Obesity

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.

SAN DIEGO – Weekly tirzepatide injections in adults with type 2 diabetes and overweight or obesity safely led to 12.8%-14.7% in-trial weight loss after 72 weeks in the SURMOUNT-2 pivotal trial, a finding that will likely lead to Food and Drug Administration approval of a new indication for weight loss for tirzepatide.

Tirzepatide received FDA approval as a treatment for type 2 diabetes in adults, marketed as Mounjaro, in 2022. The agent – a “twincretin” that acts as an agonist at both the glucagon-like peptide-1 (GLP-1) receptor and glucose-dependent insulinotropic polypeptide (GIP) receptor – had also previously scored a decisive win for weight loss in adults with overweight or obesity without diabetes in the SURMOUNT-1 pivotal trial.

Taken together, results from SURMOUNT-1 and SURMOUNT-2 appear to make a good case for a weight-loss indication that will not depend on whether a patient also has type 2 diabetes.

“We anticipate that tirzepatide will be [FDA] approved for weight loss later this year,” W. Timothy Garvey, MD, lead researcher for SURMOUNT-2, said during a press briefing at the annual scientific sessions of the American Diabetes Association.
 

Tirzepatide ‘fills the gap’

Tirzepatide “fills the gap to get [medication-driven] weight loss in the range of 15% of baseline weight or better,” Dr. Garvey noted, which puts it in a favorable position relative to a 2.4-mg weekly subcutaneous injection with the GLP-1 agonist semaglutide (Wegovy), which produced an average weight loss from baseline of about 9.6% in people with type 2 diabetes in the STEP-2 trial. 

Mitchel L. Zoler/MDedge News

Although tirzepatide has not been compared head-to-head for weight loss with any of the several available GLP-1 agonists, the reported weight-loss numbers seem to favor tirzepatide, said Dr. Garvey, director of the Diabetes Research Center of the University of Alabama at Birmingham.

“If you look at the degree of weight loss across trials, we see a clinically significant difference in weight loss” compared with semaglutide and other agents that only act on the GLP-1 receptor, he noted. (Although cross-trial comparisons of different medications often have uncertain reliability.)

“The data suggest an incremental effect from tirzepatide” compared with the GLP-1 agonists now approved for weight loss, said Marlon Pragnell, PhD, vice president, research and science, ADA, who was not involved in the tirzepatide studies.

This is a “step forward for treating people with obesity and type 2 diabetes; it’s a very promising treatment option,” Dr. Pragnell said in an interview.
 

Tirzepatide the ‘most effective agent’

Ildiko Lingvay, MD, the designated discussant for the SURMOUNT-2 presentation at the meeting, fully agreed. The new findings “confirm that tirzepatide is the most effective agent currently on the [U.S.] market to help achieve the two coprimary goals for patients with type 2 diabetes – weight loss and glycemic control – while also having favorable effects on cardiovascular risk factors,” said Dr. Lingvay, an endocrinologist at UT Southwestern Medical Center in Dallas, who was not involved with the SURMOUNT studies.

Dr. Lingvay offered as evidence the performance of tirzepatide’s main rival for weight loss semaglutide (Wegovy), delivered at the 2.4 mg/week subcutaneous injected dosage approved for weight loss. The semaglutide trial that SURMOUNT-2 most resembles is the STEP-2 trial, she said, which showed as its primary outcome a 9.6% average weight loss from baseline after 68 weeks of weekly semaglutide that compares, in a cross-trial way, with the 14.7% average drop from baseline weight with 15 mg tirzepatide weekly for 72 weeks and an average 12.8% weight loss with a weekly 10-mg tirzepatide dose.

“It’s fair to say that tirzepatide has an edge,” despite the limitations of cross-trial comparisons, Dr. Lingvay said in an interview.

But she acknowledged that superior weight loss efficacy takes a back seat in U.S. practice to access and affordability when making a prescribing decision for individual patients as these newer drugs are all expensive. 
 

Affordability and access will remain a ‘big problem’

Dr. Garvey, too, cautioned that access and affordability of tirzepatide as well as other GLP-1 agonists remains a major sticking point.

“These medications are very expensive – more than $1,000 a dose – and this cost limits access ... [which is] a big problem,” Dr. Garvey noted. U.S. health care payers “do not want to open the gates [to expensive treatments] for a disorder that’s as common as obesity.”

