Novo Nordisk’s Amycretin Emerges as a Strong Next-Generation Obesity and Diabetes Candidate in Early and Mid-Stage Trials
Key Takeaways:
- Early and mid-stage studies indicate that amycretin delivers substantial, dose-dependent weight loss in people who are overweight or have obesity, as well as in people with type 2 diabetes.
- Safety findings remain broadly consistent with GLP-1-based agents, with mainly mild to moderate gastrointestinal effects and no weight-loss plateau observed within study periods.
- Novo Nordisk’s new data signal a potentially important successor to semaglutide, strengthening the company’s obesity and diabetes pipeline as it faces patent expirations and competitive pressure from Eli Lilly.
Introduction
A new body of evidence published in The Lancet and released by Novo Nordisk suggests that amycretin, an investigational once-weekly therapy targeting multiple metabolic pathways, may offer clinically meaningful weight reduction and glycaemic improvements in adults who are overweight or have obesity, as well as in adults with type 2 diabetes. The findings come as Novo Nordisk aims to consolidate its leadership in the weight-loss market following concerns about semaglutide’s recent performance in Alzheimer’s trials and increasing competition from Eli Lilly.
Amycretin combines actions on the glucagon-like peptide 1 (GLP-1), amylin, and calcitonin receptors. This multi-pathway design is intended to amplify appetite suppression, slow gastric emptying, and improve metabolic control. Amylin’s role is particularly relevant because it complements GLP-1 signalling, and combining these effects may provide more durable weight management than existing single-pathway therapies.
Background
Obesity affects more than one billion people worldwide and increases the risk of conditions such as cardiovascular disease, type 2 diabetes, non-alcoholic fatty liver disease, and sleep apnoea. Although GLP-1 or GIP receptor agonists have transformed obesity care, many individuals still struggle to meet health goals or encounter diminishing returns over time. Enhancing these therapies with additional hormonal pathways, such as amylin, has been of growing scientific interest.
Amylin, a pancreatic hormone, naturally suppresses appetite, slows digestive transit, and moderates post-meal glucose spikes. When combined with GLP-1 activation, amylin may strengthen satiety signals and support deeper and more sustained weight reduction. Amycretin, a single peptide simultaneously targeting GLP-1, amylin, and calcitonin receptors, represents an effort to leverage these combined mechanisms.
While animal studies have shown potent metabolic effects, the safety, tolerability, and human efficacy of this multi-pathway approach had not been fully established, prompting the recently reported Phase 1b/2a trial and Novo Nordisk’s parallel mid-stage diabetes study.
Phase 1b/2a trial overview (adults who are overweight or have obesity)
Study design
Investigators conducted a five-part, randomised, placebo-controlled Phase 1b/2a trial at a single clinical site in San Antonio, Texas. Eligible adults were aged 18–55 years, had a baseline BMI between 27.0 and 39.9 kg/m², and had no major illnesses such as diabetes. Participants received subcutaneous amycretin or placebo once weekly.
The trial included:
- Part A: Single ascending doses (0.3 mg, 0.6 mg, 1.0 mg).
- Part B: Dose escalation to 60 mg over 36 weeks.
- Part C: Dose escalation to a 20 mg maintenance dose for the final 12 weeks of a 36-week period.
- Part D: Dose escalation to a 5 mg maintenance dose for the final 12 weeks of 28 weeks.
- Part E: Dose escalation to a 1.25 mg maintenance dose for the final 12 weeks of 20 weeks.
Endpoints and monitoring
The primary endpoint was the incidence of treatment-emergent adverse events. Secondary endpoints included:
- Percentage change in body weight
- Pharmacokinetic parameters
- Exploratory metabolic biomarkers (fasting glucose and HbA1c)
Participants had regular laboratory testing, ECG monitoring, and safety assessments. Analyses were adjusted for baseline weight and missing data.
Phase 1b/2a results
Participant characteristics
Between September 2023 and April 2024, the study enrolled 125 adults. A total of 101 received amycretin and 24 received placebo. Baseline BMIs ranged from 30.0 to 33.1 kg/m² across treatment groups, with an overall mean of 33.4 kg/m². Baseline weights ranged from 83.6 kg to 99.1 kg.
Tolerability and discontinuations
Thirty-eight participants receiving amycretin (37%) and four receiving placebo (17%) discontinued the study. Most discontinuations were not related to safety, and investigators noted that placebo discontinuations appeared consistent with a likely nocebo effect.
Treatment-emergent adverse events occurred in 92% of amycretin recipients and 100% of placebo recipients in Parts B–E. Gastrointestinal effects were most common and included:
- Nausea: 82%
- Vomiting: 53%
- Diarrhoea: 41%
These symptoms generally peaked during dose escalation and diminished afterwards. Dysaesthesia rates varied by cohort, ranging from 6% to 29%, and resolved in all but one participant.
One case of mild gallstone pancreatitis occurred during dose escalation in Part C (2.5 mg), later progressing to a serious recurrent episode that ultimately resolved.
No clinically meaningful ECG abnormalities were detected. A transient early rise in heart rate of about 10 bpm resolved without intervention. Antidrug antibodies appeared in 29% of Part B participants and 21% in Part C.
