Clinician Reviews

A new generation of medications designed to help individuals lose weight is in the news and stirring considerable debate within medical, insurer, and employer circles. Indeed, these drugs show striking results, compared with weight loss drugs of the past, with some research reporting a 15%-20% loss in body weight when used as an adjunct to intensive behavior therapy and intensive lifestyle intervention.
 

Obesity and associated chronic diseases are at an epidemic level in the United States and carry enormous personal, family, and societal burdens. As an exercise physiologist and a dual board-certified cardiologist and lifestyle medicine specialist, I am grateful for modern medicine and have leveraged the efficacy of many medications in patient care. I also recognize that it is in my patients’ and my own best interests to strive for health restoration rather than default to a lifetime of disease management. This is especially urgent when it comes to children.

That’s why as physicians we must not allow these new medications to overshadow an evidence-based comprehensive lifestyle approach – the first recommended treatment in most chronic disease care guidelines – as the optimal step toward achieving long-term health improvement.

As a matter of fact, too often lost in news stories about the success of obesity drugs like tirzepatide and semaglutide is that research study participants also received intensive lifestyle interventions. Regardless of whether clinicians ultimately prescribe weight loss medications, it is important that they first engage in patient-centered discussions that provide information about all the available treatment options and explore with patients an adequate dose of lifestyle intervention before pronouncing this approach a failure.

Merely advising a patient to eat better or exercise more is rarely sufficient information, much less sufficient dosing information, for significant weight loss. As a recent American College of Lifestyle Medicine position statement on the treatment of obesity put it: “While adequately dosed lifestyle interventions may unilaterally achieve success, obesity is a complex, multifactorial disease wherein patients may require approaches beyond lifestyle alone. However, lifestyle interventions are too often not adequately ‘dosed’ for success.”

Appetite suppression may reduce food intake, but optimal health requires eating nutrient-dense foods high in fiber and healthy fats, and preserving muscle mass through physical activity. Simply reducing the portion size of the same unhealthy, ultraprocessed foods that the patient ate before starting medication does not achieve optimal health, no matter what the scale says. ACLM’s position statement emphasizes that “a comprehensive lifestyle medicine approach prevents and treats many other comorbidities associated with overweight and obesity, including, but not limited to, hypertension, high cholesterol, heart disease, type 2 diabetes, and arthritis, and a lifestyle medicine approach can also reduce the risk of many types of cancer.”

This is even more critical in children, who may not fully understand how to eat healthfully. Furthermore, the long-term effects of weight loss medication on their still-developing bodies are unclear. Decades ago, we didn’t face an epidemic of childhood obesity; type 2 diabetes was called “adult-onset” because it was a lifestyle-related chronic disease that didn’t manifest until adulthood. We would never have considered weight-loss medications for children or gastric bypass for teens. Yet, this lifestyle-related chronic disease is now afflicting our youth.

We have allowed an abnormal food environment to fester, with nearly 60% of the American diet now consisting of ultraprocessed foods. Obesity within families may be related to shared genetics but may also be due to shared food, lifestyle, and environmental factors passed down through generations. A successful obesity treatment plan should address as many of those drivers of obesity as possible, as well as access to healthy food, transportation, and other social determinants of health.

Cost is a major consideration in clinical decision-making for weight loss treatment. The new obesity drugs are expensive, and patients probably must continue to take them throughout their lives to avoid regaining lost weight. With 70% of Americans and 90% of seniors already taking prescription drugs, the United States already spends more on pharmaceuticals than the rest of the world combined. Not all insurance plans cover these medications for the treatment of obesity, and as patients covered through one insurance plan may lose coverage on their next plan, they could be forced to stop the medications and pay out of pocket or experience fluctuations in their weight. Health care providers should consider the physical and emotional burden of weight cycling and strategically advance lifestyle measures to mitigate weight fluctuations in such patients.

Shared decisions between patients and their families and health care providers will become even more important in the rollout of new medications and obesity management guidelines. I’m hopeful that the elevated attention to obesity solutions will shepherd in thoughtful collaborations among board-certified obesity specialists, lifestyle medicine specialists, and primary care providers. ACLM, in support of the White House Conference on Hunger, Nutrition and Health, has offered 5.5 hours of complimentary CE/CME coursework in nutrition and food as medicine to 100,000 health professionals. This free opportunity (valued at $220) is an excellent step toward establishing a foundation of lifestyle medicine knowledge for health professionals treating patients for obesity. Clinicians can register here.

Let’s all get this right: Lifestyle behavior is the foundation of patients’ health and wellness at every stage of life, with or without adjunctive medication therapy. New tools like weight loss medications will arise but cannot truly achieve optimal health without lifestyle medicine as a continuum throughout a patient’s life.

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

A new generation of medications designed to help individuals lose weight is in the news and stirring considerable debate within medical, insurer, and employer circles. Indeed, these drugs show striking results, compared with weight loss drugs of the past, with some research reporting a 15%-20% loss in body weight when used as an adjunct to intensive behavior therapy and intensive lifestyle intervention.
 

Obesity and associated chronic diseases are at an epidemic level in the United States and carry enormous personal, family, and societal burdens. As an exercise physiologist and a dual board-certified cardiologist and lifestyle medicine specialist, I am grateful for modern medicine and have leveraged the efficacy of many medications in patient care. I also recognize that it is in my patients’ and my own best interests to strive for health restoration rather than default to a lifetime of disease management. This is especially urgent when it comes to children.

That’s why as physicians we must not allow these new medications to overshadow an evidence-based comprehensive lifestyle approach – the first recommended treatment in most chronic disease care guidelines – as the optimal step toward achieving long-term health improvement.

As a matter of fact, too often lost in news stories about the success of obesity drugs like tirzepatide and semaglutide is that research study participants also received intensive lifestyle interventions. Regardless of whether clinicians ultimately prescribe weight loss medications, it is important that they first engage in patient-centered discussions that provide information about all the available treatment options and explore with patients an adequate dose of lifestyle intervention before pronouncing this approach a failure.

Merely advising a patient to eat better or exercise more is rarely sufficient information, much less sufficient dosing information, for significant weight loss. As a recent American College of Lifestyle Medicine position statement on the treatment of obesity put it: “While adequately dosed lifestyle interventions may unilaterally achieve success, obesity is a complex, multifactorial disease wherein patients may require approaches beyond lifestyle alone. However, lifestyle interventions are too often not adequately ‘dosed’ for success.”

Appetite suppression may reduce food intake, but optimal health requires eating nutrient-dense foods high in fiber and healthy fats, and preserving muscle mass through physical activity. Simply reducing the portion size of the same unhealthy, ultraprocessed foods that the patient ate before starting medication does not achieve optimal health, no matter what the scale says. ACLM’s position statement emphasizes that “a comprehensive lifestyle medicine approach prevents and treats many other comorbidities associated with overweight and obesity, including, but not limited to, hypertension, high cholesterol, heart disease, type 2 diabetes, and arthritis, and a lifestyle medicine approach can also reduce the risk of many types of cancer.”

This is even more critical in children, who may not fully understand how to eat healthfully. Furthermore, the long-term effects of weight loss medication on their still-developing bodies are unclear. Decades ago, we didn’t face an epidemic of childhood obesity; type 2 diabetes was called “adult-onset” because it was a lifestyle-related chronic disease that didn’t manifest until adulthood. We would never have considered weight-loss medications for children or gastric bypass for teens. Yet, this lifestyle-related chronic disease is now afflicting our youth.

We have allowed an abnormal food environment to fester, with nearly 60% of the American diet now consisting of ultraprocessed foods. Obesity within families may be related to shared genetics but may also be due to shared food, lifestyle, and environmental factors passed down through generations. A successful obesity treatment plan should address as many of those drivers of obesity as possible, as well as access to healthy food, transportation, and other social determinants of health.

Cost is a major consideration in clinical decision-making for weight loss treatment. The new obesity drugs are expensive, and patients probably must continue to take them throughout their lives to avoid regaining lost weight. With 70% of Americans and 90% of seniors already taking prescription drugs, the United States already spends more on pharmaceuticals than the rest of the world combined. Not all insurance plans cover these medications for the treatment of obesity, and as patients covered through one insurance plan may lose coverage on their next plan, they could be forced to stop the medications and pay out of pocket or experience fluctuations in their weight. Health care providers should consider the physical and emotional burden of weight cycling and strategically advance lifestyle measures to mitigate weight fluctuations in such patients.

Shared decisions between patients and their families and health care providers will become even more important in the rollout of new medications and obesity management guidelines. I’m hopeful that the elevated attention to obesity solutions will shepherd in thoughtful collaborations among board-certified obesity specialists, lifestyle medicine specialists, and primary care providers. ACLM, in support of the White House Conference on Hunger, Nutrition and Health, has offered 5.5 hours of complimentary CE/CME coursework in nutrition and food as medicine to 100,000 health professionals. This free opportunity (valued at $220) is an excellent step toward establishing a foundation of lifestyle medicine knowledge for health professionals treating patients for obesity. Clinicians can register here.

Let’s all get this right: Lifestyle behavior is the foundation of patients’ health and wellness at every stage of life, with or without adjunctive medication therapy. New tools like weight loss medications will arise but cannot truly achieve optimal health without lifestyle medicine as a continuum throughout a patient’s life.

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

A new generation of medications designed to help individuals lose weight is in the news and stirring considerable debate within medical, insurer, and employer circles. Indeed, these drugs show striking results, compared with weight loss drugs of the past, with some research reporting a 15%-20% loss in body weight when used as an adjunct to intensive behavior therapy and intensive lifestyle intervention.
 

Obesity and associated chronic diseases are at an epidemic level in the United States and carry enormous personal, family, and societal burdens. As an exercise physiologist and a dual board-certified cardiologist and lifestyle medicine specialist, I am grateful for modern medicine and have leveraged the efficacy of many medications in patient care. I also recognize that it is in my patients’ and my own best interests to strive for health restoration rather than default to a lifetime of disease management. This is especially urgent when it comes to children.

That’s why as physicians we must not allow these new medications to overshadow an evidence-based comprehensive lifestyle approach – the first recommended treatment in most chronic disease care guidelines – as the optimal step toward achieving long-term health improvement.

As a matter of fact, too often lost in news stories about the success of obesity drugs like tirzepatide and semaglutide is that research study participants also received intensive lifestyle interventions. Regardless of whether clinicians ultimately prescribe weight loss medications, it is important that they first engage in patient-centered discussions that provide information about all the available treatment options and explore with patients an adequate dose of lifestyle intervention before pronouncing this approach a failure.

Merely advising a patient to eat better or exercise more is rarely sufficient information, much less sufficient dosing information, for significant weight loss. As a recent American College of Lifestyle Medicine position statement on the treatment of obesity put it: “While adequately dosed lifestyle interventions may unilaterally achieve success, obesity is a complex, multifactorial disease wherein patients may require approaches beyond lifestyle alone. However, lifestyle interventions are too often not adequately ‘dosed’ for success.”

Appetite suppression may reduce food intake, but optimal health requires eating nutrient-dense foods high in fiber and healthy fats, and preserving muscle mass through physical activity. Simply reducing the portion size of the same unhealthy, ultraprocessed foods that the patient ate before starting medication does not achieve optimal health, no matter what the scale says. ACLM’s position statement emphasizes that “a comprehensive lifestyle medicine approach prevents and treats many other comorbidities associated with overweight and obesity, including, but not limited to, hypertension, high cholesterol, heart disease, type 2 diabetes, and arthritis, and a lifestyle medicine approach can also reduce the risk of many types of cancer.”

This is even more critical in children, who may not fully understand how to eat healthfully. Furthermore, the long-term effects of weight loss medication on their still-developing bodies are unclear. Decades ago, we didn’t face an epidemic of childhood obesity; type 2 diabetes was called “adult-onset” because it was a lifestyle-related chronic disease that didn’t manifest until adulthood. We would never have considered weight-loss medications for children or gastric bypass for teens. Yet, this lifestyle-related chronic disease is now afflicting our youth.

We have allowed an abnormal food environment to fester, with nearly 60% of the American diet now consisting of ultraprocessed foods. Obesity within families may be related to shared genetics but may also be due to shared food, lifestyle, and environmental factors passed down through generations. A successful obesity treatment plan should address as many of those drivers of obesity as possible, as well as access to healthy food, transportation, and other social determinants of health.

Cost is a major consideration in clinical decision-making for weight loss treatment. The new obesity drugs are expensive, and patients probably must continue to take them throughout their lives to avoid regaining lost weight. With 70% of Americans and 90% of seniors already taking prescription drugs, the United States already spends more on pharmaceuticals than the rest of the world combined. Not all insurance plans cover these medications for the treatment of obesity, and as patients covered through one insurance plan may lose coverage on their next plan, they could be forced to stop the medications and pay out of pocket or experience fluctuations in their weight. Health care providers should consider the physical and emotional burden of weight cycling and strategically advance lifestyle measures to mitigate weight fluctuations in such patients.

Shared decisions between patients and their families and health care providers will become even more important in the rollout of new medications and obesity management guidelines. I’m hopeful that the elevated attention to obesity solutions will shepherd in thoughtful collaborations among board-certified obesity specialists, lifestyle medicine specialists, and primary care providers. ACLM, in support of the White House Conference on Hunger, Nutrition and Health, has offered 5.5 hours of complimentary CE/CME coursework in nutrition and food as medicine to 100,000 health professionals. This free opportunity (valued at $220) is an excellent step toward establishing a foundation of lifestyle medicine knowledge for health professionals treating patients for obesity. Clinicians can register here.

Let’s all get this right: Lifestyle behavior is the foundation of patients’ health and wellness at every stage of life, with or without adjunctive medication therapy. New tools like weight loss medications will arise but cannot truly achieve optimal health without lifestyle medicine as a continuum throughout a patient’s life.

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

We are all searching for happiness. But how do we achieve it? What are its greatest determinants?

The Harvard Study of Adult Development may be the most comprehensive study ever conducted, as it followed its participants for their entire adult lives. The study was started in Boston in 1938 and has already covered three generations: grandparents, parents, and children, who are now considered “baby boomers.” It analyzed more than 2,000 people throughout 85 years of longitudinal study.

In January, Robert J. Waldinger, MD, the current director of this incredible study, published the book The Good Life: Lessons From the World’s Longest Scientific Study of Happiness, coauthored with the study’s associate director, Marc Schulz, PhD.

By following this large population for more than 8 decades, the study uncovered the factors most correlated with well-being and happiness. Here, I have summarized some of the authors’ main concepts.
 

Most important factors

The study’s happiest participants had two major factors in common throughout its 85 years: Taking care of their health and building loving relationships with others.

It seems obvious that being in good health is essential to live well. However, to some surprise, researchers determined that good relationships were the most significant predictor of health and happiness during aging. Other authors have confirmed this finding, and research has sought to analyze the physiological mechanisms associated with this benefit.
 

Professional success insufficient

Professional success on its own does not guarantee happiness, even though it may be gratifying. The study revealed that those who were happiest were not isolated. In fact, the happiest people valued and fostered relationships. Levels of education and cultural awareness, which tend to be higher among those with higher salaries, were also important factors for adopting healthy habits (promoted more often as of the 1960s) and for better access to health care.

Social skills

Loneliness is increasingly common and creates challenges when dealing with stressful situations. It is essential to have someone with whom we can vent. Therefore, Dr. Waldinger recommends assessing how to foster, strengthen, and broaden relationships. He calls this maintaining social connections and, just as with physical fitness, it also requires constant practice. Friendships and relationships need regular commitment to keep them from fizzling out. A simple telephone call can help. Participating in activities that bring joy and encourage camaraderie, such as sports, hobbies, and volunteer work, may broaden the relationship network.

Happiness not constant

Social media almost always shows the positive side of people’s lives and suggests that everyone lives worry-free. However, the truth is that no one’s life is free of difficulties and challenges. Social skills contribute to resilience.

It is never too late for a turnaround and for people to change their lives through new relationships and experiences. Those who think they know everything about life are very mistaken. The study showed that good things happened to those who had given up on changing their situation, and good news appeared when they least expected it.

This study highlights the importance of having social skills and always cultivating our relationships to help us become healthier, overcome challenging moments, and achieve the happiness that we all desire.

We finally have robust evidence-based data to use when speaking on happiness.

Dr. Wajngarten is professor of cardiology, University of São Paulo, Brazil. He has disclosed no relevant financial relationships.

This article was translated from the Medscape Portuguese Edition. A version of this article appeared on Medscape.com.

We are all searching for happiness. But how do we achieve it? What are its greatest determinants?

The Harvard Study of Adult Development may be the most comprehensive study ever conducted, as it followed its participants for their entire adult lives. The study was started in Boston in 1938 and has already covered three generations: grandparents, parents, and children, who are now considered “baby boomers.” It analyzed more than 2,000 people throughout 85 years of longitudinal study.

In January, Robert J. Waldinger, MD, the current director of this incredible study, published the book The Good Life: Lessons From the World’s Longest Scientific Study of Happiness, coauthored with the study’s associate director, Marc Schulz, PhD.

By following this large population for more than 8 decades, the study uncovered the factors most correlated with well-being and happiness. Here, I have summarized some of the authors’ main concepts.
 

Most important factors

The study’s happiest participants had two major factors in common throughout its 85 years: Taking care of their health and building loving relationships with others.

It seems obvious that being in good health is essential to live well. However, to some surprise, researchers determined that good relationships were the most significant predictor of health and happiness during aging. Other authors have confirmed this finding, and research has sought to analyze the physiological mechanisms associated with this benefit.
 

Professional success insufficient

Professional success on its own does not guarantee happiness, even though it may be gratifying. The study revealed that those who were happiest were not isolated. In fact, the happiest people valued and fostered relationships. Levels of education and cultural awareness, which tend to be higher among those with higher salaries, were also important factors for adopting healthy habits (promoted more often as of the 1960s) and for better access to health care.

Social skills

Loneliness is increasingly common and creates challenges when dealing with stressful situations. It is essential to have someone with whom we can vent. Therefore, Dr. Waldinger recommends assessing how to foster, strengthen, and broaden relationships. He calls this maintaining social connections and, just as with physical fitness, it also requires constant practice. Friendships and relationships need regular commitment to keep them from fizzling out. A simple telephone call can help. Participating in activities that bring joy and encourage camaraderie, such as sports, hobbies, and volunteer work, may broaden the relationship network.

Happiness not constant

Social media almost always shows the positive side of people’s lives and suggests that everyone lives worry-free. However, the truth is that no one’s life is free of difficulties and challenges. Social skills contribute to resilience.

It is never too late for a turnaround and for people to change their lives through new relationships and experiences. Those who think they know everything about life are very mistaken. The study showed that good things happened to those who had given up on changing their situation, and good news appeared when they least expected it.

This study highlights the importance of having social skills and always cultivating our relationships to help us become healthier, overcome challenging moments, and achieve the happiness that we all desire.

We finally have robust evidence-based data to use when speaking on happiness.

Dr. Wajngarten is professor of cardiology, University of São Paulo, Brazil. He has disclosed no relevant financial relationships.

This article was translated from the Medscape Portuguese Edition. A version of this article appeared on Medscape.com.

We are all searching for happiness. But how do we achieve it? What are its greatest determinants?

The Harvard Study of Adult Development may be the most comprehensive study ever conducted, as it followed its participants for their entire adult lives. The study was started in Boston in 1938 and has already covered three generations: grandparents, parents, and children, who are now considered “baby boomers.” It analyzed more than 2,000 people throughout 85 years of longitudinal study.

In January, Robert J. Waldinger, MD, the current director of this incredible study, published the book The Good Life: Lessons From the World’s Longest Scientific Study of Happiness, coauthored with the study’s associate director, Marc Schulz, PhD.

By following this large population for more than 8 decades, the study uncovered the factors most correlated with well-being and happiness. Here, I have summarized some of the authors’ main concepts.
 

Most important factors

The study’s happiest participants had two major factors in common throughout its 85 years: Taking care of their health and building loving relationships with others.