“Access and affordability are always an issue for these medications,” agreed Janet Brown-Friday, RN, president, health care and education, ADA, who had no role in the tirzepatide studies.

SURMOUNT-2 randomized 938 adults with type 2 diabetes and overweight or obesity at 77 centers in seven countries including the United States from March 2021 to April 2023. The study had two primary outcomes: Average percent change in body weight from baseline to week 72, and percentage of participants who achieved a weight reduction from baseline of at least 5% after 72 weeks.
 

In-trial weight loss of 12.8%-14.7%

The in-trial analysis showed that a 10-mg weekly subcutaneous dose of tirzepatide resulted in an average 12.8% weight loss from baseline, and a 15-mg weekly subcutaneous dose led to an average 14.7% drop from baseline weight. People randomized to receive a placebo injection averaged a 3.2% drop from their baseline weight after 72 weeks, a finding that documents significant improvements compared with placebo with both tirzepatide doses.

The percentage of patients who achieved at least a 5% reduction in weight from baseline was 79% with the 10-mg dose of tirzepatide, 83% with the 15-mg dose, and 32% with placebo; these improvements were significant for both tirzepatide doses compared with placebo.

A 15% or greater reduction in weight from baseline occurred in 40%-48% of people who received tirzepatide compared with 3% of those who received placebo. A reduction in weight of this magnitude from baseline “will prevent a broad array of complications,” Dr. Garvey noted.

The results were simulatenously published online in The Lancet.
 

Glucose control without severe hypoglycemia

The safety profile of tirzepatide in SURMOUNT-2 was consistent with prior studies of the agent, as well as with other medications in the GLP-1 agonist class, with gastrointestinal adverse effects such as nausea and vomiting predominating, especially during the dose-escalation phase at treatment onset.

Dr. Garvey especially highlighted the overall safety of tirzepatide, and particularly its ability to produce clinically important reductions in A1c that averaged more than two percentage points from baseline values without producing a single episode of severe hypoglycemia, and an incidence of milder hypoglycemia of less than a 5%.

The absence of any severe hypoglycemia was “amazing,” Dr. Garvey said, especially given that 46%-49% of people taking tirzepatide in SURMOUNT-2 achieved normalization of their A1c to less than 5.7% on treatment compared with 4% of participants taking placebo.

The results also showed the benefit of a “big reduction in fasting insulin levels,” which averaged a 41% cut from baseline in those who received the 15-mg subcutaneous weekly dose of tirzepatide, coupled with increased insulin sensitivity, Dr. Garvey said.

Dr. Garvey disclosed ties to Eli Lilly, which sponsored SURMOUNT-2 and markets tirzepatide (Mounjaro), as well Boehringer Ingelheim, Novo Nordisk, Pfizer, Fractyl Health, Alnylam Pharmaceuticals, Inogen, and Merck. He has been an investigator for studies sponsored by Novo Nordisk, Epitomee, Neurovalens, and Pfizer. Dr. Pragnell and Dr. Brown-Friday have disclosed no relevant financial relationships.



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

SAN DIEGO – Weekly tirzepatide injections in adults with type 2 diabetes and overweight or obesity safely led to 12.8%-14.7% in-trial weight loss after 72 weeks in the SURMOUNT-2 pivotal trial, a finding that will likely lead to Food and Drug Administration approval of a new indication for weight loss for tirzepatide.

Tirzepatide received FDA approval as a treatment for type 2 diabetes in adults, marketed as Mounjaro, in 2022. The agent – a “twincretin” that acts as an agonist at both the glucagon-like peptide-1 (GLP-1) receptor and glucose-dependent insulinotropic polypeptide (GIP) receptor – had also previously scored a decisive win for weight loss in adults with overweight or obesity without diabetes in the SURMOUNT-1 pivotal trial.

Taken together, results from SURMOUNT-1 and SURMOUNT-2 appear to make a good case for a weight-loss indication that will not depend on whether a patient also has type 2 diabetes.

“We anticipate that tirzepatide will be [FDA] approved for weight loss later this year,” W. Timothy Garvey, MD, lead researcher for SURMOUNT-2, said during a press briefing at the annual scientific sessions of the American Diabetes Association.
 

Tirzepatide ‘fills the gap’

Tirzepatide “fills the gap to get [medication-driven] weight loss in the range of 15% of baseline weight or better,” Dr. Garvey noted, which puts it in a favorable position relative to a 2.4-mg weekly subcutaneous injection with the GLP-1 agonist semaglutide (Wegovy), which produced an average weight loss from baseline of about 9.6% in people with type 2 diabetes in the STEP-2 trial. 