Weight-loss effects
Weight reduction was rapid, dose-dependent, and sustained. Mean percentage weight losses at end of treatment were:
- 60 mg (week 36): 24.3%
- 20 mg (week 36): 22.0%
- 5 mg (week 28): 16.2%
- 1.25 mg (week 20): 9.7%
Placebo groups had much smaller changes: −1.1% (Part B), +1.9% (Part C), +2.3% (Part D), and +2.0% (Part E).
Superiority to placebo emerged by week 4 and continued to widen without evidence of plateau during the maintenance phases. Repeated-measures models produced nearly identical weight-loss estimates.
Metabolic effects
Exploratory findings indicated modest improvements:
- Fasting glucose reductions up to 0.8 mmol/L
- HbA1c reductions of 0.6 percentage points in the highest-dose cohort
Lipid levels and seated blood pressure remained neutral.
Novo Nordisk’s mid-stage trial in type 2 diabetes
In parallel with the early-stage obesity trial, Novo Nordisk announced promising results from a mid-stage study evaluating amycretin in adults with type 2 diabetes who had inadequate glycaemic control with metformin, with or without an SGLT2 inhibitor. The trial included 448 participants and assessed both once-weekly subcutaneous and oral formulations.
Context and competitive landscape
The announcement came one day after Novo Nordisk reported disappointing Alzheimer’s trial results for semaglutide. With patent expirations approaching and rising competition from Eli Lilly’s amylin-based agent eloralintide, analysts are closely watching amycretin’s performance.
Amycretin is widely viewed as a potential “best-in-class” therapeutic candidate. It follows CagriSema, a combination approach which had raised strong expectations but ultimately delivered less weight loss than anticipated in prior studies.
Key findings
- Weight loss:
- Up to 14.5% weight reduction with once-weekly injections over 36 weeks
- Up to 10.1% weight reduction with the oral formulation
- Both routes showed no weight-loss plateau, suggesting the potential for further reduction with longer treatment durations.
- Up to 14.5% weight reduction with once-weekly injections over 36 weeks
- Glycaemic control:
- Statistically significant HbA1c reductions
- Up to 89.1% of participants achieved HbA1c below 7%
- Side-effects were mostly mild gastrointestinal symptoms.
- Statistically significant HbA1c reductions
Novo Nordisk stated it intends to begin late-stage clinical trials in 2026.
Analyst commentary
BMO Capital analyst Evan Seigerman noted that the data represent progress for Novo Nordisk:
“The data, though not enough to completely change the narrative for Novo, marks a step in the right direction for the company.”
Kepler Cheuvreux analyst David Evans commented on amycretin’s broader potential:
“The level of weight-loss seen bodes well not only for its potential in diabetes but also in obesity.”
Morningstar analyst Karen Andersen projected substantial commercial potential, estimating peak annual sales of $8 billion by 2034, split approximately evenly between diabetes and obesity indications, assuming a 2029 launch.
Conclusion
The combined early- and mid-stage data suggest that amycretin may represent a significant development in obesity and diabetes treatment. Its multi-pathway design has shown robust weight-loss effects across populations and the possibility of improved metabolic outcomes. While long-term safety and efficacy need confirmation in Phase 3 trials, amycretin appears positioned as one of Novo Nordisk’s most important next-generation candidates at a time of high strategic importance for the company.
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Weight Training Outperforms Running in Blood Sugar Control, Virginia Tech Mice Study Shows
Key Takeaways:
- Researchers at Virginia Tech found that resistance training was more effective than running in improving glucose tolerance and reducing insulin resistance in mice fed a high-fat diet.
- Both endurance and resistance exercise reduced body fat and improved blood sugar regulation, but resistance training yielded stronger metabolic benefits.
- The study suggests that strength training could play a particularly valuable role in preventing and managing Type 2 diabetes.
Weightlifting may offer unique metabolic benefits
Running is widely recognised for its cardiovascular and calorie-burning benefits, but new preclinical findings from the Fralin Biomedical Research Institute at Virginia Tech Carilion suggest that lifting weights may be even more effective for controlling blood sugar and reducing body fat.
Published on 30 October in the Journal of Sport and Health Science, the study compared the effects of endurance and resistance exercise in mice fed a high-fat diet, a common experimental model for obesity, hyperglycaemia, and Type 2 diabetes.
The team, led by Professor Zhen Yan, an exercise medicine researcher and director of the institute’s Centre for Exercise Medicine Research, found that while both running and weight training improved the body’s ability to clear excess glucose from the bloodstream, resistance training had a stronger impact on reducing both subcutaneous and visceral fat, improving glucose tolerance, and lowering insulin resistance.
“We all want to live a long, healthy life,” said Yan. “We all know the benefits of regular exercise. There is plenty of evidence in humans that both endurance exercise, such as running, and resistance exercise, such as weightlifting, are effective in promoting insulin sensitivity.”
Although both types of activity are known to improve metabolic function, the researchers noted that there had previously been no rigorous, controlled comparison between them.
Developing a model for ‘mouse weightlifting’
To address this gap, the Virginia Tech team created a first-of-its-kind preclinical model of resistance training in mice.