It seems obvious that being in good health is essential to live well. However, to some surprise, researchers determined that good relationships were the most significant predictor of health and happiness during aging. Other authors have confirmed this finding, and research has sought to analyze the physiological mechanisms associated with this benefit.
 

Professional success insufficient

Professional success on its own does not guarantee happiness, even though it may be gratifying. The study revealed that those who were happiest were not isolated. In fact, the happiest people valued and fostered relationships. Levels of education and cultural awareness, which tend to be higher among those with higher salaries, were also important factors for adopting healthy habits (promoted more often as of the 1960s) and for better access to health care.

Social skills

Loneliness is increasingly common and creates challenges when dealing with stressful situations. It is essential to have someone with whom we can vent. Therefore, Dr. Waldinger recommends assessing how to foster, strengthen, and broaden relationships. He calls this maintaining social connections and, just as with physical fitness, it also requires constant practice. Friendships and relationships need regular commitment to keep them from fizzling out. A simple telephone call can help. Participating in activities that bring joy and encourage camaraderie, such as sports, hobbies, and volunteer work, may broaden the relationship network.

Happiness not constant

Social media almost always shows the positive side of people’s lives and suggests that everyone lives worry-free. However, the truth is that no one’s life is free of difficulties and challenges. Social skills contribute to resilience.

It is never too late for a turnaround and for people to change their lives through new relationships and experiences. Those who think they know everything about life are very mistaken. The study showed that good things happened to those who had given up on changing their situation, and good news appeared when they least expected it.

This study highlights the importance of having social skills and always cultivating our relationships to help us become healthier, overcome challenging moments, and achieve the happiness that we all desire.

We finally have robust evidence-based data to use when speaking on happiness.

Dr. Wajngarten is professor of cardiology, University of São Paulo, Brazil. He has disclosed no relevant financial relationships.

This article was translated from the Medscape Portuguese Edition. A version of this article appeared on Medscape.com.

The antiplatelet of choice for long-term, secondary prevention for patients with established coronary artery disease (CAD) may well be a P2Y12 inhibitor such as clopidogrel or ticagrelor rather than aspirin, suggests a patient-level meta-analysis of seven randomized trials.

The more than 24,000 patients in the meta-analysis, called PANTHER, had documented stable CAD, prior myocardial infarction (MI), or recent or remote surgical or percutaneous coronary revascularization.

About half of patients in each antiplatelet monotherapy trial received clopidogrel or ticagrelor, and the other half received aspirin. Follow-ups ranged from 6 months to 3 years.

Those taking a P2Y12 inhibitor showed a 12% reduction in risk (P = .012) for the primary efficacy outcome, a composite of cardiovascular (CV) death, MI, and stroke, over a median of about 1.35 years. The difference was driven primarily by a 23% reduction in risk for MI (P < .001); mortality seemed unaffected by antiplatelet treatment assignment.

Although the P2Y12 inhibitor and aspirin groups were similar with respect to risk of major bleeding, the P2Y12 inhibitor group showed significant reductions in risk for gastrointestinal (GI) bleeding, definite stent thrombosis, and hemorrhagic stroke; rates of hemorrhagic stroke were well under 1% in both groups.

The treatment effects were consistent across patient subgroups, including whether the aspirin comparison was with clopidogrel or ticagrelor.

“Taken together, our data challenge the central role of aspirin in secondary prevention and support a paradigm shift toward P2Y12 inhibitor monotherapy as long-term antiplatelet strategy in the sizable population of patients with coronary atherosclerosis,” Felice Gragnano, MD, PhD, said in an interview. “Given [their] superior efficacy and similar overall safety, P2Y12 inhibitors may be preferred [over] aspirin for the prevention of cardiovascular events in patients with CAD.”

Dr. Gragnano, of the University of Campania Luigi Vanvitelli, Caserta, Italy, who called PANTHER “the largest and most comprehensive synthesis of individual patient data from randomized trials comparing P2Y12 inhibitor monotherapy with aspirin monotherapy,” is lead author of the study, which was published online in the Journal of the American College of Cardiology.

Current guidelines recommend aspirin for antiplatelet monotherapy for patients with established CAD, Dr. Gragnano said, but “the primacy of aspirin in secondary prevention is based on historical trials conducted in the 1970s and 1980s and may not apply to contemporary practice.”

Moreover, later trials that compared P2Y12 inhibitors with aspirin for secondary prevention produced “inconsistent results,” possibly owing to their heterogeneous populations of patients with coronary, cerebrovascular, or peripheral vascular disease, he said. Study-level meta-analyses in this area “provide inconclusive evidence” because they haven’t evaluated treatment effects exclusively in patients with established CAD.

Most of the seven trials’ 24,325 participants had a history of MI, and some had peripheral artery disease (PAD); the rates were 56.2% and 9.1%, respectively. Coronary revascularization, either percutaneous or surgical, had been performed for about 70%. Most (61%) had presented with acute coronary syndromes, and the remainder had presented with chronic CAD.

About 76% of the combined cohorts were from Europe or North America; the rest were from Asia. The mean age of the patients was 64 years, and about 22% were women.

In all, 12,175 had been assigned to P2Y12 inhibitor monotherapy (62% received clopidogrel and 38% received ticagrelor); 12,147 received aspirin at dosages ranging from 75 mg to 325 mg daily.

The hazard ratio (HR) for the primary efficacy outcome, P2Y12 inhibitors vs. aspirin, was significantly reduced, at 0.88 (95% confidence interval [CI], 0.79-0.97; P = .012); the number needed to treat (NNT) to prevent one primary event over 2 years was 121, the report states.

The corresponding HR for MI was 0.77 (95% CI, 0.66-0.90; P < .001), for an NNT benefit of 136. For net adverse clinical events, the HR was 0.89 (95% CI, 0.81-0.98; P = .020), for an NNT benefit of 121.

Risk for major bleeding was not significantly different (HR, 0.87; 95% CI, 0.70-1.09; P = .23), nor were risks for stroke (HR, 0.84; 95% CI, 0.70-1.02; P = .076) or cardiovascular death (HR, 1.02; 95% CI, 0.86-1.20; P = .82).

Still, the P2Y12 inhibitor group showed significant risk reductions for the following:

• GI bleeding: HR, 0.75 (95% CI, 0.57-0.97; P = .027)
• Definite stent thrombosis: HR, 0.42 (95% CI, 0.19-0.97; P = .028)
• Hemorrhagic stroke: HR, 0.43 (95% CI, 0.23-0.83; P = .012)

The current findings are “hypothesis-generating but not definitive,” Dharam Kumbhani, MD, University of Texas Southwestern, Dallas, said in an interview.

It remains unclear “whether aspirin or P2Y12 inhibitor monotherapy is better for long-term maintenance use among patients with established CAD. Aspirin has historically been the agent of choice for this indication,” said Dr. Kumbhani, who with James A. de Lemos, MD, of the same institution, wrote an editorial accompanying the PANTHER report.

“It certainly would be appropriate to consider P2Y12 monotherapy preferentially for patients with prior or currently at high risk for GI or intracranial bleeding, for instance,” Dr. Kumbhani said. For the remainder, aspirin and P2Y12 inhibitors are both “reasonable alternatives.”

In their editorial, Dr. Kumbhani and Dr. de Lemos call the PANTHER meta-analysis “a well-done study with potentially important clinical implications.” The findings “make biological sense: P2Y12 inhibitors are more potent antiplatelet agents than aspirin and have less effect on gastrointestinal mucosal integrity.”

But for now, they wrote, “both aspirin and P2Y12 inhibitors remain viable alternatives for prevention of atherothrombotic events among patients with established CAD.”

Dr. Gragnano had no disclosures; potential conflicts for the other authors are in the report. Dr. Kumbhani reports no relevant relationships; Dr. de Lemos has received honoraria for participation in data safety monitoring boards from Eli Lilly, Novo Nordisk, AstraZeneca, and Janssen.

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

The antiplatelet of choice for long-term, secondary prevention for patients with established coronary artery disease (CAD) may well be a P2Y12 inhibitor such as clopidogrel or ticagrelor rather than aspirin, suggests a patient-level meta-analysis of seven randomized trials.

The more than 24,000 patients in the meta-analysis, called PANTHER, had documented stable CAD, prior myocardial infarction (MI), or recent or remote surgical or percutaneous coronary revascularization.

About half of patients in each antiplatelet monotherapy trial received clopidogrel or ticagrelor, and the other half received aspirin. Follow-ups ranged from 6 months to 3 years.

Those taking a P2Y12 inhibitor showed a 12% reduction in risk (P = .012) for the primary efficacy outcome, a composite of cardiovascular (CV) death, MI, and stroke, over a median of about 1.35 years. The difference was driven primarily by a 23% reduction in risk for MI (P < .001); mortality seemed unaffected by antiplatelet treatment assignment.

Although the P2Y12 inhibitor and aspirin groups were similar with respect to risk of major bleeding, the P2Y12 inhibitor group showed significant reductions in risk for gastrointestinal (GI) bleeding, definite stent thrombosis, and hemorrhagic stroke; rates of hemorrhagic stroke were well under 1% in both groups.

The treatment effects were consistent across patient subgroups, including whether the aspirin comparison was with clopidogrel or ticagrelor.

“Taken together, our data challenge the central role of aspirin in secondary prevention and support a paradigm shift toward P2Y12 inhibitor monotherapy as long-term antiplatelet strategy in the sizable population of patients with coronary atherosclerosis,” Felice Gragnano, MD, PhD, said in an interview. “Given [their] superior efficacy and similar overall safety, P2Y12 inhibitors may be preferred [over] aspirin for the prevention of cardiovascular events in patients with CAD.”

Dr. Gragnano, of the University of Campania Luigi Vanvitelli, Caserta, Italy, who called PANTHER “the largest and most comprehensive synthesis of individual patient data from randomized trials comparing P2Y12 inhibitor monotherapy with aspirin monotherapy,” is lead author of the study, which was published online in the Journal of the American College of Cardiology.

Current guidelines recommend aspirin for antiplatelet monotherapy for patients with established CAD, Dr. Gragnano said, but “the primacy of aspirin in secondary prevention is based on historical trials conducted in the 1970s and 1980s and may not apply to contemporary practice.”

Moreover, later trials that compared P2Y12 inhibitors with aspirin for secondary prevention produced “inconsistent results,” possibly owing to their heterogeneous populations of patients with coronary, cerebrovascular, or peripheral vascular disease, he said. Study-level meta-analyses in this area “provide inconclusive evidence” because they haven’t evaluated treatment effects exclusively in patients with established CAD.

Most of the seven trials’ 24,325 participants had a history of MI, and some had peripheral artery disease (PAD); the rates were 56.2% and 9.1%, respectively. Coronary revascularization, either percutaneous or surgical, had been performed for about 70%. Most (61%) had presented with acute coronary syndromes, and the remainder had presented with chronic CAD.

About 76% of the combined cohorts were from Europe or North America; the rest were from Asia. The mean age of the patients was 64 years, and about 22% were women.

In all, 12,175 had been assigned to P2Y12 inhibitor monotherapy (62% received clopidogrel and 38% received ticagrelor); 12,147 received aspirin at dosages ranging from 75 mg to 325 mg daily.

The hazard ratio (HR) for the primary efficacy outcome, P2Y12 inhibitors vs. aspirin, was significantly reduced, at 0.88 (95% confidence interval [CI], 0.79-0.97; P = .012); the number needed to treat (NNT) to prevent one primary event over 2 years was 121, the report states.

The corresponding HR for MI was 0.77 (95% CI, 0.66-0.90; P < .001), for an NNT benefit of 136. For net adverse clinical events, the HR was 0.89 (95% CI, 0.81-0.98; P = .020), for an NNT benefit of 121.

Risk for major bleeding was not significantly different (HR, 0.87; 95% CI, 0.70-1.09; P = .23), nor were risks for stroke (HR, 0.84; 95% CI, 0.70-1.02; P = .076) or cardiovascular death (HR, 1.02; 95% CI, 0.86-1.20; P = .82).

Still, the P2Y12 inhibitor group showed significant risk reductions for the following:

• GI bleeding: HR, 0.75 (95% CI, 0.57-0.97; P = .027)
• Definite stent thrombosis: HR, 0.42 (95% CI, 0.19-0.97; P = .028)
• Hemorrhagic stroke: HR, 0.43 (95% CI, 0.23-0.83; P = .012)

The current findings are “hypothesis-generating but not definitive,” Dharam Kumbhani, MD, University of Texas Southwestern, Dallas, said in an interview.

It remains unclear “whether aspirin or P2Y12 inhibitor monotherapy is better for long-term maintenance use among patients with established CAD. Aspirin has historically been the agent of choice for this indication,” said Dr. Kumbhani, who with James A. de Lemos, MD, of the same institution, wrote an editorial accompanying the PANTHER report.

“It certainly would be appropriate to consider P2Y12 monotherapy preferentially for patients with prior or currently at high risk for GI or intracranial bleeding, for instance,” Dr. Kumbhani said. For the remainder, aspirin and P2Y12 inhibitors are both “reasonable alternatives.”

In their editorial, Dr. Kumbhani and Dr. de Lemos call the PANTHER meta-analysis “a well-done study with potentially important clinical implications.” The findings “make biological sense: P2Y12 inhibitors are more potent antiplatelet agents than aspirin and have less effect on gastrointestinal mucosal integrity.”

But for now, they wrote, “both aspirin and P2Y12 inhibitors remain viable alternatives for prevention of atherothrombotic events among patients with established CAD.”

Dr. Gragnano had no disclosures; potential conflicts for the other authors are in the report. Dr. Kumbhani reports no relevant relationships; Dr. de Lemos has received honoraria for participation in data safety monitoring boards from Eli Lilly, Novo Nordisk, AstraZeneca, and Janssen.

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

The antiplatelet of choice for long-term, secondary prevention for patients with established coronary artery disease (CAD) may well be a P2Y12 inhibitor such as clopidogrel or ticagrelor rather than aspirin, suggests a patient-level meta-analysis of seven randomized trials.

The more than 24,000 patients in the meta-analysis, called PANTHER, had documented stable CAD, prior myocardial infarction (MI), or recent or remote surgical or percutaneous coronary revascularization.

About half of patients in each antiplatelet monotherapy trial received clopidogrel or ticagrelor, and the other half received aspirin. Follow-ups ranged from 6 months to 3 years.

Those taking a P2Y12 inhibitor showed a 12% reduction in risk (P = .012) for the primary efficacy outcome, a composite of cardiovascular (CV) death, MI, and stroke, over a median of about 1.35 years. The difference was driven primarily by a 23% reduction in risk for MI (P < .001); mortality seemed unaffected by antiplatelet treatment assignment.

Although the P2Y12 inhibitor and aspirin groups were similar with respect to risk of major bleeding, the P2Y12 inhibitor group showed significant reductions in risk for gastrointestinal (GI) bleeding, definite stent thrombosis, and hemorrhagic stroke; rates of hemorrhagic stroke were well under 1% in both groups.

The treatment effects were consistent across patient subgroups, including whether the aspirin comparison was with clopidogrel or ticagrelor.

“Taken together, our data challenge the central role of aspirin in secondary prevention and support a paradigm shift toward P2Y12 inhibitor monotherapy as long-term antiplatelet strategy in the sizable population of patients with coronary atherosclerosis,” Felice Gragnano, MD, PhD, said in an interview. “Given [their] superior efficacy and similar overall safety, P2Y12 inhibitors may be preferred [over] aspirin for the prevention of cardiovascular events in patients with CAD.”

Dr. Gragnano, of the University of Campania Luigi Vanvitelli, Caserta, Italy, who called PANTHER “the largest and most comprehensive synthesis of individual patient data from randomized trials comparing P2Y12 inhibitor monotherapy with aspirin monotherapy,” is lead author of the study, which was published online in the Journal of the American College of Cardiology.

Current guidelines recommend aspirin for antiplatelet monotherapy for patients with established CAD, Dr. Gragnano said, but “the primacy of aspirin in secondary prevention is based on historical trials conducted in the 1970s and 1980s and may not apply to contemporary practice.”

Moreover, later trials that compared P2Y12 inhibitors with aspirin for secondary prevention produced “inconsistent results,” possibly owing to their heterogeneous populations of patients with coronary, cerebrovascular, or peripheral vascular disease, he said. Study-level meta-analyses in this area “provide inconclusive evidence” because they haven’t evaluated treatment effects exclusively in patients with established CAD.

Most of the seven trials’ 24,325 participants had a history of MI, and some had peripheral artery disease (PAD); the rates were 56.2% and 9.1%, respectively. Coronary revascularization, either percutaneous or surgical, had been performed for about 70%. Most (61%) had presented with acute coronary syndromes, and the remainder had presented with chronic CAD.

About 76% of the combined cohorts were from Europe or North America; the rest were from Asia. The mean age of the patients was 64 years, and about 22% were women.

In all, 12,175 had been assigned to P2Y12 inhibitor monotherapy (62% received clopidogrel and 38% received ticagrelor); 12,147 received aspirin at dosages ranging from 75 mg to 325 mg daily.

The hazard ratio (HR) for the primary efficacy outcome, P2Y12 inhibitors vs. aspirin, was significantly reduced, at 0.88 (95% confidence interval [CI], 0.79-0.97; P = .012); the number needed to treat (NNT) to prevent one primary event over 2 years was 121, the report states.

The corresponding HR for MI was 0.77 (95% CI, 0.66-0.90; P < .001), for an NNT benefit of 136. For net adverse clinical events, the HR was 0.89 (95% CI, 0.81-0.98; P = .020), for an NNT benefit of 121.

Risk for major bleeding was not significantly different (HR, 0.87; 95% CI, 0.70-1.09; P = .23), nor were risks for stroke (HR, 0.84; 95% CI, 0.70-1.02; P = .076) or cardiovascular death (HR, 1.02; 95% CI, 0.86-1.20; P = .82).

Still, the P2Y12 inhibitor group showed significant risk reductions for the following:

• GI bleeding: HR, 0.75 (95% CI, 0.57-0.97; P = .027)
• Definite stent thrombosis: HR, 0.42 (95% CI, 0.19-0.97; P = .028)
• Hemorrhagic stroke: HR, 0.43 (95% CI, 0.23-0.83; P = .012)

The current findings are “hypothesis-generating but not definitive,” Dharam Kumbhani, MD, University of Texas Southwestern, Dallas, said in an interview.

It remains unclear “whether aspirin or P2Y12 inhibitor monotherapy is better for long-term maintenance use among patients with established CAD. Aspirin has historically been the agent of choice for this indication,” said Dr. Kumbhani, who with James A. de Lemos, MD, of the same institution, wrote an editorial accompanying the PANTHER report.

“It certainly would be appropriate to consider P2Y12 monotherapy preferentially for patients with prior or currently at high risk for GI or intracranial bleeding, for instance,” Dr. Kumbhani said. For the remainder, aspirin and P2Y12 inhibitors are both “reasonable alternatives.”

In their editorial, Dr. Kumbhani and Dr. de Lemos call the PANTHER meta-analysis “a well-done study with potentially important clinical implications.” The findings “make biological sense: P2Y12 inhibitors are more potent antiplatelet agents than aspirin and have less effect on gastrointestinal mucosal integrity.”

But for now, they wrote, “both aspirin and P2Y12 inhibitors remain viable alternatives for prevention of atherothrombotic events among patients with established CAD.”

Dr. Gragnano had no disclosures; potential conflicts for the other authors are in the report. Dr. Kumbhani reports no relevant relationships; Dr. de Lemos has received honoraria for participation in data safety monitoring boards from Eli Lilly, Novo Nordisk, AstraZeneca, and Janssen.

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

Recently, the glucagonlike peptide 1 (GLP-1) receptor agonist semaglutide has changed the obesity treatment landscape. This and other similar medications approaching the market are in high demand because of their ease of use, effectiveness, and lack of interactions with other medications.