Mitchel L. Zoler/MDedge News

Although tirzepatide has not been compared head-to-head for weight loss with any of the several available GLP-1 agonists, the reported weight-loss numbers seem to favor tirzepatide, said Dr. Garvey, director of the Diabetes Research Center of the University of Alabama at Birmingham.

“If you look at the degree of weight loss across trials, we see a clinically significant difference in weight loss” compared with semaglutide and other agents that only act on the GLP-1 receptor, he noted. (Although cross-trial comparisons of different medications often have uncertain reliability.)

“The data suggest an incremental effect from tirzepatide” compared with the GLP-1 agonists now approved for weight loss, said Marlon Pragnell, PhD, vice president, research and science, ADA, who was not involved in the tirzepatide studies.

This is a “step forward for treating people with obesity and type 2 diabetes; it’s a very promising treatment option,” Dr. Pragnell said in an interview.
 

Tirzepatide the ‘most effective agent’

Ildiko Lingvay, MD, the designated discussant for the SURMOUNT-2 presentation at the meeting, fully agreed. The new findings “confirm that tirzepatide is the most effective agent currently on the [U.S.] market to help achieve the two coprimary goals for patients with type 2 diabetes – weight loss and glycemic control – while also having favorable effects on cardiovascular risk factors,” said Dr. Lingvay, an endocrinologist at UT Southwestern Medical Center in Dallas, who was not involved with the SURMOUNT studies.

Dr. Lingvay offered as evidence the performance of tirzepatide’s main rival for weight loss semaglutide (Wegovy), delivered at the 2.4 mg/week subcutaneous injected dosage approved for weight loss. The semaglutide trial that SURMOUNT-2 most resembles is the STEP-2 trial, she said, which showed as its primary outcome a 9.6% average weight loss from baseline after 68 weeks of weekly semaglutide that compares, in a cross-trial way, with the 14.7% average drop from baseline weight with 15 mg tirzepatide weekly for 72 weeks and an average 12.8% weight loss with a weekly 10-mg tirzepatide dose.

“It’s fair to say that tirzepatide has an edge,” despite the limitations of cross-trial comparisons, Dr. Lingvay said in an interview.

But she acknowledged that superior weight loss efficacy takes a back seat in U.S. practice to access and affordability when making a prescribing decision for individual patients as these newer drugs are all expensive. 
 

Affordability and access will remain a ‘big problem’

Dr. Garvey, too, cautioned that access and affordability of tirzepatide as well as other GLP-1 agonists remains a major sticking point.

“These medications are very expensive – more than $1,000 a dose – and this cost limits access ... [which is] a big problem,” Dr. Garvey noted. U.S. health care payers “do not want to open the gates [to expensive treatments] for a disorder that’s as common as obesity.”

“Access and affordability are always an issue for these medications,” agreed Janet Brown-Friday, RN, president, health care and education, ADA, who had no role in the tirzepatide studies.

SURMOUNT-2 randomized 938 adults with type 2 diabetes and overweight or obesity at 77 centers in seven countries including the United States from March 2021 to April 2023. The study had two primary outcomes: Average percent change in body weight from baseline to week 72, and percentage of participants who achieved a weight reduction from baseline of at least 5% after 72 weeks.
 

In-trial weight loss of 12.8%-14.7%

The in-trial analysis showed that a 10-mg weekly subcutaneous dose of tirzepatide resulted in an average 12.8% weight loss from baseline, and a 15-mg weekly subcutaneous dose led to an average 14.7% drop from baseline weight. People randomized to receive a placebo injection averaged a 3.2% drop from their baseline weight after 72 weeks, a finding that documents significant improvements compared with placebo with both tirzepatide doses.

The percentage of patients who achieved at least a 5% reduction in weight from baseline was 79% with the 10-mg dose of tirzepatide, 83% with the 15-mg dose, and 32% with placebo; these improvements were significant for both tirzepatide doses compared with placebo.

A 15% or greater reduction in weight from baseline occurred in 40%-48% of people who received tirzepatide compared with 3% of those who received placebo. A reduction in weight of this magnitude from baseline “will prevent a broad array of complications,” Dr. Garvey noted.

The results were simulatenously published online in The Lancet.
 