In their experiment, the mice lived in custom-built cages where food was available only through a hinged, weighted lid. To eat, the mice had to lift the lid while wearing a small shoulder collar, performing a movement similar to a human squat. The load was gradually increased over time, effectively replicating progressive strength training.
Meanwhile, the endurance group of mice was given unrestricted access to a running wheel, a standard model for voluntary aerobic exercise. Control groups included sedentary mice maintained on either a normal or high-fat diet.
Over an eight-week period, the researchers monitored changes in body weight, fat distribution, and body composition. They measured exercise capacity with treadmill tests, assessed cardiovascular and muscular performance, and evaluated blood sugar regulation. Muscle tissue samples were also analysed to study insulin signalling at the molecular level.
Using their novel resistance training model, the team could directly compare the metabolic outcomes of running and strength exercise under controlled conditions.
“Our data showed that both running and weightlifting reduce fat in the abdomen and under the skin and improve blood glucose maintenance with better insulin signalling in skeletal muscle,” Yan said. “Importantly, weightlifting outperforms running in these health benefits.”
Implications for obesity and diabetes prevention
Obesity and Type 2 diabetes remain among the most pressing public health challenges, driven largely by high-fat diets and sedentary lifestyles. The new study supports existing clinical evidence showing that endurance, resistance, and high-intensity interval training all contribute to better long-term blood sugar control, reduced body mass index, lower blood pressure, and improved overall well-being.
However, this Virginia Tech study fills a critical gap by directly comparing the two types of exercise in a controlled model of diet-induced obesity. The findings may have important implications for exercise recommendations and diabetes prevention strategies.
“The findings also bring good news for people who, for any number of reasons, cannot engage in endurance-type exercise,” Yan explained. “Weight training has equal, if not better, anti-diabetes benefits.”
Exploring new mechanisms and future therapies
The researchers also observed molecular changes in skeletal muscle that may help explain the enhanced benefits of resistance training. These shifts in insulin signalling pathways could, according to the team, inform the development of new drug therapies for managing Type 2 diabetes.
Interestingly, the improvements seen with resistance training were not directly linked to increased muscle mass or superior exercise performance, suggesting that unique metabolic mechanisms may be at work.
Yan emphasised that although pharmacological interventions such as GLP-1 receptor agonists are valuable tools in diabetes management and weight loss, they cannot replace the broad, systemic benefits of physical activity.
“The take-home message is that you should do both endurance and resistance exercise, if possible, to get the most health benefit,” he said.
The study was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health and by the Red Gates Foundation, with collaborators from the University of Virginia contributing to the work.
CCH insights
This is an interesting study, but it is important to note it was conducted in mice, not humans. Having said that, perhaps the most reassuring thing about these results is that both types of exercise provided metabolic health benefits. The critical thing about physical activity is that any amount and type is better than doing none, and while a combination of endurance and resistance is probably best, if you can only manage one type or the other, it will have a positive impact.
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Thousands in Scotland’s Poorest Areas to Receive Free Weight-Loss Jabs in Landmark Obesity Study
Key Takeaways:
- Up to 5,000 adults living with obesity in Scotland’s most deprived areas will receive free weight-loss injections through the new Scotland CardioMetabolic Impact Study (SCoMIS).
- The multi-million-pound research, led by the University of Glasgow, aims to test the real-world delivery and impact of incretin-based therapies in NHS care.
- The study seeks to reduce health inequalities, improve quality of life, and lessen the long-term burden of obesity on individuals and the NHS.
Landmark initiative targets obesity in Scotland’s most deprived communities
Thousands of people from some of Scotland’s most economically deprived areas will soon be offered free weight-loss injections as part of a major UK government-funded study. The initiative, known as the Scotland CardioMetabolic Impact Study (SCoMIS), will recruit between 3,000 and 5,000 participants living with obesity to test how new weight-loss medicines can be delivered effectively and fairly in everyday NHS care.
The research is being led by the University of Glasgow and is backed by an initial £650,000 in funding from the UK government. If successful, it could pave the way for a wider rollout of the medicines across the country, offering a model for addressing both obesity and health inequality.
How the jabs work
The injections mimic or enhance the effects of naturally occurring hormones called incretins, which help control blood sugar levels. These hormones act on areas of the brain that regulate hunger and appetite and can also slow down how quickly the stomach empties. Together, these effects may support people living with obesity to better manage their eating habits and achieve sustained weight loss.
A national effort to reduce health inequality
Dr Zubir Ahmed, UK Health Innovation Minister, said:
“As a practising NHS surgeon and Glasgow MP, I know firsthand the impact of the obesity crisis that plagues Scotland – and the litany of health problems it leads to. More than 1 in 3 adults in Scotland’s most deprived areas are living with obesity. The UK government is committed to tackling inequality wherever it finds it in our country. It’s why this landmark UK government investment is targeting help where it’s needed most in Scotland and meeting people where they are and backing helping the NHS services they trust to treat them.”
Obesity is one of the leading contributors to long-term illness, including heart disease, type 2 diabetes, and several cancers. By addressing obesity through targeted intervention, the UK government hopes to help millions live longer, healthier lives while reducing the strain on the NHS and saving billions in healthcare costs each year.
Study objectives
The SCoMIS trial will evaluate several key areas of impact:
- Delivery: How weight-loss medicines can be integrated into everyday NHS care, especially within community and primary care settings.
