Obesity

Legislators in New York City recently approved a bill specifically prohibiting weight- and height-based discrimination, on par with existing protections for gender, race, sexual orientation, and other personal identities. Other U.S. cities, as well as New York state, are considering similar moves.

Weight-based discrimination in the United States has increased by an estimated 66% over the past decade, putting it on par with the prevalence of racial discrimination. More than 40% of adult Americans and 18% of children report experiencing weight discrimination in employment, school, and/or health care settings – as well as within interpersonal relationships – demonstrating a clear need to have legal protections in place.

For obesity advocates in Canada, the news from New York triggered a moment of reflection to consider how our own advocacy efforts have fared over the years, or not. Just like in the United States, body size and obesity (and appearance in general) are not specifically protected grounds under human rights legislation in Canada (for example, the Canadian Human Rights Act), unlike race, gender, sexual orientation, and religion.

Case law is uneven across the Canadian provinces when it comes to determining whether obesity is even a disease and/or a disability. And despite broad support for anti–weight discrimination policies in Canada (Front Public Health. 2023 Apr 17;11:1060794; Milbank Q. 2015 Dec;93[4]:691-731), years of advocacy at the national and provincial levels have not led to any legislative changes (Ramos Salas Obes Rev. 2017 Nov;18[11]:1323-35; Can J Diabetes. 2015 Apr. doi: 10.1016/j.jcjd.2015.01.009). A 2017 private members bill seeking to add protection for body size to Manitoba’s human rights code was defeated, with many members of the legislature citing enforcement difficulties as the reason for voting down the proposition.

Some obesity advocates have argued that people living with obesity can be protected under the grounds of disability in the Canadian Human Rights Act. To be protected, however, individuals must demonstrate that there is actual or perceived disability relating to their weight or size; yet, many people living with obesity and those who have a higher weight don’t perceive themselves as having a disability.

In our view, the disparate viewpoints on the worthiness of considering body size a human rights issue could be resolved, at least partially, by wider understanding and adoption of the relatively new clinical definition of obesity. This definition holds that obesity is not about size; an obesity diagnosis can be made only when objective clinical investigations identify that excess or abnormal adiposity (fat tissue) impairs health.

While obesity advocates use the clinical definition of obesity, weight and body size proponents disagree that obesity is a chronic disease, and in fact believe that treating it as such can be stigmatizing. In a sense, this can sometimes be true, as not all people with larger bodies have obesity per the new definition but risk being identified as “unhealthy” in the clinical world. Bias, it turns out, can be a two-way street.

Regardless of the advocacy strategy used, it’s clear that specific anti–weight discrimination laws are needed in Canada. One in four Canadian adults report experiencing discrimination in their day-to-day life, with race, gender, age, and weight being the most commonly reported forms. To refuse to protect them against some, but not all, forms of discrimination is itself unjust, and is surely rooted in the age-old misinformed concept that excess weight is the result of laziness, poor food choices, and lack of physical activity, among other moral failings.

Including body size in human rights codes may provide a mechanism to seek legal remedy from discriminatory acts, but it will do little to address rampant weight bias, in the same way that race-based legal protections don’t eradicate racism. And it’s not just the legal community that fails to understand that weight is, by and large, a product of our environment and our genes. Weight bias and stigma are well documented in media, workplaces, the home, and in health care systems.

The solution, in our minds, is meaningful education across all these domains, reinforcing that weight is not a behavior, just as health is not a size. If we truly understand and embrace these concepts, then as a society we may someday recognize that body size is not a choice, just like race, sexual orientation, gender identity, and other individual characteristics. And if it’s not a choice, if it’s not a behavior, then it deserves the same protections.

At the same time, people with obesity deserve to seek evidence-based treatment, just as those at higher weights who experience no weight or adiposity-related health issues deserve not to be identified as having a disease simply because of their size.

If we all follow the science, we might yet turn a common understanding into more equitable outcomes for all.

Dr. Ramos Salas and Mr. Hussey are research consultants for Replica Communications, Hamilton, Ont. She disclosed ties with the Canadian Institutes of Health Research, European Association for the Study of Obesity, Novo Nordisk, Obesity Canada, The Obesity Society, World Obesity, and the World Health Organization. Mr. Hussey disclosed ties with the European Association for the Study of Obesity, Novo Nordisk, Obesity Canada, and the World Health Organization (Nutrition and Food Safety).

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

Legislators in New York City recently approved a bill specifically prohibiting weight- and height-based discrimination, on par with existing protections for gender, race, sexual orientation, and other personal identities. Other U.S. cities, as well as New York state, are considering similar moves.

Weight-based discrimination in the United States has increased by an estimated 66% over the past decade, putting it on par with the prevalence of racial discrimination. More than 40% of adult Americans and 18% of children report experiencing weight discrimination in employment, school, and/or health care settings – as well as within interpersonal relationships – demonstrating a clear need to have legal protections in place.

For obesity advocates in Canada, the news from New York triggered a moment of reflection to consider how our own advocacy efforts have fared over the years, or not. Just like in the United States, body size and obesity (and appearance in general) are not specifically protected grounds under human rights legislation in Canada (for example, the Canadian Human Rights Act), unlike race, gender, sexual orientation, and religion.

Case law is uneven across the Canadian provinces when it comes to determining whether obesity is even a disease and/or a disability. And despite broad support for anti–weight discrimination policies in Canada (Front Public Health. 2023 Apr 17;11:1060794; Milbank Q. 2015 Dec;93[4]:691-731), years of advocacy at the national and provincial levels have not led to any legislative changes (Ramos Salas Obes Rev. 2017 Nov;18[11]:1323-35; Can J Diabetes. 2015 Apr. doi: 10.1016/j.jcjd.2015.01.009). A 2017 private members bill seeking to add protection for body size to Manitoba’s human rights code was defeated, with many members of the legislature citing enforcement difficulties as the reason for voting down the proposition.

Some obesity advocates have argued that people living with obesity can be protected under the grounds of disability in the Canadian Human Rights Act. To be protected, however, individuals must demonstrate that there is actual or perceived disability relating to their weight or size; yet, many people living with obesity and those who have a higher weight don’t perceive themselves as having a disability.

In our view, the disparate viewpoints on the worthiness of considering body size a human rights issue could be resolved, at least partially, by wider understanding and adoption of the relatively new clinical definition of obesity. This definition holds that obesity is not about size; an obesity diagnosis can be made only when objective clinical investigations identify that excess or abnormal adiposity (fat tissue) impairs health.

While obesity advocates use the clinical definition of obesity, weight and body size proponents disagree that obesity is a chronic disease, and in fact believe that treating it as such can be stigmatizing. In a sense, this can sometimes be true, as not all people with larger bodies have obesity per the new definition but risk being identified as “unhealthy” in the clinical world. Bias, it turns out, can be a two-way street.

Regardless of the advocacy strategy used, it’s clear that specific anti–weight discrimination laws are needed in Canada. One in four Canadian adults report experiencing discrimination in their day-to-day life, with race, gender, age, and weight being the most commonly reported forms. To refuse to protect them against some, but not all, forms of discrimination is itself unjust, and is surely rooted in the age-old misinformed concept that excess weight is the result of laziness, poor food choices, and lack of physical activity, among other moral failings.

Including body size in human rights codes may provide a mechanism to seek legal remedy from discriminatory acts, but it will do little to address rampant weight bias, in the same way that race-based legal protections don’t eradicate racism. And it’s not just the legal community that fails to understand that weight is, by and large, a product of our environment and our genes. Weight bias and stigma are well documented in media, workplaces, the home, and in health care systems.

The solution, in our minds, is meaningful education across all these domains, reinforcing that weight is not a behavior, just as health is not a size. If we truly understand and embrace these concepts, then as a society we may someday recognize that body size is not a choice, just like race, sexual orientation, gender identity, and other individual characteristics. And if it’s not a choice, if it’s not a behavior, then it deserves the same protections.

At the same time, people with obesity deserve to seek evidence-based treatment, just as those at higher weights who experience no weight or adiposity-related health issues deserve not to be identified as having a disease simply because of their size.

If we all follow the science, we might yet turn a common understanding into more equitable outcomes for all.

Dr. Ramos Salas and Mr. Hussey are research consultants for Replica Communications, Hamilton, Ont. She disclosed ties with the Canadian Institutes of Health Research, European Association for the Study of Obesity, Novo Nordisk, Obesity Canada, The Obesity Society, World Obesity, and the World Health Organization. Mr. Hussey disclosed ties with the European Association for the Study of Obesity, Novo Nordisk, Obesity Canada, and the World Health Organization (Nutrition and Food Safety).

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

Legislators in New York City recently approved a bill specifically prohibiting weight- and height-based discrimination, on par with existing protections for gender, race, sexual orientation, and other personal identities. Other U.S. cities, as well as New York state, are considering similar moves.

Weight-based discrimination in the United States has increased by an estimated 66% over the past decade, putting it on par with the prevalence of racial discrimination. More than 40% of adult Americans and 18% of children report experiencing weight discrimination in employment, school, and/or health care settings – as well as within interpersonal relationships – demonstrating a clear need to have legal protections in place.

For obesity advocates in Canada, the news from New York triggered a moment of reflection to consider how our own advocacy efforts have fared over the years, or not. Just like in the United States, body size and obesity (and appearance in general) are not specifically protected grounds under human rights legislation in Canada (for example, the Canadian Human Rights Act), unlike race, gender, sexual orientation, and religion.

Case law is uneven across the Canadian provinces when it comes to determining whether obesity is even a disease and/or a disability. And despite broad support for anti–weight discrimination policies in Canada (Front Public Health. 2023 Apr 17;11:1060794; Milbank Q. 2015 Dec;93[4]:691-731), years of advocacy at the national and provincial levels have not led to any legislative changes (Ramos Salas Obes Rev. 2017 Nov;18[11]:1323-35; Can J Diabetes. 2015 Apr. doi: 10.1016/j.jcjd.2015.01.009). A 2017 private members bill seeking to add protection for body size to Manitoba’s human rights code was defeated, with many members of the legislature citing enforcement difficulties as the reason for voting down the proposition.

Some obesity advocates have argued that people living with obesity can be protected under the grounds of disability in the Canadian Human Rights Act. To be protected, however, individuals must demonstrate that there is actual or perceived disability relating to their weight or size; yet, many people living with obesity and those who have a higher weight don’t perceive themselves as having a disability.

In our view, the disparate viewpoints on the worthiness of considering body size a human rights issue could be resolved, at least partially, by wider understanding and adoption of the relatively new clinical definition of obesity. This definition holds that obesity is not about size; an obesity diagnosis can be made only when objective clinical investigations identify that excess or abnormal adiposity (fat tissue) impairs health.

While obesity advocates use the clinical definition of obesity, weight and body size proponents disagree that obesity is a chronic disease, and in fact believe that treating it as such can be stigmatizing. In a sense, this can sometimes be true, as not all people with larger bodies have obesity per the new definition but risk being identified as “unhealthy” in the clinical world. Bias, it turns out, can be a two-way street.

Regardless of the advocacy strategy used, it’s clear that specific anti–weight discrimination laws are needed in Canada. One in four Canadian adults report experiencing discrimination in their day-to-day life, with race, gender, age, and weight being the most commonly reported forms. To refuse to protect them against some, but not all, forms of discrimination is itself unjust, and is surely rooted in the age-old misinformed concept that excess weight is the result of laziness, poor food choices, and lack of physical activity, among other moral failings.

Including body size in human rights codes may provide a mechanism to seek legal remedy from discriminatory acts, but it will do little to address rampant weight bias, in the same way that race-based legal protections don’t eradicate racism. And it’s not just the legal community that fails to understand that weight is, by and large, a product of our environment and our genes. Weight bias and stigma are well documented in media, workplaces, the home, and in health care systems.

The solution, in our minds, is meaningful education across all these domains, reinforcing that weight is not a behavior, just as health is not a size. If we truly understand and embrace these concepts, then as a society we may someday recognize that body size is not a choice, just like race, sexual orientation, gender identity, and other individual characteristics. And if it’s not a choice, if it’s not a behavior, then it deserves the same protections.

At the same time, people with obesity deserve to seek evidence-based treatment, just as those at higher weights who experience no weight or adiposity-related health issues deserve not to be identified as having a disease simply because of their size.

If we all follow the science, we might yet turn a common understanding into more equitable outcomes for all.

Dr. Ramos Salas and Mr. Hussey are research consultants for Replica Communications, Hamilton, Ont. She disclosed ties with the Canadian Institutes of Health Research, European Association for the Study of Obesity, Novo Nordisk, Obesity Canada, The Obesity Society, World Obesity, and the World Health Organization. Mr. Hussey disclosed ties with the European Association for the Study of Obesity, Novo Nordisk, Obesity Canada, and the World Health Organization (Nutrition and Food Safety).

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

This is the second in a three-part series on the obesity crisis. Part one tackles a complicated question – why does the obesity rate keep rising despite our efforts to stop it? – and can be found here. Part three shows how doctors and patients can make treatment better and can be found here. 

In the mid-1980s, Louis J. Aronne, MD, strolled into a lab at Rockefeller University in New York where a colleague was breeding mice. “I will never forget what he showed me,” said Dr. Aronne, now the director of obesity research and treatment at Weill Cornell Medicine in New York. “He had a cage with 10 mice, one severely obese and the others normal weight. He took blood from one of the thin mice and gave it to the fat mouse.”
 

When Dr. Aronne returned 3 days later, that obese mouse had turned thin. 

It was proof of something Dr. Aronne already suspected: Obesity had biological causes and wasn’t just a failure of willpower.

Years later, in 1994, that research led to the discovery of leptin, a hormone released from fat cells that’s involved in the regulation of body weight. It was a watershed moment in obesity research. 

Since then, Dr. Aronne and others have worked to build the clinical field of obesity medicine, attempting to shift the public and medical view of obesity from a purely behavioral issue to a disease worthy of medical treatment. 

All the while, the U.S. obesity rate soared. 

Now, another watershed moment: We finally have highly effective obesity drugs. The hype is real, and so are the weight loss results. 

“I’ve been saying for 30 years that when we find treatments that really work, people aren’t going to believe the results,” Dr. Aronne said. “It took longer than I expected, but it’s gratifying now to see.”

All this excitement raises a crucial question: Will the new drugs finally end the obesity crisis? Experts have their doubts.
 

The big question

The emerging class of obesity medications known as GLP-1 agonists is indeed a game changer. The weight loss drug semaglutide (Ozempic, Wegovy) showed groundbreaking results, and studies suggest a parade of even more impressive drugs is on the way.

Yes, the drugs offer new hope to millions with obesity complications. But to truly turn the tide on our 42% obesity rate, much more work remains to be done, researchers said, including answering a big question:

How do these weight loss drugs work? 

“We have new blockbuster drugs, and we don’t even know why they reduce body weight,” said Samuel Klein, MD, professor of medicine and nutritional science at Washington University in St. Louis. “It was by accident that this was discovered.”
 

Oops, we created a weight loss drug

Developed to treat diabetes, the GLP-1 drugs’ weight loss effects were a surprise. Now that those effects are confirmed, pharmaceutical companies and researchers are racing to figure out how these drugs work. 

In the 1960s, scientists discovered the incretin effect – when you eat glucose (sugar), your body makes more insulin than it does if glucose is given intravenously. Glucose passes through the GI tract and the gut releases hormones that stimulate insulin secretion. It’s “essentially a feed-forward signal to your pancreas to tell it, ‘By the way, you need to be ready because there’s a bunch of glucose coming,’ ” said Randy Seeley, MD, director of the Michigan Nutrition Obesity Research Center, funded by the National Institutes of Health. 

One of these hormones – or “incretins” – is GLP-1. In experiments, people with type 2 diabetes who were hooked up to GLP-1 saw their blood sugar go down. 

“That led to the idea that if we could take this native hormone and make it last longer, we’d have a therapy for type 2 diabetes,” said Dr. Seeley. Thanks to a GLP-1-like compound in the saliva of the Gila monster, that idea became reality in the 2000s. 

Along the way, a surprising side finding came to light: In early trials, diabetes patients on these drugs dropped weight. 

Both Ozempic and Wegovy – brand names for semaglutide – are once-weekly injections (pill forms to treat obesity are on the way), but the latter is a higher dose. 

“That dose results in about 40% of patients in the clinical trials achieving a 20% weight loss. We’ve just had nothing like that in terms of efficacy before,” said Dr. Seeley, who has worked with some of the drug companies (including Novo Nordisk, the maker of Ozempic and Wegovy, and Eli Lilly, maker of Mounjaro) that market the GLP-1s. 

By contrast, semaglutide’s once-a-day predecessor liraglutide (Saxenda, made by Novo Nordisk) can lead to about 10% weight loss. 

“And one of the ironies is, we don’t really know why,” Dr. Seeley said. “We don’t know why semaglutide is a better molecule for weight loss than liraglutide.” 

Initially, scientists believed that the drugs, in addition to telling the pancreas to secrete more insulin, were also signaling the brain that you’re full. “Turns out that’s not really the way it works,” Dr. Seeley said. “GLP-1 made from your gut probably doesn’t get into your brain very much. But you make GLP-1 in your brain as well.”

For weight loss, it’s the brain’s GLP-1 system, not the gut’s, that the drugs are thought to hijack. But exactly which parts of the brain they affect and how is unknown. “That’s something lots of people are working on, including our own lab,” Dr. Seeley said. (Another surprise: The drugs may have potential as an anti-addiction treatment.)

The diabetes medication tirzepatide (Mounjaro), expected to be approved for weight loss as early as this year, is also a weekly injection, but it has a unique feature: It starts a response not just for GLP-1 but also for another incretin called GIP. Turns out, two is better than one: Trial participants on tirzepatide lost up to 22.5% of their body weight. 

More of these hybrid drugs are on the way, Dr. Seeley said. In mid-stage clinical trials, the drug retatrutide, which targets three hormones, led to 24% weight loss. “The idea is the more bullets we can load into the gun, the more we can push the biology into a place where it’s easier to lose weight.”
 

Shifting from prevention to damage control

Less invasive and more scalable than surgery (only 1% of the eligible population gets bariatric surgery), the drugs offer doctors a safe, effective way to treat many patients with obesity. That’s cause for excitement, but concerns remain because they are expensive, costing about $800 to $1,300 per month out of pocket. Many health insurers, including Medicare, do not cover them for weight loss. 

“You have this significant advance in obesity treatment, but very few will be able to access it,” said Gary Foster, PhD, adjunct professor of psychology in psychiatry at the University of Pennsylvania, Philadelphia, and chief scientific officer at WW (formerly Weight Watchers).

There is a push, including a proposed bill, to get Medicare to cover obesity medication. But given the expense of the drugs, the health economics do not support that move, according to an editorial in the New England Journal of Medicine. If Medicare were to cover obesity meds, the budget impact would likely be huge, potentially driving up premiums. If other payers followed suit, the impact could be felt across the U.S. health care system. 