Glucose control without severe hypoglycemia

The safety profile of tirzepatide in SURMOUNT-2 was consistent with prior studies of the agent, as well as with other medications in the GLP-1 agonist class, with gastrointestinal adverse effects such as nausea and vomiting predominating, especially during the dose-escalation phase at treatment onset.

Dr. Garvey especially highlighted the overall safety of tirzepatide, and particularly its ability to produce clinically important reductions in A1c that averaged more than two percentage points from baseline values without producing a single episode of severe hypoglycemia, and an incidence of milder hypoglycemia of less than a 5%.

The absence of any severe hypoglycemia was “amazing,” Dr. Garvey said, especially given that 46%-49% of people taking tirzepatide in SURMOUNT-2 achieved normalization of their A1c to less than 5.7% on treatment compared with 4% of participants taking placebo.

The results also showed the benefit of a “big reduction in fasting insulin levels,” which averaged a 41% cut from baseline in those who received the 15-mg subcutaneous weekly dose of tirzepatide, coupled with increased insulin sensitivity, Dr. Garvey said.

Dr. Garvey disclosed ties to Eli Lilly, which sponsored SURMOUNT-2 and markets tirzepatide (Mounjaro), as well Boehringer Ingelheim, Novo Nordisk, Pfizer, Fractyl Health, Alnylam Pharmaceuticals, Inogen, and Merck. He has been an investigator for studies sponsored by Novo Nordisk, Epitomee, Neurovalens, and Pfizer. Dr. Pragnell and Dr. Brown-Friday have disclosed no relevant financial relationships.



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

SAN DIEGO – Weekly tirzepatide injections in adults with type 2 diabetes and overweight or obesity safely led to 12.8%-14.7% in-trial weight loss after 72 weeks in the SURMOUNT-2 pivotal trial, a finding that will likely lead to Food and Drug Administration approval of a new indication for weight loss for tirzepatide.

Tirzepatide received FDA approval as a treatment for type 2 diabetes in adults, marketed as Mounjaro, in 2022. The agent – a “twincretin” that acts as an agonist at both the glucagon-like peptide-1 (GLP-1) receptor and glucose-dependent insulinotropic polypeptide (GIP) receptor – had also previously scored a decisive win for weight loss in adults with overweight or obesity without diabetes in the SURMOUNT-1 pivotal trial.

Taken together, results from SURMOUNT-1 and SURMOUNT-2 appear to make a good case for a weight-loss indication that will not depend on whether a patient also has type 2 diabetes.

“We anticipate that tirzepatide will be [FDA] approved for weight loss later this year,” W. Timothy Garvey, MD, lead researcher for SURMOUNT-2, said during a press briefing at the annual scientific sessions of the American Diabetes Association.
 

Tirzepatide ‘fills the gap’

Tirzepatide “fills the gap to get [medication-driven] weight loss in the range of 15% of baseline weight or better,” Dr. Garvey noted, which puts it in a favorable position relative to a 2.4-mg weekly subcutaneous injection with the GLP-1 agonist semaglutide (Wegovy), which produced an average weight loss from baseline of about 9.6% in people with type 2 diabetes in the STEP-2 trial. 

Mitchel L. Zoler/MDedge News

Although tirzepatide has not been compared head-to-head for weight loss with any of the several available GLP-1 agonists, the reported weight-loss numbers seem to favor tirzepatide, said Dr. Garvey, director of the Diabetes Research Center of the University of Alabama at Birmingham.

“If you look at the degree of weight loss across trials, we see a clinically significant difference in weight loss” compared with semaglutide and other agents that only act on the GLP-1 receptor, he noted. (Although cross-trial comparisons of different medications often have uncertain reliability.)

“The data suggest an incremental effect from tirzepatide” compared with the GLP-1 agonists now approved for weight loss, said Marlon Pragnell, PhD, vice president, research and science, ADA, who was not involved in the tirzepatide studies.

This is a “step forward for treating people with obesity and type 2 diabetes; it’s a very promising treatment option,” Dr. Pragnell said in an interview.
 

Tirzepatide the ‘most effective agent’

Ildiko Lingvay, MD, the designated discussant for the SURMOUNT-2 presentation at the meeting, fully agreed. The new findings “confirm that tirzepatide is the most effective agent currently on the [U.S.] market to help achieve the two coprimary goals for patients with type 2 diabetes – weight loss and glycemic control – while also having favorable effects on cardiovascular risk factors,” said Dr. Lingvay, an endocrinologist at UT Southwestern Medical Center in Dallas, who was not involved with the SURMOUNT studies.