- Outcomes: The degree of weight loss achieved and improvements in quality of life, particularly among people from disadvantaged areas.
- Health impact: The effects on obesity-related conditions, NHS service use, and healthcare expenditure.
- Social benefits: Whether improved health through weight loss can help individuals remain in work, reduce sick leave, and participate more fully in society.
Leading experts and national collaboration
Professor Jason Gill, Professor of Cardiometabolic Health at the University of Glasgow and the lead investigator, said:
“While tackling obesity requires multifactorial public health action, incretin therapies add a powerful new tool to the national obesity strategy. The burden of obesity is greatest in the most deprived segments of society and the status quo risks widening health inequalities. SCoMIS aims to be a landmark real-world study evaluating a new model of obesity care, providing incretin treatment via primary and community care to Scottish adults living with obesity, with a focus on those in the most economically deprived communities.”
Equipping the primary and community care teams who will deliver these treatments is where professional training comes in, such as the College of Contemporary Health’s GLP-1RAs in Practice: Prescribing, a CPD-accredited online short course covering the safe, confident prescribing of incretin-based medicines.
The project is being developed in collaboration with the Universities of Dundee and Edinburgh, industry partners Novo Nordisk and IQVIA, and clinical leaders across Scotland. The consortium will also explore how AI-driven digital technologies can improve patient access, engagement, and data collection throughout the study.
Supporting innovation and evidence-based care
Jenni Minto, Scottish Minister for Public Health, highlighted Scotland’s leadership in advancing obesity research:
“This study places patients and communities at the heart of cutting-edge research into weight-loss medicines, ensuring we build the evidence needed to deliver the greatest benefit to those who need it most.”
UK Science Minister Lord Vallance also praised Scotland’s role in global medical innovation:
“Scotland has always been at the forefront of medical innovation and public health, and this initiative is further proof of the world-class expertise that can be found here. By learning how these weight-loss medicines work, and how we can support them to reach our most deprived areas, we can slash health inequalities in Scotland and the rest of the UK so that our obesity strategy delivers a real, lasting change.”
Looking ahead
Set to launch next year, the SCoMIS study represents one of the most ambitious real-world obesity trials in the UK to date. Its outcomes are expected to shape future national strategies on obesity care, providing a template for equitable access to advanced weight-loss treatments and supporting a healthier, more inclusive society.
CCH insights
This study is very much welcomed, although arguably long overdue. Obesity and associated diseases, most notably type 2 diabetes and cardiovascular disease, are most prevalent in communities with high levels of deprivation, and are a huge cost to the NHS. People in these communities living with obesity should be prioritised in terms for GLP-1 therapy, as this should help to drive down health inequalities and provide massive future financial savings for the health service and provide massive future financial savings for the health service. Realising that potential depends on the primary and community care teams delivering these medicines being properly equipped: CCH’s GLP-1RAs in Practice: Prescribing CPD short course (2 CPD hours, fully online, CPD-accredited) gives prescribers everything they need to use incretin-based medications safely and confidently, from patient selection and initiation through to titration and side-effect management.
Explore GLP-1RAs in Practice: Prescribing →
GLP-1 Weight Loss Drugs Linked to First National Decline in Obesity Rates, Survey Finds
Key Takeaways:
- The U.S. adult obesity rate has dropped from 39.9% to 37% over three years, coinciding with a rapid rise in GLP-1 medication use.
- Over 12% of adults now report taking injectable obesity drugs such as semaglutide or tirzepatide, more than double the proportion from early 2024.
- Experts warn that limited insurance coverage may soon hinder access, potentially reversing progress.
New survey suggests decline in U.S. obesity rates
The proportion of adults living with obesity in the United States has declined for the first time in years, according to a new Gallup National Health and Well-Being Index survey. The findings suggest that the surge in the use of injectable obesity drugs may be driving this shift.
The survey reported that 37% of U.S. adults are currently living with obesity, compared with a peak of 39.9% three years ago. Researchers attribute much of this reduction to the growing uptake of GLP-1 receptor agonists, a class of highly effective weight loss drugs that include semaglutide and tirzepatide.
Use of GLP-1 medications has more than doubled
The number of people using GLP-1-based treatments such as Ozempic and Wegovy (semaglutide), or Zepbound and Mounjaro (tirzepatide), has more than doubled over the past 18 months. According to Gallup, 12.4% of respondents reported using these drugs, up from 5.8% in February 2024, when the organisation first began tracking their use.
GLP-1 receptor agonists, which mimic a naturally occurring hormone that regulates appetite and blood sugar, were first approved for obesity treatment in 2021. Their mechanism of action involves acting on the brain and gut hormones to suppress hunger and slow digestion, helping individuals sustain weight loss.
A watershed in obesity treatment
Experts consider the introduction of GLP-1 receptor agonists to be a landmark in obesity treatment, following decades of limited progress through diet, exercise, and public health campaigns.
Gallup described the new generation of GLP-1 drugs as a “watershed in Americans’ long struggle to address obesity and related diseases.” Despite these advances, the survey also found that diabetes rates have reached a record high: 13.8% of adults reported having been diagnosed by a doctor or nurse. This highlights the scale of ongoing metabolic health challenges even as weight loss interventions improve.
