rationing rate reported for the United States in the survey is similar to that found in a recently published study from Yale University, New Haven, Conn., as reported by Medscape Medical News.

Dr. Hirsch, who is chair of Diabetes Treatment and Teaching at the University of Washington, Seattle, agreed wholeheartedly with Mr. Elliott.

“It is shameful and embarrassing sitting here with colleagues from around the world at IDF. It is time for our elected officials [in the United States] to do something instead of simply talking about it,” Dr. Hirsch said.

Many have no coverage, blood glucose test rationing also common

Overall, 66.2% of survey respondents reported having no financial coverage for diabetes expenses, many instead relying on support from family and friends, charities and nonprofit organizations, donations including online programs such as GoFundMe, and/or assistance from government or pharmaceutical company programs.

By region, the proportions reporting no coverage for diabetes supplies were 79.2% in the United States, 54.0% in other high-income countries, and 59.8% in low- and middle-income countries.

“Many countries still lack any kind of support system to help people with type 1 diabetes survive,” Mr. Elliott noted.

Also asked to comment, Edward W. Gregg, PhD, a professor in the department of epidemiology and biostatistics at Imperial College, London, said: “It’s pretty astounding to me that two thirds of people with type 1 diabetes have no coverage whatsoever for out-of-pocket costs.”

“For as much concern as we have [for the US], it’s really staggering to think about how it must be in the low- and middle-income countries where having to pay for insulin takes away a large proportion of income,” he added.

Rationing of blood glucose testing was considerably more common than insulin rationing, with 33.5% overall reporting having done so in the last year.

The proportion was higher in the United States and in low- and middle-income countries, at 38.6% and 55.5%, respectively, compared with just 17.2% of high-income countries other than the United States.

Mr. Elliott told Medscape Medical News that the recent World Health Organization’s launch of its first-ever insulin prequalification program to expand access to treatment is a “start” and that T1International is pushing to expand that beyond human insulins to also include analogues.

“It’s a tough disease to survive in lower- and middle-income countries. Oftentimes, it’s a death sentence,” Mr. Elliott said.
 

This story first appeared on Medscape.com.

Study Overview

Objective. To assess whether metformin use is associated with lower risk of fatal or nonfatal major adverse cardiovascular events (MACE) as compared to sulfonylurea use among diabetic patients with reduced kidney function.

Design. Retrospective cohort study of US Veterans receiving care within the Veterans Health Administration, with data supplemented by linkage to Medicare, Medicaid, and National Death Index data from 2001 through 2016.

Setting and participants. A retrospective cohort of Veterans Health Administration (VHA) patients, aged 18 years and older. Pharmacy data included medication, date filled, days supplied, and number of pills dispensed. For Medicare and Medicaid patients, enrollees’ claims files and prescription (Part D) data were obtained. In addition, dates and cause of death were obtained from vital status and the National Death Index files.

Patients with new-onset type 2 diabetes were identified by selecting new users of metformin, glipizide, glyburide, or glimepiride. These patients were followed longitudinally and the date of cohort entry and start of follow-up was the day of reaching a reduced kidney function threshold, defined as either an estimated glomerular filtration rate (eGFR) of less than 60 mL/min/1.73 m² or serum creatinine level of 1.5 mg/dL for men or 1.4 mg/dL for women. Patients were excluded for nonpersistence, defined as 90 days without an antidiabetic drug; censoring, defined as the 181st day of no VHA contact; or study end date of December 31, 2016.

Main outcome measures. Primary outcome was the composite of MACE including hospitalization for acute myocardial infarction (AMI), ischemic or hemorrhagic stroke, transient ischemic attack (TIA), or date of cardiovascular death. The secondary outcome excluded TIA as part of the composite MACE event because not all patients who sustain a TIA are admitted to the hospital.

Main results. From January 1, 2002 through December 30, 2015, 67,749 new metformin users and 28,976 new sulfonylurea users who persisted with treatment were identified. After using propensity score-weighted matching, 24,679 metformin users and 24,799 sulfonylurea users entered the final analysis. Cohort patients were 98% male and 81.8% white. Metformin users were younger than sulfonylurea users, with a median age of 61 years versus 71 years, respectively.