Dr. Lingvay offered as evidence the performance of tirzepatide’s main rival for weight loss semaglutide (Wegovy), delivered at the 2.4 mg/week subcutaneous injected dosage approved for weight loss. The semaglutide trial that SURMOUNT-2 most resembles is the STEP-2 trial, she said, which showed as its primary outcome a 9.6% average weight loss from baseline after 68 weeks of weekly semaglutide that compares, in a cross-trial way, with the 14.7% average drop from baseline weight with 15 mg tirzepatide weekly for 72 weeks and an average 12.8% weight loss with a weekly 10-mg tirzepatide dose.

“It’s fair to say that tirzepatide has an edge,” despite the limitations of cross-trial comparisons, Dr. Lingvay said in an interview.

But she acknowledged that superior weight loss efficacy takes a back seat in U.S. practice to access and affordability when making a prescribing decision for individual patients as these newer drugs are all expensive. 
 

Affordability and access will remain a ‘big problem’

Dr. Garvey, too, cautioned that access and affordability of tirzepatide as well as other GLP-1 agonists remains a major sticking point.

“These medications are very expensive – more than $1,000 a dose – and this cost limits access ... [which is] a big problem,” Dr. Garvey noted. U.S. health care payers “do not want to open the gates [to expensive treatments] for a disorder that’s as common as obesity.”

“Access and affordability are always an issue for these medications,” agreed Janet Brown-Friday, RN, president, health care and education, ADA, who had no role in the tirzepatide studies.

SURMOUNT-2 randomized 938 adults with type 2 diabetes and overweight or obesity at 77 centers in seven countries including the United States from March 2021 to April 2023. The study had two primary outcomes: Average percent change in body weight from baseline to week 72, and percentage of participants who achieved a weight reduction from baseline of at least 5% after 72 weeks.
 

In-trial weight loss of 12.8%-14.7%

The in-trial analysis showed that a 10-mg weekly subcutaneous dose of tirzepatide resulted in an average 12.8% weight loss from baseline, and a 15-mg weekly subcutaneous dose led to an average 14.7% drop from baseline weight. People randomized to receive a placebo injection averaged a 3.2% drop from their baseline weight after 72 weeks, a finding that documents significant improvements compared with placebo with both tirzepatide doses.

The percentage of patients who achieved at least a 5% reduction in weight from baseline was 79% with the 10-mg dose of tirzepatide, 83% with the 15-mg dose, and 32% with placebo; these improvements were significant for both tirzepatide doses compared with placebo.

A 15% or greater reduction in weight from baseline occurred in 40%-48% of people who received tirzepatide compared with 3% of those who received placebo. A reduction in weight of this magnitude from baseline “will prevent a broad array of complications,” Dr. Garvey noted.

The results were simulatenously published online in The Lancet.
 

Glucose control without severe hypoglycemia

The safety profile of tirzepatide in SURMOUNT-2 was consistent with prior studies of the agent, as well as with other medications in the GLP-1 agonist class, with gastrointestinal adverse effects such as nausea and vomiting predominating, especially during the dose-escalation phase at treatment onset.

Dr. Garvey especially highlighted the overall safety of tirzepatide, and particularly its ability to produce clinically important reductions in A1c that averaged more than two percentage points from baseline values without producing a single episode of severe hypoglycemia, and an incidence of milder hypoglycemia of less than a 5%.

The absence of any severe hypoglycemia was “amazing,” Dr. Garvey said, especially given that 46%-49% of people taking tirzepatide in SURMOUNT-2 achieved normalization of their A1c to less than 5.7% on treatment compared with 4% of participants taking placebo.

The results also showed the benefit of a “big reduction in fasting insulin levels,” which averaged a 41% cut from baseline in those who received the 15-mg subcutaneous weekly dose of tirzepatide, coupled with increased insulin sensitivity, Dr. Garvey said.

Dr. Garvey disclosed ties to Eli Lilly, which sponsored SURMOUNT-2 and markets tirzepatide (Mounjaro), as well Boehringer Ingelheim, Novo Nordisk, Pfizer, Fractyl Health, Alnylam Pharmaceuticals, Inogen, and Merck. He has been an investigator for studies sponsored by Novo Nordisk, Epitomee, Neurovalens, and Pfizer. Dr. Pragnell and Dr. Brown-Friday have disclosed no relevant financial relationships.