Impact seen most among middle-aged adults and women
The data indicate that the reduction in obesity rates has been most notable among adults aged 40 to 64, a demographic more likely to use GLP-1 medications. Among those aged 50 to 64, obesity prevalence fell by 5.0 percentage points, reaching 42.8%.
The survey also noted differences by sex: women were more likely than men to use these medications and tended to report greater weight loss benefits. This aligns with previous clinical research showing that women are often more proactive in seeking medical support for weight management.
Access and affordability remain key challenges
Despite their effectiveness, access to GLP-1 drugs remains uneven and may worsen in the coming year. Dr Fatima Cody Stanford, an obesity specialist at Harvard University, cautioned that while the correlation between increased access and reduced obesity rates is promising, it may not be sustainable if coverage declines.
“I would say this correlation happened for those that had great coverage, but it’s going to be pulled back,” she said.
Dr Stanford explained that several private insurers – including those covering most of her patients – are planning to stop covering GLP-1 medications as of next year. Without insurance, the cost of injections typically reaches around $500 per month out of pocket, she noted.
Although pharmaceutical companies are developing oral versions that may eventually reduce costs, Dr Stanford warned that these treatments will likely remain unaffordable for many in the short term.
“While drugmakers are working to bring potentially less-expensive pill versions to market, it likely still will put the treatments out of reach for many,” she said.
Slow but significant progress
While the findings do not confirm causation, they offer one of the first indications that the widespread use of GLP-1 receptor agonists could be contributing to measurable declines in obesity prevalence. Public health experts stress, however, that long-term trends will depend heavily on sustained access, equitable prescribing, and broader changes in lifestyle and preventive care.
For now, the data mark a tentative but meaningful turning point in the decades-long fight against obesity in the United States – a shift that could influence obesity strategies worldwide if sustained.
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Exercise Shown to Reduce Artery Hardening After Weight Loss in Adults With Obesity
Key Takeaways:
- Regular exercise after weight loss significantly reduces inflammation and improves blood vessel health in adults living with obesity.
- The GLP-1 receptor agonist liraglutide helped participants maintain weight but did not show the same protective effects against artery hardening.
- Researchers emphasise exercise as an essential factor for maintaining cardiovascular health after weight reduction.
Exercise and heart health after weight loss
Maintaining weight loss through regular exercise, rather than relying solely on the glucagon-like peptide-1 receptor agonist (GLP-1RA) liraglutide, appears to protect against atherosclerosis in adults living with obesity, according to new research from the University of Copenhagen. Atherosclerosis—hardening and narrowing of the arteries due to inflammation and fat deposits—is a major underlying cause of cardiovascular disease (CVD).
The findings were presented at the Annual Meeting of the European Association for the Study of Diabetes (EASD) 2025 in Vienna (15–19 September).
“Our findings reveal that regular exercise is crucial to helping people living with obesity get the full cardiovascular benefits after a substantial weight loss,” said Dr Rasmus Sandsdal, lead author of the study from the University of Copenhagen, Denmark.
Understanding the risk
Cardiovascular disease remains the leading cause of death globally. It often begins with atherosclerosis, in which chronic inflammation and lipid accumulation cause the arteries to stiffen and narrow. If left unchecked, these plaques can rupture and trigger life-threatening events such as heart attacks and strokes.
Obesity contributes to chronic low-grade inflammation and endothelial dysfunction—a condition in which blood vessels lose their ability to contract and relax properly—both of which accelerate atherosclerosis.
While both exercise and GLP-1RAs are known to lower cardiovascular event risk in people with obesity, their specific effects on the development of atherosclerosis during weight loss maintenance have remained unclear—until now.
The study design
The Danish research team conducted a randomised placebo-controlled trial involving 215 adults aged 18–65 years (63% female) living with obesity (BMI 32–43 kg/m²) but without diabetes or other serious chronic conditions.
All participants began an eight-week low-calorie diet (800 kcal per day) using the Cambridge Weight Plan. Of these, 195 participants who achieved at least a 5% reduction in body weight (average loss of 12% or 13.1 kg) entered a one-year maintenance phase. They were randomly assigned to one of four groups:
- Exercise (150 minutes/week of moderate-to-vigorous activity) plus placebo
- Liraglutide treatment (3.0 mg per day)
- Exercise combined with liraglutide
- Placebo only
Researchers measured several key biomarkers at three points—before dieting, at the start of weight maintenance, and after one year. These included inflammatory markers (interleukin-6 [IL-6] and interferon-γ [IFN-γ]), endothelial function markers (intercellular adhesion molecule [ICAM-1], vascular adhesion molecule [VCAM-1], and tissue plasminogen activator [tPA]), and carotid artery intima-media thickness [cIMT], an indicator of arterial wall health measured by ultrasound.
Exercise reduced inflammation and improved arterial health
After one year, participants in both the exercise and liraglutide groups successfully maintained their weight loss. However, significant differences emerged in their cardiovascular health profiles.
Those who exercised—whether or not they also received liraglutide—had notably lower levels of inflammatory biomarkers compared with non-exercising participants. On average, IL-6 levels were 21% lower, and IFN-γ levels were 27% lower.