For the main outcome, there were 1048 composite MACE events among metformin patients with reduced kidney function and 1394 MACE events among sulfonylurea patients, yielding 23.0 (95% confidence interval [CI], 21.7-24.4) versus 29.2 (95% CI, 27.7-30.7) events per 1000 person-years of use, respectively, after propensity score-weighting. After covariate adjustment, the cause-specific adjusted hazard ratio (aHR) for MACE was 0.80 (95% CI, 0.75-0.86) among metformin users compared with sulfonylurea users. The adjusted incidence rate difference was 5.8 (95% CI, 4.1-7.3) fewer events per 1000-person years for metformin compared with sulfonylurea users. Results were also consistent for each component of the primary outcome, including cardiovascular hospitalizations (aHR, 0.87; 95% CI, 0.80-0.95) and cardiovascular deaths (aHR, 0.70; 95% CI, 0.63-0.78).

Analysis of secondary outcomes, which included AMI, stroke, and cardiovascular death and excluded TIA, demonstrated similar results, with a cause-specific aHR of 0.78 (95% CI, 0.72-0.84) among metformin users compared with sulfonylurea users. The adjusted incidence rate difference was 5.9 (95% CI, 4.3-7.6) fewer events per 1000-person years for metformin compared with sulfonylurea users.

Conclusion. For patients with diabetes and reduced kidney function, treatment with metformin monotherapy, as compared with a sulfonylurea, was associated with a lower risk of MACE.

Commentary

There are approximately 30 million US adults with a diagnosis of type 2 diabetes (T2DM), of whom 20% also have impaired kidney function or chronic kidney disease (CKD).¹ Metformin hydrochloride has remained the preferred first-line treatment for T2DM based on safety and effectiveness, as well as low cost.² Metformin is eliminated by the kidneys and can accumulate as eGFR declines. Based on the negative clinical experience, the US Food and Drug Administration (FDA) issued a safety warning restricting metformin for patients with serum creatinine levels of 1.5 mg/dL or greater for men or 1.4 mg/dL or greater for women. The FDA recommended against starting metformin therapy in patients with CKD with eGFR between 30 and 45 mL/min/1.73 m², although patients already taking metformin can continue with caution in that setting.^1,3

There are several limitations in conducting observational studies comparing metformin to other glucose-lowering medications. First, metformin trials typically excluded patients with CKD due to the FDA warnings. Second, there is usually a time-lag bias in which patients who initiate glucose-lowering medications other than metformin are at a later stage of disease. Third, there is often an allocation bias, as there are substantial differences in baseline characteristics between metformin and sulfonylurea monotherapy users, with metformin users usually being younger and healthier.⁴

In this retrospective cohort study by Roumie et al, the authors used propensity score–weighted matching to reduce the impacts on time-lag and allocation bias. However, several major limitations remained in this study. First, the study design excluded those who began diabetes treatment after the onset of reduced kidney function; therefore, this study cannot be generalized to patients who already have reduced eGFR at the time of metformin initiation. Second, cohort entry and the start of follow-up was either an elevated serum creatinine or reduced eGFR less than 60 mL/min/1.73 m². The cohort may have included some patients with an acute kidney injury event, rather than progression to CKD, who recovered from their acute kidney injury. Third, the study population was mostly elderly white men; together with the lack of dose analysis, this study may not be generalizable to other populations.

 

 

Applications for Clinical Practice

The current study demonstrated that metformin use, as compared to sulfonylureas, has a lower risk of fatal or nonfatal major adverse cardiovascular events among patients with reduced kidney function. When clinicians are managing hyperglycemia in patients with type 2 diabetes, it is important to keep in mind that all medications have adverse effects. There are now 11 drug classes for treating diabetes, in addition to multiple insulin options, and the challenge for clinicians is to present clear information to guide patients using shared decision making, based on each patient’s clinical circumstances and preferences, to achieve individualized glycemic target ranges.

–Ka Ming Gordon Ngai, MD, MPH

Study Overview

Objective. To assess whether metformin use is associated with lower risk of fatal or nonfatal major adverse cardiovascular events (MACE) as compared to sulfonylurea use among diabetic patients with reduced kidney function.