Semaglutide is a weekly subcutaneous injection approved by the U.S. Food and Drug Administration for weight loss in conjunction with lifestyle change. It elicits an average weight loss of 15%-18% from baseline in adults with overweight or obesity (body mass index ≥ 27 with at least one obesity-related comorbidity or BMI ≥ 30) in a period of 52-68 weeks (Wilding et al; Rubino et al). Liraglutide is a daily GLP-1 agonist, which is FDA approved for treatment of overweight, with an average weight loss of 8% from treatment start.

Though GLP-1 agonists are very effective for weight loss, questions about side effects have arisen. And now, there are also concerns surrounding GLP-1 agonist–induced rapid weight loss and its resulting impact on muscle mass.

Current modalities of weight loss don’t specifically target fat mass (FM), so it is expected that, to a degree, fat-free mass (FFM), including muscle mass, will also be lost along with fat mass.

Loss of muscle mass is associated with an increased risk for lower bone density, fatigue, injuries, and decreased strength. In addition, sarcopenic obesity, a combination of high body fat percentage and low skeletal muscle mass, is concerning in patients older than 65 years and/or postmenopausal patients. Because GLP-1 agonists cause more rapid and sustainable weight loss, compared with intensive behavioral lifestyle therapy, there has been more media attention recently about possible muscle mass loss with GLP-1–agonist use.

However, proper well-rounded approaches to obesity treatment can mitigate the issue of muscle mass loss even when rapid weight loss occurs. When weight loss is achieved with very-low-calorie dietary changes alone (without exercise), it is also associated with significant reductions in lean muscle mass; however, incorporating exercise, preferably resistance training, can mitigate the muscle mass loss. The muscle-preserving effect of exercise is especially prominent in older populations where it is needed most and should be incorporated (Armanento-Villareal et al.; Winter et al.; Batsis and Zagaria; Mason et al.).

Furthermore, studies in rat models demonstrate liraglutide induces myogenesis in myoblasts and protects against muscular atrophy. In human studies, GLP-1 infusion was associated with an improved skeletal and cardiac muscle microvasculature, suggesting that GLP-1 agonists may have some positive effects on the muscle. A 2020 systematic review examined the effect of gradual vs. rapid weight loss and demonstrated no significant difference in muscle loss between the rapid weight-loss group and gradual weight-loss group. Even after gastric bypass surgery, most of the muscle mass loss occurred during the first year, when weight loss is happening. However, after the first year, skeletal muscle was maintained even without introducing additional dietary or exercise interventions.

Age, although a consideration, should not be a discriminating factor against treating obesity. Sarcopenic obesity is a serious risk especially in patients aged 65 years or older, but GLP-1–agonist therapy can be beneficial to prevent muscle atrophy and increase blood flow to skeletal and cardiac muscle. In addition, patients must be encouraged to maintain an appropriate dietary and exercise regimen to treat their obesity. Management of obesity is complex and multifaceted, and patients should understand their responsibility to follow clinician recommendations during this journey to decrease the associated side effects.

Overall, with any level of weight loss achieved with current strategies, a certain amount of muscle mass loss is expected. All efforts to actively preserve muscle mass can prevent too much muscle loss.

Therefore, providers prescribing medications like GLP-1 agonists to treat obesity must also counsel patients about incorporating aerobic exercise and resistance training as part of the treatment plan as well as ensuring they eat a high-protein diet. Generally, resistance training is preferred over aerobic exercise for muscle mass preservation and increased strength, but studies also demonstrate benefit with aerobic exercise.

In the first few visits of initiating obesity treatment, patients should be encouraged to start to incorporate light physical activity as tolerable while starting to make dietary changes to include at least 0.8g/kg/day of protein (Fappi et al.). These initial visits are also an important opportunity for clinicians to ingrain the importance of exercise as part of healthy weight loss. At every visit, physical activity level should be assessed.

Dr. Ahn is a clinical fellow in obesity medicine, Weight Management Center, at Massachusetts General Hospital, Boston. Dr. Singhal is an assistant professor of pediatrics, Harvard Medical School, Boston, and director, Pediatric Program, MGH Weight Center, Massachusetts General Hospital. Dr. Singhal reported that his spouse consults with AstraZeneca, Dilachi Pharma, Eli Lilly, Genetech, Immunomedics, Pfizer, Sanofi, and Novartis.

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

Recently, the glucagonlike peptide 1 (GLP-1) receptor agonist semaglutide has changed the obesity treatment landscape. This and other similar medications approaching the market are in high demand because of their ease of use, effectiveness, and lack of interactions with other medications.

Semaglutide is a weekly subcutaneous injection approved by the U.S. Food and Drug Administration for weight loss in conjunction with lifestyle change. It elicits an average weight loss of 15%-18% from baseline in adults with overweight or obesity (body mass index ≥ 27 with at least one obesity-related comorbidity or BMI ≥ 30) in a period of 52-68 weeks (Wilding et al; Rubino et al). Liraglutide is a daily GLP-1 agonist, which is FDA approved for treatment of overweight, with an average weight loss of 8% from treatment start.

Though GLP-1 agonists are very effective for weight loss, questions about side effects have arisen. And now, there are also concerns surrounding GLP-1 agonist–induced rapid weight loss and its resulting impact on muscle mass.

Current modalities of weight loss don’t specifically target fat mass (FM), so it is expected that, to a degree, fat-free mass (FFM), including muscle mass, will also be lost along with fat mass.

Loss of muscle mass is associated with an increased risk for lower bone density, fatigue, injuries, and decreased strength. In addition, sarcopenic obesity, a combination of high body fat percentage and low skeletal muscle mass, is concerning in patients older than 65 years and/or postmenopausal patients. Because GLP-1 agonists cause more rapid and sustainable weight loss, compared with intensive behavioral lifestyle therapy, there has been more media attention recently about possible muscle mass loss with GLP-1–agonist use.

However, proper well-rounded approaches to obesity treatment can mitigate the issue of muscle mass loss even when rapid weight loss occurs. When weight loss is achieved with very-low-calorie dietary changes alone (without exercise), it is also associated with significant reductions in lean muscle mass; however, incorporating exercise, preferably resistance training, can mitigate the muscle mass loss. The muscle-preserving effect of exercise is especially prominent in older populations where it is needed most and should be incorporated (Armanento-Villareal et al.; Winter et al.; Batsis and Zagaria; Mason et al.).

Furthermore, studies in rat models demonstrate liraglutide induces myogenesis in myoblasts and protects against muscular atrophy. In human studies, GLP-1 infusion was associated with an improved skeletal and cardiac muscle microvasculature, suggesting that GLP-1 agonists may have some positive effects on the muscle. A 2020 systematic review examined the effect of gradual vs. rapid weight loss and demonstrated no significant difference in muscle loss between the rapid weight-loss group and gradual weight-loss group. Even after gastric bypass surgery, most of the muscle mass loss occurred during the first year, when weight loss is happening. However, after the first year, skeletal muscle was maintained even without introducing additional dietary or exercise interventions.

Age, although a consideration, should not be a discriminating factor against treating obesity. Sarcopenic obesity is a serious risk especially in patients aged 65 years or older, but GLP-1–agonist therapy can be beneficial to prevent muscle atrophy and increase blood flow to skeletal and cardiac muscle. In addition, patients must be encouraged to maintain an appropriate dietary and exercise regimen to treat their obesity. Management of obesity is complex and multifaceted, and patients should understand their responsibility to follow clinician recommendations during this journey to decrease the associated side effects.

Overall, with any level of weight loss achieved with current strategies, a certain amount of muscle mass loss is expected. All efforts to actively preserve muscle mass can prevent too much muscle loss.

Therefore, providers prescribing medications like GLP-1 agonists to treat obesity must also counsel patients about incorporating aerobic exercise and resistance training as part of the treatment plan as well as ensuring they eat a high-protein diet. Generally, resistance training is preferred over aerobic exercise for muscle mass preservation and increased strength, but studies also demonstrate benefit with aerobic exercise.

In the first few visits of initiating obesity treatment, patients should be encouraged to start to incorporate light physical activity as tolerable while starting to make dietary changes to include at least 0.8g/kg/day of protein (Fappi et al.). These initial visits are also an important opportunity for clinicians to ingrain the importance of exercise as part of healthy weight loss. At every visit, physical activity level should be assessed.

Dr. Ahn is a clinical fellow in obesity medicine, Weight Management Center, at Massachusetts General Hospital, Boston. Dr. Singhal is an assistant professor of pediatrics, Harvard Medical School, Boston, and director, Pediatric Program, MGH Weight Center, Massachusetts General Hospital. Dr. Singhal reported that his spouse consults with AstraZeneca, Dilachi Pharma, Eli Lilly, Genetech, Immunomedics, Pfizer, Sanofi, and Novartis.

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

Recently, the glucagonlike peptide 1 (GLP-1) receptor agonist semaglutide has changed the obesity treatment landscape. This and other similar medications approaching the market are in high demand because of their ease of use, effectiveness, and lack of interactions with other medications.

Semaglutide is a weekly subcutaneous injection approved by the U.S. Food and Drug Administration for weight loss in conjunction with lifestyle change. It elicits an average weight loss of 15%-18% from baseline in adults with overweight or obesity (body mass index ≥ 27 with at least one obesity-related comorbidity or BMI ≥ 30) in a period of 52-68 weeks (Wilding et al; Rubino et al). Liraglutide is a daily GLP-1 agonist, which is FDA approved for treatment of overweight, with an average weight loss of 8% from treatment start.

Though GLP-1 agonists are very effective for weight loss, questions about side effects have arisen. And now, there are also concerns surrounding GLP-1 agonist–induced rapid weight loss and its resulting impact on muscle mass.

Current modalities of weight loss don’t specifically target fat mass (FM), so it is expected that, to a degree, fat-free mass (FFM), including muscle mass, will also be lost along with fat mass.

Loss of muscle mass is associated with an increased risk for lower bone density, fatigue, injuries, and decreased strength. In addition, sarcopenic obesity, a combination of high body fat percentage and low skeletal muscle mass, is concerning in patients older than 65 years and/or postmenopausal patients. Because GLP-1 agonists cause more rapid and sustainable weight loss, compared with intensive behavioral lifestyle therapy, there has been more media attention recently about possible muscle mass loss with GLP-1–agonist use.

However, proper well-rounded approaches to obesity treatment can mitigate the issue of muscle mass loss even when rapid weight loss occurs. When weight loss is achieved with very-low-calorie dietary changes alone (without exercise), it is also associated with significant reductions in lean muscle mass; however, incorporating exercise, preferably resistance training, can mitigate the muscle mass loss. The muscle-preserving effect of exercise is especially prominent in older populations where it is needed most and should be incorporated (Armanento-Villareal et al.; Winter et al.; Batsis and Zagaria; Mason et al.).

Furthermore, studies in rat models demonstrate liraglutide induces myogenesis in myoblasts and protects against muscular atrophy. In human studies, GLP-1 infusion was associated with an improved skeletal and cardiac muscle microvasculature, suggesting that GLP-1 agonists may have some positive effects on the muscle. A 2020 systematic review examined the effect of gradual vs. rapid weight loss and demonstrated no significant difference in muscle loss between the rapid weight-loss group and gradual weight-loss group. Even after gastric bypass surgery, most of the muscle mass loss occurred during the first year, when weight loss is happening. However, after the first year, skeletal muscle was maintained even without introducing additional dietary or exercise interventions.

Age, although a consideration, should not be a discriminating factor against treating obesity. Sarcopenic obesity is a serious risk especially in patients aged 65 years or older, but GLP-1–agonist therapy can be beneficial to prevent muscle atrophy and increase blood flow to skeletal and cardiac muscle. In addition, patients must be encouraged to maintain an appropriate dietary and exercise regimen to treat their obesity. Management of obesity is complex and multifaceted, and patients should understand their responsibility to follow clinician recommendations during this journey to decrease the associated side effects.

Overall, with any level of weight loss achieved with current strategies, a certain amount of muscle mass loss is expected. All efforts to actively preserve muscle mass can prevent too much muscle loss.

Therefore, providers prescribing medications like GLP-1 agonists to treat obesity must also counsel patients about incorporating aerobic exercise and resistance training as part of the treatment plan as well as ensuring they eat a high-protein diet. Generally, resistance training is preferred over aerobic exercise for muscle mass preservation and increased strength, but studies also demonstrate benefit with aerobic exercise.

In the first few visits of initiating obesity treatment, patients should be encouraged to start to incorporate light physical activity as tolerable while starting to make dietary changes to include at least 0.8g/kg/day of protein (Fappi et al.). These initial visits are also an important opportunity for clinicians to ingrain the importance of exercise as part of healthy weight loss. At every visit, physical activity level should be assessed.

Dr. Ahn is a clinical fellow in obesity medicine, Weight Management Center, at Massachusetts General Hospital, Boston. Dr. Singhal is an assistant professor of pediatrics, Harvard Medical School, Boston, and director, Pediatric Program, MGH Weight Center, Massachusetts General Hospital. Dr. Singhal reported that his spouse consults with AstraZeneca, Dilachi Pharma, Eli Lilly, Genetech, Immunomedics, Pfizer, Sanofi, and Novartis.

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

The incidence of type 1 diabetes has risen during the COVID-19 pandemic, according to a recent meta-analysis.

The review compared 2 years of data from during the pandemic to data from a prepandemic period, and showed a higher incidence of type 1 diabetes in the first year (incidence rate ratio, 1.14) and second year (IRR, 1.27) of the pandemic. The investigators also found an increase in the incidence of diabetic ketoacidosis (DKA) (IRR, 1.26).

The meta-analysis included 17 studies of 38,149 children and adolescents with newly diagnosed type 1 diabetes. “Putting them all together really gave us more confidence to say this is something that we think is real,” study author Rayzel Shulman, MD, PhD, an endocrinologist at The Hospital for Sick Children in Toronto and associate professor of pediatrics at the University of Toronto, said in an interview.

The study was published in JAMA Network Open.
 

Increased incidence

The investigators reviewed 42 studies, including 17 that examined rates of type 1 diabetes incidence, 10 on type 2 diabetes, and 15 on DKA. The included studies all had a minimum observation period of 12 months during the pandemic and at least 12 months before it. Relative to the prepandemic period, the meta-analysis found higher rates of type 1 diabetes and DKA during the pandemic.

The review was conducted in response to questions about the methodology of study results suggesting an association between the COVID-19 pandemic and the incidence of diabetes, according to Dr. Shulman.

Although this is not the first review of studies on the connection between diabetes and COVID-19, it adds to the literature by extending the study period to 2 years of the pandemic. The longer time frame helps address potential seasonal differences in incidence and increases confidence in the results.

The investigators also sought to look at the incidence of type 2 diabetes in children but found few studies that met the study criteria. Although some studies reported rates of type 2 diabetes, most lacked information about the population, specifically, the “denominator” needed for findings regarding any association with the COVID-19 pandemic.

With greater confidence in the increased incidence of type 1 diabetes, Dr. Shulman emphasized a need to ensure sufficient resources to care for newly diagnosed patients, including education and support for families.

The study’s secondary outcome was the change in incidence rate of DKA among children with newly diagnosed diabetes. Data reported in 15 studies showed a 26% increase in DKA incidence during the first year of the pandemic.

“DKA is a serious and life-threatening condition that is preventable,” said Dr. Shulman. Symptoms of type 1 diabetes include increased thirst and urination, weight loss, and fatigue. If parents or caregivers notice these signs, Dr. Shulman advises them to seek care immediately to reduce the risk of DKA.
 

Possible mechanisms

In a comment, Elizabeth Sellers, MD, an endocrinologist at the Children’s Hospital Research Institute of Manitoba and associate professor of pediatrics at the University of Manitoba, both in Winnipeg, said the study’s findings on DKA are an important reminder to be attentive to symptoms of diabetes. Dr. Sellers did not participate in the meta-analysis.

One possible explanation for the increase is a hesitancy to seek care among parents and caregivers during the pandemic. “I think we use that information and turn it into a positive,” said Dr. Sellers, by increasing recognition of the symptoms. Dr. Sellers, whose research is included in the review, is part of an initiative by the Canadian Pediatric Endocrine Group to increase diabetes awareness.

The study provides important findings, particularly the second-year results, but is not designed to answer why there has been an increase in diabetes incidence, said Dr. Sellers. “You have to identify the problem first and then you can go back and look at mechanisms.”

The meta-analysis did not seek to draw conclusions about the underlying mechanisms that would explain changes in diabetes incidence but rather indicates a need for further studies to seek a better understanding of the connection. Several theories may be considered, wrote Clemens Kamrath, MD, of the Centre of Child and Adolescent Medicine at Justus Liebig University in Giessen, Germany, and colleagues in an accompanying editorial.

Studies have suggested a direct effect of infections such as COVID-19, whereby the virus damages insulin-producing beta cells. However, the commentary notes these studies do not account for asymptomatic infections among children.

Dr. Kamrath and colleagues also considered the indirect effects of the COVID-19 pandemic, which they indicate may be more likely than direct effects. These indirect effects include autoimmunity and environmental changes that occurred during the pandemic.

Researchers will need to continue monitoring the data to see if the trend persists and continue working to determine the mechanisms, said Dr. Schulman. “I don’t think this is the end of the story.”

The study was supported in part by grant funding from the department of pediatrics at The Hospital for Sick Children. Dr. Shulman, Dr. Sellers, and Dr. Kamrath reported no relevant financial relationships.

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

The incidence of type 1 diabetes has risen during the COVID-19 pandemic, according to a recent meta-analysis.

The review compared 2 years of data from during the pandemic to data from a prepandemic period, and showed a higher incidence of type 1 diabetes in the first year (incidence rate ratio, 1.14) and second year (IRR, 1.27) of the pandemic. The investigators also found an increase in the incidence of diabetic ketoacidosis (DKA) (IRR, 1.26).

The meta-analysis included 17 studies of 38,149 children and adolescents with newly diagnosed type 1 diabetes. “Putting them all together really gave us more confidence to say this is something that we think is real,” study author Rayzel Shulman, MD, PhD, an endocrinologist at The Hospital for Sick Children in Toronto and associate professor of pediatrics at the University of Toronto, said in an interview.

The study was published in JAMA Network Open.
 

Increased incidence

The investigators reviewed 42 studies, including 17 that examined rates of type 1 diabetes incidence, 10 on type 2 diabetes, and 15 on DKA. The included studies all had a minimum observation period of 12 months during the pandemic and at least 12 months before it. Relative to the prepandemic period, the meta-analysis found higher rates of type 1 diabetes and DKA during the pandemic.

The review was conducted in response to questions about the methodology of study results suggesting an association between the COVID-19 pandemic and the incidence of diabetes, according to Dr. Shulman.

Although this is not the first review of studies on the connection between diabetes and COVID-19, it adds to the literature by extending the study period to 2 years of the pandemic. The longer time frame helps address potential seasonal differences in incidence and increases confidence in the results.

The investigators also sought to look at the incidence of type 2 diabetes in children but found few studies that met the study criteria. Although some studies reported rates of type 2 diabetes, most lacked information about the population, specifically, the “denominator” needed for findings regarding any association with the COVID-19 pandemic.

With greater confidence in the increased incidence of type 1 diabetes, Dr. Shulman emphasized a need to ensure sufficient resources to care for newly diagnosed patients, including education and support for families.

The study’s secondary outcome was the change in incidence rate of DKA among children with newly diagnosed diabetes. Data reported in 15 studies showed a 26% increase in DKA incidence during the first year of the pandemic.

“DKA is a serious and life-threatening condition that is preventable,” said Dr. Shulman. Symptoms of type 1 diabetes include increased thirst and urination, weight loss, and fatigue. If parents or caregivers notice these signs, Dr. Shulman advises them to seek care immediately to reduce the risk of DKA.
 

Possible mechanisms

In a comment, Elizabeth Sellers, MD, an endocrinologist at the Children’s Hospital Research Institute of Manitoba and associate professor of pediatrics at the University of Manitoba, both in Winnipeg, said the study’s findings on DKA are an important reminder to be attentive to symptoms of diabetes. Dr. Sellers did not participate in the meta-analysis.