Exercise also had a favourable effect on endothelial function, reflected in a 6% reduction in VCAM-1, 8% reduction in ICAM-1, and 12% reduction in tPA compared to those who did not exercise. Moreover, carotid artery thickness decreased by an average of 0.024 mm, indicating reduced arterial hardening.
In contrast, treatment with liraglutide alone did not yield any measurable improvements in inflammatory or endothelial biomarkers, nor did it affect carotid artery thickness.
“Regular exercise seems to confer a protective effect against the development of atherosclerosis in people trying to maintain weight loss,” said Dr Sandsdal. “Since both exercise and GLP-1RA treatment were successful at keeping weight off, it seems that exercise plays an important role in mitigating cardiovascular risk factors in a weight-independent manner.”
Implications for long-term health
Exercise offers multiple benefits beyond weight control, including improvements in body composition, cardiorespiratory fitness, and metabolic health. Together, these contribute to better long-term cardiovascular outcomes.
“The most important message from our findings is that, for those trying to maintain weight loss, exercise is crucial in improving long-term health,” said Professor Signe Sørensen Torekov, corresponding author from the University of Copenhagen. “Given the substantial societal and economic costs of obesity-related cardiovascular disease, these findings underscore regular exercise as a critical component of weight management and heart health.”
Study limitations and future research
The authors acknowledged several limitations. The study’s sample size was relatively small, and adherence to structured exercise in real-world conditions may be lower than in a supervised trial setting.
Future studies, they suggested, should explore longer-term interventions and evaluate newer GLP-1 receptor agonists—potentially more potent than liraglutide—in combination with consistent exercise to assess whether similar or enhanced cardiovascular benefits can be achieved.
CCH insight:
We have long known that exercise is important for cardiovascular health, so the results of this study should not be a surprise – exercise provides cardiovascular benefits whether or not you are taking a GLP-1 medication. It is also important to remember that GLP-1 receptor agonists are meant to be taken as an adjunct to a healthy diet and lifestyle, including exercise. This is not just about weight management, but also about maximising health benefits and minimising the risk of developing diseases associated with obesity – such as cardiovascular disease.
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Use of GLP-1 Drugs Soars Among People Undergoing Bariatric Surgery, Study Finds
Key Takeaways:
- The use of GLP-1 receptor agonists such as semaglutide and tirzepatide among bariatric surgery patients increased sixteenfold between 2020 and 2024.
- Both people with and without Type 2 diabetes are increasingly using these drugs, showing a shift toward combination approaches in obesity management.
- Researchers emphasise the importance of multidisciplinary care and call for evidence-based guidelines to optimise the use of GLP-1 drugs alongside surgery.
A rapid evolution in obesity care
New research has revealed a dramatic increase in the use of weight loss medications among people undergoing metabolic and bariatric surgery, signalling a major shift in the treatment of obesity and Type 2 diabetes.
The study will be presented at the American College of Surgeons (ACS) Clinical Congress 2025, held in Chicago from 4–7 October.
“There is no one-size-fits-all approach to treating obesity, metabolic syndrome, or diabetes and its related conditions,” said Dr Patrick J. Sweigert, senior author of the study and bariatric and foregut surgeon at The Ohio State University Wexner Medical Center in Columbus, Ohio. “We are entering a new world of multidisciplinary care pathways and a new frontier of weight management that is important for patients and surgeons to think about.”
About the study
The research team conducted a large cross-sectional study examining the use of glucagon-like peptide-1 receptor agonists (GLP-1RAs) – specifically semaglutide (marketed as Wegovy and Ozempic) and tirzepatide (marketed as Zepbound and Mounjaro) – among people undergoing metabolic and bariatric surgery.
Using data from the Epic Cosmos database, which aggregates over 300 million patient records from healthcare institutions across the United States, Dr Sweigert and colleagues analysed nearly 365,000 individuals who underwent primary metabolic and bariatric surgery between 2018 and 2024.
The study assessed prescription patterns for semaglutide and tirzepatide, two of the most widely prescribed GLP-1RAs, to understand how their use has evolved before surgery.
Key findings
Preliminary findings showed a striking rise in GLP-1 prescriptions in the year preceding surgery – from 1.8% in early 2020 to 29.4% by the end of 2024, representing a sixteenfold increase.
Importantly, the surge was seen among people both with and without Type 2 diabetes, demonstrating the expanding role of GLP-1 drugs in obesity treatment beyond diabetes management.
Among those without Type 2 diabetes, use of GLP-1 drugs before surgery increased elevenfold – from 2.1% in early 2022 to 23.2% by late 2024. For those with Type 2 diabetes, preoperative use quadrupled – from 11.3% to 45.2% over the same period.
The median age of participants was 43 years, with a median preoperative body mass index (BMI) of 46. Women accounted for 80% of the cohort, and 33% had a diagnosis of Type 2 diabetes.
Changing perceptions and treatment pathways
Lead author Dr Stefanie C. Rohde, a general surgery resident at The Ohio State University Wexner Medical Center, explained that the findings represent an evolution in how people view their treatment options for obesity.
“While patients previously believed they had to choose between GLP-1 receptor agonists and surgery, we are now seeing that people are using both,” said Dr Rohde. “We know that patients can use GLP-1s after bariatric surgery to amplify their weight loss. But all of this is still very new in terms of how to manage patients effectively.”