Design. Retrospective cohort study of US Veterans receiving care within the Veterans Health Administration, with data supplemented by linkage to Medicare, Medicaid, and National Death Index data from 2001 through 2016.

Setting and participants. A retrospective cohort of Veterans Health Administration (VHA) patients, aged 18 years and older. Pharmacy data included medication, date filled, days supplied, and number of pills dispensed. For Medicare and Medicaid patients, enrollees’ claims files and prescription (Part D) data were obtained. In addition, dates and cause of death were obtained from vital status and the National Death Index files.

Patients with new-onset type 2 diabetes were identified by selecting new users of metformin, glipizide, glyburide, or glimepiride. These patients were followed longitudinally and the date of cohort entry and start of follow-up was the day of reaching a reduced kidney function threshold, defined as either an estimated glomerular filtration rate (eGFR) of less than 60 mL/min/1.73 m² or serum creatinine level of 1.5 mg/dL for men or 1.4 mg/dL for women. Patients were excluded for nonpersistence, defined as 90 days without an antidiabetic drug; censoring, defined as the 181st day of no VHA contact; or study end date of December 31, 2016.

Main outcome measures. Primary outcome was the composite of MACE including hospitalization for acute myocardial infarction (AMI), ischemic or hemorrhagic stroke, transient ischemic attack (TIA), or date of cardiovascular death. The secondary outcome excluded TIA as part of the composite MACE event because not all patients who sustain a TIA are admitted to the hospital.

Main results. From January 1, 2002 through December 30, 2015, 67,749 new metformin users and 28,976 new sulfonylurea users who persisted with treatment were identified. After using propensity score-weighted matching, 24,679 metformin users and 24,799 sulfonylurea users entered the final analysis. Cohort patients were 98% male and 81.8% white. Metformin users were younger than sulfonylurea users, with a median age of 61 years versus 71 years, respectively.

For the main outcome, there were 1048 composite MACE events among metformin patients with reduced kidney function and 1394 MACE events among sulfonylurea patients, yielding 23.0 (95% confidence interval [CI], 21.7-24.4) versus 29.2 (95% CI, 27.7-30.7) events per 1000 person-years of use, respectively, after propensity score-weighting. After covariate adjustment, the cause-specific adjusted hazard ratio (aHR) for MACE was 0.80 (95% CI, 0.75-0.86) among metformin users compared with sulfonylurea users. The adjusted incidence rate difference was 5.8 (95% CI, 4.1-7.3) fewer events per 1000-person years for metformin compared with sulfonylurea users. Results were also consistent for each component of the primary outcome, including cardiovascular hospitalizations (aHR, 0.87; 95% CI, 0.80-0.95) and cardiovascular deaths (aHR, 0.70; 95% CI, 0.63-0.78).

Analysis of secondary outcomes, which included AMI, stroke, and cardiovascular death and excluded TIA, demonstrated similar results, with a cause-specific aHR of 0.78 (95% CI, 0.72-0.84) among metformin users compared with sulfonylurea users. The adjusted incidence rate difference was 5.9 (95% CI, 4.3-7.6) fewer events per 1000-person years for metformin compared with sulfonylurea users.

Conclusion. For patients with diabetes and reduced kidney function, treatment with metformin monotherapy, as compared with a sulfonylurea, was associated with a lower risk of MACE.

Commentary

There are approximately 30 million US adults with a diagnosis of type 2 diabetes (T2DM), of whom 20% also have impaired kidney function or chronic kidney disease (CKD).¹ Metformin hydrochloride has remained the preferred first-line treatment for T2DM based on safety and effectiveness, as well as low cost.² Metformin is eliminated by the kidneys and can accumulate as eGFR declines. Based on the negative clinical experience, the US Food and Drug Administration (FDA) issued a safety warning restricting metformin for patients with serum creatinine levels of 1.5 mg/dL or greater for men or 1.4 mg/dL or greater for women. The FDA recommended against starting metformin therapy in patients with CKD with eGFR between 30 and 45 mL/min/1.73 m², although patients already taking metformin can continue with caution in that setting.^1,3

