GLP-1 Medications Should Be First-Line Treatment for Obesity, Say European Experts
Key Takeaways:
- European experts recommend semaglutide and tirzepatide as the preferred first-line medications for treating obesity and related complications.
- The new European Association for the Study of Obesity (EASO) guideline highlights tailored drug choices for specific obesity-linked conditions, such as heart disease, osteoarthritis, and sleep apnoea.
- Authors emphasise that managing obesity extends beyond weight loss, encompassing mental health, physical fitness, and quality of life.
New guidelines mark a turning point in obesity care
Two of the most widely prescribed weight-loss medications – semaglutide and tirzepatide – should now be considered the first treatment option for people living with obesity and associated complications, according to new guidance issued by the European Association for the Study of Obesity (EASO).
The guideline, published in Nature Medicine, identifies semaglutide, the active compound in Novo Nordisk’s Wegovy and Ozempic, and tirzepatide, marketed as Zepbound and Mounjaro by Eli Lilly, as highly effective and clinically appropriate first-line treatments for most cases requiring substantial weight reduction.
When only moderate weight loss is needed, other pharmacological options may be suitable. These include liraglutide, an earlier and less potent medication from the same class, as well as naltrexone–bupropion and phentermine–topiramate.
Although the recommendations are non-binding for European nations, they signal a major shift in the medical management of obesity across the continent.
Transforming obesity care
“Semaglutide, tirzepatide, and other drugs from the class known as GLP-1 agonists are completely transforming care of obesity and its complications,” said co-author Dr Andreea Ciudin of Vall d’Hebron University Hospital in Barcelona.
Dr Ciudin noted that while no single treatment algorithm can replace the nuanced clinical judgement of healthcare professionals, the new guidance is intended to support evidence-based decision-making and improve the consistency of obesity care across Europe.
Tailoring treatments to specific conditions
To develop the recommendations, the EASO guideline authors reviewed previous clinical trial data assessing medication efficacy, safety, and impact in individuals with obesity-related comorbidities.
The panel determined that tirzepatide should be prioritised for those experiencing obstructive sleep apnoea, whereas semaglutide should be considered first for individuals with knee osteoarthritis.
For people with metabolic or immune-related complications, the recommendations include semaglutide as a preferred option for those with existing cardiovascular disease or a history of stroke, tirzepatide for individuals with non-alcoholic fatty liver disease, and either drug for those with prediabetes or type 2 diabetes.
GLP-1 receptor agonists were initially developed to manage type 2 diabetes but have since shown remarkable efficacy in promoting sustained weight reduction and improving obesity-related outcomes.
Balancing costs and benefits
The guideline acknowledges that GLP-1 drugs are expensive and that economic considerations are complex. However, the authors argue that health systems should account for the long-term costs of untreated obesity.
“The cost of not treating obesity at early stages, thus enabling the progression to complications and end-organ damage, should be weighed equally in health policy and clinical decision-making,” the guideline authors wrote.
They added that effective obesity management should not be confined to weight loss alone but should also prioritise mental well-being, physical fitness, social participation, and quality of life.
Emerging evidence and ongoing updates
The authors acknowledged that many newer medications have not yet been evaluated for the treatment of individual complications. Nevertheless, the consistent association between weight reduction and improvements in related conditions supports their broader therapeutic potential.
According to the guideline, there is growing evidence that GLP-1 receptor agonists may also benefit individuals with chronic kidney disease, neurodegenerative conditions, polycystic ovary syndrome, certain cancers, and mental health disorders.
“Given the rapid advances in the field of medications to treat obesity, EASO intends to update the present treatment algorithm regularly to incorporate the latest available evidence,” said Professor Volkan Yumuk, President of EASO and Professor at Istanbul University–Cerrahpaşa.
Lifestyle interventions remain essential
The EASO guidance complements a June advisory jointly issued by the American College of Lifestyle Medicine, the American Society for Nutrition, the Obesity Medicine Association, and The Obesity Society. That advisory stressed that pharmacological treatment should always be combined with lifestyle and nutritional interventions.
“Although GLP‐1s alone can produce significant weight reduction and related health benefits, several challenges limit its long‐term success for individuals and populations,” the advisory stated.
It cited factors such as gastrointestinal side effects, nutrient deficiencies, muscle and bone loss, high costs, frequent discontinuation, and the risk of weight regain.