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

People with nonalcoholic fatty liver disease (NAFLD) are more likely to develop severe infections requiring hospitalization, according to findings from a large Swedish cohort study.

The increased risk was equal to one extra severe infection in every six patients with NAFLD by 20 years after diagnosis, wrote Fahim Ebrahimi, MD, of the Karolinska Institute in Stockholm, and coauthors.

“Accumulating evidence suggests that NAFLD can affect multiple organ systems, which is not surprising, as the liver has multiple functions – regulating metabolism and being a central organ of the immune system,” Dr. Ebrahimi said in an interview.

The study was published online in Clinical Gastroenterology and Hepatology.

“Up to a fifth of cells in the liver are immune cells that process numerous antigens and pathogens from the gastrointestinal tract,” Dr. Ebrahimi noted. “We were intrigued by experimental studies showing that, in NAFLD, many of these key immune cells become dysfunctional at various levels, which may affect disease progression, but at the same time also increase the susceptibility to viral, bacterial, and fungal infections.”

Patients with NAFLD have metabolic risk factors known to increase infection risk, but a smaller study by a different research group had found that NAFLD could independently predispose patients to bacterial infections.

To further explore a connection between NAFLD and infection risk, the researchers looked at data for 12,133 Swedish adults with simple steatosis, nonfibrotic steatohepatitis, noncirrhotic fibrosis, or cirrhosis caused by NAFLD confirmed by liver biopsies performed between 1969 and 2017.

Each patient was matched to five or more contemporary controls from the general population by age, sex, and region of residence. The authors conducted an additional analysis that also adjusted for education, country of birth, and baseline clinical comorbidities, including diabetes, obesity, dyslipidemia, and hypertension, as well as hospitalization preceding the biopsy and chronic obstructive pulmonary disease.

The primary endpoint was severe infections requiring hospital admission. Secondary endpoints included seven prespecified infection subgroups: sepsis; respiratory tract; most gastrointestinal infections; bacterial peritonitis; urogenital; muscle, skin, and soft tissue; and other infections.
 

Elevated risk at all NAFLD stages

Dr. Ebrahimi and colleagues found that over a median follow-up of 14 years, patients with NAFLD had a higher incidence of severe infections – most often respiratory or urinary tract infections – compared with those without NAFLD (32% vs. 17%, respectively).

Biopsy-confirmed NAFLD was also associated with a 71% higher hazard and a 20-year absolute excess risk of 17.3% for severe infections requiring hospital admission versus comparators. The elevated risk showed up in patients with steatosis and increased with the severity of NAFLD. Simple steatosis saw a 64% higher risk (adjusted hazard ratio, 1.64; 95% confidence interval, 1.55-1.73), whereas patients with cirrhosis saw a more than twofold higher risk, compared with controls (aHR, 2.32; 95% CI, 1.92-2.82).

When Dr. Ebrahimi and colleagues adjusted for parameters of the metabolic syndrome, they found an independent increased risk for severe infection. For patients with NAFLD, the increased risk may come from greater susceptibility to infections in general or to a more severe course of infections.

“Our study clearly demonstrates the complexity and high disease burden associated with NAFLD,” Dr. Ebrahimi said. “We are beginning to understand the different layers involved and will eventually move away from a liver-centric view to a more holistic view of the disease.”

Clinicians caring for patients with NAFLD need to be aware of the increased risk for infection, Dr. Ebrahimi said. They also should assess their patients’ vaccination status, and seek to control modifiable risk factors, such as diabetes.

Nancy Reau, MD, of Rush University, Chicago, described the study’s message as important.

“Patients with NAFLD and advancing liver disease are at risk for severe infections,” Dr. Reau said. “When we consider the fact that patients with advanced liver disease tend to die from infectious complications, awareness leading to early recognition and efficient treatment is imperative.”

The authors acknowledged the following limitations: only severe infections requiring hospitalization could be captured; whether infection led to decompensation or vice versa among patients with cirrhosis could not be determined; and detailed data on smoking, alcohol, vaccinations, body mass, and other potentially relevant measures were not available.

The Swiss National Science Foundation, Syskonen Svensson Foundation, and Bengt Ihre Foundation provided grants to Dr. Ebrahimi or coauthors. One coauthor disclosed previous research funding from Janssen and MSD. Dr. Reau disclosed receiving research support and consulting fees from AbbVie and Gilead, as well as consulting fees from Arbutus, Intercept, and Salix.