One possible explanation for the increase is a hesitancy to seek care among parents and caregivers during the pandemic. “I think we use that information and turn it into a positive,” said Dr. Sellers, by increasing recognition of the symptoms. Dr. Sellers, whose research is included in the review, is part of an initiative by the Canadian Pediatric Endocrine Group to increase diabetes awareness.

The study provides important findings, particularly the second-year results, but is not designed to answer why there has been an increase in diabetes incidence, said Dr. Sellers. “You have to identify the problem first and then you can go back and look at mechanisms.”

The meta-analysis did not seek to draw conclusions about the underlying mechanisms that would explain changes in diabetes incidence but rather indicates a need for further studies to seek a better understanding of the connection. Several theories may be considered, wrote Clemens Kamrath, MD, of the Centre of Child and Adolescent Medicine at Justus Liebig University in Giessen, Germany, and colleagues in an accompanying editorial.

Studies have suggested a direct effect of infections such as COVID-19, whereby the virus damages insulin-producing beta cells. However, the commentary notes these studies do not account for asymptomatic infections among children.

Dr. Kamrath and colleagues also considered the indirect effects of the COVID-19 pandemic, which they indicate may be more likely than direct effects. These indirect effects include autoimmunity and environmental changes that occurred during the pandemic.

Researchers will need to continue monitoring the data to see if the trend persists and continue working to determine the mechanisms, said Dr. Schulman. “I don’t think this is the end of the story.”

The study was supported in part by grant funding from the department of pediatrics at The Hospital for Sick Children. Dr. Shulman, Dr. Sellers, and Dr. Kamrath reported no relevant financial relationships.

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

The incidence of type 1 diabetes has risen during the COVID-19 pandemic, according to a recent meta-analysis.

The review compared 2 years of data from during the pandemic to data from a prepandemic period, and showed a higher incidence of type 1 diabetes in the first year (incidence rate ratio, 1.14) and second year (IRR, 1.27) of the pandemic. The investigators also found an increase in the incidence of diabetic ketoacidosis (DKA) (IRR, 1.26).

The meta-analysis included 17 studies of 38,149 children and adolescents with newly diagnosed type 1 diabetes. “Putting them all together really gave us more confidence to say this is something that we think is real,” study author Rayzel Shulman, MD, PhD, an endocrinologist at The Hospital for Sick Children in Toronto and associate professor of pediatrics at the University of Toronto, said in an interview.

The study was published in JAMA Network Open.
 

Increased incidence

The investigators reviewed 42 studies, including 17 that examined rates of type 1 diabetes incidence, 10 on type 2 diabetes, and 15 on DKA. The included studies all had a minimum observation period of 12 months during the pandemic and at least 12 months before it. Relative to the prepandemic period, the meta-analysis found higher rates of type 1 diabetes and DKA during the pandemic.

The review was conducted in response to questions about the methodology of study results suggesting an association between the COVID-19 pandemic and the incidence of diabetes, according to Dr. Shulman.

Although this is not the first review of studies on the connection between diabetes and COVID-19, it adds to the literature by extending the study period to 2 years of the pandemic. The longer time frame helps address potential seasonal differences in incidence and increases confidence in the results.

The investigators also sought to look at the incidence of type 2 diabetes in children but found few studies that met the study criteria. Although some studies reported rates of type 2 diabetes, most lacked information about the population, specifically, the “denominator” needed for findings regarding any association with the COVID-19 pandemic.

With greater confidence in the increased incidence of type 1 diabetes, Dr. Shulman emphasized a need to ensure sufficient resources to care for newly diagnosed patients, including education and support for families.

The study’s secondary outcome was the change in incidence rate of DKA among children with newly diagnosed diabetes. Data reported in 15 studies showed a 26% increase in DKA incidence during the first year of the pandemic.

“DKA is a serious and life-threatening condition that is preventable,” said Dr. Shulman. Symptoms of type 1 diabetes include increased thirst and urination, weight loss, and fatigue. If parents or caregivers notice these signs, Dr. Shulman advises them to seek care immediately to reduce the risk of DKA.
 

Possible mechanisms

In a comment, Elizabeth Sellers, MD, an endocrinologist at the Children’s Hospital Research Institute of Manitoba and associate professor of pediatrics at the University of Manitoba, both in Winnipeg, said the study’s findings on DKA are an important reminder to be attentive to symptoms of diabetes. Dr. Sellers did not participate in the meta-analysis.

One possible explanation for the increase is a hesitancy to seek care among parents and caregivers during the pandemic. “I think we use that information and turn it into a positive,” said Dr. Sellers, by increasing recognition of the symptoms. Dr. Sellers, whose research is included in the review, is part of an initiative by the Canadian Pediatric Endocrine Group to increase diabetes awareness.

The study provides important findings, particularly the second-year results, but is not designed to answer why there has been an increase in diabetes incidence, said Dr. Sellers. “You have to identify the problem first and then you can go back and look at mechanisms.”

The meta-analysis did not seek to draw conclusions about the underlying mechanisms that would explain changes in diabetes incidence but rather indicates a need for further studies to seek a better understanding of the connection. Several theories may be considered, wrote Clemens Kamrath, MD, of the Centre of Child and Adolescent Medicine at Justus Liebig University in Giessen, Germany, and colleagues in an accompanying editorial.

Studies have suggested a direct effect of infections such as COVID-19, whereby the virus damages insulin-producing beta cells. However, the commentary notes these studies do not account for asymptomatic infections among children.

Dr. Kamrath and colleagues also considered the indirect effects of the COVID-19 pandemic, which they indicate may be more likely than direct effects. These indirect effects include autoimmunity and environmental changes that occurred during the pandemic.

Researchers will need to continue monitoring the data to see if the trend persists and continue working to determine the mechanisms, said Dr. Schulman. “I don’t think this is the end of the story.”

The study was supported in part by grant funding from the department of pediatrics at The Hospital for Sick Children. Dr. Shulman, Dr. Sellers, and Dr. Kamrath reported no relevant financial relationships.

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

What is a healthy weight? A definitive answer to this seemingly innocent question continues to evade the medical community. In 1832, Belgian statistician Adolphe Quetelet introduced the concept of body mass index (BMI) – one’s weight (in kilograms) divided by the square of one’s height (in meters) as a measurement of ideal body weight. Approximately 140 years later, nutritional epidemiologist Ancel Keys proposed the use of BMI as a surrogate marker for evaluating body fat percentage within a population.

For the past 50 years, the scientific and medical communities have relied on BMI as a research and study tool to categorize patients’ weight (that is, severely underweight, underweight, normal weight, overweight, and obesity). The World Health Organization, National Institutes of Health, and U.S. Centers for Disease Control and Prevention use the following BMI weight classifications for adult patients:

• Underweight: BMI < 18.5
• Normal weight: BMI ≥ 18.5 to 24.9
• Overweight: BMI ≥ 25 to 29.9
• Obesity: BMI ≥ 30

Of note, BMI categories for children and adolescents (aged 2-19 years) are based on sex- and age-specific percentiles and will not be addressed in this article.

BMI appears to be a straightforward, easy, and cost-effective way to identify “healthy” weight and assess a patient’s risk for related conditions. For example, studies show that a BMI ≥ 35 kg/m² correlates to higher prevalence of type 2 diabetes, hypertension, dyslipidemia, and decreased lifespan. At least 13 types of cancer have been linked to obesity, regardless of dietary or physical activity behaviors. While the health dangers associated with BMI ≥ 35 are substantial and difficult to dispute, concerns arise when BMI alone is used to determine healthy weight and disease risk in patients with a BMI of 25-35.
 

BMI limitations

There are troubling limitations to using BMI alone to assess a patient’s weight and health status. BMI only takes into account a patient’s height and weight, neither of which are sole determinants of health. Moreover, BMI measurements do not distinguish between fat mass and fat-free mass, each of which has very distinct effects on health. High fat mass is associated with an increased risk for disease and mortality, while higher lean body mass correlates with increased physical fitness and longevity. BMI also does not consider age, sex, race, ethnicity, or types of adipose tissue, all of which tremendously influence disease risk across all BMI categories.

Body composition and adipose tissue

Body composition and type of excess adipose tissue better correlate disease risk than does BMI. The World Health Organization defines obesity as having a body fat percentage > 25% for men and > 35% for women. Body composition can be measured by skin-fold thickness, bioelectrical impedance, dual-energy x-ray absorptiometry (DXA), CT, or MRI.

A cross-sectional study by Shah and colleagues) comparing BMI and DXA found that BMI underestimated obesity prevalence. In the study, BMI characterized 26% of participants as obese while DXA (a direct measurement of fat) characterized 64%. Further, 39% of patients categorized as nonobese based on BMI were found to be obese on DXA. Also, BMI misclassified 25% of men and 48% of women in the study. These findings and those of other studies suggest that BMI has a high specificity but low sensitivity for diagnosing obesity, questioning its reliability as a clinical screening tool.

Current guideline recommendations on pharmacologic and surgical treatment options for patients with overweight or obesity, including those of the American Association of Clinical Endocrinology and American College of Endocrinology (AACE/ACE) and the American College of Cardiology/American Heart Association and The Obesity Society (ACC/AHA/TOS), rely on BMI, diminishing their utilization. For example, a recent literature search by Li and associates found that Asian American patients with lower BMIs and BMIs of 25 or 27 are at increased risk for metabolic disease. On the basis of study findings, some organizations recommend considering pharmacotherapy at a lower BMI cutoff of ≥ 25.0 or ≥ 27.5 for Asian people to ensure early treatment intervention in this patient population because guidelines do not recommend pharmacologic treatment unless the BMI is 27 with weight-related complications or 30. Under the current guidelines, a patient of Asian descent has greater disease severity with potentially more complications by the time pharmacotherapy is initiated.

As previously noted, body composition, which requires the use of special equipment (skinfold calipers, DXA, CT, MRI, body impedance scale), best captures the ratio of fat mass to fat-free mass. DXA is frequently used in research studies looking at body composition because of its lower cost, faster time to obtain the study, and ability to measure bone density. MRI has been found to be as accurate as CT for assessing visceral adipose tissue (VAT), skeletal muscle mass, and organ mass, and does not expose patients to ionizing radiation like CT does. MRI clinical use, however, is limited because of its high cost, and it may be problematic for patients with claustrophobia or who are unable to remain immobile for an extended period.

Patients with a high VAT mass, compared with subcutaneous adipose tissue (SAT), are at increased risk for metabolic syndrome, nonalcoholic fatty liver disease, and cardiovascular disease regardless of BMI, underscoring the clinical usefulness of measuring visceral adiposity over BMI.

One of the barriers to implementing VAT assessment in clinical practice is the cost of imaging studies. Fortunately, data suggest that waist circumference and/or waist-to-hip ratio measurements can be a valuable surrogate for VAT measurement. A waist circumference greater than 35 inches (88 cm) or a waist-to-hip ratio greater than 0.8 for women, and greater than 40 inches (102 cm) or a waist-to-hip ratio greater than 0.95 for men, increases metabolic disease risk. Obtaining these measurements requires a tape measure and a few extra minutes and offers more potent data than BMI alone. For example, a large cardiometabolic study found that within each BMI category, increasing gender-specific waist circumferences were associated with significantly higher VAT, liver fat, and a more harmful cardiometabolic risk profile. Men and women with a lower or normal BMI and a high waist circumference are at greatest relative health risk, compared with those with low waist circumference values. Yet, using the BMI alone in these patients would not raise any clinical concern, which is a missed opportunity for cardiometabolic risk reduction.
 

Biomarkers

Specific biomarkers are closely related to obesity. Leptin and resistin protein levels increase with adipose mass, while adiponectin decreases, probably contributing to insulin resistance. The higher levels of tumor necrosis factor–alpha and interleukin-6 from obesity contribute to chronic inflammation. The combined effect of chronic inflammation and insulin resistance allows greater bioavailability of insulinlike growth factor-1 (IGF-1), which has a role in initiating type 2 diabetes, cardiovascular disease, and cancer. Ideally, measuring these biomarkers could provide more advantageous information than BMI. Unfortunately, for now, the lack of standardized assays and imperfect knowledge of exactly how these biomarkers elicit disease prevents clinical use.

Obesity is a common, highly complex, chronic, and relapsing disease. Thankfully, a number of effective treatments and interventions are available. Although an accurate diagnosis of obesity is essential, underdiagnosed cases and missed opportunities for metabolic disease risk reduction persist. Overdiagnosing obesity, however, has the potential to incur unnecessary health care costs and result in weight bias and stigma.

While BMI is a quick and inexpensive means to assess obesity, by itself it lacks the necessary components for an accurate diagnosis. Particularly for individuals with a normal BMI or less severe overweight/obesity (BMI 27-34.9), other factors must be accounted for, including age, gender, and race. At a minimum, waist circumference should be measured to best risk-stratify and determine treatment intensity. Body composition analysis with BMI calculation refines the diagnosis of obesity.

Finally, clinicians may find best practices by using BMI delta change models. As with so many other clinical measurements, the trajectory tells the most astute story. For example, a patient whose BMI decreased from 45 to 35 may warrant less intensive treatment than a patient whose BMI increased from 26 to 31. Any change in BMI warrants clinical attention. A rapidly or consistently increasing BMI, even within normal range, should prompt clinicians to assess other factors related to obesity and metabolic disease risk (for example, lifestyle factors, waist circumference, blood pressure, cholesterol, diabetes screening) and initiate a conversation about weight management. Similarly, a consistently or rapidly decreasing BMI – even in elevated ranges and particularly with unintentional weight loss – should prompt evaluation.

Although BMI continues to be useful in clinical practice, epidemiology, and research, it should be used in combination with other clinical factors to provide the utmost quality of care.

Dr. Bartfield is assistant professor, obesity medicine specialist, Wake Forest Baptists Medical Center/Atrium Health Weight Management Center, Greensboro, N.C. She has disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

What is a healthy weight? A definitive answer to this seemingly innocent question continues to evade the medical community. In 1832, Belgian statistician Adolphe Quetelet introduced the concept of body mass index (BMI) – one’s weight (in kilograms) divided by the square of one’s height (in meters) as a measurement of ideal body weight. Approximately 140 years later, nutritional epidemiologist Ancel Keys proposed the use of BMI as a surrogate marker for evaluating body fat percentage within a population.

For the past 50 years, the scientific and medical communities have relied on BMI as a research and study tool to categorize patients’ weight (that is, severely underweight, underweight, normal weight, overweight, and obesity). The World Health Organization, National Institutes of Health, and U.S. Centers for Disease Control and Prevention use the following BMI weight classifications for adult patients:

• Underweight: BMI < 18.5
• Normal weight: BMI ≥ 18.5 to 24.9
• Overweight: BMI ≥ 25 to 29.9
• Obesity: BMI ≥ 30

Of note, BMI categories for children and adolescents (aged 2-19 years) are based on sex- and age-specific percentiles and will not be addressed in this article.

BMI appears to be a straightforward, easy, and cost-effective way to identify “healthy” weight and assess a patient’s risk for related conditions. For example, studies show that a BMI ≥ 35 kg/m² correlates to higher prevalence of type 2 diabetes, hypertension, dyslipidemia, and decreased lifespan. At least 13 types of cancer have been linked to obesity, regardless of dietary or physical activity behaviors. While the health dangers associated with BMI ≥ 35 are substantial and difficult to dispute, concerns arise when BMI alone is used to determine healthy weight and disease risk in patients with a BMI of 25-35.
 

BMI limitations

There are troubling limitations to using BMI alone to assess a patient’s weight and health status. BMI only takes into account a patient’s height and weight, neither of which are sole determinants of health. Moreover, BMI measurements do not distinguish between fat mass and fat-free mass, each of which has very distinct effects on health. High fat mass is associated with an increased risk for disease and mortality, while higher lean body mass correlates with increased physical fitness and longevity. BMI also does not consider age, sex, race, ethnicity, or types of adipose tissue, all of which tremendously influence disease risk across all BMI categories.

Body composition and adipose tissue

Body composition and type of excess adipose tissue better correlate disease risk than does BMI. The World Health Organization defines obesity as having a body fat percentage > 25% for men and > 35% for women. Body composition can be measured by skin-fold thickness, bioelectrical impedance, dual-energy x-ray absorptiometry (DXA), CT, or MRI.

A cross-sectional study by Shah and colleagues) comparing BMI and DXA found that BMI underestimated obesity prevalence. In the study, BMI characterized 26% of participants as obese while DXA (a direct measurement of fat) characterized 64%. Further, 39% of patients categorized as nonobese based on BMI were found to be obese on DXA. Also, BMI misclassified 25% of men and 48% of women in the study. These findings and those of other studies suggest that BMI has a high specificity but low sensitivity for diagnosing obesity, questioning its reliability as a clinical screening tool.

Current guideline recommendations on pharmacologic and surgical treatment options for patients with overweight or obesity, including those of the American Association of Clinical Endocrinology and American College of Endocrinology (AACE/ACE) and the American College of Cardiology/American Heart Association and The Obesity Society (ACC/AHA/TOS), rely on BMI, diminishing their utilization. For example, a recent literature search by Li and associates found that Asian American patients with lower BMIs and BMIs of 25 or 27 are at increased risk for metabolic disease. On the basis of study findings, some organizations recommend considering pharmacotherapy at a lower BMI cutoff of ≥ 25.0 or ≥ 27.5 for Asian people to ensure early treatment intervention in this patient population because guidelines do not recommend pharmacologic treatment unless the BMI is 27 with weight-related complications or 30. Under the current guidelines, a patient of Asian descent has greater disease severity with potentially more complications by the time pharmacotherapy is initiated.

As previously noted, body composition, which requires the use of special equipment (skinfold calipers, DXA, CT, MRI, body impedance scale), best captures the ratio of fat mass to fat-free mass. DXA is frequently used in research studies looking at body composition because of its lower cost, faster time to obtain the study, and ability to measure bone density. MRI has been found to be as accurate as CT for assessing visceral adipose tissue (VAT), skeletal muscle mass, and organ mass, and does not expose patients to ionizing radiation like CT does. MRI clinical use, however, is limited because of its high cost, and it may be problematic for patients with claustrophobia or who are unable to remain immobile for an extended period.

Patients with a high VAT mass, compared with subcutaneous adipose tissue (SAT), are at increased risk for metabolic syndrome, nonalcoholic fatty liver disease, and cardiovascular disease regardless of BMI, underscoring the clinical usefulness of measuring visceral adiposity over BMI.

One of the barriers to implementing VAT assessment in clinical practice is the cost of imaging studies. Fortunately, data suggest that waist circumference and/or waist-to-hip ratio measurements can be a valuable surrogate for VAT measurement. A waist circumference greater than 35 inches (88 cm) or a waist-to-hip ratio greater than 0.8 for women, and greater than 40 inches (102 cm) or a waist-to-hip ratio greater than 0.95 for men, increases metabolic disease risk. Obtaining these measurements requires a tape measure and a few extra minutes and offers more potent data than BMI alone. For example, a large cardiometabolic study found that within each BMI category, increasing gender-specific waist circumferences were associated with significantly higher VAT, liver fat, and a more harmful cardiometabolic risk profile. Men and women with a lower or normal BMI and a high waist circumference are at greatest relative health risk, compared with those with low waist circumference values. Yet, using the BMI alone in these patients would not raise any clinical concern, which is a missed opportunity for cardiometabolic risk reduction.
 

Biomarkers

Specific biomarkers are closely related to obesity. Leptin and resistin protein levels increase with adipose mass, while adiponectin decreases, probably contributing to insulin resistance. The higher levels of tumor necrosis factor–alpha and interleukin-6 from obesity contribute to chronic inflammation. The combined effect of chronic inflammation and insulin resistance allows greater bioavailability of insulinlike growth factor-1 (IGF-1), which has a role in initiating type 2 diabetes, cardiovascular disease, and cancer. Ideally, measuring these biomarkers could provide more advantageous information than BMI. Unfortunately, for now, the lack of standardized assays and imperfect knowledge of exactly how these biomarkers elicit disease prevents clinical use.