There are several limitations in conducting observational studies comparing metformin to other glucose-lowering medications. First, metformin trials typically excluded patients with CKD due to the FDA warnings. Second, there is usually a time-lag bias in which patients who initiate glucose-lowering medications other than metformin are at a later stage of disease. Third, there is often an allocation bias, as there are substantial differences in baseline characteristics between metformin and sulfonylurea monotherapy users, with metformin users usually being younger and healthier.⁴

In this retrospective cohort study by Roumie et al, the authors used propensity score–weighted matching to reduce the impacts on time-lag and allocation bias. However, several major limitations remained in this study. First, the study design excluded those who began diabetes treatment after the onset of reduced kidney function; therefore, this study cannot be generalized to patients who already have reduced eGFR at the time of metformin initiation. Second, cohort entry and the start of follow-up was either an elevated serum creatinine or reduced eGFR less than 60 mL/min/1.73 m². The cohort may have included some patients with an acute kidney injury event, rather than progression to CKD, who recovered from their acute kidney injury. Third, the study population was mostly elderly white men; together with the lack of dose analysis, this study may not be generalizable to other populations.

 

 

Applications for Clinical Practice

The current study demonstrated that metformin use, as compared to sulfonylureas, has a lower risk of fatal or nonfatal major adverse cardiovascular events among patients with reduced kidney function. When clinicians are managing hyperglycemia in patients with type 2 diabetes, it is important to keep in mind that all medications have adverse effects. There are now 11 drug classes for treating diabetes, in addition to multiple insulin options, and the challenge for clinicians is to present clear information to guide patients using shared decision making, based on each patient’s clinical circumstances and preferences, to achieve individualized glycemic target ranges.

–Ka Ming Gordon Ngai, MD, MPH

Study Overview

Objective. To assess whether metformin use is associated with lower risk of fatal or nonfatal major adverse cardiovascular events (MACE) as compared to sulfonylurea use among diabetic patients with reduced kidney function.

Design. Retrospective cohort study of US Veterans receiving care within the Veterans Health Administration, with data supplemented by linkage to Medicare, Medicaid, and National Death Index data from 2001 through 2016.

Setting and participants. A retrospective cohort of Veterans Health Administration (VHA) patients, aged 18 years and older. Pharmacy data included medication, date filled, days supplied, and number of pills dispensed. For Medicare and Medicaid patients, enrollees’ claims files and prescription (Part D) data were obtained. In addition, dates and cause of death were obtained from vital status and the National Death Index files.

Patients with new-onset type 2 diabetes were identified by selecting new users of metformin, glipizide, glyburide, or glimepiride. These patients were followed longitudinally and the date of cohort entry and start of follow-up was the day of reaching a reduced kidney function threshold, defined as either an estimated glomerular filtration rate (eGFR) of less than 60 mL/min/1.73 m² or serum creatinine level of 1.5 mg/dL for men or 1.4 mg/dL for women. Patients were excluded for nonpersistence, defined as 90 days without an antidiabetic drug; censoring, defined as the 181st day of no VHA contact; or study end date of December 31, 2016.

Main outcome measures. Primary outcome was the composite of MACE including hospitalization for acute myocardial infarction (AMI), ischemic or hemorrhagic stroke, transient ischemic attack (TIA), or date of cardiovascular death. The secondary outcome excluded TIA as part of the composite MACE event because not all patients who sustain a TIA are admitted to the hospital.

Main results. From January 1, 2002 through December 30, 2015, 67,749 new metformin users and 28,976 new sulfonylurea users who persisted with treatment were identified. After using propensity score-weighted matching, 24,679 metformin users and 24,799 sulfonylurea users entered the final analysis. Cohort patients were 98% male and 81.8% white. Metformin users were younger than sulfonylurea users, with a median age of 61 years versus 71 years, respectively.

For the main outcome, there were 1048 composite MACE events among metformin patients with reduced kidney function and 1394 MACE events among sulfonylurea patients, yielding 23.0 (95% confidence interval [CI], 21.7-24.4) versus 29.2 (95% CI, 27.7-30.7) events per 1000 person-years of use, respectively, after propensity score-weighting. After covariate adjustment, the cause-specific adjusted hazard ratio (aHR) for MACE was 0.80 (95% CI, 0.75-0.86) among metformin users compared with sulfonylurea users. The adjusted incidence rate difference was 5.8 (95% CI, 4.1-7.3) fewer events per 1000-person years for metformin compared with sulfonylurea users. Results were also consistent for each component of the primary outcome, including cardiovascular hospitalizations (aHR, 0.87; 95% CI, 0.80-0.95) and cardiovascular deaths (aHR, 0.70; 95% CI, 0.63-0.78).