Other drawbacks include side effects – including nausea, diarrhea, stomach pain, and vomiting – that can be so bad that some patients can’t tolerate them.

And critically, the drugs do not deal with the root cause of the problem, said Robert Lustig, MD, an endocrinologist and pediatrician at the University of California, San Francisco, who has suggested that excess insulin is driving obesity. “No one has the disease that these drugs are treating. No one has GLP-1 deficiency. They’re bypassing the problem. They’re band-aiding the problem.” 

Because the drugs work by mimicking starvation – they appear to curb hunger, so you eat less – people on them lose not just fat but also healthy lean mass, Dr. Lustig said. 

Concerns about pancreatitis did not really bear out in postmarketing reports. (The drugs are still not recommended in people with pancreatitis or multiple endocrine neoplasia.) But predicting longer-term outcomes can be difficult, noted Dr. Lustig.

Then there are philosophical questions, said James Hill, PhD, director of the Nutrition Obesity Research Center at the University of Alabama at Birmingham.. “If you’re continuing to not exercise and eat not healthy foods and take a medication, is that success? Have we won when people are at a lower weight but not doing a healthy behavior?”

‘We can’t treat our way out of this’

The fact is, ending the obesity epidemic is a tall order, even for drugs as impressive as these. 

“We can’t treat our way out of this,” said Jamy Ard, MD, codirector of Wake Forest Baptist Health Weight Management Center in Winston-Salem, N.C. “The treatments we have now are great, and there will be more coming. But we do need to figure out the prevention side of things.” 

Dr. Seeley agreed but added that we can’t diet-and-exercise our way out either. 

“There’s no switch to be flipped,” Dr. Seeley said. “If you told me we shouldn’t spend all this money on these drugs, we should spend it on prevention – great! What would we do?” 

And prevention efforts won’t help the millions already living with health problems from obesity, Dr. Aronne said. 

“Getting people to stop smoking prevents lung cancer. But stopping smoking doesn’t treat lung cancer,” Dr. Aronne said. “Once the physical changes occur in the lung that cause a tumor to grow, it’s too late. You have to think of obesity the same way.” 

Dr. Seeley pointed out that “fearmongering” around the drugs highlights our lingering bias that obesity is a lifestyle issue that should not be medically treated. 

“People say, ‘When you stop taking it, you’re going to gain the weight back,’ ” Dr. Seeley said. “There’s truth to that, but when you stop taking your hypertension medication, your blood pressure goes up. We don’t think of that as a [reason] for why you shouldn’t take your blood pressure medication. But that gets trumpeted into all these conversations about whether people [with obesity] should be treated at all.”

Like obesity, blood pressure was once thought to be a behavioral problem, Dr. Aronne said. But blood pressure meds prevent heart attacks and strokes. And it’s likely obesity meds will do the same. 

One 55-year-old patient on the road to kidney failure lost weight on obesity medications, including semaglutide, Dr. Aronne said. Now, 6 years later, his kidney function is back to normal. “Normally, we think of kidney disease as irreversible,” Dr. Aronne said. 

In that respect, these drugs should save money in the long run by virtue of heading off those health care costs, said Dr. Seeley, who imagines a future where obesity is not gone but better managed, like high blood pressure is now. 

In the end, the drugs are another step toward what Dr. Aronne and many others have always pushed for: Treating obesity as a disease. 
 

A version of this article originally appeared on WebMD.com.

This is the second in a three-part series on the obesity crisis. Part one tackles a complicated question – why does the obesity rate keep rising despite our efforts to stop it? – and can be found here. Part three shows how doctors and patients can make treatment better and can be found here. 

In the mid-1980s, Louis J. Aronne, MD, strolled into a lab at Rockefeller University in New York where a colleague was breeding mice. “I will never forget what he showed me,” said Dr. Aronne, now the director of obesity research and treatment at Weill Cornell Medicine in New York. “He had a cage with 10 mice, one severely obese and the others normal weight. He took blood from one of the thin mice and gave it to the fat mouse.”
 

When Dr. Aronne returned 3 days later, that obese mouse had turned thin. 

It was proof of something Dr. Aronne already suspected: Obesity had biological causes and wasn’t just a failure of willpower.

Years later, in 1994, that research led to the discovery of leptin, a hormone released from fat cells that’s involved in the regulation of body weight. It was a watershed moment in obesity research. 

Since then, Dr. Aronne and others have worked to build the clinical field of obesity medicine, attempting to shift the public and medical view of obesity from a purely behavioral issue to a disease worthy of medical treatment. 

All the while, the U.S. obesity rate soared. 

Now, another watershed moment: We finally have highly effective obesity drugs. The hype is real, and so are the weight loss results. 

“I’ve been saying for 30 years that when we find treatments that really work, people aren’t going to believe the results,” Dr. Aronne said. “It took longer than I expected, but it’s gratifying now to see.”

All this excitement raises a crucial question: Will the new drugs finally end the obesity crisis? Experts have their doubts.
 

The big question

The emerging class of obesity medications known as GLP-1 agonists is indeed a game changer. The weight loss drug semaglutide (Ozempic, Wegovy) showed groundbreaking results, and studies suggest a parade of even more impressive drugs is on the way.

Yes, the drugs offer new hope to millions with obesity complications. But to truly turn the tide on our 42% obesity rate, much more work remains to be done, researchers said, including answering a big question:

How do these weight loss drugs work? 

“We have new blockbuster drugs, and we don’t even know why they reduce body weight,” said Samuel Klein, MD, professor of medicine and nutritional science at Washington University in St. Louis. “It was by accident that this was discovered.”
 

Oops, we created a weight loss drug

Developed to treat diabetes, the GLP-1 drugs’ weight loss effects were a surprise. Now that those effects are confirmed, pharmaceutical companies and researchers are racing to figure out how these drugs work. 

In the 1960s, scientists discovered the incretin effect – when you eat glucose (sugar), your body makes more insulin than it does if glucose is given intravenously. Glucose passes through the GI tract and the gut releases hormones that stimulate insulin secretion. It’s “essentially a feed-forward signal to your pancreas to tell it, ‘By the way, you need to be ready because there’s a bunch of glucose coming,’ ” said Randy Seeley, MD, director of the Michigan Nutrition Obesity Research Center, funded by the National Institutes of Health. 

One of these hormones – or “incretins” – is GLP-1. In experiments, people with type 2 diabetes who were hooked up to GLP-1 saw their blood sugar go down. 

“That led to the idea that if we could take this native hormone and make it last longer, we’d have a therapy for type 2 diabetes,” said Dr. Seeley. Thanks to a GLP-1-like compound in the saliva of the Gila monster, that idea became reality in the 2000s. 

Along the way, a surprising side finding came to light: In early trials, diabetes patients on these drugs dropped weight. 

Both Ozempic and Wegovy – brand names for semaglutide – are once-weekly injections (pill forms to treat obesity are on the way), but the latter is a higher dose. 

“That dose results in about 40% of patients in the clinical trials achieving a 20% weight loss. We’ve just had nothing like that in terms of efficacy before,” said Dr. Seeley, who has worked with some of the drug companies (including Novo Nordisk, the maker of Ozempic and Wegovy, and Eli Lilly, maker of Mounjaro) that market the GLP-1s. 

By contrast, semaglutide’s once-a-day predecessor liraglutide (Saxenda, made by Novo Nordisk) can lead to about 10% weight loss. 

“And one of the ironies is, we don’t really know why,” Dr. Seeley said. “We don’t know why semaglutide is a better molecule for weight loss than liraglutide.” 

Initially, scientists believed that the drugs, in addition to telling the pancreas to secrete more insulin, were also signaling the brain that you’re full. “Turns out that’s not really the way it works,” Dr. Seeley said. “GLP-1 made from your gut probably doesn’t get into your brain very much. But you make GLP-1 in your brain as well.”

For weight loss, it’s the brain’s GLP-1 system, not the gut’s, that the drugs are thought to hijack. But exactly which parts of the brain they affect and how is unknown. “That’s something lots of people are working on, including our own lab,” Dr. Seeley said. (Another surprise: The drugs may have potential as an anti-addiction treatment.)

The diabetes medication tirzepatide (Mounjaro), expected to be approved for weight loss as early as this year, is also a weekly injection, but it has a unique feature: It starts a response not just for GLP-1 but also for another incretin called GIP. Turns out, two is better than one: Trial participants on tirzepatide lost up to 22.5% of their body weight. 

More of these hybrid drugs are on the way, Dr. Seeley said. In mid-stage clinical trials, the drug retatrutide, which targets three hormones, led to 24% weight loss. “The idea is the more bullets we can load into the gun, the more we can push the biology into a place where it’s easier to lose weight.”
 

Shifting from prevention to damage control

Less invasive and more scalable than surgery (only 1% of the eligible population gets bariatric surgery), the drugs offer doctors a safe, effective way to treat many patients with obesity. That’s cause for excitement, but concerns remain because they are expensive, costing about $800 to $1,300 per month out of pocket. Many health insurers, including Medicare, do not cover them for weight loss. 

“You have this significant advance in obesity treatment, but very few will be able to access it,” said Gary Foster, PhD, adjunct professor of psychology in psychiatry at the University of Pennsylvania, Philadelphia, and chief scientific officer at WW (formerly Weight Watchers).

There is a push, including a proposed bill, to get Medicare to cover obesity medication. But given the expense of the drugs, the health economics do not support that move, according to an editorial in the New England Journal of Medicine. If Medicare were to cover obesity meds, the budget impact would likely be huge, potentially driving up premiums. If other payers followed suit, the impact could be felt across the U.S. health care system. 

Other drawbacks include side effects – including nausea, diarrhea, stomach pain, and vomiting – that can be so bad that some patients can’t tolerate them.

And critically, the drugs do not deal with the root cause of the problem, said Robert Lustig, MD, an endocrinologist and pediatrician at the University of California, San Francisco, who has suggested that excess insulin is driving obesity. “No one has the disease that these drugs are treating. No one has GLP-1 deficiency. They’re bypassing the problem. They’re band-aiding the problem.” 

Because the drugs work by mimicking starvation – they appear to curb hunger, so you eat less – people on them lose not just fat but also healthy lean mass, Dr. Lustig said. 

Concerns about pancreatitis did not really bear out in postmarketing reports. (The drugs are still not recommended in people with pancreatitis or multiple endocrine neoplasia.) But predicting longer-term outcomes can be difficult, noted Dr. Lustig.

Then there are philosophical questions, said James Hill, PhD, director of the Nutrition Obesity Research Center at the University of Alabama at Birmingham.. “If you’re continuing to not exercise and eat not healthy foods and take a medication, is that success? Have we won when people are at a lower weight but not doing a healthy behavior?”

‘We can’t treat our way out of this’

The fact is, ending the obesity epidemic is a tall order, even for drugs as impressive as these. 

“We can’t treat our way out of this,” said Jamy Ard, MD, codirector of Wake Forest Baptist Health Weight Management Center in Winston-Salem, N.C. “The treatments we have now are great, and there will be more coming. But we do need to figure out the prevention side of things.” 

Dr. Seeley agreed but added that we can’t diet-and-exercise our way out either. 

“There’s no switch to be flipped,” Dr. Seeley said. “If you told me we shouldn’t spend all this money on these drugs, we should spend it on prevention – great! What would we do?” 

And prevention efforts won’t help the millions already living with health problems from obesity, Dr. Aronne said. 

“Getting people to stop smoking prevents lung cancer. But stopping smoking doesn’t treat lung cancer,” Dr. Aronne said. “Once the physical changes occur in the lung that cause a tumor to grow, it’s too late. You have to think of obesity the same way.” 

Dr. Seeley pointed out that “fearmongering” around the drugs highlights our lingering bias that obesity is a lifestyle issue that should not be medically treated. 

“People say, ‘When you stop taking it, you’re going to gain the weight back,’ ” Dr. Seeley said. “There’s truth to that, but when you stop taking your hypertension medication, your blood pressure goes up. We don’t think of that as a [reason] for why you shouldn’t take your blood pressure medication. But that gets trumpeted into all these conversations about whether people [with obesity] should be treated at all.”

Like obesity, blood pressure was once thought to be a behavioral problem, Dr. Aronne said. But blood pressure meds prevent heart attacks and strokes. And it’s likely obesity meds will do the same. 

One 55-year-old patient on the road to kidney failure lost weight on obesity medications, including semaglutide, Dr. Aronne said. Now, 6 years later, his kidney function is back to normal. “Normally, we think of kidney disease as irreversible,” Dr. Aronne said. 

In that respect, these drugs should save money in the long run by virtue of heading off those health care costs, said Dr. Seeley, who imagines a future where obesity is not gone but better managed, like high blood pressure is now. 

In the end, the drugs are another step toward what Dr. Aronne and many others have always pushed for: Treating obesity as a disease. 
 

A version of this article originally appeared on WebMD.com.

This is the second in a three-part series on the obesity crisis. Part one tackles a complicated question – why does the obesity rate keep rising despite our efforts to stop it? – and can be found here. Part three shows how doctors and patients can make treatment better and can be found here. 

In the mid-1980s, Louis J. Aronne, MD, strolled into a lab at Rockefeller University in New York where a colleague was breeding mice. “I will never forget what he showed me,” said Dr. Aronne, now the director of obesity research and treatment at Weill Cornell Medicine in New York. “He had a cage with 10 mice, one severely obese and the others normal weight. He took blood from one of the thin mice and gave it to the fat mouse.”
 

When Dr. Aronne returned 3 days later, that obese mouse had turned thin. 

It was proof of something Dr. Aronne already suspected: Obesity had biological causes and wasn’t just a failure of willpower.

Years later, in 1994, that research led to the discovery of leptin, a hormone released from fat cells that’s involved in the regulation of body weight. It was a watershed moment in obesity research. 

Since then, Dr. Aronne and others have worked to build the clinical field of obesity medicine, attempting to shift the public and medical view of obesity from a purely behavioral issue to a disease worthy of medical treatment. 

All the while, the U.S. obesity rate soared. 

Now, another watershed moment: We finally have highly effective obesity drugs. The hype is real, and so are the weight loss results. 

“I’ve been saying for 30 years that when we find treatments that really work, people aren’t going to believe the results,” Dr. Aronne said. “It took longer than I expected, but it’s gratifying now to see.”

All this excitement raises a crucial question: Will the new drugs finally end the obesity crisis? Experts have their doubts.
 

The big question

The emerging class of obesity medications known as GLP-1 agonists is indeed a game changer. The weight loss drug semaglutide (Ozempic, Wegovy) showed groundbreaking results, and studies suggest a parade of even more impressive drugs is on the way.

Yes, the drugs offer new hope to millions with obesity complications. But to truly turn the tide on our 42% obesity rate, much more work remains to be done, researchers said, including answering a big question:

How do these weight loss drugs work? 

“We have new blockbuster drugs, and we don’t even know why they reduce body weight,” said Samuel Klein, MD, professor of medicine and nutritional science at Washington University in St. Louis. “It was by accident that this was discovered.”
 

Oops, we created a weight loss drug

Developed to treat diabetes, the GLP-1 drugs’ weight loss effects were a surprise. Now that those effects are confirmed, pharmaceutical companies and researchers are racing to figure out how these drugs work. 

In the 1960s, scientists discovered the incretin effect – when you eat glucose (sugar), your body makes more insulin than it does if glucose is given intravenously. Glucose passes through the GI tract and the gut releases hormones that stimulate insulin secretion. It’s “essentially a feed-forward signal to your pancreas to tell it, ‘By the way, you need to be ready because there’s a bunch of glucose coming,’ ” said Randy Seeley, MD, director of the Michigan Nutrition Obesity Research Center, funded by the National Institutes of Health. 

One of these hormones – or “incretins” – is GLP-1. In experiments, people with type 2 diabetes who were hooked up to GLP-1 saw their blood sugar go down. 

“That led to the idea that if we could take this native hormone and make it last longer, we’d have a therapy for type 2 diabetes,” said Dr. Seeley. Thanks to a GLP-1-like compound in the saliva of the Gila monster, that idea became reality in the 2000s. 

Along the way, a surprising side finding came to light: In early trials, diabetes patients on these drugs dropped weight. 

Both Ozempic and Wegovy – brand names for semaglutide – are once-weekly injections (pill forms to treat obesity are on the way), but the latter is a higher dose. 

“That dose results in about 40% of patients in the clinical trials achieving a 20% weight loss. We’ve just had nothing like that in terms of efficacy before,” said Dr. Seeley, who has worked with some of the drug companies (including Novo Nordisk, the maker of Ozempic and Wegovy, and Eli Lilly, maker of Mounjaro) that market the GLP-1s. 

By contrast, semaglutide’s once-a-day predecessor liraglutide (Saxenda, made by Novo Nordisk) can lead to about 10% weight loss. 

“And one of the ironies is, we don’t really know why,” Dr. Seeley said. “We don’t know why semaglutide is a better molecule for weight loss than liraglutide.” 

Initially, scientists believed that the drugs, in addition to telling the pancreas to secrete more insulin, were also signaling the brain that you’re full. “Turns out that’s not really the way it works,” Dr. Seeley said. “GLP-1 made from your gut probably doesn’t get into your brain very much. But you make GLP-1 in your brain as well.”

For weight loss, it’s the brain’s GLP-1 system, not the gut’s, that the drugs are thought to hijack. But exactly which parts of the brain they affect and how is unknown. “That’s something lots of people are working on, including our own lab,” Dr. Seeley said. (Another surprise: The drugs may have potential as an anti-addiction treatment.)

The diabetes medication tirzepatide (Mounjaro), expected to be approved for weight loss as early as this year, is also a weekly injection, but it has a unique feature: It starts a response not just for GLP-1 but also for another incretin called GIP. Turns out, two is better than one: Trial participants on tirzepatide lost up to 22.5% of their body weight. 

More of these hybrid drugs are on the way, Dr. Seeley said. In mid-stage clinical trials, the drug retatrutide, which targets three hormones, led to 24% weight loss. “The idea is the more bullets we can load into the gun, the more we can push the biology into a place where it’s easier to lose weight.”
 

Shifting from prevention to damage control

Less invasive and more scalable than surgery (only 1% of the eligible population gets bariatric surgery), the drugs offer doctors a safe, effective way to treat many patients with obesity. That’s cause for excitement, but concerns remain because they are expensive, costing about $800 to $1,300 per month out of pocket. Many health insurers, including Medicare, do not cover them for weight loss. 

“You have this significant advance in obesity treatment, but very few will be able to access it,” said Gary Foster, PhD, adjunct professor of psychology in psychiatry at the University of Pennsylvania, Philadelphia, and chief scientific officer at WW (formerly Weight Watchers).