Obesity is a common, highly complex, chronic, and relapsing disease. Thankfully, a number of effective treatments and interventions are available. Although an accurate diagnosis of obesity is essential, underdiagnosed cases and missed opportunities for metabolic disease risk reduction persist. Overdiagnosing obesity, however, has the potential to incur unnecessary health care costs and result in weight bias and stigma.

While BMI is a quick and inexpensive means to assess obesity, by itself it lacks the necessary components for an accurate diagnosis. Particularly for individuals with a normal BMI or less severe overweight/obesity (BMI 27-34.9), other factors must be accounted for, including age, gender, and race. At a minimum, waist circumference should be measured to best risk-stratify and determine treatment intensity. Body composition analysis with BMI calculation refines the diagnosis of obesity.

Finally, clinicians may find best practices by using BMI delta change models. As with so many other clinical measurements, the trajectory tells the most astute story. For example, a patient whose BMI decreased from 45 to 35 may warrant less intensive treatment than a patient whose BMI increased from 26 to 31. Any change in BMI warrants clinical attention. A rapidly or consistently increasing BMI, even within normal range, should prompt clinicians to assess other factors related to obesity and metabolic disease risk (for example, lifestyle factors, waist circumference, blood pressure, cholesterol, diabetes screening) and initiate a conversation about weight management. Similarly, a consistently or rapidly decreasing BMI – even in elevated ranges and particularly with unintentional weight loss – should prompt evaluation.

Although BMI continues to be useful in clinical practice, epidemiology, and research, it should be used in combination with other clinical factors to provide the utmost quality of care.

Dr. Bartfield is assistant professor, obesity medicine specialist, Wake Forest Baptists Medical Center/Atrium Health Weight Management Center, Greensboro, N.C. She has disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

What is a healthy weight? A definitive answer to this seemingly innocent question continues to evade the medical community. In 1832, Belgian statistician Adolphe Quetelet introduced the concept of body mass index (BMI) – one’s weight (in kilograms) divided by the square of one’s height (in meters) as a measurement of ideal body weight. Approximately 140 years later, nutritional epidemiologist Ancel Keys proposed the use of BMI as a surrogate marker for evaluating body fat percentage within a population.

For the past 50 years, the scientific and medical communities have relied on BMI as a research and study tool to categorize patients’ weight (that is, severely underweight, underweight, normal weight, overweight, and obesity). The World Health Organization, National Institutes of Health, and U.S. Centers for Disease Control and Prevention use the following BMI weight classifications for adult patients:

• Underweight: BMI < 18.5
• Normal weight: BMI ≥ 18.5 to 24.9
• Overweight: BMI ≥ 25 to 29.9
• Obesity: BMI ≥ 30

Of note, BMI categories for children and adolescents (aged 2-19 years) are based on sex- and age-specific percentiles and will not be addressed in this article.

BMI appears to be a straightforward, easy, and cost-effective way to identify “healthy” weight and assess a patient’s risk for related conditions. For example, studies show that a BMI ≥ 35 kg/m² correlates to higher prevalence of type 2 diabetes, hypertension, dyslipidemia, and decreased lifespan. At least 13 types of cancer have been linked to obesity, regardless of dietary or physical activity behaviors. While the health dangers associated with BMI ≥ 35 are substantial and difficult to dispute, concerns arise when BMI alone is used to determine healthy weight and disease risk in patients with a BMI of 25-35.
 

BMI limitations

There are troubling limitations to using BMI alone to assess a patient’s weight and health status. BMI only takes into account a patient’s height and weight, neither of which are sole determinants of health. Moreover, BMI measurements do not distinguish between fat mass and fat-free mass, each of which has very distinct effects on health. High fat mass is associated with an increased risk for disease and mortality, while higher lean body mass correlates with increased physical fitness and longevity. BMI also does not consider age, sex, race, ethnicity, or types of adipose tissue, all of which tremendously influence disease risk across all BMI categories.

Body composition and adipose tissue

Body composition and type of excess adipose tissue better correlate disease risk than does BMI. The World Health Organization defines obesity as having a body fat percentage > 25% for men and > 35% for women. Body composition can be measured by skin-fold thickness, bioelectrical impedance, dual-energy x-ray absorptiometry (DXA), CT, or MRI.

A cross-sectional study by Shah and colleagues) comparing BMI and DXA found that BMI underestimated obesity prevalence. In the study, BMI characterized 26% of participants as obese while DXA (a direct measurement of fat) characterized 64%. Further, 39% of patients categorized as nonobese based on BMI were found to be obese on DXA. Also, BMI misclassified 25% of men and 48% of women in the study. These findings and those of other studies suggest that BMI has a high specificity but low sensitivity for diagnosing obesity, questioning its reliability as a clinical screening tool.

Current guideline recommendations on pharmacologic and surgical treatment options for patients with overweight or obesity, including those of the American Association of Clinical Endocrinology and American College of Endocrinology (AACE/ACE) and the American College of Cardiology/American Heart Association and The Obesity Society (ACC/AHA/TOS), rely on BMI, diminishing their utilization. For example, a recent literature search by Li and associates found that Asian American patients with lower BMIs and BMIs of 25 or 27 are at increased risk for metabolic disease. On the basis of study findings, some organizations recommend considering pharmacotherapy at a lower BMI cutoff of ≥ 25.0 or ≥ 27.5 for Asian people to ensure early treatment intervention in this patient population because guidelines do not recommend pharmacologic treatment unless the BMI is 27 with weight-related complications or 30. Under the current guidelines, a patient of Asian descent has greater disease severity with potentially more complications by the time pharmacotherapy is initiated.

As previously noted, body composition, which requires the use of special equipment (skinfold calipers, DXA, CT, MRI, body impedance scale), best captures the ratio of fat mass to fat-free mass. DXA is frequently used in research studies looking at body composition because of its lower cost, faster time to obtain the study, and ability to measure bone density. MRI has been found to be as accurate as CT for assessing visceral adipose tissue (VAT), skeletal muscle mass, and organ mass, and does not expose patients to ionizing radiation like CT does. MRI clinical use, however, is limited because of its high cost, and it may be problematic for patients with claustrophobia or who are unable to remain immobile for an extended period.

Patients with a high VAT mass, compared with subcutaneous adipose tissue (SAT), are at increased risk for metabolic syndrome, nonalcoholic fatty liver disease, and cardiovascular disease regardless of BMI, underscoring the clinical usefulness of measuring visceral adiposity over BMI.

One of the barriers to implementing VAT assessment in clinical practice is the cost of imaging studies. Fortunately, data suggest that waist circumference and/or waist-to-hip ratio measurements can be a valuable surrogate for VAT measurement. A waist circumference greater than 35 inches (88 cm) or a waist-to-hip ratio greater than 0.8 for women, and greater than 40 inches (102 cm) or a waist-to-hip ratio greater than 0.95 for men, increases metabolic disease risk. Obtaining these measurements requires a tape measure and a few extra minutes and offers more potent data than BMI alone. For example, a large cardiometabolic study found that within each BMI category, increasing gender-specific waist circumferences were associated with significantly higher VAT, liver fat, and a more harmful cardiometabolic risk profile. Men and women with a lower or normal BMI and a high waist circumference are at greatest relative health risk, compared with those with low waist circumference values. Yet, using the BMI alone in these patients would not raise any clinical concern, which is a missed opportunity for cardiometabolic risk reduction.
 

Biomarkers

Specific biomarkers are closely related to obesity. Leptin and resistin protein levels increase with adipose mass, while adiponectin decreases, probably contributing to insulin resistance. The higher levels of tumor necrosis factor–alpha and interleukin-6 from obesity contribute to chronic inflammation. The combined effect of chronic inflammation and insulin resistance allows greater bioavailability of insulinlike growth factor-1 (IGF-1), which has a role in initiating type 2 diabetes, cardiovascular disease, and cancer. Ideally, measuring these biomarkers could provide more advantageous information than BMI. Unfortunately, for now, the lack of standardized assays and imperfect knowledge of exactly how these biomarkers elicit disease prevents clinical use.

Obesity is a common, highly complex, chronic, and relapsing disease. Thankfully, a number of effective treatments and interventions are available. Although an accurate diagnosis of obesity is essential, underdiagnosed cases and missed opportunities for metabolic disease risk reduction persist. Overdiagnosing obesity, however, has the potential to incur unnecessary health care costs and result in weight bias and stigma.

While BMI is a quick and inexpensive means to assess obesity, by itself it lacks the necessary components for an accurate diagnosis. Particularly for individuals with a normal BMI or less severe overweight/obesity (BMI 27-34.9), other factors must be accounted for, including age, gender, and race. At a minimum, waist circumference should be measured to best risk-stratify and determine treatment intensity. Body composition analysis with BMI calculation refines the diagnosis of obesity.

Finally, clinicians may find best practices by using BMI delta change models. As with so many other clinical measurements, the trajectory tells the most astute story. For example, a patient whose BMI decreased from 45 to 35 may warrant less intensive treatment than a patient whose BMI increased from 26 to 31. Any change in BMI warrants clinical attention. A rapidly or consistently increasing BMI, even within normal range, should prompt clinicians to assess other factors related to obesity and metabolic disease risk (for example, lifestyle factors, waist circumference, blood pressure, cholesterol, diabetes screening) and initiate a conversation about weight management. Similarly, a consistently or rapidly decreasing BMI – even in elevated ranges and particularly with unintentional weight loss – should prompt evaluation.

Although BMI continues to be useful in clinical practice, epidemiology, and research, it should be used in combination with other clinical factors to provide the utmost quality of care.

Dr. Bartfield is assistant professor, obesity medicine specialist, Wake Forest Baptists Medical Center/Atrium Health Weight Management Center, Greensboro, N.C. She has disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

SAN DIEGO – Should pharmacologic treatment of type 2 diabetes start with combination therapy or metformin monotherapy, adding other agents over time?

This question was debated by two well-known clinician-researchers in the diabetes world at the recent annual scientific sessions of the American Diabetes Association.

Ralph A. DeFronzo, MD, argued for combination therapy at the time of diagnosis, and David M. Nathan, MD, countered that sequential therapy is a better way to go.
 

‘The ominous octet’: Addressing multiple underlying defects

Of course, Dr. DeFronzo said, the right agents must be selected. “The drugs we’re going to use as combination at a minimum have to correct the underlying insulin resistance and beta-cell failure, or we are not going to be successful.”

In addition, he said, these drugs should also provide protection against cardiovascular, kidney, and fatty liver disease, because “[managing] diabetes is more than just controlling the glucose.”

Recent U.S. data suggest that half of people with diabetes have a hemoglobin A1c above 7%, and a quarter remain above 8%. “We’re not really doing a very good job in terms of glycemic control,” said Dr. DeFronzo, chief of the diabetes division at University of Texas, San Antonio.

One reason for this failure, he said, is the complex pathophysiology of type 2 diabetes represented by eight major defects, what he called the “ominous octet”: decreased pancreatic insulin secretion, gut incretin effects, glucose uptake in the muscle, increased lipolysis, glucose reabsorption in the kidney, hepatic glucose production, increased glucagon secretion, and neurotransmitter dysfunction.

“There are eight problems, so you’re going to need multiple drugs in combination ... not ones that just lower the A1c.”

And, Dr. DeFronzo said, these drugs “must be started early in the natural history of type 2 diabetes if progressive beta-cell failure is to be prevented.”

He pointed to the United Kingdom Prospective Diabetes Study (UKPDS), in which the sulfonylurea glyburide was used first, followed by metformin. With each drug, the A1c decreased initially but then rose within 3 years. By 15 years, 65% of participants were taking insulin.

More recently, the GRADE study examined the effects of adding four different glucose-lowering agents (glimepiride, sitagliptin, liraglutide, or insulin glargine) in people who hadn’t achieved target A1c with metformin.

“So, by definition, drug number one failed,” he observed.

During the study, all participants showed an initial A1c drop, followed by progressive failure, “again ... showing that stepwise therapy doesn’t work.”

All patients with type 2 diabetes at his center are treated using the “DeFronzo algorithm” consisting of three drug classes: a glucagon-like peptide-1 (GLP-1) agonist, a sodium-glucose cotransporter-2 (SGLT2) inhibitor, and pioglitazone, as each of them targets more than one of the “ominous octet” defects.

“The drugs that clearly do not work on a long-term basis are metformin and sulfonylureas,” he emphasized.

Several studies demonstrate the efficacy of combination therapy, he said. In one, DURATION 8, the combination of exenatide and dapagliflozin was superior to either agent individually in lowering A1c, cardiovascular events, and all-cause mortality over 2 years.

And in the 5-year VERIFY study, early combination therapy with vildagliptin plus metformin proved superior in A1c-lowering to starting patients on metformin and adding vildagliptin later.

Dr. DeFronzo’s own “knock-out punch” study, EDICT, in people with new-onset type 2 diabetes, compared the initial combination of metformin, pioglitazone, and exenatide with conventional sequential add-on therapy with metformin, glipizide, and insulin glargine.

The primary endpoint – the difference in the proportion of patients with A1c less than 6.5% – was 70% versus 29% with combination compared with sequential therapy, a difference “as robust as you can be going against the stepwise approach” at P < .00001, he said.

The combination therapy virtually normalized both insulin sensitivity and beta-cell function, whereas the conventional therapy did neither.

Also from Dr. DeFronzo’s group, in the Qatar study, which compared exenatide plus pioglitazone with basal-bolus insulin in people with about 10 years’ duration of type 2 diabetes and A1c above 7.5% taking sulfonylurea plus metformin, the combination therapy produced an A1c of 6.2% versus 7.1% with insulin.

Dr. DeFronzo pointed to new language added to the ADA Standards of Medical Care in Diabetes in 2022.

While still endorsing stepwise therapy, the document also says that “there are data to support initial combination therapy for more rapid attainment of glycemic targets and longer durability of glycemic effect.” The two references cited are EDICT and VERIFY.

“Finally, the American Diabetes Association has gotten the message,” he concluded.
 

Sequential therapy: Far more data, lower cost

Dr. Nathan began by pointing out that the ADA Standards of Care continue to advise use of metformin as first-line therapy for type 2 diabetes “because of its high efficacy in lowering A1c, minimal hypoglycemia risk when used as monotherapy, weight neutrality with the potential for modest weight loss, good safety profile, and low cost.”

He emphasized that he was not arguing “against the use of early or even initial combination therapy when there are co-existent morbidities [such as cardiovascular or chronic kidney disease] that merit use of demonstrably effective medications.” But Dr. Nathan pointed out, those patients are not the majority with type 2 diabetes.

He laid out four main arguments for choosing traditional sequential therapy over initial combination therapy. For one, it “enables determination of efficacy of adding individual medications, while initial combination precludes determining benefits of individual drugs.”

Second, traditional sequential therapy allows for assessment of side effects from individual drugs.

“With Dr. DeFronzo’s algorithm you throw everything at them, and if they get nausea, vomiting, or diarrhea, you won’t know which drug it is ... If they get an allergic reaction, you won’t know which medication it is,” observed Dr. Nathan, who is director of the clinical research center and the diabetes center at Massachusetts General Hospital, Boston.

Moreover, he said, traditional sequential therapy “promotes individualization, with selection of drugs, which is something we’re laboring to achieve. Initial combination obviously limits that.”

Further, sequential therapy is “parsimonious and cost-effective, whereas initial combination therapy is expensive, with modest advantages at most.”

And, there are “lots of data” supporting traditional sequential therapy and relatively little for initial combination therapy.

Dr. Nathan added that when he searched the literature for relevant randomized clinical trials, he found 16 investigating initial combination therapy versus monotherapy, but only three that examined combination versus sequential therapy.

“Very few of them, except for EDICT and VERIFY, actually include the sequential therapy that we would use in practice,” he said.

Moreover, he observed, except for the VERIFY study, most are less than half a year in duration. And in VERIFY, there was an initial 20% difference in the proportions of patients with A1c below 7.0%, but by 12 months, that difference had shrunk to just 5%-6%.

“So, looking over time is very important,” Dr. Nathan cautioned. “We really have to be careful ... Six months is barely enough time to see A1c equilibrate ... You really need to study a long-term, chronic, progressive disease like type 2 diabetes over a long enough period of time to be clinically meaningful.”

Dr. Nathan acknowledged to Dr. DeFronzo that the latter’s EDICT study was “well conducted” and “long enough,” and that the researchers did examine monotherapy versus sequential therapy. However, he pointed out that it was a small study with 249 patients and the dropout rate was high, with 58% of patients remaining in the study with triple therapy versus 68% for conventional treatment. “That’s a bit problematic,” Dr. Nathan noted.

At 2 years, the “trivial” difference in A1c was 6.5% with conventional therapy versus 6.0% with triple therapy. “This is all on the very flat complications curve with regard to A1c,” he observed.

Patients treated with sequential therapy with sulfonylurea and insulin had higher rates of hypoglycemia and weight gain, whereas the combination triple therapy group had more gastrointestinal side effects and edema.

However, the most dramatic difference was cost: the average wholesale price for sequential therapy totaled about $85 per month, compared with $1,310 for initial combination therapy. For the approximately 1.5 million patients with new-onset type 2 diabetes in the United States, that difference comes to an additional cost per year of about $22 billion, Dr. Nathan calculated.

“Although current sequential therapy leaves much to be desired ... initial combination therapy has generally only been tested for brief, clinically insufficient periods.

“And therefore, I think sequential therapy is still what is called for,” he concluded. “Well-powered, acceptable-duration studies need to be performed before we can adopt initial/early combination therapy as the standard of care.”

Dr. DeFronzo has reported receiving research support from Boehringer Ingelheim, AstraZeneca, and Merck; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AstraZeneca; and participation on a data safety monitoring board or advisory board for AstraZeneca, Intarcia, Novo Nordisk, and Boehringer Ingelheim. Dr. Nathan has reported no relevant financial relationships.

A version of this article appeared on Medscape.com.

SAN DIEGO – Should pharmacologic treatment of type 2 diabetes start with combination therapy or metformin monotherapy, adding other agents over time?

This question was debated by two well-known clinician-researchers in the diabetes world at the recent annual scientific sessions of the American Diabetes Association.

Ralph A. DeFronzo, MD, argued for combination therapy at the time of diagnosis, and David M. Nathan, MD, countered that sequential therapy is a better way to go.
 

‘The ominous octet’: Addressing multiple underlying defects

Of course, Dr. DeFronzo said, the right agents must be selected. “The drugs we’re going to use as combination at a minimum have to correct the underlying insulin resistance and beta-cell failure, or we are not going to be successful.”

In addition, he said, these drugs should also provide protection against cardiovascular, kidney, and fatty liver disease, because “[managing] diabetes is more than just controlling the glucose.”

Recent U.S. data suggest that half of people with diabetes have a hemoglobin A1c above 7%, and a quarter remain above 8%. “We’re not really doing a very good job in terms of glycemic control,” said Dr. DeFronzo, chief of the diabetes division at University of Texas, San Antonio.

One reason for this failure, he said, is the complex pathophysiology of type 2 diabetes represented by eight major defects, what he called the “ominous octet”: decreased pancreatic insulin secretion, gut incretin effects, glucose uptake in the muscle, increased lipolysis, glucose reabsorption in the kidney, hepatic glucose production, increased glucagon secretion, and neurotransmitter dysfunction.

“There are eight problems, so you’re going to need multiple drugs in combination ... not ones that just lower the A1c.”

And, Dr. DeFronzo said, these drugs “must be started early in the natural history of type 2 diabetes if progressive beta-cell failure is to be prevented.”

He pointed to the United Kingdom Prospective Diabetes Study (UKPDS), in which the sulfonylurea glyburide was used first, followed by metformin. With each drug, the A1c decreased initially but then rose within 3 years. By 15 years, 65% of participants were taking insulin.

More recently, the GRADE study examined the effects of adding four different glucose-lowering agents (glimepiride, sitagliptin, liraglutide, or insulin glargine) in people who hadn’t achieved target A1c with metformin.

“So, by definition, drug number one failed,” he observed.

