EASO Recommends GLP-1 Agonists as First-Line Treatment for Obesity and Complications

New framework prioritizes semaglutide and tirzepatide across most obesity-related conditions

The European Association for the Study of Obesity (EASO) has released new guidance positioning the incretin mimetics semaglutide and tirzepatide as first-line pharmacologic treatments for obesity and for most of its complications. The framework, published in Nature Medicine, represents a significant shift in obesity management strategy by organizing treatment recommendations around the presence or absence of obesity-related complications rather than weight loss alone.

"Even though there are several options on the market, the reality is that semaglutide and tirzepatide are so effective that they should be the first choice in almost all cases," co-first author Andreea Ciudin, MD, PhD, of Vall d'Hebron University Hospital in Barcelona, said in an EASO statement.

Obesity management should extend beyond weight loss to focus on preventing and improving complications, supporting mental health, enhancing physical fitness and social functioning, and promoting overall quality of life, the framework authors wrote. Core strategies include behavioral changes, eg, nutrition therapy, physical activity, stress reduction, and better sleep, augmented when needed by psychological support, pharmacotherapy, and metabolic or bariatric interventions.

Complications at the Center

The new algorithm diverges from traditional obesity treatment frameworks by using obesity-related complications as the primary factor guiding medication selection. "It is the first framework guided by the presence or absence of obesity-related complications, since weight loss is not the only goal of treatment when complications are present," EASO co-chair Barbara McGowan, MBBS, PhD, of Guy's & St Thomas's Hospital NHS Foundation Trust in London, said.

The international team of obesity experts, led by co-chairs of the EASO Obesity Management Working Group McGowan and Ciudin, evaluated each medication based on 3 criteria:

• Effectiveness in promoting total weight loss
• Impact on complications
• Safety profile

Evidence Base and Weight Loss Efficacy

Based on traditional and network meta-analyses of clinical trials, the authors concluded that tirzepatide, a dual gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, and semaglutide, a GLP-1 receptor agonist, should be considered first-choice medications when substantial total body weight loss is required.

For individuals who have less weight to lose, other medications remain viable options, including liraglutide, naltrexone-bupropion, and phentermine-topiramate.

Fat Mass Disease vs Sick Fat Disease

The framework distinguishes between 2 categories of obesity-related complications: fat mass disease, characterized by mechanical complications, and sick fat disease, marked by immunologic and metabolic complications. Even with this conceptual distinction, semaglutide and tirzepatide emerged as first-line recommendations across both categories.

Fat Mass Disease Complications

Obstructive sleep apnea: Tirzepatide is recommended as first-line treatment for patients with obesity and OSA, though this recommendation currently rests on a single randomized controlled trial.

Knee osteoarthritis: Semaglutide is recommended as first-line treatment based on available RCT evidence showing superior pain reduction.

Sick Fat Disease Complications

Prediabetes and type 2 diabetes: Both tirzepatide and semaglutide are recommended as first-choice medications, with liraglutide and naltrexone-bupropion designated as second-line treatments.

Cardiovascular disease: Semaglutide is recommended as first-line treatment based on the authors' meta-analysis showing significant reduction in major adverse cardiovascular events (MACE) in individuals with previous cardiovascular events.

Heart failure: While noting that additional data are needed, current evidence supports either tirzepatide or semaglutide as first-line treatments.

Metabolic dysfunction-associated steatotic liver disease (MASH): Tirzepatide is currently recommended as first-line treatment. However, the authors note that the phase 3 ESSENCE trial,³ published after the algorithm's January 31, 2025, cutoff date, showed semaglutide achieved similar improvements in MASH and liver fibrosis. Algorithm authors expect updates to include semaglutide as a first-line option for this indication.

Evidence Gaps and Potential

The authors acknowledge significant gaps in the evidence base, noting that most medications have not been specifically evaluated for treatment of individual complications. While some benefits may be inferred from total body weight loss effects, direct evidence for many conditions remains limited.

Nevertheless, McGowan et al highlight growing potential for these medications to influence a broader range of complications, including chronic kidney disease, neurodegenerative disorders, polycystic ovary syndrome, certain cancers, and mental health conditions.

Personalized Medicine

Professor McGowan emphasized the complexity of individualizing treatment: "Tailoring treatment to the individual is a complex task that must consider several factors, including the severity of adiposity, the presence and extent of complications, comorbidities and concurrent therapies. Socioeconomic context, patient values, expectations, and personal goals must also be considered."

Ciudin noted that while no algorithm can replace clinical judgment, the framework serves as a valuable tool to support therapeutic decision-making. "This new class of GLP-1 agonists and GIP/GLP-1 dual agonists is completely transforming care of obesity and its complications," she said.

Economic Considerations

The economic considerations surrounding the incretin mimetic class are complex and vary across national healthcare contexts. McGowan, Ciudin and colleagues however, argue for a balanced approach: "The cost of not treating obesity and adipose tissue dysfunction at early stages," which typically drives progression to complications and end-organ damage, "should be weighed equally in health policy and clinical decision-making."

Looking Ahead

EASO President professor Volkan Yumuk, MD, of Istanbul University-Cerrahpaşa indicated the organization's commitment to keeping pace with the rapidly evolving field: "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," Yumuk said in the statement.¹

As the number of available obesity medications continues to expand, this framework provides clinicians with evidence-based guidance for navigating an increasingly complex therapeutic landscape while prioritizing both weight loss and complication management in personalized care.

References

1. McGowan B, Ciudin A, Baker JL, et al. Framework for the pharmacological treatment of obesity and its complications from the European Association for the Study of Obesity (EASO). Nat Med. Published online October 2, 2025. doi:10.1038/s41591-025-03765-w
2. Semaglutide and tirzepatide recommended as first-line treatment of obesity and most of its complications in new guidance from European Association for the Study of Obesity (EASO). News release. EASO. October 2, 2025. Accessed October 2, 2025. https://easo.org/semaglutide-and-tirzepatide-recommended-as-first-line-treatment-of-obesity-and-most-of-its-complications-in-new-guidance-from-european-association-for-the-study-of-obesity-easo/
3. Sanyal AJ, Newsome PN, Kliers I, et al. Phase 3 trial of semaglutide in metabolic dysfunction-associated steatohepatitis. N Engl J Med. 2025;392(21):2089-2099. doi:10.1056/NEJMoa2413258