There is a push, including a proposed bill, to get Medicare to cover obesity medication. But given the expense of the drugs, the health economics do not support that move, according to an editorial in the New England Journal of Medicine. If Medicare were to cover obesity meds, the budget impact would likely be huge, potentially driving up premiums. If other payers followed suit, the impact could be felt across the U.S. health care system. 

Other drawbacks include side effects – including nausea, diarrhea, stomach pain, and vomiting – that can be so bad that some patients can’t tolerate them.

And critically, the drugs do not deal with the root cause of the problem, said Robert Lustig, MD, an endocrinologist and pediatrician at the University of California, San Francisco, who has suggested that excess insulin is driving obesity. “No one has the disease that these drugs are treating. No one has GLP-1 deficiency. They’re bypassing the problem. They’re band-aiding the problem.” 

Because the drugs work by mimicking starvation – they appear to curb hunger, so you eat less – people on them lose not just fat but also healthy lean mass, Dr. Lustig said. 

Concerns about pancreatitis did not really bear out in postmarketing reports. (The drugs are still not recommended in people with pancreatitis or multiple endocrine neoplasia.) But predicting longer-term outcomes can be difficult, noted Dr. Lustig.

Then there are philosophical questions, said James Hill, PhD, director of the Nutrition Obesity Research Center at the University of Alabama at Birmingham.. “If you’re continuing to not exercise and eat not healthy foods and take a medication, is that success? Have we won when people are at a lower weight but not doing a healthy behavior?”

‘We can’t treat our way out of this’

The fact is, ending the obesity epidemic is a tall order, even for drugs as impressive as these. 

“We can’t treat our way out of this,” said Jamy Ard, MD, codirector of Wake Forest Baptist Health Weight Management Center in Winston-Salem, N.C. “The treatments we have now are great, and there will be more coming. But we do need to figure out the prevention side of things.” 

Dr. Seeley agreed but added that we can’t diet-and-exercise our way out either. 

“There’s no switch to be flipped,” Dr. Seeley said. “If you told me we shouldn’t spend all this money on these drugs, we should spend it on prevention – great! What would we do?” 

And prevention efforts won’t help the millions already living with health problems from obesity, Dr. Aronne said. 

“Getting people to stop smoking prevents lung cancer. But stopping smoking doesn’t treat lung cancer,” Dr. Aronne said. “Once the physical changes occur in the lung that cause a tumor to grow, it’s too late. You have to think of obesity the same way.” 

Dr. Seeley pointed out that “fearmongering” around the drugs highlights our lingering bias that obesity is a lifestyle issue that should not be medically treated. 

“People say, ‘When you stop taking it, you’re going to gain the weight back,’ ” Dr. Seeley said. “There’s truth to that, but when you stop taking your hypertension medication, your blood pressure goes up. We don’t think of that as a [reason] for why you shouldn’t take your blood pressure medication. But that gets trumpeted into all these conversations about whether people [with obesity] should be treated at all.”

Like obesity, blood pressure was once thought to be a behavioral problem, Dr. Aronne said. But blood pressure meds prevent heart attacks and strokes. And it’s likely obesity meds will do the same. 

One 55-year-old patient on the road to kidney failure lost weight on obesity medications, including semaglutide, Dr. Aronne said. Now, 6 years later, his kidney function is back to normal. “Normally, we think of kidney disease as irreversible,” Dr. Aronne said. 

In that respect, these drugs should save money in the long run by virtue of heading off those health care costs, said Dr. Seeley, who imagines a future where obesity is not gone but better managed, like high blood pressure is now. 

In the end, the drugs are another step toward what Dr. Aronne and many others have always pushed for: Treating obesity as a disease. 
 

A version of this article originally appeared on WebMD.com.

The advent of subcutaneously injectable glucagonlike peptide–1 (GLP-1) receptor agonists for the management of type 2 diabetes during 2005 was arguably one of the greatest therapeutic advances for the condition since metformin.

I was an early advocate of the class, given its potent glucose-lowering efficacy, secondary benefits of significant weight reduction, and a low risk for hypoglycemia (if not used alongside sulfonylureas or insulin).

During 2016, the first cardiovascular outcomes trial for a GLP-1 agonist, in the form of the LEADER study, was reported. These trials were mandated by the Food and Drug Administration in the aftermath of the rosiglitazone debacle in which the type 2 diabetes drug had its use restricted because of cardiovascular events attributed to it in a meta-analysis. These events weren’t seen in a subsequent trial, and the FDA’s restrictions were later lifted.

LEADER examined the once-daily GLP-1 agonist liraglutide and showed that, in addition to its glucose-lowering effects, liraglutide brought cardiovascular benefits to the table. Moreover, during 2019, the REWIND trial, the cardiovascular outcome trial for once-weekly subcutaneous dulaglutide, revealed the same cardiovascular benefits but also demonstrated a lower incidence of macroalbuminuria, albeit with no significant improvements in hard renal endpoints such as estimated glomerular filtration decline or rates of dialysis.

Despite these compelling benefits, the uptake of GLP-1 agonists has always been slower than that of other compelling agents such as the sodium-glucose cotransporter 2 inhibitors, mainly because the latter are oral drugs, while GLP-1 agonists were initially injectable medications. This difference has proven to be a barrier for patients and clinicians alike.

However, in 2019, oral semaglutide, in doses of 7 mg and 14 mg, was approved by the FDA as the first (and still only) commercially available oral GLP-1 agonist to improve glycemic control in adults with type 2 diabetes. This approval was hailed as a “game changer” at the time. The treatment had no proven cardiovascular benefits, only lack of cardiovascular harm in PIONEER 6. The SOUL cardiovascular outcome trial for oral semaglutide in doses of 7 mg and 14 mg is due to be completed during 2024. But semaglutide certainly had compelling glucose-lowering efficacy and secondary benefits of significant weight loss similar to those of its injectable counterparts.

Cardiovascular benefits of injectable semaglutide for type 2 diabetes were demonstrated in the SUSTAIN-6 trial in 2016, and the U.S. label for Ozempic was amended accordingly in 2020.

Again, I was an early adopter of oral semaglutide, and it has been great for my patients with type 2 diabetes to have the option of a noninjectable GLP-1 agonist. However, it is not without its drawbacks: Oral semaglutide must be taken on an empty stomach, at least 30 minutes before any other food, drink, or medication, and with no more than 120 mL water to maximize absorption and bioavailability.

I am of South Asian origin and have a strong family history of type 2 diabetes. If I develop type 2 diabetes in the future and require treatment escalation to a GLP-1 agonist, I will most likely opt for a weekly injectable, as it would best fit my lifestyle. But having choices of preparation has been a huge advantage in helping my patients best individualize their therapies.

I attended the recent American Diabetes Association congress in San Diego, which had two interesting oral GLP-1 agonist sessions on the program.

The first discussed the efficacy and safety of a new daily oral nonpeptide GLP-1 agonist, orforglipron, for weight reduction in adults with obesity. The phase 2 results were impressive, with clinically significant reductions in weight and cardiometabolic parameters, and a reassuring safety profile similar to that of the injectable GLP-1 agonists.

Notably, because orforglipron is a nonpeptide, it can be taken without any food, water, or medication restrictions. This indeed could turn out to be a real game changer by simplifying the complex administration of oral semaglutide, which no doubt has hampered compliance.

In fact, an Association of British Clinical Diabetologists real-world audit (also presented at the ADA Congress as a poster) of oral semaglutide use for type 2 diabetes found clinically significant hemoglobin A1c and weight reductions, but perhaps less than expected when compared with the clinical trial program, which could be a sign of poor adherence.

A phase 3 trial of orforglipron is underway (ATTAIN-2), exploring its efficacy and safety in adults with obesity or overweight and type 2 diabetes, but it is not due to be completed until 2027.

I also attended the session presenting the results of the OASIS 1 and PIONEER-PLUS trials of higher-dose oral semaglutide.

OASIS 1 explored the efficacy and safety of high-dose oral semaglutide, 50 mg once daily, for the treatment of adults with overweight or obesity without type 2 diabetes. The investigators found clinically significant reductions in body weight of around 15%-17% from baseline, compared with placebo. This result was similar to the weight loss observed in the STEP 1 trial of 2.4 mg weekly subcutaneous injectable semaglutide in adults with obesity (a much lower dose is needed when GLP-1 agonists are given as injectables because the oral forms are not very bioavailable). The side-effect profile was also similar.

PIONEER PLUS explored the efficacy and safety of high-dose oral semaglutide 25 mg and 50 mg in adults with inadequately controlled type 2 diabetes. Patients treated with 50 mg oral semaglutide had around a 2% reduction in A1c and an 8-kg (18-lb) reduction in weight from baseline. It is well known that people with obesity and type 2 diabetes lose less weight than those with obesity alone, so this result was impressive. Again, the safety profile was similar to that of the wider class, with predictably high levels of gastrointestinal side effects.

So, the future appears very bright for oral GLP-1 agonists. I hope that future developments bring the class to an even wider demographic and perhaps reduce some of the global inequities in managing type 2 diabetes and obesity. It should be easier (and cheaper) to mass-produce and distribute an oral medication, compared with an injectable one.

However, it should be noted that, in the United Kingdom, the National Health Service tariff cost of oral semaglutide (at usual doses for type 2 diabetes) remains similar to that of injectable semaglutide (at doses for type 2 diabetes rather than obesity). And notably, the U.K. National Institute for Health and Care Excellence, which decides whether new drugs will be funded on the NHS, has recently delayed its decision on approving tirzepatide, a dual GLP-1 and GIP agonist, for type 2 diabetes, citing the requirement for further evidence for its clinical and cost-effectiveness. This is not uncommon for NICE, and I fully expect tirzepatide to gain NICE approval on resubmission later in 2023.

One solution to contain costs might be a phased approach to the management of obesity, with initial stages using highly efficacious obesity drugs such as tirzepatide, injectable semaglutide, or high-dose oral semaglutide, and then transitioning to lower-efficacy and cheaper obesity drugs for weight maintenance.

On this note, a generic version of liraglutide (a once-daily injectable GLP-1 agonist) will be available during 2024. Moreover, it will be interesting to see the cost of orforglipron, assuming that it is approved, when it becomes commercially available in a few years, given that a nonpeptide agent should be cheaper to produce than a peptide-like semaglutide.

This phased approach is analogous to the treatment of rheumatoid arthritis, where potent targeted biologic therapy is often used early on to achieve remission of rheumatoid arthritis, followed by a switch to a conventional disease-modifying antirheumatic drug for maintenance therapy, for reasons of long-term safety and health economics.

Using this approach for obesity management might help the sustainability of health care systems.

Dr. Fernando is a general practitioner near Edinburgh. He reported receiving speaker fees from Eli Lilly and Novo Nordisk.

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

The advent of subcutaneously injectable glucagonlike peptide–1 (GLP-1) receptor agonists for the management of type 2 diabetes during 2005 was arguably one of the greatest therapeutic advances for the condition since metformin.

I was an early advocate of the class, given its potent glucose-lowering efficacy, secondary benefits of significant weight reduction, and a low risk for hypoglycemia (if not used alongside sulfonylureas or insulin).

During 2016, the first cardiovascular outcomes trial for a GLP-1 agonist, in the form of the LEADER study, was reported. These trials were mandated by the Food and Drug Administration in the aftermath of the rosiglitazone debacle in which the type 2 diabetes drug had its use restricted because of cardiovascular events attributed to it in a meta-analysis. These events weren’t seen in a subsequent trial, and the FDA’s restrictions were later lifted.

LEADER examined the once-daily GLP-1 agonist liraglutide and showed that, in addition to its glucose-lowering effects, liraglutide brought cardiovascular benefits to the table. Moreover, during 2019, the REWIND trial, the cardiovascular outcome trial for once-weekly subcutaneous dulaglutide, revealed the same cardiovascular benefits but also demonstrated a lower incidence of macroalbuminuria, albeit with no significant improvements in hard renal endpoints such as estimated glomerular filtration decline or rates of dialysis.

Despite these compelling benefits, the uptake of GLP-1 agonists has always been slower than that of other compelling agents such as the sodium-glucose cotransporter 2 inhibitors, mainly because the latter are oral drugs, while GLP-1 agonists were initially injectable medications. This difference has proven to be a barrier for patients and clinicians alike.

However, in 2019, oral semaglutide, in doses of 7 mg and 14 mg, was approved by the FDA as the first (and still only) commercially available oral GLP-1 agonist to improve glycemic control in adults with type 2 diabetes. This approval was hailed as a “game changer” at the time. The treatment had no proven cardiovascular benefits, only lack of cardiovascular harm in PIONEER 6. The SOUL cardiovascular outcome trial for oral semaglutide in doses of 7 mg and 14 mg is due to be completed during 2024. But semaglutide certainly had compelling glucose-lowering efficacy and secondary benefits of significant weight loss similar to those of its injectable counterparts.

Cardiovascular benefits of injectable semaglutide for type 2 diabetes were demonstrated in the SUSTAIN-6 trial in 2016, and the U.S. label for Ozempic was amended accordingly in 2020.

Again, I was an early adopter of oral semaglutide, and it has been great for my patients with type 2 diabetes to have the option of a noninjectable GLP-1 agonist. However, it is not without its drawbacks: Oral semaglutide must be taken on an empty stomach, at least 30 minutes before any other food, drink, or medication, and with no more than 120 mL water to maximize absorption and bioavailability.

I am of South Asian origin and have a strong family history of type 2 diabetes. If I develop type 2 diabetes in the future and require treatment escalation to a GLP-1 agonist, I will most likely opt for a weekly injectable, as it would best fit my lifestyle. But having choices of preparation has been a huge advantage in helping my patients best individualize their therapies.

I attended the recent American Diabetes Association congress in San Diego, which had two interesting oral GLP-1 agonist sessions on the program.

The first discussed the efficacy and safety of a new daily oral nonpeptide GLP-1 agonist, orforglipron, for weight reduction in adults with obesity. The phase 2 results were impressive, with clinically significant reductions in weight and cardiometabolic parameters, and a reassuring safety profile similar to that of the injectable GLP-1 agonists.

Notably, because orforglipron is a nonpeptide, it can be taken without any food, water, or medication restrictions. This indeed could turn out to be a real game changer by simplifying the complex administration of oral semaglutide, which no doubt has hampered compliance.

In fact, an Association of British Clinical Diabetologists real-world audit (also presented at the ADA Congress as a poster) of oral semaglutide use for type 2 diabetes found clinically significant hemoglobin A1c and weight reductions, but perhaps less than expected when compared with the clinical trial program, which could be a sign of poor adherence.

A phase 3 trial of orforglipron is underway (ATTAIN-2), exploring its efficacy and safety in adults with obesity or overweight and type 2 diabetes, but it is not due to be completed until 2027.

I also attended the session presenting the results of the OASIS 1 and PIONEER-PLUS trials of higher-dose oral semaglutide.

OASIS 1 explored the efficacy and safety of high-dose oral semaglutide, 50 mg once daily, for the treatment of adults with overweight or obesity without type 2 diabetes. The investigators found clinically significant reductions in body weight of around 15%-17% from baseline, compared with placebo. This result was similar to the weight loss observed in the STEP 1 trial of 2.4 mg weekly subcutaneous injectable semaglutide in adults with obesity (a much lower dose is needed when GLP-1 agonists are given as injectables because the oral forms are not very bioavailable). The side-effect profile was also similar.

PIONEER PLUS explored the efficacy and safety of high-dose oral semaglutide 25 mg and 50 mg in adults with inadequately controlled type 2 diabetes. Patients treated with 50 mg oral semaglutide had around a 2% reduction in A1c and an 8-kg (18-lb) reduction in weight from baseline. It is well known that people with obesity and type 2 diabetes lose less weight than those with obesity alone, so this result was impressive. Again, the safety profile was similar to that of the wider class, with predictably high levels of gastrointestinal side effects.

So, the future appears very bright for oral GLP-1 agonists. I hope that future developments bring the class to an even wider demographic and perhaps reduce some of the global inequities in managing type 2 diabetes and obesity. It should be easier (and cheaper) to mass-produce and distribute an oral medication, compared with an injectable one.

However, it should be noted that, in the United Kingdom, the National Health Service tariff cost of oral semaglutide (at usual doses for type 2 diabetes) remains similar to that of injectable semaglutide (at doses for type 2 diabetes rather than obesity). And notably, the U.K. National Institute for Health and Care Excellence, which decides whether new drugs will be funded on the NHS, has recently delayed its decision on approving tirzepatide, a dual GLP-1 and GIP agonist, for type 2 diabetes, citing the requirement for further evidence for its clinical and cost-effectiveness. This is not uncommon for NICE, and I fully expect tirzepatide to gain NICE approval on resubmission later in 2023.

One solution to contain costs might be a phased approach to the management of obesity, with initial stages using highly efficacious obesity drugs such as tirzepatide, injectable semaglutide, or high-dose oral semaglutide, and then transitioning to lower-efficacy and cheaper obesity drugs for weight maintenance.

On this note, a generic version of liraglutide (a once-daily injectable GLP-1 agonist) will be available during 2024. Moreover, it will be interesting to see the cost of orforglipron, assuming that it is approved, when it becomes commercially available in a few years, given that a nonpeptide agent should be cheaper to produce than a peptide-like semaglutide.

This phased approach is analogous to the treatment of rheumatoid arthritis, where potent targeted biologic therapy is often used early on to achieve remission of rheumatoid arthritis, followed by a switch to a conventional disease-modifying antirheumatic drug for maintenance therapy, for reasons of long-term safety and health economics.

Using this approach for obesity management might help the sustainability of health care systems.

Dr. Fernando is a general practitioner near Edinburgh. He reported receiving speaker fees from Eli Lilly and Novo Nordisk.

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

The advent of subcutaneously injectable glucagonlike peptide–1 (GLP-1) receptor agonists for the management of type 2 diabetes during 2005 was arguably one of the greatest therapeutic advances for the condition since metformin.

I was an early advocate of the class, given its potent glucose-lowering efficacy, secondary benefits of significant weight reduction, and a low risk for hypoglycemia (if not used alongside sulfonylureas or insulin).

During 2016, the first cardiovascular outcomes trial for a GLP-1 agonist, in the form of the LEADER study, was reported. These trials were mandated by the Food and Drug Administration in the aftermath of the rosiglitazone debacle in which the type 2 diabetes drug had its use restricted because of cardiovascular events attributed to it in a meta-analysis. These events weren’t seen in a subsequent trial, and the FDA’s restrictions were later lifted.

LEADER examined the once-daily GLP-1 agonist liraglutide and showed that, in addition to its glucose-lowering effects, liraglutide brought cardiovascular benefits to the table. Moreover, during 2019, the REWIND trial, the cardiovascular outcome trial for once-weekly subcutaneous dulaglutide, revealed the same cardiovascular benefits but also demonstrated a lower incidence of macroalbuminuria, albeit with no significant improvements in hard renal endpoints such as estimated glomerular filtration decline or rates of dialysis.