During the study, all participants showed an initial A1c drop, followed by progressive failure, “again ... showing that stepwise therapy doesn’t work.”

All patients with type 2 diabetes at his center are treated using the “DeFronzo algorithm” consisting of three drug classes: a glucagon-like peptide-1 (GLP-1) agonist, a sodium-glucose cotransporter-2 (SGLT2) inhibitor, and pioglitazone, as each of them targets more than one of the “ominous octet” defects.

“The drugs that clearly do not work on a long-term basis are metformin and sulfonylureas,” he emphasized.

Several studies demonstrate the efficacy of combination therapy, he said. In one, DURATION 8, the combination of exenatide and dapagliflozin was superior to either agent individually in lowering A1c, cardiovascular events, and all-cause mortality over 2 years.

And in the 5-year VERIFY study, early combination therapy with vildagliptin plus metformin proved superior in A1c-lowering to starting patients on metformin and adding vildagliptin later.

Dr. DeFronzo’s own “knock-out punch” study, EDICT, in people with new-onset type 2 diabetes, compared the initial combination of metformin, pioglitazone, and exenatide with conventional sequential add-on therapy with metformin, glipizide, and insulin glargine.

The primary endpoint – the difference in the proportion of patients with A1c less than 6.5% – was 70% versus 29% with combination compared with sequential therapy, a difference “as robust as you can be going against the stepwise approach” at P < .00001, he said.

The combination therapy virtually normalized both insulin sensitivity and beta-cell function, whereas the conventional therapy did neither.

Also from Dr. DeFronzo’s group, in the Qatar study, which compared exenatide plus pioglitazone with basal-bolus insulin in people with about 10 years’ duration of type 2 diabetes and A1c above 7.5% taking sulfonylurea plus metformin, the combination therapy produced an A1c of 6.2% versus 7.1% with insulin.

Dr. DeFronzo pointed to new language added to the ADA Standards of Medical Care in Diabetes in 2022.

While still endorsing stepwise therapy, the document also says that “there are data to support initial combination therapy for more rapid attainment of glycemic targets and longer durability of glycemic effect.” The two references cited are EDICT and VERIFY.

“Finally, the American Diabetes Association has gotten the message,” he concluded.
 

Sequential therapy: Far more data, lower cost

Dr. Nathan began by pointing out that the ADA Standards of Care continue to advise use of metformin as first-line therapy for type 2 diabetes “because of its high efficacy in lowering A1c, minimal hypoglycemia risk when used as monotherapy, weight neutrality with the potential for modest weight loss, good safety profile, and low cost.”

He emphasized that he was not arguing “against the use of early or even initial combination therapy when there are co-existent morbidities [such as cardiovascular or chronic kidney disease] that merit use of demonstrably effective medications.” But Dr. Nathan pointed out, those patients are not the majority with type 2 diabetes.

He laid out four main arguments for choosing traditional sequential therapy over initial combination therapy. For one, it “enables determination of efficacy of adding individual medications, while initial combination precludes determining benefits of individual drugs.”

Second, traditional sequential therapy allows for assessment of side effects from individual drugs.

“With Dr. DeFronzo’s algorithm you throw everything at them, and if they get nausea, vomiting, or diarrhea, you won’t know which drug it is ... If they get an allergic reaction, you won’t know which medication it is,” observed Dr. Nathan, who is director of the clinical research center and the diabetes center at Massachusetts General Hospital, Boston.

Moreover, he said, traditional sequential therapy “promotes individualization, with selection of drugs, which is something we’re laboring to achieve. Initial combination obviously limits that.”

Further, sequential therapy is “parsimonious and cost-effective, whereas initial combination therapy is expensive, with modest advantages at most.”

And, there are “lots of data” supporting traditional sequential therapy and relatively little for initial combination therapy.

Dr. Nathan added that when he searched the literature for relevant randomized clinical trials, he found 16 investigating initial combination therapy versus monotherapy, but only three that examined combination versus sequential therapy.

“Very few of them, except for EDICT and VERIFY, actually include the sequential therapy that we would use in practice,” he said.

Moreover, he observed, except for the VERIFY study, most are less than half a year in duration. And in VERIFY, there was an initial 20% difference in the proportions of patients with A1c below 7.0%, but by 12 months, that difference had shrunk to just 5%-6%.

“So, looking over time is very important,” Dr. Nathan cautioned. “We really have to be careful ... Six months is barely enough time to see A1c equilibrate ... You really need to study a long-term, chronic, progressive disease like type 2 diabetes over a long enough period of time to be clinically meaningful.”

Dr. Nathan acknowledged to Dr. DeFronzo that the latter’s EDICT study was “well conducted” and “long enough,” and that the researchers did examine monotherapy versus sequential therapy. However, he pointed out that it was a small study with 249 patients and the dropout rate was high, with 58% of patients remaining in the study with triple therapy versus 68% for conventional treatment. “That’s a bit problematic,” Dr. Nathan noted.

At 2 years, the “trivial” difference in A1c was 6.5% with conventional therapy versus 6.0% with triple therapy. “This is all on the very flat complications curve with regard to A1c,” he observed.

Patients treated with sequential therapy with sulfonylurea and insulin had higher rates of hypoglycemia and weight gain, whereas the combination triple therapy group had more gastrointestinal side effects and edema.

However, the most dramatic difference was cost: the average wholesale price for sequential therapy totaled about $85 per month, compared with $1,310 for initial combination therapy. For the approximately 1.5 million patients with new-onset type 2 diabetes in the United States, that difference comes to an additional cost per year of about $22 billion, Dr. Nathan calculated.

“Although current sequential therapy leaves much to be desired ... initial combination therapy has generally only been tested for brief, clinically insufficient periods.

“And therefore, I think sequential therapy is still what is called for,” he concluded. “Well-powered, acceptable-duration studies need to be performed before we can adopt initial/early combination therapy as the standard of care.”

Dr. DeFronzo has reported receiving research support from Boehringer Ingelheim, AstraZeneca, and Merck; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AstraZeneca; and participation on a data safety monitoring board or advisory board for AstraZeneca, Intarcia, Novo Nordisk, and Boehringer Ingelheim. Dr. Nathan has reported no relevant financial relationships.

A version of this article appeared on Medscape.com.

SAN DIEGO – Should pharmacologic treatment of type 2 diabetes start with combination therapy or metformin monotherapy, adding other agents over time?

This question was debated by two well-known clinician-researchers in the diabetes world at the recent annual scientific sessions of the American Diabetes Association.

Ralph A. DeFronzo, MD, argued for combination therapy at the time of diagnosis, and David M. Nathan, MD, countered that sequential therapy is a better way to go.
 

‘The ominous octet’: Addressing multiple underlying defects

Of course, Dr. DeFronzo said, the right agents must be selected. “The drugs we’re going to use as combination at a minimum have to correct the underlying insulin resistance and beta-cell failure, or we are not going to be successful.”

In addition, he said, these drugs should also provide protection against cardiovascular, kidney, and fatty liver disease, because “[managing] diabetes is more than just controlling the glucose.”

Recent U.S. data suggest that half of people with diabetes have a hemoglobin A1c above 7%, and a quarter remain above 8%. “We’re not really doing a very good job in terms of glycemic control,” said Dr. DeFronzo, chief of the diabetes division at University of Texas, San Antonio.

One reason for this failure, he said, is the complex pathophysiology of type 2 diabetes represented by eight major defects, what he called the “ominous octet”: decreased pancreatic insulin secretion, gut incretin effects, glucose uptake in the muscle, increased lipolysis, glucose reabsorption in the kidney, hepatic glucose production, increased glucagon secretion, and neurotransmitter dysfunction.

“There are eight problems, so you’re going to need multiple drugs in combination ... not ones that just lower the A1c.”

And, Dr. DeFronzo said, these drugs “must be started early in the natural history of type 2 diabetes if progressive beta-cell failure is to be prevented.”

He pointed to the United Kingdom Prospective Diabetes Study (UKPDS), in which the sulfonylurea glyburide was used first, followed by metformin. With each drug, the A1c decreased initially but then rose within 3 years. By 15 years, 65% of participants were taking insulin.

More recently, the GRADE study examined the effects of adding four different glucose-lowering agents (glimepiride, sitagliptin, liraglutide, or insulin glargine) in people who hadn’t achieved target A1c with metformin.

“So, by definition, drug number one failed,” he observed.

During the study, all participants showed an initial A1c drop, followed by progressive failure, “again ... showing that stepwise therapy doesn’t work.”

All patients with type 2 diabetes at his center are treated using the “DeFronzo algorithm” consisting of three drug classes: a glucagon-like peptide-1 (GLP-1) agonist, a sodium-glucose cotransporter-2 (SGLT2) inhibitor, and pioglitazone, as each of them targets more than one of the “ominous octet” defects.

“The drugs that clearly do not work on a long-term basis are metformin and sulfonylureas,” he emphasized.

Several studies demonstrate the efficacy of combination therapy, he said. In one, DURATION 8, the combination of exenatide and dapagliflozin was superior to either agent individually in lowering A1c, cardiovascular events, and all-cause mortality over 2 years.

And in the 5-year VERIFY study, early combination therapy with vildagliptin plus metformin proved superior in A1c-lowering to starting patients on metformin and adding vildagliptin later.

Dr. DeFronzo’s own “knock-out punch” study, EDICT, in people with new-onset type 2 diabetes, compared the initial combination of metformin, pioglitazone, and exenatide with conventional sequential add-on therapy with metformin, glipizide, and insulin glargine.

The primary endpoint – the difference in the proportion of patients with A1c less than 6.5% – was 70% versus 29% with combination compared with sequential therapy, a difference “as robust as you can be going against the stepwise approach” at P < .00001, he said.

The combination therapy virtually normalized both insulin sensitivity and beta-cell function, whereas the conventional therapy did neither.

Also from Dr. DeFronzo’s group, in the Qatar study, which compared exenatide plus pioglitazone with basal-bolus insulin in people with about 10 years’ duration of type 2 diabetes and A1c above 7.5% taking sulfonylurea plus metformin, the combination therapy produced an A1c of 6.2% versus 7.1% with insulin.

Dr. DeFronzo pointed to new language added to the ADA Standards of Medical Care in Diabetes in 2022.

While still endorsing stepwise therapy, the document also says that “there are data to support initial combination therapy for more rapid attainment of glycemic targets and longer durability of glycemic effect.” The two references cited are EDICT and VERIFY.

“Finally, the American Diabetes Association has gotten the message,” he concluded.
 

Sequential therapy: Far more data, lower cost

Dr. Nathan began by pointing out that the ADA Standards of Care continue to advise use of metformin as first-line therapy for type 2 diabetes “because of its high efficacy in lowering A1c, minimal hypoglycemia risk when used as monotherapy, weight neutrality with the potential for modest weight loss, good safety profile, and low cost.”

He emphasized that he was not arguing “against the use of early or even initial combination therapy when there are co-existent morbidities [such as cardiovascular or chronic kidney disease] that merit use of demonstrably effective medications.” But Dr. Nathan pointed out, those patients are not the majority with type 2 diabetes.

He laid out four main arguments for choosing traditional sequential therapy over initial combination therapy. For one, it “enables determination of efficacy of adding individual medications, while initial combination precludes determining benefits of individual drugs.”

Second, traditional sequential therapy allows for assessment of side effects from individual drugs.

“With Dr. DeFronzo’s algorithm you throw everything at them, and if they get nausea, vomiting, or diarrhea, you won’t know which drug it is ... If they get an allergic reaction, you won’t know which medication it is,” observed Dr. Nathan, who is director of the clinical research center and the diabetes center at Massachusetts General Hospital, Boston.

Moreover, he said, traditional sequential therapy “promotes individualization, with selection of drugs, which is something we’re laboring to achieve. Initial combination obviously limits that.”

Further, sequential therapy is “parsimonious and cost-effective, whereas initial combination therapy is expensive, with modest advantages at most.”

And, there are “lots of data” supporting traditional sequential therapy and relatively little for initial combination therapy.

Dr. Nathan added that when he searched the literature for relevant randomized clinical trials, he found 16 investigating initial combination therapy versus monotherapy, but only three that examined combination versus sequential therapy.

“Very few of them, except for EDICT and VERIFY, actually include the sequential therapy that we would use in practice,” he said.

Moreover, he observed, except for the VERIFY study, most are less than half a year in duration. And in VERIFY, there was an initial 20% difference in the proportions of patients with A1c below 7.0%, but by 12 months, that difference had shrunk to just 5%-6%.

“So, looking over time is very important,” Dr. Nathan cautioned. “We really have to be careful ... Six months is barely enough time to see A1c equilibrate ... You really need to study a long-term, chronic, progressive disease like type 2 diabetes over a long enough period of time to be clinically meaningful.”

Dr. Nathan acknowledged to Dr. DeFronzo that the latter’s EDICT study was “well conducted” and “long enough,” and that the researchers did examine monotherapy versus sequential therapy. However, he pointed out that it was a small study with 249 patients and the dropout rate was high, with 58% of patients remaining in the study with triple therapy versus 68% for conventional treatment. “That’s a bit problematic,” Dr. Nathan noted.

At 2 years, the “trivial” difference in A1c was 6.5% with conventional therapy versus 6.0% with triple therapy. “This is all on the very flat complications curve with regard to A1c,” he observed.

Patients treated with sequential therapy with sulfonylurea and insulin had higher rates of hypoglycemia and weight gain, whereas the combination triple therapy group had more gastrointestinal side effects and edema.

However, the most dramatic difference was cost: the average wholesale price for sequential therapy totaled about $85 per month, compared with $1,310 for initial combination therapy. For the approximately 1.5 million patients with new-onset type 2 diabetes in the United States, that difference comes to an additional cost per year of about $22 billion, Dr. Nathan calculated.

“Although current sequential therapy leaves much to be desired ... initial combination therapy has generally only been tested for brief, clinically insufficient periods.

“And therefore, I think sequential therapy is still what is called for,” he concluded. “Well-powered, acceptable-duration studies need to be performed before we can adopt initial/early combination therapy as the standard of care.”

Dr. DeFronzo has reported receiving research support from Boehringer Ingelheim, AstraZeneca, and Merck; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AstraZeneca; and participation on a data safety monitoring board or advisory board for AstraZeneca, Intarcia, Novo Nordisk, and Boehringer Ingelheim. Dr. Nathan has reported no relevant financial relationships.

A version of this article appeared on Medscape.com.

Use of inhalers with long-acting muscarinic antagonists and long-acting beta-agonists reduced COPD exacerbations and pneumonia hospitalizations compared with inhalers with corticosteroids and long-acting beta-agonists, based on data from more than 30,000 individuals.

Current clinical guidelines for chronic obstructive pulmonary disease (COPD) patients recommend inhalers with long-acting muscarinic antagonists (LAMAs) and long-acting beta-agonists (LABAs) over those with inhaled corticosteroids (ICSs) and LABAs, but data comparing the two formulations have been inconsistent, and concerns about generalizability persist, wrote William B. Feldman, MD, of Brigham and Women’s Hospital, Boston, and colleagues.

In a study published in JAMA Internal Medicine, the researchers reviewed data from a commercial insurance claims database of individuals diagnosed with COPD who filled a new prescription for a LAMA-LABA inhaler or ICS-LABA inhaler between Jan. 1, 2014, and Dec. 31, 2019. Patients with asthma and those younger than 40 years were excluded. The study population included 137,833 individuals with a mean age of 70.2 years; 50.4% were female. Of the 107,004 ICS-LABA users and 30,829 LAMA-LABA users, 30,216 matched pairs were included in a 1:1 propensity score matched study. The primary outcomes were effectiveness, based on the rate of first moderate or severe COPD exacerbation, and safety, based on the rate of first pneumonia hospitalization.

Use of LAMA-LABA inhalers was associated with an 8% reduction in the rate of first moderate or severe COPD exacerbation and a 20% reduction in the rate of first pneumonia hospitalization compared with use of ICS-LABA (hazard ratios 0.92 and 0.80, respectively). The absolute rate reductions with LAMA-LABA inhalers for first moderate or severe COPD exacerbations and for first pneumonia hospitalizations were was 43.0 events per 1,000 person-years and 91.8 events per person-years, respectively.

The overall rates of total moderate to severe COPD and pneumonia hospitalizations were 5% and 17% lower, respectively, among patients who used LAMA-LABA than those treated with ICS-LABA. The results were consistently robust in subgroup and sensitivity analyses, the researchers wrote in their discussion. However, the results must be interpreted cautiously in comparison to other large studies because of the significant differences in the cohorts of patients studied, notably that most patients in the current study had no received previous inhaler therapy.

The study findings were limited by several factors including the relatively short follow-up time and reliance on prescription fills as an indicator of medication use, the researchers noted. Other limitations included notable differences between the LAMA-LABA patients and ICS-LABA patients, such as more severe COPD and less access to respiratory care, they wrote.

Although the current study is not the definitive answer to conflicting results from previous trials, it is the largest know to date to compare LAMA-LABA with ICS-LABA, and the results support LAMA-LABA as the preferred therapy for COPD patients, the researchers concluded.
 

Findings clarify clinical practice guidelines

“This study was required to provide clarity regarding the optimal choice of treatment for COPD given conflicting data from other recent trials,” Suman Pal, MBBS, of the University of New Mexico, Albuquerque, said in an interview.

“The study findings reinforce the benefits of combined LAMA-LABA in improving clinical outcomes in COPD in a real-world setting,” and the data provide further support for choosing LAMA-LABA over ICS-LABA in COPD patients, said Dr. Pal, who was not involved in the study.

However, availability and affordability of LAMA-LABA inhalers may be barriers to expanding their use in clinical practice, he noted.

“Additional research is needed to accurately define which patient populations would benefit most from the therapy and whether patients who have previously been stabilized on ICS-LABA would derive additional benefit from a change in therapy,” Dr. Pal said.

The study was supported by the National Heart, Lung, and Blood Institute and funding from the Commonwealth Fund and Arnold Ventures.

Dr. Feldman disclosed receiving personal fees from Alosa Health and Aetion, serving as an expert witness in litigation against inhaler manufacturers, and receiving an honorarium for a presentation to Blue Cross Blue Shield of Massachusetts unrelated to the current study. Dr. Pal had no financial conflicts to disclose.

Use of inhalers with long-acting muscarinic antagonists and long-acting beta-agonists reduced COPD exacerbations and pneumonia hospitalizations compared with inhalers with corticosteroids and long-acting beta-agonists, based on data from more than 30,000 individuals.

Current clinical guidelines for chronic obstructive pulmonary disease (COPD) patients recommend inhalers with long-acting muscarinic antagonists (LAMAs) and long-acting beta-agonists (LABAs) over those with inhaled corticosteroids (ICSs) and LABAs, but data comparing the two formulations have been inconsistent, and concerns about generalizability persist, wrote William B. Feldman, MD, of Brigham and Women’s Hospital, Boston, and colleagues.

In a study published in JAMA Internal Medicine, the researchers reviewed data from a commercial insurance claims database of individuals diagnosed with COPD who filled a new prescription for a LAMA-LABA inhaler or ICS-LABA inhaler between Jan. 1, 2014, and Dec. 31, 2019. Patients with asthma and those younger than 40 years were excluded. The study population included 137,833 individuals with a mean age of 70.2 years; 50.4% were female. Of the 107,004 ICS-LABA users and 30,829 LAMA-LABA users, 30,216 matched pairs were included in a 1:1 propensity score matched study. The primary outcomes were effectiveness, based on the rate of first moderate or severe COPD exacerbation, and safety, based on the rate of first pneumonia hospitalization.

Use of LAMA-LABA inhalers was associated with an 8% reduction in the rate of first moderate or severe COPD exacerbation and a 20% reduction in the rate of first pneumonia hospitalization compared with use of ICS-LABA (hazard ratios 0.92 and 0.80, respectively). The absolute rate reductions with LAMA-LABA inhalers for first moderate or severe COPD exacerbations and for first pneumonia hospitalizations were was 43.0 events per 1,000 person-years and 91.8 events per person-years, respectively.