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

People with nonalcoholic fatty liver disease (NAFLD) are more likely to develop severe infections requiring hospitalization, according to findings from a large Swedish cohort study.

The increased risk was equal to one extra severe infection in every six patients with NAFLD by 20 years after diagnosis, wrote Fahim Ebrahimi, MD, of the Karolinska Institute in Stockholm, and coauthors.

“Accumulating evidence suggests that NAFLD can affect multiple organ systems, which is not surprising, as the liver has multiple functions – regulating metabolism and being a central organ of the immune system,” Dr. Ebrahimi said in an interview.

The study was published online in Clinical Gastroenterology and Hepatology.

“Up to a fifth of cells in the liver are immune cells that process numerous antigens and pathogens from the gastrointestinal tract,” Dr. Ebrahimi noted. “We were intrigued by experimental studies showing that, in NAFLD, many of these key immune cells become dysfunctional at various levels, which may affect disease progression, but at the same time also increase the susceptibility to viral, bacterial, and fungal infections.”

Patients with NAFLD have metabolic risk factors known to increase infection risk, but a smaller study by a different research group had found that NAFLD could independently predispose patients to bacterial infections.

To further explore a connection between NAFLD and infection risk, the researchers looked at data for 12,133 Swedish adults with simple steatosis, nonfibrotic steatohepatitis, noncirrhotic fibrosis, or cirrhosis caused by NAFLD confirmed by liver biopsies performed between 1969 and 2017.

Each patient was matched to five or more contemporary controls from the general population by age, sex, and region of residence. The authors conducted an additional analysis that also adjusted for education, country of birth, and baseline clinical comorbidities, including diabetes, obesity, dyslipidemia, and hypertension, as well as hospitalization preceding the biopsy and chronic obstructive pulmonary disease.

The primary endpoint was severe infections requiring hospital admission. Secondary endpoints included seven prespecified infection subgroups: sepsis; respiratory tract; most gastrointestinal infections; bacterial peritonitis; urogenital; muscle, skin, and soft tissue; and other infections.
 

Elevated risk at all NAFLD stages

Dr. Ebrahimi and colleagues found that over a median follow-up of 14 years, patients with NAFLD had a higher incidence of severe infections – most often respiratory or urinary tract infections – compared with those without NAFLD (32% vs. 17%, respectively).

Biopsy-confirmed NAFLD was also associated with a 71% higher hazard and a 20-year absolute excess risk of 17.3% for severe infections requiring hospital admission versus comparators. The elevated risk showed up in patients with steatosis and increased with the severity of NAFLD. Simple steatosis saw a 64% higher risk (adjusted hazard ratio, 1.64; 95% confidence interval, 1.55-1.73), whereas patients with cirrhosis saw a more than twofold higher risk, compared with controls (aHR, 2.32; 95% CI, 1.92-2.82).

When Dr. Ebrahimi and colleagues adjusted for parameters of the metabolic syndrome, they found an independent increased risk for severe infection. For patients with NAFLD, the increased risk may come from greater susceptibility to infections in general or to a more severe course of infections.

“Our study clearly demonstrates the complexity and high disease burden associated with NAFLD,” Dr. Ebrahimi said. “We are beginning to understand the different layers involved and will eventually move away from a liver-centric view to a more holistic view of the disease.”

Clinicians caring for patients with NAFLD need to be aware of the increased risk for infection, Dr. Ebrahimi said. They also should assess their patients’ vaccination status, and seek to control modifiable risk factors, such as diabetes.

Nancy Reau, MD, of Rush University, Chicago, described the study’s message as important.

“Patients with NAFLD and advancing liver disease are at risk for severe infections,” Dr. Reau said. “When we consider the fact that patients with advanced liver disease tend to die from infectious complications, awareness leading to early recognition and efficient treatment is imperative.”

The authors acknowledged the following limitations: only severe infections requiring hospitalization could be captured; whether infection led to decompensation or vice versa among patients with cirrhosis could not be determined; and detailed data on smoking, alcohol, vaccinations, body mass, and other potentially relevant measures were not available.

The Swiss National Science Foundation, Syskonen Svensson Foundation, and Bengt Ihre Foundation provided grants to Dr. Ebrahimi or coauthors. One coauthor disclosed previous research funding from Janssen and MSD. Dr. Reau disclosed receiving research support and consulting fees from AbbVie and Gilead, as well as consulting fees from Arbutus, Intercept, and Salix.