Analysis of secondary outcomes, which included AMI, stroke, and cardiovascular death and excluded TIA, demonstrated similar results, with a cause-specific aHR of 0.78 (95% CI, 0.72-0.84) among metformin users compared with sulfonylurea users. The adjusted incidence rate difference was 5.9 (95% CI, 4.3-7.6) fewer events per 1000-person years for metformin compared with sulfonylurea users.

Conclusion. For patients with diabetes and reduced kidney function, treatment with metformin monotherapy, as compared with a sulfonylurea, was associated with a lower risk of MACE.

Commentary

There are approximately 30 million US adults with a diagnosis of type 2 diabetes (T2DM), of whom 20% also have impaired kidney function or chronic kidney disease (CKD).¹ Metformin hydrochloride has remained the preferred first-line treatment for T2DM based on safety and effectiveness, as well as low cost.² Metformin is eliminated by the kidneys and can accumulate as eGFR declines. Based on the negative clinical experience, the US Food and Drug Administration (FDA) issued a safety warning restricting metformin for patients with serum creatinine levels of 1.5 mg/dL or greater for men or 1.4 mg/dL or greater for women. The FDA recommended against starting metformin therapy in patients with CKD with eGFR between 30 and 45 mL/min/1.73 m², although patients already taking metformin can continue with caution in that setting.^1,3

There are several limitations in conducting observational studies comparing metformin to other glucose-lowering medications. First, metformin trials typically excluded patients with CKD due to the FDA warnings. Second, there is usually a time-lag bias in which patients who initiate glucose-lowering medications other than metformin are at a later stage of disease. Third, there is often an allocation bias, as there are substantial differences in baseline characteristics between metformin and sulfonylurea monotherapy users, with metformin users usually being younger and healthier.⁴

In this retrospective cohort study by Roumie et al, the authors used propensity score–weighted matching to reduce the impacts on time-lag and allocation bias. However, several major limitations remained in this study. First, the study design excluded those who began diabetes treatment after the onset of reduced kidney function; therefore, this study cannot be generalized to patients who already have reduced eGFR at the time of metformin initiation. Second, cohort entry and the start of follow-up was either an elevated serum creatinine or reduced eGFR less than 60 mL/min/1.73 m². The cohort may have included some patients with an acute kidney injury event, rather than progression to CKD, who recovered from their acute kidney injury. Third, the study population was mostly elderly white men; together with the lack of dose analysis, this study may not be generalizable to other populations.

 

 

Applications for Clinical Practice

The current study demonstrated that metformin use, as compared to sulfonylureas, has a lower risk of fatal or nonfatal major adverse cardiovascular events among patients with reduced kidney function. When clinicians are managing hyperglycemia in patients with type 2 diabetes, it is important to keep in mind that all medications have adverse effects. There are now 11 drug classes for treating diabetes, in addition to multiple insulin options, and the challenge for clinicians is to present clear information to guide patients using shared decision making, based on each patient’s clinical circumstances and preferences, to achieve individualized glycemic target ranges.

–Ka Ming Gordon Ngai, MD, MPH

Nearly one in five adolescents and one in four young adults in the United States have prediabetes, with a higher prevalence among males, a study has found.

copyright Martynasfoto/Thinkstock

Linda J. Andes, PhD, from the Centers for Disease Control and Prevention and coauthors reported in JAMA Pediatrics their analysis of data from 2,606 adolescent (12-18 years) and 3,180 young adult (19-34 years) participants in the 2005-2016 National Health and Nutrition Examination Surveys.

This found that the percentage with prediabetes – defined as either impaired fasting glucose (IFG), impaired glucose tolerance (IGT) or increased hemoglobin A_1c (HbA_1c) level – was 18% among adolescents and 24% among young adults.