Despite these compelling benefits, the uptake of GLP-1 agonists has always been slower than that of other compelling agents such as the sodium-glucose cotransporter 2 inhibitors, mainly because the latter are oral drugs, while GLP-1 agonists were initially injectable medications. This difference has proven to be a barrier for patients and clinicians alike.

However, in 2019, oral semaglutide, in doses of 7 mg and 14 mg, was approved by the FDA as the first (and still only) commercially available oral GLP-1 agonist to improve glycemic control in adults with type 2 diabetes. This approval was hailed as a “game changer” at the time. The treatment had no proven cardiovascular benefits, only lack of cardiovascular harm in PIONEER 6. The SOUL cardiovascular outcome trial for oral semaglutide in doses of 7 mg and 14 mg is due to be completed during 2024. But semaglutide certainly had compelling glucose-lowering efficacy and secondary benefits of significant weight loss similar to those of its injectable counterparts.

Cardiovascular benefits of injectable semaglutide for type 2 diabetes were demonstrated in the SUSTAIN-6 trial in 2016, and the U.S. label for Ozempic was amended accordingly in 2020.

Again, I was an early adopter of oral semaglutide, and it has been great for my patients with type 2 diabetes to have the option of a noninjectable GLP-1 agonist. However, it is not without its drawbacks: Oral semaglutide must be taken on an empty stomach, at least 30 minutes before any other food, drink, or medication, and with no more than 120 mL water to maximize absorption and bioavailability.

I am of South Asian origin and have a strong family history of type 2 diabetes. If I develop type 2 diabetes in the future and require treatment escalation to a GLP-1 agonist, I will most likely opt for a weekly injectable, as it would best fit my lifestyle. But having choices of preparation has been a huge advantage in helping my patients best individualize their therapies.

I attended the recent American Diabetes Association congress in San Diego, which had two interesting oral GLP-1 agonist sessions on the program.

The first discussed the efficacy and safety of a new daily oral nonpeptide GLP-1 agonist, orforglipron, for weight reduction in adults with obesity. The phase 2 results were impressive, with clinically significant reductions in weight and cardiometabolic parameters, and a reassuring safety profile similar to that of the injectable GLP-1 agonists.

Notably, because orforglipron is a nonpeptide, it can be taken without any food, water, or medication restrictions. This indeed could turn out to be a real game changer by simplifying the complex administration of oral semaglutide, which no doubt has hampered compliance.

In fact, an Association of British Clinical Diabetologists real-world audit (also presented at the ADA Congress as a poster) of oral semaglutide use for type 2 diabetes found clinically significant hemoglobin A1c and weight reductions, but perhaps less than expected when compared with the clinical trial program, which could be a sign of poor adherence.

A phase 3 trial of orforglipron is underway (ATTAIN-2), exploring its efficacy and safety in adults with obesity or overweight and type 2 diabetes, but it is not due to be completed until 2027.

I also attended the session presenting the results of the OASIS 1 and PIONEER-PLUS trials of higher-dose oral semaglutide.

OASIS 1 explored the efficacy and safety of high-dose oral semaglutide, 50 mg once daily, for the treatment of adults with overweight or obesity without type 2 diabetes. The investigators found clinically significant reductions in body weight of around 15%-17% from baseline, compared with placebo. This result was similar to the weight loss observed in the STEP 1 trial of 2.4 mg weekly subcutaneous injectable semaglutide in adults with obesity (a much lower dose is needed when GLP-1 agonists are given as injectables because the oral forms are not very bioavailable). The side-effect profile was also similar.

PIONEER PLUS explored the efficacy and safety of high-dose oral semaglutide 25 mg and 50 mg in adults with inadequately controlled type 2 diabetes. Patients treated with 50 mg oral semaglutide had around a 2% reduction in A1c and an 8-kg (18-lb) reduction in weight from baseline. It is well known that people with obesity and type 2 diabetes lose less weight than those with obesity alone, so this result was impressive. Again, the safety profile was similar to that of the wider class, with predictably high levels of gastrointestinal side effects.

So, the future appears very bright for oral GLP-1 agonists. I hope that future developments bring the class to an even wider demographic and perhaps reduce some of the global inequities in managing type 2 diabetes and obesity. It should be easier (and cheaper) to mass-produce and distribute an oral medication, compared with an injectable one.

However, it should be noted that, in the United Kingdom, the National Health Service tariff cost of oral semaglutide (at usual doses for type 2 diabetes) remains similar to that of injectable semaglutide (at doses for type 2 diabetes rather than obesity). And notably, the U.K. National Institute for Health and Care Excellence, which decides whether new drugs will be funded on the NHS, has recently delayed its decision on approving tirzepatide, a dual GLP-1 and GIP agonist, for type 2 diabetes, citing the requirement for further evidence for its clinical and cost-effectiveness. This is not uncommon for NICE, and I fully expect tirzepatide to gain NICE approval on resubmission later in 2023.

One solution to contain costs might be a phased approach to the management of obesity, with initial stages using highly efficacious obesity drugs such as tirzepatide, injectable semaglutide, or high-dose oral semaglutide, and then transitioning to lower-efficacy and cheaper obesity drugs for weight maintenance.

On this note, a generic version of liraglutide (a once-daily injectable GLP-1 agonist) will be available during 2024. Moreover, it will be interesting to see the cost of orforglipron, assuming that it is approved, when it becomes commercially available in a few years, given that a nonpeptide agent should be cheaper to produce than a peptide-like semaglutide.

This phased approach is analogous to the treatment of rheumatoid arthritis, where potent targeted biologic therapy is often used early on to achieve remission of rheumatoid arthritis, followed by a switch to a conventional disease-modifying antirheumatic drug for maintenance therapy, for reasons of long-term safety and health economics.

Using this approach for obesity management might help the sustainability of health care systems.

Dr. Fernando is a general practitioner near Edinburgh. He reported receiving speaker fees from Eli Lilly and Novo Nordisk.

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

SAN DIEGO – Survodutide, a dual glucagonlike peptide–1 (GLP-1) and glucagon receptor agonist, led to “striking” weight loss in a phase 2 dosing trial in people with overweight/obesity but without type 2 diabetes.

Close to 40% of people who were taking the highest dose lost 20% or more of their starting weight at 46 weeks, Carel Le Roux, MBChB, PhD, reported at the annual scientific sessions of the American Diabetes Association.

Boehringer Ingelheim and Zealand Pharma are developing survodutide (formerly BI 456906) to treat obesity and nonalcoholic fatty liver disease (NAFLD), according to a company press release.

Glucagon receptor agonism increases energy expenditure, and GLP-1 receptor agonism inhibits appetite, both part of the mechanism of action, Dr. Le Roux, a professor at University College in Dublin, explained.

The trial showed a “striking” and clear dose-response in terms of weight loss, with no new unexpected safety signals, he reported.

Invited to comment, session moderator Elisabetta Patorno, MD, DrPH, noted that “Obesity is one of the main risk factors for [type 2] diabetes.”

“It’s very stimulating to see this new medication class make such a big impact on weight loss in such a short amount of time,” Dr. Patorno, associate professor of medicine at Harvard Medical School, Boston, said in an interview. However, whether the weight loss can be maintained over time remains to be determined in further research, she said.

Head-to-head weight-loss studies of the dual agonist survodutide versus the mono GLP-1 agonist semaglutide (Ozempic, Wegovy, Novo Nordisk) have not been conducted, Dr. Le Roux said during a press briefing.

“What we don’t know is if somebody doesn’t respond to [weight-loss drug] product A, will they respond to product B?” he said. Because survodutide acts on two types of receptors, “you could argue that you would not only increase the absolute amount of weight but you might also increase the number of patients who would respond, but that’s theoretical at the moment,” he explained.
 

Close to 400 patients, five doses, 46-week endpoint

The researchers randomized 387 adults aged 18-75 who had a body mass index (BMI) ≥ 27 kg/m² (overweight or obesity) without type 2 diabetes at sites in North America, Europe, Australia/New Zealand, and Asia.

On average, patients were 49 years old with a body weight of 106 kg (234 lb) and a BMI of 37 kg/m², and 68% were women.

They were randomized to receive a planned weekly subcutaneous maintenance survodutide dose of 0.6 mg (76 patients), 2.4 mg (78 patients), 3.6 mg (76 patients), or 4.8 mg (76 patients), or placebo (77 patients).

The dose was escalated rapidly (monthly) during a 20-week dose-escalation phase, followed by a 26-week maintenance phase.

Patients who did not reach the planned dose remained on a lower dose during the maintenance phase.

In terms of actual treatment, during the maintenance phase, 76 patients were taking placebo, 88 patients were taking 0.6 mg survodutide, 92 were taking 2.4 mg survodutide, 71 were taking 3.6 mg survodutide, and 54 were taking 4.8 mg survodutide, all given as weekly subcutaneous injections.

Primary outcome was the percentage change in body weight from baseline to week 46.

Secondary outcomes included the percentage of patients who reached a body weight reduction of ≥ 5%, ≥ 10%, and ≥ 15% from baseline to week 46.

Mean weight loss at 46 weeks in the planned treatment analysis (where some patients in each group were taking a lower than planned dose during maintenance) was 6.2% in the 0.6-mg survodutide group, 12.5% in the 2.4-mg group, 13.2% in the 3.6-mg group, 14.9% in the 4.8-mg group, and 2.8% in the placebo group.

Among participants who did reach and stay on their assigned dose during the maintenance phase, average weight loss was 6.8% in the 0.6-mg survodutide group,13.6% with 2.4 mg survodutide,16.7% with 3.6 mg survodutide, 18.6% with 4.8 mg survodutide, and 2.0% with placebo.

That is, patients reaching and staying on a weekly subcutaneous dose of 4.8 mg survodutide lost 18.6% of their body weight at 46 weeks, Dr. Le Roux emphasized.

In terms of secondary outcomes, in the group of patients with a planned weekly dose of 4.8 mg survodutide, 83%, 69%, and 55% attained weight loss of ≥ 5%, ≥ 10%, and ≥ 15% of their initial weight, respectively, at 46 weeks.

In the group of patients with an actual weekly dose of 4.8 mg survodutide, 98%, 82%, and 67% attained weight loss of ≥ 5%, ≥ 10%, and ≥ 15% of their initial weight, respectively, at 46 weeks.

Moreover, 33% of patients in the group with a planned weekly dose of 4.8 mg survodutide and 38% of patients with an actual weekly dose of 4.8 mg survodutide lost ≥ 20% of their baseline body weight by week 46.

Adverse events occurred in 91% of patients in the survodutide groups and 75% in the placebo group. The most common side effects were nausea, vomiting, diarrhea, and constipation, which were mostly mild to moderate and mainly occurred during dose escalation. These effects may potentially be mitigated by more gradual dose escalation, Dr. Le Roux said.

There were no unexpected safety or tolerability concerns, and no serious drug-related adverse events.

These “encouraging data” support further study of survodutide for weight loss in larger phase 3 trials, Dr. Le Roux and colleagues conclude.
 

Survodutide has FDA fast track designation for NASH

Survodutide has received U.S. Food and Drug Administration Fast Track Designation for adults with NASH. The drug is currently being evaluated in a phase 2 study in adults with NASH and stages F1/F2/F3 liver fibrosis, with trial completion expected in the last quarter of 2023.

The current trial was funded by Boehringer Ingelheim. Dr. Le Roux has reported being on an advisory panel for Boehringer Ingelheim and being on advisory panels and receiving research funding from multiple other pharmaceutical companies. Two study authors are Boehringer Ingelheim employees.

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

SAN DIEGO – Survodutide, a dual glucagonlike peptide–1 (GLP-1) and glucagon receptor agonist, led to “striking” weight loss in a phase 2 dosing trial in people with overweight/obesity but without type 2 diabetes.

Close to 40% of people who were taking the highest dose lost 20% or more of their starting weight at 46 weeks, Carel Le Roux, MBChB, PhD, reported at the annual scientific sessions of the American Diabetes Association.

Boehringer Ingelheim and Zealand Pharma are developing survodutide (formerly BI 456906) to treat obesity and nonalcoholic fatty liver disease (NAFLD), according to a company press release.

Glucagon receptor agonism increases energy expenditure, and GLP-1 receptor agonism inhibits appetite, both part of the mechanism of action, Dr. Le Roux, a professor at University College in Dublin, explained.

The trial showed a “striking” and clear dose-response in terms of weight loss, with no new unexpected safety signals, he reported.

Invited to comment, session moderator Elisabetta Patorno, MD, DrPH, noted that “Obesity is one of the main risk factors for [type 2] diabetes.”

“It’s very stimulating to see this new medication class make such a big impact on weight loss in such a short amount of time,” Dr. Patorno, associate professor of medicine at Harvard Medical School, Boston, said in an interview. However, whether the weight loss can be maintained over time remains to be determined in further research, she said.

Head-to-head weight-loss studies of the dual agonist survodutide versus the mono GLP-1 agonist semaglutide (Ozempic, Wegovy, Novo Nordisk) have not been conducted, Dr. Le Roux said during a press briefing.

“What we don’t know is if somebody doesn’t respond to [weight-loss drug] product A, will they respond to product B?” he said. Because survodutide acts on two types of receptors, “you could argue that you would not only increase the absolute amount of weight but you might also increase the number of patients who would respond, but that’s theoretical at the moment,” he explained.
 

Close to 400 patients, five doses, 46-week endpoint

The researchers randomized 387 adults aged 18-75 who had a body mass index (BMI) ≥ 27 kg/m² (overweight or obesity) without type 2 diabetes at sites in North America, Europe, Australia/New Zealand, and Asia.

On average, patients were 49 years old with a body weight of 106 kg (234 lb) and a BMI of 37 kg/m², and 68% were women.

They were randomized to receive a planned weekly subcutaneous maintenance survodutide dose of 0.6 mg (76 patients), 2.4 mg (78 patients), 3.6 mg (76 patients), or 4.8 mg (76 patients), or placebo (77 patients).

The dose was escalated rapidly (monthly) during a 20-week dose-escalation phase, followed by a 26-week maintenance phase.

Patients who did not reach the planned dose remained on a lower dose during the maintenance phase.

In terms of actual treatment, during the maintenance phase, 76 patients were taking placebo, 88 patients were taking 0.6 mg survodutide, 92 were taking 2.4 mg survodutide, 71 were taking 3.6 mg survodutide, and 54 were taking 4.8 mg survodutide, all given as weekly subcutaneous injections.

Primary outcome was the percentage change in body weight from baseline to week 46.

Secondary outcomes included the percentage of patients who reached a body weight reduction of ≥ 5%, ≥ 10%, and ≥ 15% from baseline to week 46.

Mean weight loss at 46 weeks in the planned treatment analysis (where some patients in each group were taking a lower than planned dose during maintenance) was 6.2% in the 0.6-mg survodutide group, 12.5% in the 2.4-mg group, 13.2% in the 3.6-mg group, 14.9% in the 4.8-mg group, and 2.8% in the placebo group.

Among participants who did reach and stay on their assigned dose during the maintenance phase, average weight loss was 6.8% in the 0.6-mg survodutide group,13.6% with 2.4 mg survodutide,16.7% with 3.6 mg survodutide, 18.6% with 4.8 mg survodutide, and 2.0% with placebo.

That is, patients reaching and staying on a weekly subcutaneous dose of 4.8 mg survodutide lost 18.6% of their body weight at 46 weeks, Dr. Le Roux emphasized.

In terms of secondary outcomes, in the group of patients with a planned weekly dose of 4.8 mg survodutide, 83%, 69%, and 55% attained weight loss of ≥ 5%, ≥ 10%, and ≥ 15% of their initial weight, respectively, at 46 weeks.

In the group of patients with an actual weekly dose of 4.8 mg survodutide, 98%, 82%, and 67% attained weight loss of ≥ 5%, ≥ 10%, and ≥ 15% of their initial weight, respectively, at 46 weeks.

Moreover, 33% of patients in the group with a planned weekly dose of 4.8 mg survodutide and 38% of patients with an actual weekly dose of 4.8 mg survodutide lost ≥ 20% of their baseline body weight by week 46.

Adverse events occurred in 91% of patients in the survodutide groups and 75% in the placebo group. The most common side effects were nausea, vomiting, diarrhea, and constipation, which were mostly mild to moderate and mainly occurred during dose escalation. These effects may potentially be mitigated by more gradual dose escalation, Dr. Le Roux said.

There were no unexpected safety or tolerability concerns, and no serious drug-related adverse events.

These “encouraging data” support further study of survodutide for weight loss in larger phase 3 trials, Dr. Le Roux and colleagues conclude.
 

Survodutide has FDA fast track designation for NASH

Survodutide has received U.S. Food and Drug Administration Fast Track Designation for adults with NASH. The drug is currently being evaluated in a phase 2 study in adults with NASH and stages F1/F2/F3 liver fibrosis, with trial completion expected in the last quarter of 2023.

The current trial was funded by Boehringer Ingelheim. Dr. Le Roux has reported being on an advisory panel for Boehringer Ingelheim and being on advisory panels and receiving research funding from multiple other pharmaceutical companies. Two study authors are Boehringer Ingelheim employees.

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

SAN DIEGO – Survodutide, a dual glucagonlike peptide–1 (GLP-1) and glucagon receptor agonist, led to “striking” weight loss in a phase 2 dosing trial in people with overweight/obesity but without type 2 diabetes.

Close to 40% of people who were taking the highest dose lost 20% or more of their starting weight at 46 weeks, Carel Le Roux, MBChB, PhD, reported at the annual scientific sessions of the American Diabetes Association.

Boehringer Ingelheim and Zealand Pharma are developing survodutide (formerly BI 456906) to treat obesity and nonalcoholic fatty liver disease (NAFLD), according to a company press release.

Glucagon receptor agonism increases energy expenditure, and GLP-1 receptor agonism inhibits appetite, both part of the mechanism of action, Dr. Le Roux, a professor at University College in Dublin, explained.

The trial showed a “striking” and clear dose-response in terms of weight loss, with no new unexpected safety signals, he reported.

Invited to comment, session moderator Elisabetta Patorno, MD, DrPH, noted that “Obesity is one of the main risk factors for [type 2] diabetes.”

“It’s very stimulating to see this new medication class make such a big impact on weight loss in such a short amount of time,” Dr. Patorno, associate professor of medicine at Harvard Medical School, Boston, said in an interview. However, whether the weight loss can be maintained over time remains to be determined in further research, she said.

Head-to-head weight-loss studies of the dual agonist survodutide versus the mono GLP-1 agonist semaglutide (Ozempic, Wegovy, Novo Nordisk) have not been conducted, Dr. Le Roux said during a press briefing.