She added that real-world data such as that provided by the Epic Cosmos network could play a critical role in establishing evidence-based clinical guidelines for how and when to integrate GLP-1 therapies – whether before surgery, in combination with it, or during postoperative follow-up.
Limitations and next steps
The researchers acknowledged several limitations. As with many analyses of large health databases, there may be inaccuracies in medical record data. The study was also unable to confirm whether individuals filled or took their prescribed medications, which could affect the reliability of prescription data.
Despite these caveats, the authors believe the study offers valuable insights into emerging trends in combined pharmacological and surgical approaches to obesity care.
Study co-author Mahmoud Abdel-Rasoul, MS, MPH, contributed to the data analysis and interpretation.
Looking ahead
The rapid rise in GLP-1 use among bariatric surgery candidates reflects a broader transformation in obesity treatment – one increasingly characterised by personalised, multidisciplinary, and data-informed care.
As Dr Sweigert noted, “We are entering a new world of multidisciplinary care pathways.” The challenge now lies in defining the most effective, safe, and sustainable ways to integrate these groundbreaking medications into established surgical treatment frameworks.
CCH insight:
These findings from the ACS, showing GLP-1 drug use prior to bariatric surgery, follow on from another study showing that many patients use GLP-1 drugs after surgery, in order to prevent weight regain. This will hopefully help to shift the thinking around obesity treatment. There is still a common perception that patients with obesity have the option of medication or bariatric surgery, and that it is a ‘one-and-done’ treatment. However, we know that obesity is a complex, chronic, relapsing disease which requires a long-term, multi-disciplinary approach. So we need medications, we need surgery and we need behavioural support and other interventions, used together in various combinations, at different times, to provide the life-long care that obesity patients require.
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Oral GLP-1 Therapy Orforglipron Demonstrates Significant Weight Loss in Landmark Trial
Key Takeaways:
- The ATTAIN-1 phase III trial found that the oral GLP-1 drug orforglipron led to clinically meaningful weight loss and metabolic improvements in people living with obesity or overweight.
- Average weight loss reached 12.4% with the highest dose, alongside significant improvements in waist circumference, blood pressure, and lipid profiles.
- Orforglipron may provide a more accessible alternative for individuals reluctant to use injections or living in areas with limited cold-storage infrastructure.
A new oral alternative to injectable GLP-1 therapies
An investigational oral GLP-1 drug, orforglipron, has been shown to promote substantial weight loss and improve cardiovascular and metabolic health markers in a large, international phase III clinical trial. The ATTAIN-1 study, published on 17 September in The New England Journal of Medicine, was led by researchers from Weill Cornell Medicine, McMaster University, York University, and collaborating institutions.
The study enrolled 3,127 participants with obesity or overweight who had obesity-related complications such as hypertension. None of the participants had diabetes. Participants were randomised to receive a placebo or one of three daily oral doses of orforglipron – 6 mg, 12 mg, or 36 mg – alongside guidance on maintaining a healthy diet and regular physical activity.
Meaningful weight loss across all doses
Over 72 weeks, individuals treated with orforglipron experienced dose-dependent weight loss:
- 7.8% reduction in body weight with the 6 mg dose
- 9.3% reduction with the 12 mg dose
- 12.4% reduction with the 36 mg dose
By comparison, participants in the placebo group lost an average of just 2.1% of their initial body weight.
Adverse events were consistent with those observed for other GLP-1 receptor agonists, mainly mild to moderate gastrointestinal effects including nausea, vomiting, and diarrhoea.
Clinical and public health implications
“The findings suggest that orforglipron could offer an important new option for people with obesity, especially those reluctant to use injections or who live in places where cold storage for injectable medications is limited,” said Dr Louis Aronne, Director of the Comprehensive Weight Control Center and Sanford I. Weill Professor of Metabolic Research at Weill Cornell Medicine, who served as a lead investigator for the ATTAIN-1 trial.
“ATTAIN-1 represents another milestone in developing effective treatments for obesity. In addition, the distribution and storage of a small molecule is less expensive, and scalability is simpler. Given the worldwide demand, these are important factors in making treatment available to those in need,” Dr Aronne added.
Dr Aronne is also an internist specialising in diabetes and obesity at NewYork-Presbyterian/Weill Cornell Medical Center.
Improvements beyond weight loss
Although the weight reduction achieved with orforglipron was slightly lower than that typically seen with injectable GLP-1 therapies such as semaglutide or tirzepatide, the study reported robust cardiometabolic benefits. Participants on orforglipron demonstrated greater reductions in:
- Waist circumference
- Systolic blood pressure
- Non-HDL cholesterol and triglyceride levels
- Glycated haemoglobin (HbA1c)
These improvements underline the drug’s potential to reduce the risk of major obesity-related complications, including cardiovascular disease and type 2 diabetes.
Why oral GLP-1 drugs could be game-changing
Injectable GLP-1 drugs, which are peptide-based therapies, have already transformed obesity and type 2 diabetes management worldwide. When taken long-term, they can help people lose more than 15% of their body weight and substantially lower the risk of heart attack, stroke, kidney disease, and sleep apnoea.