The most common condition was IFG, which was seen in 11% of adolescents and 16% of young adults. The rate of IGT was 4% in adolescents and 6% of young adults, while elevated HbA_1c levels were seen in 5% of adolescents and 8% of young adults.

This information is important because “In adults, these three phenotypes increase the risk of developing type 2 diabetes as well as cardiovascular diseases,” Dr. Andes and coauthors wrote. “In 2011-2012, the overall prevalence of prediabetes among U.S. adults, defined as the presence of any of the three glucose metabolism dysregulation phenotypes, was 38% and it increased to about 50% in persons 65 years and older.”

Dr. Andes and associates noted that isolated IFG was the most common glucose dysregulation seen in both adolescents and young adults. “While individuals with IFG are at increased risk for type 2 diabetes, few primary prevention trials have included individuals selected for the presence of IFG and none have been conducted in adolescents with IFG or IGT to our knowledge.”

The study saw some key gender differences in prevalence. For example, the prevalence of IFG was significantly lower in adolescent girls than in boys (7% vs. 15%; P less than .001), and in young women, compared with young men (10% vs. 22%; P less than .001).

“These findings are consistent with those of other studies in adults; however, the underlying mechanisms for explaining this discrepancy are still unclear,” Dr. Andes and coauthors wrote.

Ethnicity also appeared to influence risk, with the prevalence of IFG significantly lower in non-Hispanic black adolescents, compared with Hispanic adolescents. However, increased HbA_1c levels were significantly more prevalent in non-Hispanic black adolescents, compared with Hispanic or non-Hispanic white adolescents.

“These findings highlight the need for additional studies on the long-term consequences and preventive strategies of abnormal glucose metabolism as measured by HbA_1c levels in adolescents and young adults, especially of minority racial/ethnic groups,” the authors wrote.

Adolescents with prediabetes had significantly higher systolic blood pressure, non-HDL cholesterol, waist-to-height ratio, higher body mass index, and lower insulin sensitivity, compared with those with normal glucose tolerance. Among young adults with prediabetes, there was significantly higher systolic blood pressure and non-HDL cholesterol, compared with individuals with normal glucose tolerance.

No funding or conflicts of interest were declared.

SOURCE: Andes LJ et al. JAMA Pediatr. 2019 Dec 2. doi: 10.1001/jamapediatrics.2019.4498.

Nearly one in five adolescents and one in four young adults in the United States have prediabetes, with a higher prevalence among males, a study has found.

copyright Martynasfoto/Thinkstock

Linda J. Andes, PhD, from the Centers for Disease Control and Prevention and coauthors reported in JAMA Pediatrics their analysis of data from 2,606 adolescent (12-18 years) and 3,180 young adult (19-34 years) participants in the 2005-2016 National Health and Nutrition Examination Surveys.

This found that the percentage with prediabetes – defined as either impaired fasting glucose (IFG), impaired glucose tolerance (IGT) or increased hemoglobin A_1c (HbA_1c) level – was 18% among adolescents and 24% among young adults.

The most common condition was IFG, which was seen in 11% of adolescents and 16% of young adults. The rate of IGT was 4% in adolescents and 6% of young adults, while elevated HbA_1c levels were seen in 5% of adolescents and 8% of young adults.

This information is important because “In adults, these three phenotypes increase the risk of developing type 2 diabetes as well as cardiovascular diseases,” Dr. Andes and coauthors wrote. “In 2011-2012, the overall prevalence of prediabetes among U.S. adults, defined as the presence of any of the three glucose metabolism dysregulation phenotypes, was 38% and it increased to about 50% in persons 65 years and older.”

Dr. Andes and associates noted that isolated IFG was the most common glucose dysregulation seen in both adolescents and young adults. “While individuals with IFG are at increased risk for type 2 diabetes, few primary prevention trials have included individuals selected for the presence of IFG and none have been conducted in adolescents with IFG or IGT to our knowledge.”

The study saw some key gender differences in prevalence. For example, the prevalence of IFG was significantly lower in adolescent girls than in boys (7% vs. 15%; P less than .001), and in young women, compared with young men (10% vs. 22%; P less than .001).