“What we don’t know is if somebody doesn’t respond to [weight-loss drug] product A, will they respond to product B?” he said. Because survodutide acts on two types of receptors, “you could argue that you would not only increase the absolute amount of weight but you might also increase the number of patients who would respond, but that’s theoretical at the moment,” he explained.
 

Close to 400 patients, five doses, 46-week endpoint

The researchers randomized 387 adults aged 18-75 who had a body mass index (BMI) ≥ 27 kg/m² (overweight or obesity) without type 2 diabetes at sites in North America, Europe, Australia/New Zealand, and Asia.

On average, patients were 49 years old with a body weight of 106 kg (234 lb) and a BMI of 37 kg/m², and 68% were women.

They were randomized to receive a planned weekly subcutaneous maintenance survodutide dose of 0.6 mg (76 patients), 2.4 mg (78 patients), 3.6 mg (76 patients), or 4.8 mg (76 patients), or placebo (77 patients).

The dose was escalated rapidly (monthly) during a 20-week dose-escalation phase, followed by a 26-week maintenance phase.

Patients who did not reach the planned dose remained on a lower dose during the maintenance phase.

In terms of actual treatment, during the maintenance phase, 76 patients were taking placebo, 88 patients were taking 0.6 mg survodutide, 92 were taking 2.4 mg survodutide, 71 were taking 3.6 mg survodutide, and 54 were taking 4.8 mg survodutide, all given as weekly subcutaneous injections.

Primary outcome was the percentage change in body weight from baseline to week 46.

Secondary outcomes included the percentage of patients who reached a body weight reduction of ≥ 5%, ≥ 10%, and ≥ 15% from baseline to week 46.

Mean weight loss at 46 weeks in the planned treatment analysis (where some patients in each group were taking a lower than planned dose during maintenance) was 6.2% in the 0.6-mg survodutide group, 12.5% in the 2.4-mg group, 13.2% in the 3.6-mg group, 14.9% in the 4.8-mg group, and 2.8% in the placebo group.

Among participants who did reach and stay on their assigned dose during the maintenance phase, average weight loss was 6.8% in the 0.6-mg survodutide group,13.6% with 2.4 mg survodutide,16.7% with 3.6 mg survodutide, 18.6% with 4.8 mg survodutide, and 2.0% with placebo.

That is, patients reaching and staying on a weekly subcutaneous dose of 4.8 mg survodutide lost 18.6% of their body weight at 46 weeks, Dr. Le Roux emphasized.

In terms of secondary outcomes, in the group of patients with a planned weekly dose of 4.8 mg survodutide, 83%, 69%, and 55% attained weight loss of ≥ 5%, ≥ 10%, and ≥ 15% of their initial weight, respectively, at 46 weeks.

In the group of patients with an actual weekly dose of 4.8 mg survodutide, 98%, 82%, and 67% attained weight loss of ≥ 5%, ≥ 10%, and ≥ 15% of their initial weight, respectively, at 46 weeks.

Moreover, 33% of patients in the group with a planned weekly dose of 4.8 mg survodutide and 38% of patients with an actual weekly dose of 4.8 mg survodutide lost ≥ 20% of their baseline body weight by week 46.

Adverse events occurred in 91% of patients in the survodutide groups and 75% in the placebo group. The most common side effects were nausea, vomiting, diarrhea, and constipation, which were mostly mild to moderate and mainly occurred during dose escalation. These effects may potentially be mitigated by more gradual dose escalation, Dr. Le Roux said.

There were no unexpected safety or tolerability concerns, and no serious drug-related adverse events.

These “encouraging data” support further study of survodutide for weight loss in larger phase 3 trials, Dr. Le Roux and colleagues conclude.
 

Survodutide has FDA fast track designation for NASH

Survodutide has received U.S. Food and Drug Administration Fast Track Designation for adults with NASH. The drug is currently being evaluated in a phase 2 study in adults with NASH and stages F1/F2/F3 liver fibrosis, with trial completion expected in the last quarter of 2023.

The current trial was funded by Boehringer Ingelheim. Dr. Le Roux has reported being on an advisory panel for Boehringer Ingelheim and being on advisory panels and receiving research funding from multiple other pharmaceutical companies. Two study authors are Boehringer Ingelheim employees.

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

The World Health Organization is set to list the artificial sweetener aspartame as a possible carcinogen.

The move, reported by multiple media sources, is expected during a July 14 meeting of WHO research experts – the International Agency for Research on Cancer. Reuters cited two unnamed sources “with knowledge of the process,” noting that aspartame is one of the world’s most commonly used sweeteners. 

Aspartame is 200 times sweeter than sugar and was first approved by the Food and Drug Administration in 1974 for use as a tabletop sweetener and in chewing gum and cold breakfast cereals, as well as instant coffee, gelatins, puddings and fillings, and dairy products. Up to 95% of carbonated soft drinks that have a sweetener use aspartame, and the substance is often added by consumers to beverages (it’s the blue packet of sweetener in the array of packets that appear on diner and restaurant tables),  The Washington Post  reported. 

The WHO currently lists 126 agents as known to be carcinogenic to humans, ranging from alcohol and tobacco to outdoor air pollution. The WHO also lists 94 agents as “probably” carcinogenic to humans and 322 agents as “possibly” carcinogenic to humans. Aspartame would join the “possibly” group, which includes gasoline engine exhaust and working as a dry cleaner.

Earlier this year, the WHO warned that people should not use nonsugar sweeteners to control their weight because of potential health risks. 
 

A version of this article originally appeared on WebMD.com.

The World Health Organization is set to list the artificial sweetener aspartame as a possible carcinogen.

The move, reported by multiple media sources, is expected during a July 14 meeting of WHO research experts – the International Agency for Research on Cancer. Reuters cited two unnamed sources “with knowledge of the process,” noting that aspartame is one of the world’s most commonly used sweeteners. 

Aspartame is 200 times sweeter than sugar and was first approved by the Food and Drug Administration in 1974 for use as a tabletop sweetener and in chewing gum and cold breakfast cereals, as well as instant coffee, gelatins, puddings and fillings, and dairy products. Up to 95% of carbonated soft drinks that have a sweetener use aspartame, and the substance is often added by consumers to beverages (it’s the blue packet of sweetener in the array of packets that appear on diner and restaurant tables),  The Washington Post  reported. 

The WHO currently lists 126 agents as known to be carcinogenic to humans, ranging from alcohol and tobacco to outdoor air pollution. The WHO also lists 94 agents as “probably” carcinogenic to humans and 322 agents as “possibly” carcinogenic to humans. Aspartame would join the “possibly” group, which includes gasoline engine exhaust and working as a dry cleaner.

Earlier this year, the WHO warned that people should not use nonsugar sweeteners to control their weight because of potential health risks. 
 

A version of this article originally appeared on WebMD.com.

The World Health Organization is set to list the artificial sweetener aspartame as a possible carcinogen.

The move, reported by multiple media sources, is expected during a July 14 meeting of WHO research experts – the International Agency for Research on Cancer. Reuters cited two unnamed sources “with knowledge of the process,” noting that aspartame is one of the world’s most commonly used sweeteners. 

Aspartame is 200 times sweeter than sugar and was first approved by the Food and Drug Administration in 1974 for use as a tabletop sweetener and in chewing gum and cold breakfast cereals, as well as instant coffee, gelatins, puddings and fillings, and dairy products. Up to 95% of carbonated soft drinks that have a sweetener use aspartame, and the substance is often added by consumers to beverages (it’s the blue packet of sweetener in the array of packets that appear on diner and restaurant tables),  The Washington Post  reported. 

The WHO currently lists 126 agents as known to be carcinogenic to humans, ranging from alcohol and tobacco to outdoor air pollution. The WHO also lists 94 agents as “probably” carcinogenic to humans and 322 agents as “possibly” carcinogenic to humans. Aspartame would join the “possibly” group, which includes gasoline engine exhaust and working as a dry cleaner.

Earlier this year, the WHO warned that people should not use nonsugar sweeteners to control their weight because of potential health risks. 
 

A version of this article originally appeared on WebMD.com.

As a general practitioner with a specialist interest in diabetes, I am increasingly diagnosing younger people living with type 2 diabetes and obesity. Sadly, my youngest patient living with type 2 diabetes and obesity is only in her early 20s.
 

In fact, in England, there are now more people under the age of 40 years living with type 2 diabetes than type 1 diabetes. These younger individuals tend to present with very high hemoglobin A1c levels; I am routinely seeing double-digit A1c percentage levels in my practice. Indeed, the patient mentioned above presented with an A1c of more than 13%.

The lifetime cardiometabolic risk of individuals like her is considerable and very worrying: Younger adults with type 2 diabetes often have adverse cardiometabolic risk profiles at diagnosis, with higher body mass indices, marked dyslipidemia, hypertension, and abnormal liver profiles suggesting nonalcoholic fatty liver disease. The cumulative impact of this risk profile is a significant impact on quality and quantity of life. Evidence tells us that a younger age of diagnosis with type 2 diabetes is associated with an increased risk for premature death, especially from cardiovascular disease.

Early treatment intensification is warranted in younger individuals living with type 2 diabetes and obesity. My patient above is now on triple therapy with metformin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, and a glucagonlike peptide–1 (GLP-1) receptor agonist. I gave her an urgent referral to my local weight management service for weight, nutritional, and psychological support. I have also issued her a real-time continuous glucose monitoring (rt-CGM) device: Whilst she does not meet any current U.K. criteria for using rt-CGM, I feel that the role of CGM as an educational tool for her is invaluable and equally important to her pharmacologic therapies. We are in desperate need of effective pharmacologic and lifestyle interventions to tackle this epidemic of cardiometabolic disease in the young.

I attended the recent ADA 2023 congress in San Diego, including the presentation of the SURMOUNT-2 trial data. SURMOUNT-2 explored the efficacy and safety of the dual GLP-GIP agonist tirzepatide for weight management in patients with obesity and type 2 diabetes. Tirzepatide was associated with significant reductions in weight (average weight loss, 14-16 kg after 72 weeks) and glycemia (2.1% reduction in A1c after 72 weeks), as well as reductions in clinically meaningful cardiometabolic risk factors, including systolic blood pressure, liver enzymes, and fasting non–HDL cholesterol levels. The overall safety profile of tirzepatide was also reassuring and consistent with the GLP-1 class. Most adverse effects were gastrointestinal and of mild to moderate severity. These adverse effects decreased over time.

These results perfectly position tirzepatide for my younger patients like the young woman mentioned above. The significant improvements in weight, glycemia, and cardiometabolic risk factors will not only help mitigate her future cardiometabolic risk but also help the sustainability of the U.K.’s National Health System. The cost of diabetes to the NHS in the United Kingdom is more than 10% of the entire NHS budget for England and Wales. More than 80% of this cost, however, is related not to the medications and devices we prescribe for diabetes but to the downstream complications of diabetes, such as hospital admissions for cardiovascular events and amputations, as well as regular hospital attendance for dialysis for end-stage kidney disease.

There is no doubt, however, that modern obesity medications such as semaglutide and tirzepatide are expensive, and demand has been astronomical. This demand has been driven by private weight-management services and celebrity influencers, and has resulted in major U.K.-wide GLP-1 shortages.

This situation is tragically widening health inequalities, as many of my patients who have been on GLP-1 receptor agonists for many years are unable to obtain them. I am having to consider switching therapies, often to less efficacious options without the compelling cardiorenal benefits. Furthermore, the GLP-1 shortages have prevented GLP-1 initiation for my other high-risk younger patients, potentially increasing future cardiometabolic risk.

There remain unanswered questions for tirzepatide: What is the durability of effect of tirzepatide after 72 weeks (that is, the trial duration of SURMOUNT-2)? Crucially, what is the effect of withdrawal of tirzepatide on weight loss maintenance? Previous evidence has suggested weight regain after discontinuation of a GLP-1 receptor agonist for obesity. This, of course, has further financial and sustainability implications for health care systems such as the NHS.

Finally, we are increasingly seeing younger women of childbearing age with or at risk for cardiometabolic disease. Again, my patient above is one example. Many of the therapies we use for cardiometabolic disease management, including GLP-1 receptor agonists and tirzepatide, have not been studied, and hence have not been licensed in pregnant women. Therefore, frank discussions are required with patients about future family plans and the importance of contraception. Often, the significant weight loss seen with GLP-1 receptor agonists can improve hormonal profiles and fertility in women and result in unexpected pregnancies if robust contraception is not in place.

Tirzepatide has yet to be made commercially available in the United Kingdom, and its price has also yet to be set. But I already envision a clear role for tirzepatide in my treatment armamentarium. I will be positioning tirzepatide as my first injectable of choice after oral treatment escalation with metformin and an SGLT2 inhibitor in all my patients who require treatment intensification – not just my younger, higher-risk individuals. This may remain an aspirational goal until supply chains and cost are defined. There is no doubt, however, that the compelling weight and glycemic benefits of tirzepatide alongside individualized lifestyle interventions can help improve the quality and quantity of life of my patients living with type 2 diabetes and obesity.

Dr. Fernando is a general practitioner near Edinburgh. He reported receiving speaker fees from Eli Lilly and Novo Nordisk..

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

As a general practitioner with a specialist interest in diabetes, I am increasingly diagnosing younger people living with type 2 diabetes and obesity. Sadly, my youngest patient living with type 2 diabetes and obesity is only in her early 20s.
 

In fact, in England, there are now more people under the age of 40 years living with type 2 diabetes than type 1 diabetes. These younger individuals tend to present with very high hemoglobin A1c levels; I am routinely seeing double-digit A1c percentage levels in my practice. Indeed, the patient mentioned above presented with an A1c of more than 13%.

The lifetime cardiometabolic risk of individuals like her is considerable and very worrying: Younger adults with type 2 diabetes often have adverse cardiometabolic risk profiles at diagnosis, with higher body mass indices, marked dyslipidemia, hypertension, and abnormal liver profiles suggesting nonalcoholic fatty liver disease. The cumulative impact of this risk profile is a significant impact on quality and quantity of life. Evidence tells us that a younger age of diagnosis with type 2 diabetes is associated with an increased risk for premature death, especially from cardiovascular disease.

Early treatment intensification is warranted in younger individuals living with type 2 diabetes and obesity. My patient above is now on triple therapy with metformin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, and a glucagonlike peptide–1 (GLP-1) receptor agonist. I gave her an urgent referral to my local weight management service for weight, nutritional, and psychological support. I have also issued her a real-time continuous glucose monitoring (rt-CGM) device: Whilst she does not meet any current U.K. criteria for using rt-CGM, I feel that the role of CGM as an educational tool for her is invaluable and equally important to her pharmacologic therapies. We are in desperate need of effective pharmacologic and lifestyle interventions to tackle this epidemic of cardiometabolic disease in the young.

I attended the recent ADA 2023 congress in San Diego, including the presentation of the SURMOUNT-2 trial data. SURMOUNT-2 explored the efficacy and safety of the dual GLP-GIP agonist tirzepatide for weight management in patients with obesity and type 2 diabetes. Tirzepatide was associated with significant reductions in weight (average weight loss, 14-16 kg after 72 weeks) and glycemia (2.1% reduction in A1c after 72 weeks), as well as reductions in clinically meaningful cardiometabolic risk factors, including systolic blood pressure, liver enzymes, and fasting non–HDL cholesterol levels. The overall safety profile of tirzepatide was also reassuring and consistent with the GLP-1 class. Most adverse effects were gastrointestinal and of mild to moderate severity. These adverse effects decreased over time.

These results perfectly position tirzepatide for my younger patients like the young woman mentioned above. The significant improvements in weight, glycemia, and cardiometabolic risk factors will not only help mitigate her future cardiometabolic risk but also help the sustainability of the U.K.’s National Health System. The cost of diabetes to the NHS in the United Kingdom is more than 10% of the entire NHS budget for England and Wales. More than 80% of this cost, however, is related not to the medications and devices we prescribe for diabetes but to the downstream complications of diabetes, such as hospital admissions for cardiovascular events and amputations, as well as regular hospital attendance for dialysis for end-stage kidney disease.

There is no doubt, however, that modern obesity medications such as semaglutide and tirzepatide are expensive, and demand has been astronomical. This demand has been driven by private weight-management services and celebrity influencers, and has resulted in major U.K.-wide GLP-1 shortages.

This situation is tragically widening health inequalities, as many of my patients who have been on GLP-1 receptor agonists for many years are unable to obtain them. I am having to consider switching therapies, often to less efficacious options without the compelling cardiorenal benefits. Furthermore, the GLP-1 shortages have prevented GLP-1 initiation for my other high-risk younger patients, potentially increasing future cardiometabolic risk.

There remain unanswered questions for tirzepatide: What is the durability of effect of tirzepatide after 72 weeks (that is, the trial duration of SURMOUNT-2)? Crucially, what is the effect of withdrawal of tirzepatide on weight loss maintenance? Previous evidence has suggested weight regain after discontinuation of a GLP-1 receptor agonist for obesity. This, of course, has further financial and sustainability implications for health care systems such as the NHS.

Finally, we are increasingly seeing younger women of childbearing age with or at risk for cardiometabolic disease. Again, my patient above is one example. Many of the therapies we use for cardiometabolic disease management, including GLP-1 receptor agonists and tirzepatide, have not been studied, and hence have not been licensed in pregnant women. Therefore, frank discussions are required with patients about future family plans and the importance of contraception. Often, the significant weight loss seen with GLP-1 receptor agonists can improve hormonal profiles and fertility in women and result in unexpected pregnancies if robust contraception is not in place.

Tirzepatide has yet to be made commercially available in the United Kingdom, and its price has also yet to be set. But I already envision a clear role for tirzepatide in my treatment armamentarium. I will be positioning tirzepatide as my first injectable of choice after oral treatment escalation with metformin and an SGLT2 inhibitor in all my patients who require treatment intensification – not just my younger, higher-risk individuals. This may remain an aspirational goal until supply chains and cost are defined. There is no doubt, however, that the compelling weight and glycemic benefits of tirzepatide alongside individualized lifestyle interventions can help improve the quality and quantity of life of my patients living with type 2 diabetes and obesity.

Dr. Fernando is a general practitioner near Edinburgh. He reported receiving speaker fees from Eli Lilly and Novo Nordisk..

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

As a general practitioner with a specialist interest in diabetes, I am increasingly diagnosing younger people living with type 2 diabetes and obesity. Sadly, my youngest patient living with type 2 diabetes and obesity is only in her early 20s.
 

In fact, in England, there are now more people under the age of 40 years living with type 2 diabetes than type 1 diabetes. These younger individuals tend to present with very high hemoglobin A1c levels; I am routinely seeing double-digit A1c percentage levels in my practice. Indeed, the patient mentioned above presented with an A1c of more than 13%.