The overall rates of total moderate to severe COPD and pneumonia hospitalizations were 5% and 17% lower, respectively, among patients who used LAMA-LABA than those treated with ICS-LABA. The results were consistently robust in subgroup and sensitivity analyses, the researchers wrote in their discussion. However, the results must be interpreted cautiously in comparison to other large studies because of the significant differences in the cohorts of patients studied, notably that most patients in the current study had no received previous inhaler therapy.

The study findings were limited by several factors including the relatively short follow-up time and reliance on prescription fills as an indicator of medication use, the researchers noted. Other limitations included notable differences between the LAMA-LABA patients and ICS-LABA patients, such as more severe COPD and less access to respiratory care, they wrote.

Although the current study is not the definitive answer to conflicting results from previous trials, it is the largest know to date to compare LAMA-LABA with ICS-LABA, and the results support LAMA-LABA as the preferred therapy for COPD patients, the researchers concluded.
 

Findings clarify clinical practice guidelines

“This study was required to provide clarity regarding the optimal choice of treatment for COPD given conflicting data from other recent trials,” Suman Pal, MBBS, of the University of New Mexico, Albuquerque, said in an interview.

“The study findings reinforce the benefits of combined LAMA-LABA in improving clinical outcomes in COPD in a real-world setting,” and the data provide further support for choosing LAMA-LABA over ICS-LABA in COPD patients, said Dr. Pal, who was not involved in the study.

However, availability and affordability of LAMA-LABA inhalers may be barriers to expanding their use in clinical practice, he noted.

“Additional research is needed to accurately define which patient populations would benefit most from the therapy and whether patients who have previously been stabilized on ICS-LABA would derive additional benefit from a change in therapy,” Dr. Pal said.

The study was supported by the National Heart, Lung, and Blood Institute and funding from the Commonwealth Fund and Arnold Ventures.

Dr. Feldman disclosed receiving personal fees from Alosa Health and Aetion, serving as an expert witness in litigation against inhaler manufacturers, and receiving an honorarium for a presentation to Blue Cross Blue Shield of Massachusetts unrelated to the current study. Dr. Pal had no financial conflicts to disclose.

Use of inhalers with long-acting muscarinic antagonists and long-acting beta-agonists reduced COPD exacerbations and pneumonia hospitalizations compared with inhalers with corticosteroids and long-acting beta-agonists, based on data from more than 30,000 individuals.

Current clinical guidelines for chronic obstructive pulmonary disease (COPD) patients recommend inhalers with long-acting muscarinic antagonists (LAMAs) and long-acting beta-agonists (LABAs) over those with inhaled corticosteroids (ICSs) and LABAs, but data comparing the two formulations have been inconsistent, and concerns about generalizability persist, wrote William B. Feldman, MD, of Brigham and Women’s Hospital, Boston, and colleagues.

In a study published in JAMA Internal Medicine, the researchers reviewed data from a commercial insurance claims database of individuals diagnosed with COPD who filled a new prescription for a LAMA-LABA inhaler or ICS-LABA inhaler between Jan. 1, 2014, and Dec. 31, 2019. Patients with asthma and those younger than 40 years were excluded. The study population included 137,833 individuals with a mean age of 70.2 years; 50.4% were female. Of the 107,004 ICS-LABA users and 30,829 LAMA-LABA users, 30,216 matched pairs were included in a 1:1 propensity score matched study. The primary outcomes were effectiveness, based on the rate of first moderate or severe COPD exacerbation, and safety, based on the rate of first pneumonia hospitalization.

Use of LAMA-LABA inhalers was associated with an 8% reduction in the rate of first moderate or severe COPD exacerbation and a 20% reduction in the rate of first pneumonia hospitalization compared with use of ICS-LABA (hazard ratios 0.92 and 0.80, respectively). The absolute rate reductions with LAMA-LABA inhalers for first moderate or severe COPD exacerbations and for first pneumonia hospitalizations were was 43.0 events per 1,000 person-years and 91.8 events per person-years, respectively.

The overall rates of total moderate to severe COPD and pneumonia hospitalizations were 5% and 17% lower, respectively, among patients who used LAMA-LABA than those treated with ICS-LABA. The results were consistently robust in subgroup and sensitivity analyses, the researchers wrote in their discussion. However, the results must be interpreted cautiously in comparison to other large studies because of the significant differences in the cohorts of patients studied, notably that most patients in the current study had no received previous inhaler therapy.

The study findings were limited by several factors including the relatively short follow-up time and reliance on prescription fills as an indicator of medication use, the researchers noted. Other limitations included notable differences between the LAMA-LABA patients and ICS-LABA patients, such as more severe COPD and less access to respiratory care, they wrote.

Although the current study is not the definitive answer to conflicting results from previous trials, it is the largest know to date to compare LAMA-LABA with ICS-LABA, and the results support LAMA-LABA as the preferred therapy for COPD patients, the researchers concluded.
 

Findings clarify clinical practice guidelines

“This study was required to provide clarity regarding the optimal choice of treatment for COPD given conflicting data from other recent trials,” Suman Pal, MBBS, of the University of New Mexico, Albuquerque, said in an interview.

“The study findings reinforce the benefits of combined LAMA-LABA in improving clinical outcomes in COPD in a real-world setting,” and the data provide further support for choosing LAMA-LABA over ICS-LABA in COPD patients, said Dr. Pal, who was not involved in the study.

However, availability and affordability of LAMA-LABA inhalers may be barriers to expanding their use in clinical practice, he noted.

“Additional research is needed to accurately define which patient populations would benefit most from the therapy and whether patients who have previously been stabilized on ICS-LABA would derive additional benefit from a change in therapy,” Dr. Pal said.

The study was supported by the National Heart, Lung, and Blood Institute and funding from the Commonwealth Fund and Arnold Ventures.

Dr. Feldman disclosed receiving personal fees from Alosa Health and Aetion, serving as an expert witness in litigation against inhaler manufacturers, and receiving an honorarium for a presentation to Blue Cross Blue Shield of Massachusetts unrelated to the current study. Dr. Pal had no financial conflicts to disclose.

Stop me if you’ve heard this before. There’s a controversy over blood pressure targets. Some argue for 140/90 mm Hg, others for 130/80 mm Hg, and some super ambitious folks think that we should aim for 120/80 mm Hg. If this sounds familiar, it should. We did it in 2017. It’s unclear what, if anything, we learned from the experience. On the upside, it’s not as bad as it was 100 years ago.

When high blood pressure was a ‘good’ thing

Back then, many believed that you needed higher blood pressure as you got older to push the blood through your progressively stiffened and hardened arteries. Hence the name “essential” hypertension. The concern was that lowering blood pressure would hypoperfuse your organs and be dangerous. In the 1930s, John Hay told an audience at a British Medical Association lecture: “The greatest danger to a man with high blood pressure lies in its discovery, because then some fool is certain to try and reduce it.”

The 1900s were a simpler time when people had fatal strokes in their 50s, and their families were consoled by the knowledge that they had lived a good life.

If our thinking around blood pressure had evolved slightly faster, perhaps President Roosevelt wouldn’t have died of a stroke during World War II as his doctors watched his systolic blood pressure climb above 200 mm Hg and suggested massages and barbiturates to take the edge off.
 

The current controversy

Not that long ago, 180 mm Hg was considered mild hypertension. Now, we are arguing about a systolic blood pressure of 140 versus 130 mm Hg.

The American Academy of Family Physicians takes the view that 140/90 mm Hg is good enough for most people. Their most recent clinical practice guideline, based primarily on two 2020 Cochrane Reviews of blood pressure targets in patients with and without cardiovascular disease, did not find any mortality benefit for a lower blood pressure threshold.

This puts the AAFP guideline in conflict with the 2017 guideline issued jointly by the American College of Cardiology, American Heart Association, and nine other groups, which recommended a target of 130/80 mm Hg for pretty much everyone. Though they say greater than 140/90 mm Hg should be the threshold for low-risk patients or for starting therapy post stroke, we often forget those nuances. The main point of contention is that the AAFP guideline was looking for a mortality benefit, whereas the ACC/AHA/everyone else guideline was looking at preventing cardiovascular events. The latter guideline was driven mainly by the results of the SPRINT trial. ACC/AHA argue for more aggressive targets to prevent the things that cardiologists care about, namely heart attacks.

The AAFP guideline conceded that more aggressive control will result in fewer myocardial infarctions but warn that it comes with more adverse events. Treating 1,000 patients to this lower target would theoretically prevent four MIs, possibly prevent three strokes, but result in 30 adverse events.

In the end, what we are seeing here is not so much a debate over the evidence as a debate over priorities. The AAFP’s main focus is all-cause mortality; the ACC/AHA’s is cardiovascular events. Interventions that don’t improve mortality can be questioned in terms of their cost effectiveness. But you probably don’t want to have a heart attack (even a nonfatal one). And you certainly don’t want to have a stroke. However, lower blood pressure targets inevitably require more medications. Notwithstanding the economic costs, the dangers of polypharmacy, medication interactions, side effects, and syncope leading to falls cannot be ignored. Falls are not benign adverse events, especially in older adults.

The counter argument is that physicians are human and often let things slide. Set the target at 140/90 mm Hg, and many physicians won’t jump on a systolic blood pressure of 144 mm Hg. Set the target at 130 mm Hg, and maybe they’ll be more likely to react. There’s a fine line between permissiveness and complacency.

If you zoom out and look at the multitude of blood pressure guidelines, you start to notice an important fact. There is not much daylight between them. There are subtle differences in what constitutes high risk and different definitions of older (older should be defined as 10 years older than the reader’s current age). But otherwise, the blood pressure targets are not that different.

Does that final 10 mm Hg really matter when barriers to care mean that tens of millions in the United States are unaware they have hypertension? Even among those diagnosed, many are either untreated or inadequately treated.

With this context, perhaps the most insightful thing that can be said about the blood pressure guideline controversy is that it’s not all that controversial. We can likely all agree that we need to be better at treating hypertension and that creative solutions to reach underserved communities are necessary.

Arguing about 140/90 mm Hg or 130/80 mm Hg is less important than acknowledging that we should be aggressive in screening for and treating hypertension. We should acknowledge that beyond a certain point any cardiovascular benefit comes at the cost of hypotension and side effects. That tipping point will be different for different groups, and probably at a higher set point in older patients.

Individualizing care isn’t difficult. We do it all the time. We just shouldn’t be letting people walk around with untreated hypertension. It’s not the 1900s anymore.

Dr. Labos is a cardiologist at Hôpital Notre-Dame, Montreal. He reported no conflicts of interest.

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

Stop me if you’ve heard this before. There’s a controversy over blood pressure targets. Some argue for 140/90 mm Hg, others for 130/80 mm Hg, and some super ambitious folks think that we should aim for 120/80 mm Hg. If this sounds familiar, it should. We did it in 2017. It’s unclear what, if anything, we learned from the experience. On the upside, it’s not as bad as it was 100 years ago.

When high blood pressure was a ‘good’ thing

Back then, many believed that you needed higher blood pressure as you got older to push the blood through your progressively stiffened and hardened arteries. Hence the name “essential” hypertension. The concern was that lowering blood pressure would hypoperfuse your organs and be dangerous. In the 1930s, John Hay told an audience at a British Medical Association lecture: “The greatest danger to a man with high blood pressure lies in its discovery, because then some fool is certain to try and reduce it.”

The 1900s were a simpler time when people had fatal strokes in their 50s, and their families were consoled by the knowledge that they had lived a good life.

If our thinking around blood pressure had evolved slightly faster, perhaps President Roosevelt wouldn’t have died of a stroke during World War II as his doctors watched his systolic blood pressure climb above 200 mm Hg and suggested massages and barbiturates to take the edge off.
 

The current controversy

Not that long ago, 180 mm Hg was considered mild hypertension. Now, we are arguing about a systolic blood pressure of 140 versus 130 mm Hg.

The American Academy of Family Physicians takes the view that 140/90 mm Hg is good enough for most people. Their most recent clinical practice guideline, based primarily on two 2020 Cochrane Reviews of blood pressure targets in patients with and without cardiovascular disease, did not find any mortality benefit for a lower blood pressure threshold.

This puts the AAFP guideline in conflict with the 2017 guideline issued jointly by the American College of Cardiology, American Heart Association, and nine other groups, which recommended a target of 130/80 mm Hg for pretty much everyone. Though they say greater than 140/90 mm Hg should be the threshold for low-risk patients or for starting therapy post stroke, we often forget those nuances. The main point of contention is that the AAFP guideline was looking for a mortality benefit, whereas the ACC/AHA/everyone else guideline was looking at preventing cardiovascular events. The latter guideline was driven mainly by the results of the SPRINT trial. ACC/AHA argue for more aggressive targets to prevent the things that cardiologists care about, namely heart attacks.

The AAFP guideline conceded that more aggressive control will result in fewer myocardial infarctions but warn that it comes with more adverse events. Treating 1,000 patients to this lower target would theoretically prevent four MIs, possibly prevent three strokes, but result in 30 adverse events.

In the end, what we are seeing here is not so much a debate over the evidence as a debate over priorities. The AAFP’s main focus is all-cause mortality; the ACC/AHA’s is cardiovascular events. Interventions that don’t improve mortality can be questioned in terms of their cost effectiveness. But you probably don’t want to have a heart attack (even a nonfatal one). And you certainly don’t want to have a stroke. However, lower blood pressure targets inevitably require more medications. Notwithstanding the economic costs, the dangers of polypharmacy, medication interactions, side effects, and syncope leading to falls cannot be ignored. Falls are not benign adverse events, especially in older adults.

The counter argument is that physicians are human and often let things slide. Set the target at 140/90 mm Hg, and many physicians won’t jump on a systolic blood pressure of 144 mm Hg. Set the target at 130 mm Hg, and maybe they’ll be more likely to react. There’s a fine line between permissiveness and complacency.

If you zoom out and look at the multitude of blood pressure guidelines, you start to notice an important fact. There is not much daylight between them. There are subtle differences in what constitutes high risk and different definitions of older (older should be defined as 10 years older than the reader’s current age). But otherwise, the blood pressure targets are not that different.

Does that final 10 mm Hg really matter when barriers to care mean that tens of millions in the United States are unaware they have hypertension? Even among those diagnosed, many are either untreated or inadequately treated.

With this context, perhaps the most insightful thing that can be said about the blood pressure guideline controversy is that it’s not all that controversial. We can likely all agree that we need to be better at treating hypertension and that creative solutions to reach underserved communities are necessary.

Arguing about 140/90 mm Hg or 130/80 mm Hg is less important than acknowledging that we should be aggressive in screening for and treating hypertension. We should acknowledge that beyond a certain point any cardiovascular benefit comes at the cost of hypotension and side effects. That tipping point will be different for different groups, and probably at a higher set point in older patients.

Individualizing care isn’t difficult. We do it all the time. We just shouldn’t be letting people walk around with untreated hypertension. It’s not the 1900s anymore.

Dr. Labos is a cardiologist at Hôpital Notre-Dame, Montreal. He reported no conflicts of interest.

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

Stop me if you’ve heard this before. There’s a controversy over blood pressure targets. Some argue for 140/90 mm Hg, others for 130/80 mm Hg, and some super ambitious folks think that we should aim for 120/80 mm Hg. If this sounds familiar, it should. We did it in 2017. It’s unclear what, if anything, we learned from the experience. On the upside, it’s not as bad as it was 100 years ago.

When high blood pressure was a ‘good’ thing

Back then, many believed that you needed higher blood pressure as you got older to push the blood through your progressively stiffened and hardened arteries. Hence the name “essential” hypertension. The concern was that lowering blood pressure would hypoperfuse your organs and be dangerous. In the 1930s, John Hay told an audience at a British Medical Association lecture: “The greatest danger to a man with high blood pressure lies in its discovery, because then some fool is certain to try and reduce it.”

The 1900s were a simpler time when people had fatal strokes in their 50s, and their families were consoled by the knowledge that they had lived a good life.

If our thinking around blood pressure had evolved slightly faster, perhaps President Roosevelt wouldn’t have died of a stroke during World War II as his doctors watched his systolic blood pressure climb above 200 mm Hg and suggested massages and barbiturates to take the edge off.
 

The current controversy

Not that long ago, 180 mm Hg was considered mild hypertension. Now, we are arguing about a systolic blood pressure of 140 versus 130 mm Hg.

The American Academy of Family Physicians takes the view that 140/90 mm Hg is good enough for most people. Their most recent clinical practice guideline, based primarily on two 2020 Cochrane Reviews of blood pressure targets in patients with and without cardiovascular disease, did not find any mortality benefit for a lower blood pressure threshold.

This puts the AAFP guideline in conflict with the 2017 guideline issued jointly by the American College of Cardiology, American Heart Association, and nine other groups, which recommended a target of 130/80 mm Hg for pretty much everyone. Though they say greater than 140/90 mm Hg should be the threshold for low-risk patients or for starting therapy post stroke, we often forget those nuances. The main point of contention is that the AAFP guideline was looking for a mortality benefit, whereas the ACC/AHA/everyone else guideline was looking at preventing cardiovascular events. The latter guideline was driven mainly by the results of the SPRINT trial. ACC/AHA argue for more aggressive targets to prevent the things that cardiologists care about, namely heart attacks.

The AAFP guideline conceded that more aggressive control will result in fewer myocardial infarctions but warn that it comes with more adverse events. Treating 1,000 patients to this lower target would theoretically prevent four MIs, possibly prevent three strokes, but result in 30 adverse events.

In the end, what we are seeing here is not so much a debate over the evidence as a debate over priorities. The AAFP’s main focus is all-cause mortality; the ACC/AHA’s is cardiovascular events. Interventions that don’t improve mortality can be questioned in terms of their cost effectiveness. But you probably don’t want to have a heart attack (even a nonfatal one). And you certainly don’t want to have a stroke. However, lower blood pressure targets inevitably require more medications. Notwithstanding the economic costs, the dangers of polypharmacy, medication interactions, side effects, and syncope leading to falls cannot be ignored. Falls are not benign adverse events, especially in older adults.

The counter argument is that physicians are human and often let things slide. Set the target at 140/90 mm Hg, and many physicians won’t jump on a systolic blood pressure of 144 mm Hg. Set the target at 130 mm Hg, and maybe they’ll be more likely to react. There’s a fine line between permissiveness and complacency.

If you zoom out and look at the multitude of blood pressure guidelines, you start to notice an important fact. There is not much daylight between them. There are subtle differences in what constitutes high risk and different definitions of older (older should be defined as 10 years older than the reader’s current age). But otherwise, the blood pressure targets are not that different.

Does that final 10 mm Hg really matter when barriers to care mean that tens of millions in the United States are unaware they have hypertension? Even among those diagnosed, many are either untreated or inadequately treated.

With this context, perhaps the most insightful thing that can be said about the blood pressure guideline controversy is that it’s not all that controversial. We can likely all agree that we need to be better at treating hypertension and that creative solutions to reach underserved communities are necessary.

Arguing about 140/90 mm Hg or 130/80 mm Hg is less important than acknowledging that we should be aggressive in screening for and treating hypertension. We should acknowledge that beyond a certain point any cardiovascular benefit comes at the cost of hypotension and side effects. That tipping point will be different for different groups, and probably at a higher set point in older patients.

Individualizing care isn’t difficult. We do it all the time. We just shouldn’t be letting people walk around with untreated hypertension. It’s not the 1900s anymore.

Dr. Labos is a cardiologist at Hôpital Notre-Dame, Montreal. He reported no conflicts of interest.

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

Berberine, a plant-derived compound historically used in traditional Chinese medicine, is experiencing increased popularity thanks to social media, especially TikTok, where the hashtag #berberine has more than 75 million views at the time of this writing. Social media influencers are promoting the compound, calling it “nature’s Ozempic,” saying they lost weight taking the supplement.

Off-the-shelf berberine comes as a yellow-orange powder usually encased in a capsule or mixed into tablet form. It’s extracted from the roots, stems, and leaves of various plants, including goldenseal and barberry.