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Bariatric Surgery Delivers Greater Long-Term Benefits Than GLP-1 Medicines Alone, Cleveland Clinic Study Finds
Key Takeaways:
- People with obesity and type 2 diabetes who underwent bariatric surgery lived longer and experienced fewer serious complications than those treated with GLP-1 receptor agonist medicines alone.
- Surgery was associated with a lower risk of death, cardiovascular disease, kidney disease, and diabetes-related eye damage over a 10-year period.
- Patients who had surgery lost more weight, achieved better blood sugar control, and relied less on medications for diabetes, blood pressure, and cholesterol.
Major Cleveland Clinic study compares treatments
A large-scale study conducted by Cleveland Clinic has shown that people living with obesity and type 2 diabetes who undergo bariatric (metabolic) surgery experience significantly better long-term outcomes compared with those treated only with GLP-1 receptor agonist (GLP-1RA) medicines.
The research, published in Nature Medicine, followed nearly 4,000 patients and found that surgery was linked to longer life expectancy, greater weight loss, improved blood sugar control, and reduced reliance on diabetes and cardiovascular medicines.
“Even with today’s best medicines, metabolic surgery offers unique and lasting benefits for people with obesity and diabetes,” said Ali Aminian, M.D., Director of Cleveland Clinic’s Bariatric & Metabolic Institute and primary investigator of the study. “The benefits we observed went beyond weight loss. Surgery was linked to fewer heart problems, less kidney disease and even lower rates of diabetes-related eye damage.”
Study design and findings
The M6 study (Macrovascular and Microvascular Morbidity and Mortality after Metabolic Surgery versus Medicines) included 3,932 adults with both diabetes and obesity who received care at Cleveland Clinic over a period of up to 10 years.
- 1,657 participants underwent metabolic surgery, including gastric bypass or sleeve gastrectomy.
- 2,275 participants were treated with GLP-1 medicines such as liraglutide, dulaglutide, exenatide, semaglutide, and tirzepatide.
The median follow-up was 5.9 years (interquartile range 4.4–7.6 years).
Key outcomes:
At the 10-year mark, patients who underwent metabolic surgery had significantly better outcomes:
- 32% lower risk of death
- 35% lower risk of major adverse cardiovascular events (MACE), including heart attack, heart failure, or stroke
- 47% lower risk of chronic kidney disease (CKD)
- 54% lower risk of diabetes-related retinopathy (eye damage)
The 10-year cumulative incidence of all-cause mortality was 9.0% (95% CI 6.8–10.8%) in the metabolic surgery group, compared with 12.4% (95% CI 9.9–15.2%) in the GLP-1RA group (adjusted hazard ratio 0.68, 95% CI 0.48–0.96; P = 0.028).
The 10-year cumulative incidence of MACE was 23.7% (95% CI 20.0–27.6%) in the metabolic surgery group and 34.0% (95% CI 28.1–44.2%) in the GLP-1RA group (adjusted hazard ratio 0.65, 95% CI 0.51–0.82; P < 0.001).
On average:
- People who had surgery lost 21.6% of their body weight over 10 years.
- People treated with GLP-1 medicines lost 6.8% of their body weight.
- Haemoglobin A1c (HbA1c), a key marker of average blood sugar, improved by -0.86% with surgery compared with -0.23% with GLP-1 medicines.
In addition, surgery patients required fewer prescriptions for diabetes, blood pressure, and cholesterol management.
Expert perspectives
The findings underscore the long-term advantages of bariatric surgery even in the current era of advanced GLP-1 treatments.
“Even in the era of these powerful new drugs to treat obesity and diabetes, metabolic surgery may provide additional benefits, including a survival advantage,” said Steven Nissen, M.D., Chief Academic Officer of the Heart, Vascular & Thoracic Institute at Cleveland Clinic and senior author of the study.
Dr Aminian emphasised the importance of maintaining surgery as a treatment option:
“Our findings indicate that surgery should remain an important treatment option for obesity and diabetes. These long-term benefits are harder to achieve with GLP-1 medicines alone, as many patients stop using the medications over time.”
Study limitations and future research
The authors highlighted that the study was observational, not a randomised controlled trial. This means that while strong associations were observed, direct comparisons may be influenced by unmeasured factors.
In addition, the study did not focus exclusively on the most recent and highly effective GLP-1 medicines. The authors noted that future trials should directly compare metabolic surgery with newer GLP-1 therapies, such as semaglutide and tirzepatide, to help guide clinical decision-making.
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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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