“These findings are consistent with those of other studies in adults; however, the underlying mechanisms for explaining this discrepancy are still unclear,” Dr. Andes and coauthors wrote.

Ethnicity also appeared to influence risk, with the prevalence of IFG significantly lower in non-Hispanic black adolescents, compared with Hispanic adolescents. However, increased HbA_1c levels were significantly more prevalent in non-Hispanic black adolescents, compared with Hispanic or non-Hispanic white adolescents.

“These findings highlight the need for additional studies on the long-term consequences and preventive strategies of abnormal glucose metabolism as measured by HbA_1c levels in adolescents and young adults, especially of minority racial/ethnic groups,” the authors wrote.

Adolescents with prediabetes had significantly higher systolic blood pressure, non-HDL cholesterol, waist-to-height ratio, higher body mass index, and lower insulin sensitivity, compared with those with normal glucose tolerance. Among young adults with prediabetes, there was significantly higher systolic blood pressure and non-HDL cholesterol, compared with individuals with normal glucose tolerance.

No funding or conflicts of interest were declared.

SOURCE: Andes LJ et al. JAMA Pediatr. 2019 Dec 2. doi: 10.1001/jamapediatrics.2019.4498.

Nearly one in five adolescents and one in four young adults in the United States have prediabetes, with a higher prevalence among males, a study has found.

copyright Martynasfoto/Thinkstock

Linda J. Andes, PhD, from the Centers for Disease Control and Prevention and coauthors reported in JAMA Pediatrics their analysis of data from 2,606 adolescent (12-18 years) and 3,180 young adult (19-34 years) participants in the 2005-2016 National Health and Nutrition Examination Surveys.

This found that the percentage with prediabetes – defined as either impaired fasting glucose (IFG), impaired glucose tolerance (IGT) or increased hemoglobin A_1c (HbA_1c) level – was 18% among adolescents and 24% among young adults.

The most common condition was IFG, which was seen in 11% of adolescents and 16% of young adults. The rate of IGT was 4% in adolescents and 6% of young adults, while elevated HbA_1c levels were seen in 5% of adolescents and 8% of young adults.

This information is important because “In adults, these three phenotypes increase the risk of developing type 2 diabetes as well as cardiovascular diseases,” Dr. Andes and coauthors wrote. “In 2011-2012, the overall prevalence of prediabetes among U.S. adults, defined as the presence of any of the three glucose metabolism dysregulation phenotypes, was 38% and it increased to about 50% in persons 65 years and older.”

Dr. Andes and associates noted that isolated IFG was the most common glucose dysregulation seen in both adolescents and young adults. “While individuals with IFG are at increased risk for type 2 diabetes, few primary prevention trials have included individuals selected for the presence of IFG and none have been conducted in adolescents with IFG or IGT to our knowledge.”

The study saw some key gender differences in prevalence. For example, the prevalence of IFG was significantly lower in adolescent girls than in boys (7% vs. 15%; P less than .001), and in young women, compared with young men (10% vs. 22%; P less than .001).

“These findings are consistent with those of other studies in adults; however, the underlying mechanisms for explaining this discrepancy are still unclear,” Dr. Andes and coauthors wrote.

Ethnicity also appeared to influence risk, with the prevalence of IFG significantly lower in non-Hispanic black adolescents, compared with Hispanic adolescents. However, increased HbA_1c levels were significantly more prevalent in non-Hispanic black adolescents, compared with Hispanic or non-Hispanic white adolescents.

“These findings highlight the need for additional studies on the long-term consequences and preventive strategies of abnormal glucose metabolism as measured by HbA_1c levels in adolescents and young adults, especially of minority racial/ethnic groups,” the authors wrote.

Adolescents with prediabetes had significantly higher systolic blood pressure, non-HDL cholesterol, waist-to-height ratio, higher body mass index, and lower insulin sensitivity, compared with those with normal glucose tolerance. Among young adults with prediabetes, there was significantly higher systolic blood pressure and non-HDL cholesterol, compared with individuals with normal glucose tolerance.

No funding or conflicts of interest were declared.

SOURCE: Andes LJ et al. JAMA Pediatr. 2019 Dec 2. doi: 10.1001/jamapediatrics.2019.4498.