Its use is additionally promoted for insulin resistance, polycystic ovary syndrome, and even cancer, but medical experts are warning potential users that it lacks robust evidence to support its use.

“There’s not that much data on it,” says Reshmi Srinath, MD, director of the Mount Sinai weight and metabolism management program, New York. “It’s sort of shocking now that it’s popped up into the media, to be frank.”

In response to berberine’s online popularity, the National Center for Complementary and Integrative Health issued a warning, stating that “there isn’t enough rigorous scientific evidence to determine whether it is effective.”
 

Overstated claims, lack of scientific research?

Other endocrinologists and weight management experts agree. “The claims are pretty overstated when it comes to the impact on weight loss, based on the evidence in the literature that’s currently available,” says Jaime Almandoz, MD, medical director of the UT Southwestern Medical Center, Dallas, weight wellness program.

A review of 12 randomized controlled trials evaluating berberine’s effects on obesity concluded that the treatment moderately decreased body weight. The trials included were conducted over only a few months and had small numbers of participants, and weight loss was not the primary outcome measure.

“There are few randomized controlled trials,” says Ivania Rizo, MD, an endocrinologist at Boston University. “It appears that they all have some low quality of methods which essentially can lead to an increased risk of bias.”

Another review, of 35 studies – most of them on animals and human cells and similarly underpowered – concluded that berberine showed promise for reducing blood glucose. A separate study found that berberine treatment actually increased the body weight and appetite of rats.

How exactly berberine elicits these effects is not entirely clear. Several studies point to its activation of AMP-activated protein kinase, which improves glucose tolerance in rats, as the mechanism for weight loss. Metformin, a drug used to improve glycemic control in people with type 2 diabetes, works in a similar way. Other researchers have hypothesized a link between berberine and the gut microbiome to explain its effect on type 2 diabetes and weight loss, though the clinical data to substantiate this link are shaky.

“I caution my patients about dietary supplements for weight management because we do not have high-quality data demonstrating efficacy,” Katherine Saunders, MD, DABOM, an obesity expert and cofounder of Intellihealth, a platform for obesity management, said in an email.
 

Experimenting with berberine

Despite the lack of substantial evidence supporting berberine’s use for weight management and obesity, interest in the supplement seems to be increasing. One reason could be that lifestyle interventions aren’t sufficient for most people with obesity to lose a significant amount of weight, with many requiring medical intervention, according to Dr. Saunders.

But access to treatment providers is limited. “As a result, it is not uncommon for individuals with obesity to experiment with dietary supplements like berberine,” she observed.

Dr. Srinath, the Mount Sinai doctor, says many patients have asked for her thoughts on berberine as a weight loss supplement. “I say, you know, it’s something you’re welcome to try, but we don’t have enough data at this time to recommend it.”

The hype surrounding the supplement isn’t all that surprising. About 42% of adults in the United States have obesity, according to 2019-2023 National Health and Nutrition Examination Survey data, pointing to a serious need for accessible drugs to address the condition. Berberine is available over the counter and is far cheaper than most of the newer U.S. Food and Drug Administration–approved drugs for weight loss.

Wegovy, semaglutide approved to treat obesity, can cost as much as $1,300 per package; and Ozempic, semaglutide approved to treat type 2 diabetes, can cost more than $1,000 per month. “That’s a very steep price to pay,” says Dr. Srinath.

Many insurance companies won’t cover the drugs, curbing access to Americans who need them, says Dr. Almandoz. Federally sponsored programs such as Medicare and Medicaid also don’t cover the drugs, which are approved for obesity and weight management. “That’s been a huge hole in our health care system,” says Dr. Srinath. “That’s sort of what’s been driving interest in supplements and things like that.”

Among adults trying to lose weight, only about 3% said they took prescription medication for weight loss, according to a report from the U.S. Government Accountability Office. This report includes 2013-2016 data, predating Wegovy’s approval for chronic weight management.

“These classes are notorious for being quite pricey and not well covered by insurance,” says Dr. Almandoz. “It’s easy to see why someone would promote something that someone may have more access to.”

Comparing Ozempic or Wegovy with berberine can be misleading. Those drugs work by mimicking the effect of the hormone GLP-1 to help reduce appetite.

A clinical trial assessing the efficacy of semaglutide found that adults with obesity who took the drug for 68 weeks lost approximately 15% of their body weight in combination with lifestyle changes. The FDA approval was based on this trial and three others that showed similarly substantial reductions in weight.

The trials also document the many side effects of taking the drugs, primarily gastrointestinal in nature. The short- and long-term effects of berberine, on the other hand, are less clear. Some of the clinical trials reported diarrhea and stomach upset as the most common adverse effects.

Its perception as a naturally derived option for weight loss, though, might encourage people to overlook the potential interactions that berberine could have with other drugs, according to Dr. Almandoz.

He says clinicians considering natural products or nutraceuticals for patients should check for potential side effects and find reliable database sources to determine any potential medication interactions for patients. But the unregulated nature of berberine makes this challenging, Dr. Almandoz adds.

The dosage, formulations, and quality of berberine vary in each study and each product because supplements don’t need to pass through the checks and balances of the FDA to land on shelves.

The lack of regulation could incentivize some companies to add stimulants to enhance any weight loss effect that the supplement may have. Those additives might interact with other health conditions or cause side effects like anxiety, says Dr. Almandoz.

Berberine should also not be taken during pregnancy or while breastfeeding, and it is unsafe for young children; in newborns and children, the supplement can cause higher levels of bilirubin in the blood, worsening any jaundice at birth and posing a greater risk for kernicterus.

Dr. Rizo urges patients, before they ask for berberine, to first ask for safe and effective interventions they can access. “I don’t want to have people not use effective interventions that are currently available to them, and instead use something that needs to be better studied and needs to be better regulated,” she says.

While the “nature’s Ozempic” catchphrase could be drawing in potential users with its dubious comparison, berberine’s escalating popularity might also be a symptom of people seeking a quick fix, the experts worry.

“That’s my fear,” says Dr. Srinath. “ ‘Let me get this medicine, let me lose the weight fast,’ but at the end of the day, weight management is a long-term journey. It takes time, it takes effort, it is not easy, and there is no quick fix.”

This is another concern for doctors; for people who’ve struggled with losing weight for years, not seeing results from berberine could feel like another failure.

“It will give them another opportunity to feel like they are being unsuccessful or that they are failing at weight loss again,” says Dr. Almandoz. “It feeds into the hopelessness that many people with obesity have around their weight management.”

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

Berberine, a plant-derived compound historically used in traditional Chinese medicine, is experiencing increased popularity thanks to social media, especially TikTok, where the hashtag #berberine has more than 75 million views at the time of this writing. Social media influencers are promoting the compound, calling it “nature’s Ozempic,” saying they lost weight taking the supplement.

Off-the-shelf berberine comes as a yellow-orange powder usually encased in a capsule or mixed into tablet form. It’s extracted from the roots, stems, and leaves of various plants, including goldenseal and barberry.

Its use is additionally promoted for insulin resistance, polycystic ovary syndrome, and even cancer, but medical experts are warning potential users that it lacks robust evidence to support its use.

“There’s not that much data on it,” says Reshmi Srinath, MD, director of the Mount Sinai weight and metabolism management program, New York. “It’s sort of shocking now that it’s popped up into the media, to be frank.”

In response to berberine’s online popularity, the National Center for Complementary and Integrative Health issued a warning, stating that “there isn’t enough rigorous scientific evidence to determine whether it is effective.”
 

Overstated claims, lack of scientific research?

Other endocrinologists and weight management experts agree. “The claims are pretty overstated when it comes to the impact on weight loss, based on the evidence in the literature that’s currently available,” says Jaime Almandoz, MD, medical director of the UT Southwestern Medical Center, Dallas, weight wellness program.

A review of 12 randomized controlled trials evaluating berberine’s effects on obesity concluded that the treatment moderately decreased body weight. The trials included were conducted over only a few months and had small numbers of participants, and weight loss was not the primary outcome measure.

“There are few randomized controlled trials,” says Ivania Rizo, MD, an endocrinologist at Boston University. “It appears that they all have some low quality of methods which essentially can lead to an increased risk of bias.”

Another review, of 35 studies – most of them on animals and human cells and similarly underpowered – concluded that berberine showed promise for reducing blood glucose. A separate study found that berberine treatment actually increased the body weight and appetite of rats.

How exactly berberine elicits these effects is not entirely clear. Several studies point to its activation of AMP-activated protein kinase, which improves glucose tolerance in rats, as the mechanism for weight loss. Metformin, a drug used to improve glycemic control in people with type 2 diabetes, works in a similar way. Other researchers have hypothesized a link between berberine and the gut microbiome to explain its effect on type 2 diabetes and weight loss, though the clinical data to substantiate this link are shaky.

“I caution my patients about dietary supplements for weight management because we do not have high-quality data demonstrating efficacy,” Katherine Saunders, MD, DABOM, an obesity expert and cofounder of Intellihealth, a platform for obesity management, said in an email.
 

Experimenting with berberine

Despite the lack of substantial evidence supporting berberine’s use for weight management and obesity, interest in the supplement seems to be increasing. One reason could be that lifestyle interventions aren’t sufficient for most people with obesity to lose a significant amount of weight, with many requiring medical intervention, according to Dr. Saunders.

But access to treatment providers is limited. “As a result, it is not uncommon for individuals with obesity to experiment with dietary supplements like berberine,” she observed.

Dr. Srinath, the Mount Sinai doctor, says many patients have asked for her thoughts on berberine as a weight loss supplement. “I say, you know, it’s something you’re welcome to try, but we don’t have enough data at this time to recommend it.”

The hype surrounding the supplement isn’t all that surprising. About 42% of adults in the United States have obesity, according to 2019-2023 National Health and Nutrition Examination Survey data, pointing to a serious need for accessible drugs to address the condition. Berberine is available over the counter and is far cheaper than most of the newer U.S. Food and Drug Administration–approved drugs for weight loss.

Wegovy, semaglutide approved to treat obesity, can cost as much as $1,300 per package; and Ozempic, semaglutide approved to treat type 2 diabetes, can cost more than $1,000 per month. “That’s a very steep price to pay,” says Dr. Srinath.

Many insurance companies won’t cover the drugs, curbing access to Americans who need them, says Dr. Almandoz. Federally sponsored programs such as Medicare and Medicaid also don’t cover the drugs, which are approved for obesity and weight management. “That’s been a huge hole in our health care system,” says Dr. Srinath. “That’s sort of what’s been driving interest in supplements and things like that.”

Among adults trying to lose weight, only about 3% said they took prescription medication for weight loss, according to a report from the U.S. Government Accountability Office. This report includes 2013-2016 data, predating Wegovy’s approval for chronic weight management.

“These classes are notorious for being quite pricey and not well covered by insurance,” says Dr. Almandoz. “It’s easy to see why someone would promote something that someone may have more access to.”

Comparing Ozempic or Wegovy with berberine can be misleading. Those drugs work by mimicking the effect of the hormone GLP-1 to help reduce appetite.

A clinical trial assessing the efficacy of semaglutide found that adults with obesity who took the drug for 68 weeks lost approximately 15% of their body weight in combination with lifestyle changes. The FDA approval was based on this trial and three others that showed similarly substantial reductions in weight.

The trials also document the many side effects of taking the drugs, primarily gastrointestinal in nature. The short- and long-term effects of berberine, on the other hand, are less clear. Some of the clinical trials reported diarrhea and stomach upset as the most common adverse effects.

Its perception as a naturally derived option for weight loss, though, might encourage people to overlook the potential interactions that berberine could have with other drugs, according to Dr. Almandoz.

He says clinicians considering natural products or nutraceuticals for patients should check for potential side effects and find reliable database sources to determine any potential medication interactions for patients. But the unregulated nature of berberine makes this challenging, Dr. Almandoz adds.

The dosage, formulations, and quality of berberine vary in each study and each product because supplements don’t need to pass through the checks and balances of the FDA to land on shelves.

The lack of regulation could incentivize some companies to add stimulants to enhance any weight loss effect that the supplement may have. Those additives might interact with other health conditions or cause side effects like anxiety, says Dr. Almandoz.

Berberine should also not be taken during pregnancy or while breastfeeding, and it is unsafe for young children; in newborns and children, the supplement can cause higher levels of bilirubin in the blood, worsening any jaundice at birth and posing a greater risk for kernicterus.

Dr. Rizo urges patients, before they ask for berberine, to first ask for safe and effective interventions they can access. “I don’t want to have people not use effective interventions that are currently available to them, and instead use something that needs to be better studied and needs to be better regulated,” she says.

While the “nature’s Ozempic” catchphrase could be drawing in potential users with its dubious comparison, berberine’s escalating popularity might also be a symptom of people seeking a quick fix, the experts worry.

“That’s my fear,” says Dr. Srinath. “ ‘Let me get this medicine, let me lose the weight fast,’ but at the end of the day, weight management is a long-term journey. It takes time, it takes effort, it is not easy, and there is no quick fix.”

This is another concern for doctors; for people who’ve struggled with losing weight for years, not seeing results from berberine could feel like another failure.

“It will give them another opportunity to feel like they are being unsuccessful or that they are failing at weight loss again,” says Dr. Almandoz. “It feeds into the hopelessness that many people with obesity have around their weight management.”

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

Berberine, a plant-derived compound historically used in traditional Chinese medicine, is experiencing increased popularity thanks to social media, especially TikTok, where the hashtag #berberine has more than 75 million views at the time of this writing. Social media influencers are promoting the compound, calling it “nature’s Ozempic,” saying they lost weight taking the supplement.

Off-the-shelf berberine comes as a yellow-orange powder usually encased in a capsule or mixed into tablet form. It’s extracted from the roots, stems, and leaves of various plants, including goldenseal and barberry.

Its use is additionally promoted for insulin resistance, polycystic ovary syndrome, and even cancer, but medical experts are warning potential users that it lacks robust evidence to support its use.

“There’s not that much data on it,” says Reshmi Srinath, MD, director of the Mount Sinai weight and metabolism management program, New York. “It’s sort of shocking now that it’s popped up into the media, to be frank.”

In response to berberine’s online popularity, the National Center for Complementary and Integrative Health issued a warning, stating that “there isn’t enough rigorous scientific evidence to determine whether it is effective.”
 

Overstated claims, lack of scientific research?

Other endocrinologists and weight management experts agree. “The claims are pretty overstated when it comes to the impact on weight loss, based on the evidence in the literature that’s currently available,” says Jaime Almandoz, MD, medical director of the UT Southwestern Medical Center, Dallas, weight wellness program.

A review of 12 randomized controlled trials evaluating berberine’s effects on obesity concluded that the treatment moderately decreased body weight. The trials included were conducted over only a few months and had small numbers of participants, and weight loss was not the primary outcome measure.

“There are few randomized controlled trials,” says Ivania Rizo, MD, an endocrinologist at Boston University. “It appears that they all have some low quality of methods which essentially can lead to an increased risk of bias.”

Another review, of 35 studies – most of them on animals and human cells and similarly underpowered – concluded that berberine showed promise for reducing blood glucose. A separate study found that berberine treatment actually increased the body weight and appetite of rats.

How exactly berberine elicits these effects is not entirely clear. Several studies point to its activation of AMP-activated protein kinase, which improves glucose tolerance in rats, as the mechanism for weight loss. Metformin, a drug used to improve glycemic control in people with type 2 diabetes, works in a similar way. Other researchers have hypothesized a link between berberine and the gut microbiome to explain its effect on type 2 diabetes and weight loss, though the clinical data to substantiate this link are shaky.

“I caution my patients about dietary supplements for weight management because we do not have high-quality data demonstrating efficacy,” Katherine Saunders, MD, DABOM, an obesity expert and cofounder of Intellihealth, a platform for obesity management, said in an email.
 

Experimenting with berberine

Despite the lack of substantial evidence supporting berberine’s use for weight management and obesity, interest in the supplement seems to be increasing. One reason could be that lifestyle interventions aren’t sufficient for most people with obesity to lose a significant amount of weight, with many requiring medical intervention, according to Dr. Saunders.

But access to treatment providers is limited. “As a result, it is not uncommon for individuals with obesity to experiment with dietary supplements like berberine,” she observed.

Dr. Srinath, the Mount Sinai doctor, says many patients have asked for her thoughts on berberine as a weight loss supplement. “I say, you know, it’s something you’re welcome to try, but we don’t have enough data at this time to recommend it.”

The hype surrounding the supplement isn’t all that surprising. About 42% of adults in the United States have obesity, according to 2019-2023 National Health and Nutrition Examination Survey data, pointing to a serious need for accessible drugs to address the condition. Berberine is available over the counter and is far cheaper than most of the newer U.S. Food and Drug Administration–approved drugs for weight loss.

Wegovy, semaglutide approved to treat obesity, can cost as much as $1,300 per package; and Ozempic, semaglutide approved to treat type 2 diabetes, can cost more than $1,000 per month. “That’s a very steep price to pay,” says Dr. Srinath.

Many insurance companies won’t cover the drugs, curbing access to Americans who need them, says Dr. Almandoz. Federally sponsored programs such as Medicare and Medicaid also don’t cover the drugs, which are approved for obesity and weight management. “That’s been a huge hole in our health care system,” says Dr. Srinath. “That’s sort of what’s been driving interest in supplements and things like that.”

Among adults trying to lose weight, only about 3% said they took prescription medication for weight loss, according to a report from the U.S. Government Accountability Office. This report includes 2013-2016 data, predating Wegovy’s approval for chronic weight management.

“These classes are notorious for being quite pricey and not well covered by insurance,” says Dr. Almandoz. “It’s easy to see why someone would promote something that someone may have more access to.”

Comparing Ozempic or Wegovy with berberine can be misleading. Those drugs work by mimicking the effect of the hormone GLP-1 to help reduce appetite.

A clinical trial assessing the efficacy of semaglutide found that adults with obesity who took the drug for 68 weeks lost approximately 15% of their body weight in combination with lifestyle changes. The FDA approval was based on this trial and three others that showed similarly substantial reductions in weight.

The trials also document the many side effects of taking the drugs, primarily gastrointestinal in nature. The short- and long-term effects of berberine, on the other hand, are less clear. Some of the clinical trials reported diarrhea and stomach upset as the most common adverse effects.

Its perception as a naturally derived option for weight loss, though, might encourage people to overlook the potential interactions that berberine could have with other drugs, according to Dr. Almandoz.

He says clinicians considering natural products or nutraceuticals for patients should check for potential side effects and find reliable database sources to determine any potential medication interactions for patients. But the unregulated nature of berberine makes this challenging, Dr. Almandoz adds.

The dosage, formulations, and quality of berberine vary in each study and each product because supplements don’t need to pass through the checks and balances of the FDA to land on shelves.

The lack of regulation could incentivize some companies to add stimulants to enhance any weight loss effect that the supplement may have. Those additives might interact with other health conditions or cause side effects like anxiety, says Dr. Almandoz.

Berberine should also not be taken during pregnancy or while breastfeeding, and it is unsafe for young children; in newborns and children, the supplement can cause higher levels of bilirubin in the blood, worsening any jaundice at birth and posing a greater risk for kernicterus.

Dr. Rizo urges patients, before they ask for berberine, to first ask for safe and effective interventions they can access. “I don’t want to have people not use effective interventions that are currently available to them, and instead use something that needs to be better studied and needs to be better regulated,” she says.

While the “nature’s Ozempic” catchphrase could be drawing in potential users with its dubious comparison, berberine’s escalating popularity might also be a symptom of people seeking a quick fix, the experts worry.

“That’s my fear,” says Dr. Srinath. “ ‘Let me get this medicine, let me lose the weight fast,’ but at the end of the day, weight management is a long-term journey. It takes time, it takes effort, it is not easy, and there is no quick fix.”

This is another concern for doctors; for people who’ve struggled with losing weight for years, not seeing results from berberine could feel like another failure.

“It will give them another opportunity to feel like they are being unsuccessful or that they are failing at weight loss again,” says Dr. Almandoz. “It feeds into the hopelessness that many people with obesity have around their weight management.”

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