However, injectable GLP-1 medications require cold storage and are vulnerable to breakdown by stomach enzymes if taken orally. Orforglipron is different – it is a “small-molecule” drug designed to be taken as a pill, potentially lowering costs and simplifying global distribution.
Study scope and sponsorship
The ATTAIN-1 trial was sponsored by Eli Lilly and Company, which manufactures orforglipron as well as the injectable GLP-1 drug tirzepatide (marketed as Mounjaro for type 2 diabetes and Zepbound for chronic weight management). The trial was conducted across 137 sites in nine countries, including the United States, Canada, Japan, Brazil, Spain, and Saudi Arabia.
Disclosure: Dr Louis Aronne serves as a paid consultant and advisory board member for Eli Lilly and Company.
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Higher Dose of Semaglutide Delivers Greater Weight Loss and Metabolic Improvements
Key Takeaways:
- Tripling the standard dose of semaglutide led to significantly greater weight loss and improved metabolic outcomes, without an increase in serious adverse effects.
- Participants on the higher dose achieved clinically meaningful reductions in body weight, waist circumference, and HbA1C levels, with nearly one-third losing 25% or more of their starting weight.
- Side effects were mostly mild and transient, suggesting that the higher dose may be a safe option for people requiring more intensive obesity treatment.
Landmark findings from the STEP UP trials
Tripling the standard dose of semaglutide – a widely prescribed glucagon-like peptide-1 receptor agonist (GLP-1RA) – resulted in markedly greater weight loss and cardiometabolic benefits, according to results from two large multicentre clinical trials led by UT Southwestern Medical Center. The studies, published in The Lancet Diabetes & Endocrinology, indicate that patients may be able to safely take a higher semaglutide dose than currently approved if they need to lose additional weight.
“Semaglutide and other drugs in its class have been life-changing for people living with obesity around the world. Our new findings suggest that increasing the dose can lead to even greater benefits and may be appropriate for some patients,” said study leader Dr Ildiko Lingvay, Professor of Internal Medicine in the Division of Endocrinology and in the Peter O’Donnell Jr. School of Public Health at UT Southwestern.
Context: The global obesity challenge
Obesity affects nearly one billion people worldwide, according to the World Health Organization, and is a major driver of conditions such as Type 2 diabetes, cardiovascular disease, certain cancers, and liver disease. GLP-1RAs, first authorised in the early 2000s, have transformed the management of Type 2 diabetes and, more recently, chronic weight management and cardiovascular risk reduction.
Semaglutide received approval from the US Food and Drug Administration (FDA) in 2017 for people with Type 2 diabetes and has since been approved at a 2.4 mg weekly dose for weight management in both the United States and European Union. While this dose can produce significant weight loss, many patients do not achieve their treatment goals.
The STEP UP trials: Design and participants
To explore whether higher doses could deliver additional benefits, researchers conducted two phase 3b clinical trials – STEP UP Diabetes and STEP UP Obesity – to compare the effects of a weekly 7.2 mg dose of semaglutide with the standard 2.4 mg dose and placebo.
In the STEP UP Diabetes trial, 512 adults with both obesity and Type 2 diabetes were randomly assigned to three groups:
- 307 participants received 7.2 mg semaglutide weekly.
- 103 participants received 2.4 mg semaglutide weekly.
- 102 participants received placebo.
Participants were followed for 72 weeks at 68 trial sites across eight countries in Europe, southern Africa, and North America, including UT Southwestern. All participants received counselling every four weeks to encourage reduced-calorie diets and increased physical activity.
Results: Substantial weight loss and metabolic gains
Weight loss outcomes
As seen in earlier studies, the standard 2.4 mg dose produced a mean weight loss of 10.4% of starting weight, compared with 3.9% in the placebo group. However, participants taking the higher 7.2 mg dose achieved an even greater mean weight loss of 13.2%.
In addition, those receiving 7.2 mg were significantly more likely to:
- Reach a 20% reduction in waist circumference – a key measure of cardiometabolic health.
- Achieve superior improvements in HbA1C, an indicator of blood sugar control.
Outcomes in people without type 2 diabetes
The STEP UP Obesity trial, which focused on people with obesity but without Type 2 diabetes, showed even more striking results. Nearly one-third of participants on the higher dose lost 25% or more of their starting weight, compared with 15% of those on the standard dose and none on placebo.
Safety profile and side effects
The most frequently reported side effects were gastrointestinal symptoms, such as nausea, diarrhoea, and constipation. These affected approximately half of participants taking semaglutide and about a quarter of those on placebo. Most symptoms occurred during the dose-escalation period and tended to diminish over time.
The only side effect reported more frequently in the higher dose group was dysaesthesia (a change in touch sensation), experienced by approximately 20% of participants taking 7.2 mg, compared with 5% of those on the lower dose. Importantly, there was no increase in serious adverse events associated with the higher dose.
“These findings reinforce the promise of semaglutide and other GLP-1RAs, with benefits that appear to increase at higher doses without compromising patient safety,” Dr Lingvay concluded.
Funding and disclosures
Both STEP UP trials were funded by Novo Nordisk A/S, the manufacturer of semaglutide. Dr Lingvay reports receiving personal consulting fees from Novo Nordisk.
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