The lifetime cardiometabolic risk of individuals like her is considerable and very worrying: Younger adults with type 2 diabetes often have adverse cardiometabolic risk profiles at diagnosis, with higher body mass indices, marked dyslipidemia, hypertension, and abnormal liver profiles suggesting nonalcoholic fatty liver disease. The cumulative impact of this risk profile is a significant impact on quality and quantity of life. Evidence tells us that a younger age of diagnosis with type 2 diabetes is associated with an increased risk for premature death, especially from cardiovascular disease.

Early treatment intensification is warranted in younger individuals living with type 2 diabetes and obesity. My patient above is now on triple therapy with metformin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, and a glucagonlike peptide–1 (GLP-1) receptor agonist. I gave her an urgent referral to my local weight management service for weight, nutritional, and psychological support. I have also issued her a real-time continuous glucose monitoring (rt-CGM) device: Whilst she does not meet any current U.K. criteria for using rt-CGM, I feel that the role of CGM as an educational tool for her is invaluable and equally important to her pharmacologic therapies. We are in desperate need of effective pharmacologic and lifestyle interventions to tackle this epidemic of cardiometabolic disease in the young.

I attended the recent ADA 2023 congress in San Diego, including the presentation of the SURMOUNT-2 trial data. SURMOUNT-2 explored the efficacy and safety of the dual GLP-GIP agonist tirzepatide for weight management in patients with obesity and type 2 diabetes. Tirzepatide was associated with significant reductions in weight (average weight loss, 14-16 kg after 72 weeks) and glycemia (2.1% reduction in A1c after 72 weeks), as well as reductions in clinically meaningful cardiometabolic risk factors, including systolic blood pressure, liver enzymes, and fasting non–HDL cholesterol levels. The overall safety profile of tirzepatide was also reassuring and consistent with the GLP-1 class. Most adverse effects were gastrointestinal and of mild to moderate severity. These adverse effects decreased over time.

These results perfectly position tirzepatide for my younger patients like the young woman mentioned above. The significant improvements in weight, glycemia, and cardiometabolic risk factors will not only help mitigate her future cardiometabolic risk but also help the sustainability of the U.K.’s National Health System. The cost of diabetes to the NHS in the United Kingdom is more than 10% of the entire NHS budget for England and Wales. More than 80% of this cost, however, is related not to the medications and devices we prescribe for diabetes but to the downstream complications of diabetes, such as hospital admissions for cardiovascular events and amputations, as well as regular hospital attendance for dialysis for end-stage kidney disease.

There is no doubt, however, that modern obesity medications such as semaglutide and tirzepatide are expensive, and demand has been astronomical. This demand has been driven by private weight-management services and celebrity influencers, and has resulted in major U.K.-wide GLP-1 shortages.

This situation is tragically widening health inequalities, as many of my patients who have been on GLP-1 receptor agonists for many years are unable to obtain them. I am having to consider switching therapies, often to less efficacious options without the compelling cardiorenal benefits. Furthermore, the GLP-1 shortages have prevented GLP-1 initiation for my other high-risk younger patients, potentially increasing future cardiometabolic risk.

There remain unanswered questions for tirzepatide: What is the durability of effect of tirzepatide after 72 weeks (that is, the trial duration of SURMOUNT-2)? Crucially, what is the effect of withdrawal of tirzepatide on weight loss maintenance? Previous evidence has suggested weight regain after discontinuation of a GLP-1 receptor agonist for obesity. This, of course, has further financial and sustainability implications for health care systems such as the NHS.

Finally, we are increasingly seeing younger women of childbearing age with or at risk for cardiometabolic disease. Again, my patient above is one example. Many of the therapies we use for cardiometabolic disease management, including GLP-1 receptor agonists and tirzepatide, have not been studied, and hence have not been licensed in pregnant women. Therefore, frank discussions are required with patients about future family plans and the importance of contraception. Often, the significant weight loss seen with GLP-1 receptor agonists can improve hormonal profiles and fertility in women and result in unexpected pregnancies if robust contraception is not in place.

Tirzepatide has yet to be made commercially available in the United Kingdom, and its price has also yet to be set. But I already envision a clear role for tirzepatide in my treatment armamentarium. I will be positioning tirzepatide as my first injectable of choice after oral treatment escalation with metformin and an SGLT2 inhibitor in all my patients who require treatment intensification – not just my younger, higher-risk individuals. This may remain an aspirational goal until supply chains and cost are defined. There is no doubt, however, that the compelling weight and glycemic benefits of tirzepatide alongside individualized lifestyle interventions can help improve the quality and quantity of life of my patients living with type 2 diabetes and obesity.

Dr. Fernando is a general practitioner near Edinburgh. He reported receiving speaker fees from Eli Lilly and Novo Nordisk..

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

Patients with head and neck cancer and overweight saw better treatment response and survival after chemoradiation, compared with patients with the same type of cancer but a normal weight, a new study finds.

The findings, published in JAMA Network Open, are the latest to parse the complex relationship between body mass index (BMI) and treatment in cancers that is sometimes called the “obesity paradox.” The researchers compared outcomes among patients with normal weight, overweight, and obesity.

While higher BMI is an established risk factor for many types of cancer and for cancer-specific mortality overall, studies in some cancers have shown that patients with higher BMI do better, possibly because excess BMI acts as a nutrient reserve against treatment-associated weight loss.
 

Methods and results

For their research, Sung Jun Ma, MD, of Roswell Park Comprehensive Cancer Center, Buffalo, N.Y., and colleagues looked at records for 445 patients (84% men, median age 61) at Dr. Ma’s institution with nonmetastatic head and neck cancer who underwent chemoradiotherapy between 2005 and 2021. Patients were followed up for a median 48 months, and those with underweight at treatment initiation were excluded.

The researchers found that overweight BMI (25-29.9 kg/m²) was associated with improved overall survival at 5 years (71% vs. 58% of patients with normal weight), as well as 5-year progression-free survival (68% vs. 51%). No overall or progression-free survival benefit link was seen in patients with a BMI of 30 or higher, in contrast to some previous studies of patients with head and neck cancers. BMI was not associated with improved survival outcomes among human papillomavirus–positive patients.

Both overweight and obesity were associated with complete response on follow-up PET-CT, with nearly 92% of patients with overweight and 91% of patients with obesity (defined as having a BMI of 30 or higher) seeing a complete metabolic response, compared with 74% of patients with normal weight.

Having an overweight BMI was also associated with improvements in tumor recurrence, with fewer of patients with this type of BMI experiencing 5-year locoregional failure than patients with normal weight (7% vs 26%). Having an obese BMI was not associated with improvements in recurrence. All the reported differences reached statistical significance.

The study authors surmised that the discrepancies between outcomes for patients with overweight and obesity “may be due to a nonlinear association between BMI and survival, with the highest survival seen in the overweight BMI range.”

It was important to note that this study saw no differences in treatment interruptions between the BMI groups that could account for differences in outcomes. Only three patients in the cohort saw their radiotherapy treatment interrupted, Dr. Ma said in an interview.

“If we felt that the obesity paradox happens because people with normal BMI lose too much weight during the treatment course, treatment gets interrupted, and they get worse outcomes from suboptimal treatments, then we would have seen more treatment interruptions among those with normal BMI. However, that was not the case in our study,” he said. Rather, the results point to “a complex interaction among cancer, [a person’s build], and nutritional status.”

Clinicians should be aware, Dr. Ma added, “that the same head and neck cancer may behave more aggressively among patients with normal BMI, compared to others with overweight BMI. Patients with normal BMI may need to be monitored more closely and carefully for potentially worse outcomes.” 

The investigators acknowledged several weaknesses of their study, including its retrospective design, the measure of BMI using cutoffs rather than a continuum, and the collection of BMI information at a single time point. While 84% of patients in the study received cisplatin, the study did not contain information on cumulative cisplatin dose.
 

Importance of nutritional support during treatment highlighted

In an interview, Ari Rosenberg, MD, of the University of Chicago Medicine, commented that the findings highlighted the importance of expert nutritional supportive care during treatment and monitoring for patients with advanced head and neck cancers undergoing chemoradiation.

“Nutritional status is very important both at baseline and during treatment,” Dr. Rosenberg said. “Even small changes in weight or BMI can be a key indicator of supportive care during chemoradiation and represent a biomarker to guide supportive management. ... The take home message is that patients should be treated at centers that have a high volume of advanced head and neck cancer patients, which have all the supportive components and expertise to optimize treatment delivery and maximize survival.”

Dr. Ma and colleagues’ study was funded by the National Cancer Institute Cancer Center. None of its authors declared financial conflicts of interest. Dr. Rosenberg disclosed receiving consulting fees from EMD Serono related to head and neck cancer treatment.
 

Patients with head and neck cancer and overweight saw better treatment response and survival after chemoradiation, compared with patients with the same type of cancer but a normal weight, a new study finds.

The findings, published in JAMA Network Open, are the latest to parse the complex relationship between body mass index (BMI) and treatment in cancers that is sometimes called the “obesity paradox.” The researchers compared outcomes among patients with normal weight, overweight, and obesity.

While higher BMI is an established risk factor for many types of cancer and for cancer-specific mortality overall, studies in some cancers have shown that patients with higher BMI do better, possibly because excess BMI acts as a nutrient reserve against treatment-associated weight loss.
 

Methods and results

For their research, Sung Jun Ma, MD, of Roswell Park Comprehensive Cancer Center, Buffalo, N.Y., and colleagues looked at records for 445 patients (84% men, median age 61) at Dr. Ma’s institution with nonmetastatic head and neck cancer who underwent chemoradiotherapy between 2005 and 2021. Patients were followed up for a median 48 months, and those with underweight at treatment initiation were excluded.

The researchers found that overweight BMI (25-29.9 kg/m²) was associated with improved overall survival at 5 years (71% vs. 58% of patients with normal weight), as well as 5-year progression-free survival (68% vs. 51%). No overall or progression-free survival benefit link was seen in patients with a BMI of 30 or higher, in contrast to some previous studies of patients with head and neck cancers. BMI was not associated with improved survival outcomes among human papillomavirus–positive patients.

Both overweight and obesity were associated with complete response on follow-up PET-CT, with nearly 92% of patients with overweight and 91% of patients with obesity (defined as having a BMI of 30 or higher) seeing a complete metabolic response, compared with 74% of patients with normal weight.

Having an overweight BMI was also associated with improvements in tumor recurrence, with fewer of patients with this type of BMI experiencing 5-year locoregional failure than patients with normal weight (7% vs 26%). Having an obese BMI was not associated with improvements in recurrence. All the reported differences reached statistical significance.

The study authors surmised that the discrepancies between outcomes for patients with overweight and obesity “may be due to a nonlinear association between BMI and survival, with the highest survival seen in the overweight BMI range.”

It was important to note that this study saw no differences in treatment interruptions between the BMI groups that could account for differences in outcomes. Only three patients in the cohort saw their radiotherapy treatment interrupted, Dr. Ma said in an interview.

“If we felt that the obesity paradox happens because people with normal BMI lose too much weight during the treatment course, treatment gets interrupted, and they get worse outcomes from suboptimal treatments, then we would have seen more treatment interruptions among those with normal BMI. However, that was not the case in our study,” he said. Rather, the results point to “a complex interaction among cancer, [a person’s build], and nutritional status.”

Clinicians should be aware, Dr. Ma added, “that the same head and neck cancer may behave more aggressively among patients with normal BMI, compared to others with overweight BMI. Patients with normal BMI may need to be monitored more closely and carefully for potentially worse outcomes.” 

The investigators acknowledged several weaknesses of their study, including its retrospective design, the measure of BMI using cutoffs rather than a continuum, and the collection of BMI information at a single time point. While 84% of patients in the study received cisplatin, the study did not contain information on cumulative cisplatin dose.
 

Importance of nutritional support during treatment highlighted

In an interview, Ari Rosenberg, MD, of the University of Chicago Medicine, commented that the findings highlighted the importance of expert nutritional supportive care during treatment and monitoring for patients with advanced head and neck cancers undergoing chemoradiation.

“Nutritional status is very important both at baseline and during treatment,” Dr. Rosenberg said. “Even small changes in weight or BMI can be a key indicator of supportive care during chemoradiation and represent a biomarker to guide supportive management. ... The take home message is that patients should be treated at centers that have a high volume of advanced head and neck cancer patients, which have all the supportive components and expertise to optimize treatment delivery and maximize survival.”

Dr. Ma and colleagues’ study was funded by the National Cancer Institute Cancer Center. None of its authors declared financial conflicts of interest. Dr. Rosenberg disclosed receiving consulting fees from EMD Serono related to head and neck cancer treatment.
 

Patients with head and neck cancer and overweight saw better treatment response and survival after chemoradiation, compared with patients with the same type of cancer but a normal weight, a new study finds.

The findings, published in JAMA Network Open, are the latest to parse the complex relationship between body mass index (BMI) and treatment in cancers that is sometimes called the “obesity paradox.” The researchers compared outcomes among patients with normal weight, overweight, and obesity.

While higher BMI is an established risk factor for many types of cancer and for cancer-specific mortality overall, studies in some cancers have shown that patients with higher BMI do better, possibly because excess BMI acts as a nutrient reserve against treatment-associated weight loss.
 

Methods and results

For their research, Sung Jun Ma, MD, of Roswell Park Comprehensive Cancer Center, Buffalo, N.Y., and colleagues looked at records for 445 patients (84% men, median age 61) at Dr. Ma’s institution with nonmetastatic head and neck cancer who underwent chemoradiotherapy between 2005 and 2021. Patients were followed up for a median 48 months, and those with underweight at treatment initiation were excluded.

The researchers found that overweight BMI (25-29.9 kg/m²) was associated with improved overall survival at 5 years (71% vs. 58% of patients with normal weight), as well as 5-year progression-free survival (68% vs. 51%). No overall or progression-free survival benefit link was seen in patients with a BMI of 30 or higher, in contrast to some previous studies of patients with head and neck cancers. BMI was not associated with improved survival outcomes among human papillomavirus–positive patients.

Both overweight and obesity were associated with complete response on follow-up PET-CT, with nearly 92% of patients with overweight and 91% of patients with obesity (defined as having a BMI of 30 or higher) seeing a complete metabolic response, compared with 74% of patients with normal weight.

Having an overweight BMI was also associated with improvements in tumor recurrence, with fewer of patients with this type of BMI experiencing 5-year locoregional failure than patients with normal weight (7% vs 26%). Having an obese BMI was not associated with improvements in recurrence. All the reported differences reached statistical significance.

The study authors surmised that the discrepancies between outcomes for patients with overweight and obesity “may be due to a nonlinear association between BMI and survival, with the highest survival seen in the overweight BMI range.”

It was important to note that this study saw no differences in treatment interruptions between the BMI groups that could account for differences in outcomes. Only three patients in the cohort saw their radiotherapy treatment interrupted, Dr. Ma said in an interview.

“If we felt that the obesity paradox happens because people with normal BMI lose too much weight during the treatment course, treatment gets interrupted, and they get worse outcomes from suboptimal treatments, then we would have seen more treatment interruptions among those with normal BMI. However, that was not the case in our study,” he said. Rather, the results point to “a complex interaction among cancer, [a person’s build], and nutritional status.”

Clinicians should be aware, Dr. Ma added, “that the same head and neck cancer may behave more aggressively among patients with normal BMI, compared to others with overweight BMI. Patients with normal BMI may need to be monitored more closely and carefully for potentially worse outcomes.” 

The investigators acknowledged several weaknesses of their study, including its retrospective design, the measure of BMI using cutoffs rather than a continuum, and the collection of BMI information at a single time point. While 84% of patients in the study received cisplatin, the study did not contain information on cumulative cisplatin dose.
 

Importance of nutritional support during treatment highlighted

In an interview, Ari Rosenberg, MD, of the University of Chicago Medicine, commented that the findings highlighted the importance of expert nutritional supportive care during treatment and monitoring for patients with advanced head and neck cancers undergoing chemoradiation.

“Nutritional status is very important both at baseline and during treatment,” Dr. Rosenberg said. “Even small changes in weight or BMI can be a key indicator of supportive care during chemoradiation and represent a biomarker to guide supportive management. ... The take home message is that patients should be treated at centers that have a high volume of advanced head and neck cancer patients, which have all the supportive components and expertise to optimize treatment delivery and maximize survival.”

Dr. Ma and colleagues’ study was funded by the National Cancer Institute Cancer Center. None of its authors declared financial conflicts of interest. Dr. Rosenberg disclosed receiving consulting fees from EMD Serono related to head and neck cancer treatment.
 

Eight-hour intermittent fasting had similar weight loss results to calorie counting in adults with obesity, a new study published online in Annals of Internal Medicine has found. The small, unblinded study compared weight loss in 77 participants who either intermittently fasted, adhered to a calorie-restricted diet, or were in a control group with no eating restrictions.

Compared with the control group, absolute weight loss for people in the intermittent fasting group was about 4.6 kg (10 lb), compared with 5.4 kg (12 lb) for those in the calorie-restriction group, after 12 months, with no significant difference between the intervention groups.

Intermittent fasting, or time-restricted eating, relies on the idea that the time you eat is more important for weight loss than what or how much you eat. The term is a catch-all for eating patterns that could include several full days of fasting per week or time-restricted eating during the day.

The effect of having less time to eat is thought to lead to the consumption of fewer calories, thought to be the main reason the approach works. Indeed, this trial found the intermittent fasting group ate 425 fewer calories per day, compared with 405 fewer calories per day in the calorie-restricted group. 

“Time-restricted eating is undoubtedly an attractive approach to weight loss in that it does not require the purchase of expensive food products, allows persons to continue consuming familiar foods, and omits complicated calorie tracking,” Shuhao Lin, RD, University of Illinois at Chicago, and colleagues write.

During the trial, participants were in a weight-loss phase for 6 months. The intermittent fasting group could eat anything they wanted to between 12 p.m. and 8 p.m., and didn’t have to count calories. The later time window is on par with the eating pattern of most people in the United States who fast.

The calorie-restriction group had to cut 25% of their daily calorie intake based on their total energy expenditure. They were also told to fill half of every plate with fruits or vegetables, and consume about half their energy as carbohydrates, 30% as fat, and 20% as protein.

The weight-loss phase was followed by a 6-month weight-maintenance phase. During this phase, the window for eating was extended from 10 a.m. to 8 p.m. for the intermittent fasting group, and the calorie-restriction group was told to match their energy needs, which overall, had reduced by about 15%, compared with baseline.

Most participants were women with a mean body weight of about 100 kg (220 pounds) at baseline.

Both the time-restricted eating and calorie-restriction groups regularly met with dietitians, which the authors of an accompanying editorial say could have made the intermittent fasting more effective than in previous trials.

An earlier, shorter trial found about 0.9 kg (2 lb) weight loss after 12 weeks of adhering to a similar eating window, a more modest result, compared with the 4 kg (9 lb) weight loss at 6 months in this trial.