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

People with nonalcoholic fatty liver disease (NAFLD) are more likely to develop severe infections requiring hospitalization, according to findings from a large Swedish cohort study.

The increased risk was equal to one extra severe infection in every six patients with NAFLD by 20 years after diagnosis, wrote Fahim Ebrahimi, MD, of the Karolinska Institute in Stockholm, and coauthors.

“Accumulating evidence suggests that NAFLD can affect multiple organ systems, which is not surprising, as the liver has multiple functions – regulating metabolism and being a central organ of the immune system,” Dr. Ebrahimi said in an interview.

The study was published online in Clinical Gastroenterology and Hepatology.

“Up to a fifth of cells in the liver are immune cells that process numerous antigens and pathogens from the gastrointestinal tract,” Dr. Ebrahimi noted. “We were intrigued by experimental studies showing that, in NAFLD, many of these key immune cells become dysfunctional at various levels, which may affect disease progression, but at the same time also increase the susceptibility to viral, bacterial, and fungal infections.”

Patients with NAFLD have metabolic risk factors known to increase infection risk, but a smaller study by a different research group had found that NAFLD could independently predispose patients to bacterial infections.

To further explore a connection between NAFLD and infection risk, the researchers looked at data for 12,133 Swedish adults with simple steatosis, nonfibrotic steatohepatitis, noncirrhotic fibrosis, or cirrhosis caused by NAFLD confirmed by liver biopsies performed between 1969 and 2017.

Each patient was matched to five or more contemporary controls from the general population by age, sex, and region of residence. The authors conducted an additional analysis that also adjusted for education, country of birth, and baseline clinical comorbidities, including diabetes, obesity, dyslipidemia, and hypertension, as well as hospitalization preceding the biopsy and chronic obstructive pulmonary disease.

The primary endpoint was severe infections requiring hospital admission. Secondary endpoints included seven prespecified infection subgroups: sepsis; respiratory tract; most gastrointestinal infections; bacterial peritonitis; urogenital; muscle, skin, and soft tissue; and other infections.
 

Elevated risk at all NAFLD stages

Dr. Ebrahimi and colleagues found that over a median follow-up of 14 years, patients with NAFLD had a higher incidence of severe infections – most often respiratory or urinary tract infections – compared with those without NAFLD (32% vs. 17%, respectively).

Biopsy-confirmed NAFLD was also associated with a 71% higher hazard and a 20-year absolute excess risk of 17.3% for severe infections requiring hospital admission versus comparators. The elevated risk showed up in patients with steatosis and increased with the severity of NAFLD. Simple steatosis saw a 64% higher risk (adjusted hazard ratio, 1.64; 95% confidence interval, 1.55-1.73), whereas patients with cirrhosis saw a more than twofold higher risk, compared with controls (aHR, 2.32; 95% CI, 1.92-2.82).

When Dr. Ebrahimi and colleagues adjusted for parameters of the metabolic syndrome, they found an independent increased risk for severe infection. For patients with NAFLD, the increased risk may come from greater susceptibility to infections in general or to a more severe course of infections.

“Our study clearly demonstrates the complexity and high disease burden associated with NAFLD,” Dr. Ebrahimi said. “We are beginning to understand the different layers involved and will eventually move away from a liver-centric view to a more holistic view of the disease.”

Clinicians caring for patients with NAFLD need to be aware of the increased risk for infection, Dr. Ebrahimi said. They also should assess their patients’ vaccination status, and seek to control modifiable risk factors, such as diabetes.

Nancy Reau, MD, of Rush University, Chicago, described the study’s message as important.

“Patients with NAFLD and advancing liver disease are at risk for severe infections,” Dr. Reau said. “When we consider the fact that patients with advanced liver disease tend to die from infectious complications, awareness leading to early recognition and efficient treatment is imperative.”

The authors acknowledged the following limitations: only severe infections requiring hospitalization could be captured; whether infection led to decompensation or vice versa among patients with cirrhosis could not be determined; and detailed data on smoking, alcohol, vaccinations, body mass, and other potentially relevant measures were not available.

The Swiss National Science Foundation, Syskonen Svensson Foundation, and Bengt Ihre Foundation provided grants to Dr. Ebrahimi or coauthors. One coauthor disclosed previous research funding from Janssen and MSD. Dr. Reau disclosed receiving research support and consulting fees from AbbVie and Gilead, as well as consulting fees from Arbutus, Intercept, and Salix.

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