“The difference in outcomes between these two trials is likely attributable to differences in dietary counseling,” write the editorialists, Adam Gilden, MD, and Victoria Catenacci, MD, from University of Colorado at Denver, Aurora.

Previous studies of intermittent fasting have been short and showed similar findings, compared with a calorie-restricted diet.

The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health.

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

Eight-hour intermittent fasting had similar weight loss results to calorie counting in adults with obesity, a new study published online in Annals of Internal Medicine has found. The small, unblinded study compared weight loss in 77 participants who either intermittently fasted, adhered to a calorie-restricted diet, or were in a control group with no eating restrictions.

Compared with the control group, absolute weight loss for people in the intermittent fasting group was about 4.6 kg (10 lb), compared with 5.4 kg (12 lb) for those in the calorie-restriction group, after 12 months, with no significant difference between the intervention groups.

Intermittent fasting, or time-restricted eating, relies on the idea that the time you eat is more important for weight loss than what or how much you eat. The term is a catch-all for eating patterns that could include several full days of fasting per week or time-restricted eating during the day.

The effect of having less time to eat is thought to lead to the consumption of fewer calories, thought to be the main reason the approach works. Indeed, this trial found the intermittent fasting group ate 425 fewer calories per day, compared with 405 fewer calories per day in the calorie-restricted group. 

“Time-restricted eating is undoubtedly an attractive approach to weight loss in that it does not require the purchase of expensive food products, allows persons to continue consuming familiar foods, and omits complicated calorie tracking,” Shuhao Lin, RD, University of Illinois at Chicago, and colleagues write.

During the trial, participants were in a weight-loss phase for 6 months. The intermittent fasting group could eat anything they wanted to between 12 p.m. and 8 p.m., and didn’t have to count calories. The later time window is on par with the eating pattern of most people in the United States who fast.

The calorie-restriction group had to cut 25% of their daily calorie intake based on their total energy expenditure. They were also told to fill half of every plate with fruits or vegetables, and consume about half their energy as carbohydrates, 30% as fat, and 20% as protein.

The weight-loss phase was followed by a 6-month weight-maintenance phase. During this phase, the window for eating was extended from 10 a.m. to 8 p.m. for the intermittent fasting group, and the calorie-restriction group was told to match their energy needs, which overall, had reduced by about 15%, compared with baseline.

Most participants were women with a mean body weight of about 100 kg (220 pounds) at baseline.

Both the time-restricted eating and calorie-restriction groups regularly met with dietitians, which the authors of an accompanying editorial say could have made the intermittent fasting more effective than in previous trials.

An earlier, shorter trial found about 0.9 kg (2 lb) weight loss after 12 weeks of adhering to a similar eating window, a more modest result, compared with the 4 kg (9 lb) weight loss at 6 months in this trial.

“The difference in outcomes between these two trials is likely attributable to differences in dietary counseling,” write the editorialists, Adam Gilden, MD, and Victoria Catenacci, MD, from University of Colorado at Denver, Aurora.

Previous studies of intermittent fasting have been short and showed similar findings, compared with a calorie-restricted diet.

The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health.

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

Eight-hour intermittent fasting had similar weight loss results to calorie counting in adults with obesity, a new study published online in Annals of Internal Medicine has found. The small, unblinded study compared weight loss in 77 participants who either intermittently fasted, adhered to a calorie-restricted diet, or were in a control group with no eating restrictions.

Compared with the control group, absolute weight loss for people in the intermittent fasting group was about 4.6 kg (10 lb), compared with 5.4 kg (12 lb) for those in the calorie-restriction group, after 12 months, with no significant difference between the intervention groups.

Intermittent fasting, or time-restricted eating, relies on the idea that the time you eat is more important for weight loss than what or how much you eat. The term is a catch-all for eating patterns that could include several full days of fasting per week or time-restricted eating during the day.

The effect of having less time to eat is thought to lead to the consumption of fewer calories, thought to be the main reason the approach works. Indeed, this trial found the intermittent fasting group ate 425 fewer calories per day, compared with 405 fewer calories per day in the calorie-restricted group. 

“Time-restricted eating is undoubtedly an attractive approach to weight loss in that it does not require the purchase of expensive food products, allows persons to continue consuming familiar foods, and omits complicated calorie tracking,” Shuhao Lin, RD, University of Illinois at Chicago, and colleagues write.

During the trial, participants were in a weight-loss phase for 6 months. The intermittent fasting group could eat anything they wanted to between 12 p.m. and 8 p.m., and didn’t have to count calories. The later time window is on par with the eating pattern of most people in the United States who fast.

The calorie-restriction group had to cut 25% of their daily calorie intake based on their total energy expenditure. They were also told to fill half of every plate with fruits or vegetables, and consume about half their energy as carbohydrates, 30% as fat, and 20% as protein.

The weight-loss phase was followed by a 6-month weight-maintenance phase. During this phase, the window for eating was extended from 10 a.m. to 8 p.m. for the intermittent fasting group, and the calorie-restriction group was told to match their energy needs, which overall, had reduced by about 15%, compared with baseline.

Most participants were women with a mean body weight of about 100 kg (220 pounds) at baseline.

Both the time-restricted eating and calorie-restriction groups regularly met with dietitians, which the authors of an accompanying editorial say could have made the intermittent fasting more effective than in previous trials.

An earlier, shorter trial found about 0.9 kg (2 lb) weight loss after 12 weeks of adhering to a similar eating window, a more modest result, compared with the 4 kg (9 lb) weight loss at 6 months in this trial.

“The difference in outcomes between these two trials is likely attributable to differences in dietary counseling,” write the editorialists, Adam Gilden, MD, and Victoria Catenacci, MD, from University of Colorado at Denver, Aurora.

Previous studies of intermittent fasting have been short and showed similar findings, compared with a calorie-restricted diet.

The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health.

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

SAN DIEGO – New designer molecules that target weight loss via multiple mechanisms continue to raise the bar of how many pounds people with overweight or obesity can lose.

Retatrutide (Eli Lilly), an investigational agent that combines agonism to three key hormones that influence eating and metabolism into a single molecule, safely produced weight loss at levels never seen before in a pair of phase 2 studies that together randomized more than 600 people with overweight or obesity, with or without type 2 diabetes.

Among 338 randomized people with overweight or obesity and no type 2 diabetes, 48 weeks of treatment with retatrutide at a 12-mg dose given by weekly subcutaneous injection (the highest dose tested) safely produced an average 24% drop from baseline bodyweight.

Among 281 randomized people with overweight or obesity and type 2 diabetes, the same dose of retatrutide produced a nearly 17% cut in weight from baseline after 36 weeks of treatment.
 

Never before seen weight loss

“I have never seen weight loss at this level” after nearly 1 year of treatment, Ania M. Jastreboff, MD, PhD, who led the obesity study, said during a press briefing at the annual scientific sessions of the American Diabetes Association.

The average weight loss by study participants taking high-dose retatrutide in the two studies “is really impressive, way beyond my wildest dreams,” said Carel le Roux, MBChB, PhD, an obesity and diabetes researcher at University College Dublin, Ireland, who was not involved with the retatrutide studies.

And Robert A. Gabbay, MD, chief scientific and medical officer of the ADA, called the results “stunning,” and added, “we are now witnessing the first triple-hormone combination being highly effective for not only weight loss but liver disease and diabetes.”

Joslin Diabetes Center

Adding glucagon agonism ups liver-fat clearance

“When you add glucagon activity,” one of the three agonist actions of retatrutide, “liver-fat clearance goes up tremendously,” said Dr. Kaplan, director of the Obesity, Metabolism and Nutrition Institute at Massachusetts General Hospital in Boston.

“To my knowledge, no mono-agonist of the glucagon-like peptide-1 (GLP-1) receptor [such as semaglutide or liraglutide] produces more than 50% clearance of liver fat,” added Dr. Kaplan.

The separate, randomized study of people with type 2 diabetes showed that in addition to producing an unprecedented average level of weight loss at the highest retatrutide dose, the agent also produced an average reduction from baseline levels of A1c of about 2 percentage points, an efficacy roughly comparable to maximum doses of the most potent GLP-1 mono-agonist semaglutide (Ozempic, Novo Nordisk), as well as by tirzepatide (Mounjaro, Eli Lilly), a dual agonist for the GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) receptors.

“No other medication has shown an average 17% reduction from baseline bodyweight after 36 weeks in people with type 2 diabetes,” said Julio Rosenstock, MD, director of the Dallas Diabetes Research Center at Medical City, Texas, who presented the results from the type 2 diabetes study of retatrutide.

For the obesity study, people with a body mass index of 27-50 kg/m² and no diabetes were randomized to placebo or any of four retatrutide target dosages using specified dose-escalation protocols. Participants were an average of 48 years old, and by design, 52% were men. (The study sought to enroll roughly equal numbers of men and women.) Average BMI at study entry was 37 kg/m².

Weight loss levels after 24 and 48 weeks of retatrutide treatment followed a clear dose-related pattern. (Weight loss averaged about 2% among the 70 controls who received placebo.)
 

Twenty-six percent without diabetes lost at least 30% of body weight

Every person who escalated to receive the 8-mg or 12-mg weekly dose of retatrutide lost at least 5% of their bodyweight after 48 weeks, 83% of those taking the 12-mg dose lost at least 15%, 63% of those on the 12-mg dose lost at least 20%, and 26% of those on the highest dose lost at least 30% of their starting bodyweight, reported Dr. Jastreboff, director of the Yale Obesity Research Center of Yale University in New Haven, Conn.

The highest dose was also associated with an average 40% relative reduction in triglyceride levels from baseline and an average 22% relative drop in LDL cholesterol levels.

The results were simultaneously published online in the New England Journal of Medicine.

The incidence of serious adverse events with retatrutide was low, similar to the rate in those who received placebo, and showed no dose relationship.

The most common adverse events were gastrointestinal, in as many as 16% of those on the highest dose; these were mild to moderate in severity and usually occurred during dose escalation. In general, adverse events were comparable to what is seen with a GLP-1 agonist or the dual agonist tirzepatide, Dr. Jastreboff said.
 

A1c normalization in 26% at the highest dose

A similar safety pattern occurred in the study of people with type 2 diabetes, which randomized people with an average A1c of 8.3% and an average BMI of 35.0 kg/m². After 36 weeks of treatment, the 12-mg weekly dose of retatrutide led to normalization of A1c < 5.7% in 27% of people and A1c ≤ 6.5% in 77%.

“The number of people we were able to revert to a normal A1c was impressive,” said Dr. Rosenstock. These results were simultaneously published online in The Lancet.

The additional findings on liver-fat mobilization in people without diabetes enrolled in the obesity study are notable because no agent currently has labeling from the Food and Drug Administration for the indication of reducing excess liver fat, said Dr. Kaplan.

The researchers measured liver fat at baseline and then during treatment using MRI.

“With the level of fat clearance from the liver that we see with retatrutide it is highly likely that we’ll also see improvements in liver fibrosis” in retatrutide-treated patients, Dr. Kaplan predicted.

Next up for retatrutide is testing in pivotal trials, including the TRIUMPH-3 trial that will enroll about 1,800 people with severe obesity and cardiovascular disease, with findings expected toward the end of 2025.

The retatrutide studies are sponsored by Eli Lilly. Dr. Jastreboff, Dr. Rosenstock, Dr. Kaplan, and Dr. Le Roux have reported financial relationships with Eli Lilly as well as other companies.

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

SAN DIEGO – New designer molecules that target weight loss via multiple mechanisms continue to raise the bar of how many pounds people with overweight or obesity can lose.

Retatrutide (Eli Lilly), an investigational agent that combines agonism to three key hormones that influence eating and metabolism into a single molecule, safely produced weight loss at levels never seen before in a pair of phase 2 studies that together randomized more than 600 people with overweight or obesity, with or without type 2 diabetes.

Among 338 randomized people with overweight or obesity and no type 2 diabetes, 48 weeks of treatment with retatrutide at a 12-mg dose given by weekly subcutaneous injection (the highest dose tested) safely produced an average 24% drop from baseline bodyweight.

Among 281 randomized people with overweight or obesity and type 2 diabetes, the same dose of retatrutide produced a nearly 17% cut in weight from baseline after 36 weeks of treatment.
 

Never before seen weight loss

“I have never seen weight loss at this level” after nearly 1 year of treatment, Ania M. Jastreboff, MD, PhD, who led the obesity study, said during a press briefing at the annual scientific sessions of the American Diabetes Association.

The average weight loss by study participants taking high-dose retatrutide in the two studies “is really impressive, way beyond my wildest dreams,” said Carel le Roux, MBChB, PhD, an obesity and diabetes researcher at University College Dublin, Ireland, who was not involved with the retatrutide studies.

And Robert A. Gabbay, MD, chief scientific and medical officer of the ADA, called the results “stunning,” and added, “we are now witnessing the first triple-hormone combination being highly effective for not only weight loss but liver disease and diabetes.”

Joslin Diabetes Center

Adding glucagon agonism ups liver-fat clearance

“When you add glucagon activity,” one of the three agonist actions of retatrutide, “liver-fat clearance goes up tremendously,” said Dr. Kaplan, director of the Obesity, Metabolism and Nutrition Institute at Massachusetts General Hospital in Boston.

“To my knowledge, no mono-agonist of the glucagon-like peptide-1 (GLP-1) receptor [such as semaglutide or liraglutide] produces more than 50% clearance of liver fat,” added Dr. Kaplan.

The separate, randomized study of people with type 2 diabetes showed that in addition to producing an unprecedented average level of weight loss at the highest retatrutide dose, the agent also produced an average reduction from baseline levels of A1c of about 2 percentage points, an efficacy roughly comparable to maximum doses of the most potent GLP-1 mono-agonist semaglutide (Ozempic, Novo Nordisk), as well as by tirzepatide (Mounjaro, Eli Lilly), a dual agonist for the GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) receptors.

“No other medication has shown an average 17% reduction from baseline bodyweight after 36 weeks in people with type 2 diabetes,” said Julio Rosenstock, MD, director of the Dallas Diabetes Research Center at Medical City, Texas, who presented the results from the type 2 diabetes study of retatrutide.

For the obesity study, people with a body mass index of 27-50 kg/m² and no diabetes were randomized to placebo or any of four retatrutide target dosages using specified dose-escalation protocols. Participants were an average of 48 years old, and by design, 52% were men. (The study sought to enroll roughly equal numbers of men and women.) Average BMI at study entry was 37 kg/m².

Weight loss levels after 24 and 48 weeks of retatrutide treatment followed a clear dose-related pattern. (Weight loss averaged about 2% among the 70 controls who received placebo.)
 

Twenty-six percent without diabetes lost at least 30% of body weight

Every person who escalated to receive the 8-mg or 12-mg weekly dose of retatrutide lost at least 5% of their bodyweight after 48 weeks, 83% of those taking the 12-mg dose lost at least 15%, 63% of those on the 12-mg dose lost at least 20%, and 26% of those on the highest dose lost at least 30% of their starting bodyweight, reported Dr. Jastreboff, director of the Yale Obesity Research Center of Yale University in New Haven, Conn.

The highest dose was also associated with an average 40% relative reduction in triglyceride levels from baseline and an average 22% relative drop in LDL cholesterol levels.

The results were simultaneously published online in the New England Journal of Medicine.

The incidence of serious adverse events with retatrutide was low, similar to the rate in those who received placebo, and showed no dose relationship.

The most common adverse events were gastrointestinal, in as many as 16% of those on the highest dose; these were mild to moderate in severity and usually occurred during dose escalation. In general, adverse events were comparable to what is seen with a GLP-1 agonist or the dual agonist tirzepatide, Dr. Jastreboff said.
 

A1c normalization in 26% at the highest dose

A similar safety pattern occurred in the study of people with type 2 diabetes, which randomized people with an average A1c of 8.3% and an average BMI of 35.0 kg/m². After 36 weeks of treatment, the 12-mg weekly dose of retatrutide led to normalization of A1c < 5.7% in 27% of people and A1c ≤ 6.5% in 77%.

“The number of people we were able to revert to a normal A1c was impressive,” said Dr. Rosenstock. These results were simultaneously published online in The Lancet.

The additional findings on liver-fat mobilization in people without diabetes enrolled in the obesity study are notable because no agent currently has labeling from the Food and Drug Administration for the indication of reducing excess liver fat, said Dr. Kaplan.

The researchers measured liver fat at baseline and then during treatment using MRI.

“With the level of fat clearance from the liver that we see with retatrutide it is highly likely that we’ll also see improvements in liver fibrosis” in retatrutide-treated patients, Dr. Kaplan predicted.

Next up for retatrutide is testing in pivotal trials, including the TRIUMPH-3 trial that will enroll about 1,800 people with severe obesity and cardiovascular disease, with findings expected toward the end of 2025.

The retatrutide studies are sponsored by Eli Lilly. Dr. Jastreboff, Dr. Rosenstock, Dr. Kaplan, and Dr. Le Roux have reported financial relationships with Eli Lilly as well as other companies.

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

SAN DIEGO – New designer molecules that target weight loss via multiple mechanisms continue to raise the bar of how many pounds people with overweight or obesity can lose.

Retatrutide (Eli Lilly), an investigational agent that combines agonism to three key hormones that influence eating and metabolism into a single molecule, safely produced weight loss at levels never seen before in a pair of phase 2 studies that together randomized more than 600 people with overweight or obesity, with or without type 2 diabetes.

Among 338 randomized people with overweight or obesity and no type 2 diabetes, 48 weeks of treatment with retatrutide at a 12-mg dose given by weekly subcutaneous injection (the highest dose tested) safely produced an average 24% drop from baseline bodyweight.

Among 281 randomized people with overweight or obesity and type 2 diabetes, the same dose of retatrutide produced a nearly 17% cut in weight from baseline after 36 weeks of treatment.
 

Never before seen weight loss

“I have never seen weight loss at this level” after nearly 1 year of treatment, Ania M. Jastreboff, MD, PhD, who led the obesity study, said during a press briefing at the annual scientific sessions of the American Diabetes Association.

The average weight loss by study participants taking high-dose retatrutide in the two studies “is really impressive, way beyond my wildest dreams,” said Carel le Roux, MBChB, PhD, an obesity and diabetes researcher at University College Dublin, Ireland, who was not involved with the retatrutide studies.

And Robert A. Gabbay, MD, chief scientific and medical officer of the ADA, called the results “stunning,” and added, “we are now witnessing the first triple-hormone combination being highly effective for not only weight loss but liver disease and diabetes.”

Joslin Diabetes Center

Adding glucagon agonism ups liver-fat clearance

“When you add glucagon activity,” one of the three agonist actions of retatrutide, “liver-fat clearance goes up tremendously,” said Dr. Kaplan, director of the Obesity, Metabolism and Nutrition Institute at Massachusetts General Hospital in Boston.

“To my knowledge, no mono-agonist of the glucagon-like peptide-1 (GLP-1) receptor [such as semaglutide or liraglutide] produces more than 50% clearance of liver fat,” added Dr. Kaplan.

The separate, randomized study of people with type 2 diabetes showed that in addition to producing an unprecedented average level of weight loss at the highest retatrutide dose, the agent also produced an average reduction from baseline levels of A1c of about 2 percentage points, an efficacy roughly comparable to maximum doses of the most potent GLP-1 mono-agonist semaglutide (Ozempic, Novo Nordisk), as well as by tirzepatide (Mounjaro, Eli Lilly), a dual agonist for the GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) receptors.

“No other medication has shown an average 17% reduction from baseline bodyweight after 36 weeks in people with type 2 diabetes,” said Julio Rosenstock, MD, director of the Dallas Diabetes Research Center at Medical City, Texas, who presented the results from the type 2 diabetes study of retatrutide.

For the obesity study, people with a body mass index of 27-50 kg/m² and no diabetes were randomized to placebo or any of four retatrutide target dosages using specified dose-escalation protocols. Participants were an average of 48 years old, and by design, 52% were men. (The study sought to enroll roughly equal numbers of men and women.) Average BMI at study entry was 37 kg/m².

Weight loss levels after 24 and 48 weeks of retatrutide treatment followed a clear dose-related pattern. (Weight loss averaged about 2% among the 70 controls who received placebo.)
 

Twenty-six percent without diabetes lost at least 30% of body weight

Every person who escalated to receive the 8-mg or 12-mg weekly dose of retatrutide lost at least 5% of their bodyweight after 48 weeks, 83% of those taking the 12-mg dose lost at least 15%, 63% of those on the 12-mg dose lost at least 20%, and 26% of those on the highest dose lost at least 30% of their starting bodyweight, reported Dr. Jastreboff, director of the Yale Obesity Research Center of Yale University in New Haven, Conn.

The highest dose was also associated with an average 40% relative reduction in triglyceride levels from baseline and an average 22% relative drop in LDL cholesterol levels.

The results were simultaneously published online in the New England Journal of Medicine.

The incidence of serious adverse events with retatrutide was low, similar to the rate in those who received placebo, and showed no dose relationship.

The most common adverse events were gastrointestinal, in as many as 16% of those on the highest dose; these were mild to moderate in severity and usually occurred during dose escalation. In general, adverse events were comparable to what is seen with a GLP-1 agonist or the dual agonist tirzepatide, Dr. Jastreboff said.
 

A1c normalization in 26% at the highest dose

A similar safety pattern occurred in the study of people with type 2 diabetes, which randomized people with an average A1c of 8.3% and an average BMI of 35.0 kg/m². After 36 weeks of treatment, the 12-mg weekly dose of retatrutide led to normalization of A1c < 5.7% in 27% of people and A1c ≤ 6.5% in 77%.

“The number of people we were able to revert to a normal A1c was impressive,” said Dr. Rosenstock. These results were simultaneously published online in The Lancet.

The additional findings on liver-fat mobilization in people without diabetes enrolled in the obesity study are notable because no agent currently has labeling from the Food and Drug Administration for the indication of reducing excess liver fat, said Dr. Kaplan.

The researchers measured liver fat at baseline and then during treatment using MRI.

“With the level of fat clearance from the liver that we see with retatrutide it is highly likely that we’ll also see improvements in liver fibrosis” in retatrutide-treated patients, Dr. Kaplan predicted.

Next up for retatrutide is testing in pivotal trials, including the TRIUMPH-3 trial that will enroll about 1,800 people with severe obesity and cardiovascular disease, with findings expected toward the end of 2025.

The retatrutide studies are sponsored by Eli Lilly. Dr. Jastreboff, Dr. Rosenstock, Dr. Kaplan, and Dr. Le Roux have reported financial relationships with Eli Lilly as well as other companies.

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

Higher doses of oral semaglutide than the 14-mg/day dose that is currently approved for type 2 diabetes may be additional options for patients with prediabetes or diabetes and obesity, according to the results of two new phase 3 clinical trials.

The two trials, OASIS in patients with overweight or obesity without diabetes and PIONEER PLUS in patients with inadequately controlled type 2 diabetes, were presented at the annual scientific sessions of the American Diabetes Association and simultaneously published in The Lancet.

Filip K. Knop, MD, PhD, University of Copenhagen, presented highlights of the OASIS-1 results, and Vanita R. Aroda, MD, Brigham and Women’s Hospital and Harvard University, Boston, presented key findings of PIONEER PLUS, during a press briefing prior to the ADA session.

OASIS-1 showed that “oral semaglutide 50 mg may represent an effective option for the treatment of obesity, particularly in patients who prefer oral administration,” Dr. Knop summarized.

And “the PIONEER PLUS trial showed superior glycemic control and body-weight loss and improvement in cardiometabolic risk factors, with higher doses of once-daily oral semaglutide (25 mg and 50 mg) compared with the currently [highest] approved 14-mg dose,” said Dr. Aroda.

Session chair Marion Pragnell, PhD, vice president of research & science at ADA, said in an interview there is a need for multiple treatment options, as different patients respond differently to individual drugs. The oral dose of semaglutide has to be higher than that approved for subcutaneous injection (as Ozempic or Wegovy) because of bioavailability, but small-molecule research is advancing such that in future lower doses of oral drugs may have the same effect as the current lower subcutaneous doses of the drug.

The oral version of semaglutide (Rybelsus) was approved in the United States for type 2 diabetes in doses of 7 mg or 14 mg per day in 2019; it has not been approved for use in obesity.

Dr. Knop remarked that, in his clinical practice, about 25% of patients with type 2 diabetes prefer daily oral semaglutide and the rest prefer weekly injected semaglutide.

“Having an oral formulation of semaglutide in addition to the subcutaneous, or injectable, formula available will allow people who struggle to lose weight with diet and physical activity alone to take this effective medication in a way that best suits them,” he added.

Participants in OASIS and PIONEER PLUS were instructed to take the once-daily study drug tablet in the morning, in the fasting state, with up to half a glass of water (120 mL) at least 30 minutes before intake of any other food, beverage, or oral medication.
 

OASIS: 50-mg daily pill in adults with overweight or obesity

OASIS is, to their knowledge, “the first trial to assess the bodyweight-lowering effect of an oral GLP-1 agonist (semaglutide 50 mg taken once per day) in adults with overweight or obesity, without type 2 diabetes,” Dr. Knop and colleagues wrote.

The 50-mg dose induced clinically meaningful reductions in bodyweight, with accompanying improvements in cardiometabolic risk factors, consistent with results reported for subcutaneous semaglutide 2.4 mg once weekly (Wegovy) in a similar population.

As an adjunct to diet and physical activity, oral semaglutide 50 mg led to a mean bodyweight reduction of 15.1%, compared with 2.4% in the placebo group, and greater percentages of participants reaching bodyweight reduction targets of at least 5%, 10%, 15%, and 20%.

Body-weight reductions were accompanied by significant improvements in cardiometabolic risk factors, compared with placebo.

“These results indicate that oral semaglutide 50 mg could provide an effective, future option for people with overweight or obesity who would benefit from a GLP-1 receptor agonist,” they concluded.
 

PIONEER PLUS: Inadequately controlled type 2 diabetes

Reporting the PIONEER PLUS data, Dr. Aroda and colleagues said: “For people with inadequately controlled type 2 diabetes on a stable dose of one to three oral glucose-lowering drugs, higher doses (25 mg and 50 mg) of once-daily oral semaglutide provided more effective glycemic control and greater bodyweight loss than 14 mg semaglutide, without additional safety concerns.”

PIONEER PLUS is the first study to indicate that these bigger doses of semaglutide might provide a highly effective oral option to improve both glycemic control and weight loss in type 2 diabetes.

“This trial provides compelling evidence that the availability of a wider range of doses of oral semaglutide will allow for individualized dosing to the desired effect, and the ability to intensify treatment as needed,” said Dr. Aroda. “We are hopeful that these results encourage earlier effective management of type 2 diabetes and allow for broader management in the primary care setting.”

In an accompanying editorial Christina H. Sherrill, PharmD, and Andrew Y. Hwang, PharmD, write: “This expansion in dosing titration might provide clinicians with more opportunities to obtain the maximum efficacy of this oral GLP-1 agonist.”

But additional investigations “to establish whether the superior glycemic reduction seen at these higher doses translates into cardiovascular risk reduction” are needed, said Dr. Sherrill, of High Point (N.C.) University, and Dr. Hwang, of Massachusetts College of Pharmacy and Health Sciences University, Boston.

Such investigations “would further elucidate the place in therapy of high-dose oral semaglutide,” they concluded.

Dr. Aroda and colleagues agreed: “Future real-world studies will be needed to investigate the clinical impact of the availability of higher doses of oral semaglutide.”

The trials were funded by Novo Nordisk.

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

Higher doses of oral semaglutide than the 14-mg/day dose that is currently approved for type 2 diabetes may be additional options for patients with prediabetes or diabetes and obesity, according to the results of two new phase 3 clinical trials.

The two trials, OASIS in patients with overweight or obesity without diabetes and PIONEER PLUS in patients with inadequately controlled type 2 diabetes, were presented at the annual scientific sessions of the American Diabetes Association and simultaneously published in The Lancet.

Filip K. Knop, MD, PhD, University of Copenhagen, presented highlights of the OASIS-1 results, and Vanita R. Aroda, MD, Brigham and Women’s Hospital and Harvard University, Boston, presented key findings of PIONEER PLUS, during a press briefing prior to the ADA session.

OASIS-1 showed that “oral semaglutide 50 mg may represent an effective option for the treatment of obesity, particularly in patients who prefer oral administration,” Dr. Knop summarized.

And “the PIONEER PLUS trial showed superior glycemic control and body-weight loss and improvement in cardiometabolic risk factors, with higher doses of once-daily oral semaglutide (25 mg and 50 mg) compared with the currently [highest] approved 14-mg dose,” said Dr. Aroda.

Session chair Marion Pragnell, PhD, vice president of research & science at ADA, said in an interview there is a need for multiple treatment options, as different patients respond differently to individual drugs. The oral dose of semaglutide has to be higher than that approved for subcutaneous injection (as Ozempic or Wegovy) because of bioavailability, but small-molecule research is advancing such that in future lower doses of oral drugs may have the same effect as the current lower subcutaneous doses of the drug.

The oral version of semaglutide (Rybelsus) was approved in the United States for type 2 diabetes in doses of 7 mg or 14 mg per day in 2019; it has not been approved for use in obesity.

Dr. Knop remarked that, in his clinical practice, about 25% of patients with type 2 diabetes prefer daily oral semaglutide and the rest prefer weekly injected semaglutide.

“Having an oral formulation of semaglutide in addition to the subcutaneous, or injectable, formula available will allow people who struggle to lose weight with diet and physical activity alone to take this effective medication in a way that best suits them,” he added.

Participants in OASIS and PIONEER PLUS were instructed to take the once-daily study drug tablet in the morning, in the fasting state, with up to half a glass of water (120 mL) at least 30 minutes before intake of any other food, beverage, or oral medication.
 

OASIS: 50-mg daily pill in adults with overweight or obesity

OASIS is, to their knowledge, “the first trial to assess the bodyweight-lowering effect of an oral GLP-1 agonist (semaglutide 50 mg taken once per day) in adults with overweight or obesity, without type 2 diabetes,” Dr. Knop and colleagues wrote.

The 50-mg dose induced clinically meaningful reductions in bodyweight, with accompanying improvements in cardiometabolic risk factors, consistent with results reported for subcutaneous semaglutide 2.4 mg once weekly (Wegovy) in a similar population.

As an adjunct to diet and physical activity, oral semaglutide 50 mg led to a mean bodyweight reduction of 15.1%, compared with 2.4% in the placebo group, and greater percentages of participants reaching bodyweight reduction targets of at least 5%, 10%, 15%, and 20%.

Body-weight reductions were accompanied by significant improvements in cardiometabolic risk factors, compared with placebo.

“These results indicate that oral semaglutide 50 mg could provide an effective, future option for people with overweight or obesity who would benefit from a GLP-1 receptor agonist,” they concluded.
 

PIONEER PLUS: Inadequately controlled type 2 diabetes

Reporting the PIONEER PLUS data, Dr. Aroda and colleagues said: “For people with inadequately controlled type 2 diabetes on a stable dose of one to three oral glucose-lowering drugs, higher doses (25 mg and 50 mg) of once-daily oral semaglutide provided more effective glycemic control and greater bodyweight loss than 14 mg semaglutide, without additional safety concerns.”

PIONEER PLUS is the first study to indicate that these bigger doses of semaglutide might provide a highly effective oral option to improve both glycemic control and weight loss in type 2 diabetes.

“This trial provides compelling evidence that the availability of a wider range of doses of oral semaglutide will allow for individualized dosing to the desired effect, and the ability to intensify treatment as needed,” said Dr. Aroda. “We are hopeful that these results encourage earlier effective management of type 2 diabetes and allow for broader management in the primary care setting.”

In an accompanying editorial Christina H. Sherrill, PharmD, and Andrew Y. Hwang, PharmD, write: “This expansion in dosing titration might provide clinicians with more opportunities to obtain the maximum efficacy of this oral GLP-1 agonist.”

But additional investigations “to establish whether the superior glycemic reduction seen at these higher doses translates into cardiovascular risk reduction” are needed, said Dr. Sherrill, of High Point (N.C.) University, and Dr. Hwang, of Massachusetts College of Pharmacy and Health Sciences University, Boston.

Such investigations “would further elucidate the place in therapy of high-dose oral semaglutide,” they concluded.

Dr. Aroda and colleagues agreed: “Future real-world studies will be needed to investigate the clinical impact of the availability of higher doses of oral semaglutide.”

The trials were funded by Novo Nordisk.

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

Higher doses of oral semaglutide than the 14-mg/day dose that is currently approved for type 2 diabetes may be additional options for patients with prediabetes or diabetes and obesity, according to the results of two new phase 3 clinical trials.

The two trials, OASIS in patients with overweight or obesity without diabetes and PIONEER PLUS in patients with inadequately controlled type 2 diabetes, were presented at the annual scientific sessions of the American Diabetes Association and simultaneously published in The Lancet.

Filip K. Knop, MD, PhD, University of Copenhagen, presented highlights of the OASIS-1 results, and Vanita R. Aroda, MD, Brigham and Women’s Hospital and Harvard University, Boston, presented key findings of PIONEER PLUS, during a press briefing prior to the ADA session.

OASIS-1 showed that “oral semaglutide 50 mg may represent an effective option for the treatment of obesity, particularly in patients who prefer oral administration,” Dr. Knop summarized.

And “the PIONEER PLUS trial showed superior glycemic control and body-weight loss and improvement in cardiometabolic risk factors, with higher doses of once-daily oral semaglutide (25 mg and 50 mg) compared with the currently [highest] approved 14-mg dose,” said Dr. Aroda.

Session chair Marion Pragnell, PhD, vice president of research & science at ADA, said in an interview there is a need for multiple treatment options, as different patients respond differently to individual drugs. The oral dose of semaglutide has to be higher than that approved for subcutaneous injection (as Ozempic or Wegovy) because of bioavailability, but small-molecule research is advancing such that in future lower doses of oral drugs may have the same effect as the current lower subcutaneous doses of the drug.

The oral version of semaglutide (Rybelsus) was approved in the United States for type 2 diabetes in doses of 7 mg or 14 mg per day in 2019; it has not been approved for use in obesity.

Dr. Knop remarked that, in his clinical practice, about 25% of patients with type 2 diabetes prefer daily oral semaglutide and the rest prefer weekly injected semaglutide.

“Having an oral formulation of semaglutide in addition to the subcutaneous, or injectable, formula available will allow people who struggle to lose weight with diet and physical activity alone to take this effective medication in a way that best suits them,” he added.

Participants in OASIS and PIONEER PLUS were instructed to take the once-daily study drug tablet in the morning, in the fasting state, with up to half a glass of water (120 mL) at least 30 minutes before intake of any other food, beverage, or oral medication.
 

OASIS: 50-mg daily pill in adults with overweight or obesity

OASIS is, to their knowledge, “the first trial to assess the bodyweight-lowering effect of an oral GLP-1 agonist (semaglutide 50 mg taken once per day) in adults with overweight or obesity, without type 2 diabetes,” Dr. Knop and colleagues wrote.

The 50-mg dose induced clinically meaningful reductions in bodyweight, with accompanying improvements in cardiometabolic risk factors, consistent with results reported for subcutaneous semaglutide 2.4 mg once weekly (Wegovy) in a similar population.

As an adjunct to diet and physical activity, oral semaglutide 50 mg led to a mean bodyweight reduction of 15.1%, compared with 2.4% in the placebo group, and greater percentages of participants reaching bodyweight reduction targets of at least 5%, 10%, 15%, and 20%.

Body-weight reductions were accompanied by significant improvements in cardiometabolic risk factors, compared with placebo.

“These results indicate that oral semaglutide 50 mg could provide an effective, future option for people with overweight or obesity who would benefit from a GLP-1 receptor agonist,” they concluded.
 

PIONEER PLUS: Inadequately controlled type 2 diabetes

Reporting the PIONEER PLUS data, Dr. Aroda and colleagues said: “For people with inadequately controlled type 2 diabetes on a stable dose of one to three oral glucose-lowering drugs, higher doses (25 mg and 50 mg) of once-daily oral semaglutide provided more effective glycemic control and greater bodyweight loss than 14 mg semaglutide, without additional safety concerns.”

PIONEER PLUS is the first study to indicate that these bigger doses of semaglutide might provide a highly effective oral option to improve both glycemic control and weight loss in type 2 diabetes.

“This trial provides compelling evidence that the availability of a wider range of doses of oral semaglutide will allow for individualized dosing to the desired effect, and the ability to intensify treatment as needed,” said Dr. Aroda. “We are hopeful that these results encourage earlier effective management of type 2 diabetes and allow for broader management in the primary care setting.”

In an accompanying editorial Christina H. Sherrill, PharmD, and Andrew Y. Hwang, PharmD, write: “This expansion in dosing titration might provide clinicians with more opportunities to obtain the maximum efficacy of this oral GLP-1 agonist.”

But additional investigations “to establish whether the superior glycemic reduction seen at these higher doses translates into cardiovascular risk reduction” are needed, said Dr. Sherrill, of High Point (N.C.) University, and Dr. Hwang, of Massachusetts College of Pharmacy and Health Sciences University, Boston.

Such investigations “would further elucidate the place in therapy of high-dose oral semaglutide,” they concluded.

Dr. Aroda and colleagues agreed: “Future real-world studies will be needed to investigate the clinical impact of the availability of higher doses of oral semaglutide.”

The trials were funded by Novo Nordisk.

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