Semaglutide or tirzepatide should be first-line drugs for obesity and most of its related complications, new guidance from the European Association for the Study of Obesity recommended.

The authors of the new framework for the pharmacological treatment of obesity and its complications proposed an algorithm to assist clinicians “by aligning each patient’s health background with the action profiles of the available medications.” The algorithm was published online in Nature Medicine.

“Even though there are several options on the market, the reality is that semaglutide and tirzepatide are so effective they should be the first choice in almost all cases,” Andreea Ciudin, MD, co-author of the new guidance and co-chair of the EASO Obesity Management Task Force, said in a statement.

‘Medications of Choice’

The authors, members of an international team of obesity experts, used the presence or absence of obesity-related complications as the primary factor to guide the selection of an appropriate treatment. Each drug was evaluated based on its effectiveness in promoting total weight loss, its impact on complications, and its safety profile.

On the basis of the results of clinical trials included in traditional and network meta-analyses through January 2025, the authors concluded that tirzepatide and semaglutide should be considered the “medications of choice” when a substantial total body weight loss is required.

When a lesser degree of weight loss is the target, other drugs can be considered, including liraglutide, naltrexone-bupropion, and phentermine-topiramate.

When looking at complications, the authors separated their analysis into two parts. They distinguished fat mass diseases (more prone to mechanical complications, eg, obstructive sleep apnea and knee osteoarthritis) and sick fat diseases (more prone to immunological and metabolic complications, eg, prediabetes and type 2 diabetes, cardiovascular disease, heart failure, and metabolic dysfunction-associated steatohepatitis [MASH]).

For fat mass diseases, tirzepatide is recommended as the first-line treatment for people with obesity and obstructive sleep apnea, based on a single randomized controlled trial (RCT).

For obesity and knee osteoarthritis, the only available RCTs show semaglutide to be the most effective treatment for pain reduction, so semaglutide is recommended as the first-line treatment.

For sick fat diseases, the authors analyzed four diseases with available evidence: prediabetes and type 2 diabetes; cardiovascular disease; heart failure; and MASH.

For people with obesity and prediabetes or type 2 diabetes, tirzepatide and semaglutide were recommended as first-choice medications. Liraglutide and naltrexone-bupropion were recommended as second-line treatments in individuals with obesity and abnormal blood sugar profiles.

For obesity and cardiovascular disease, the authors’ meta-analysis showed a significant reduction in the incidence of major adverse cardiovascular events in those with previous cardiovascular events that were treated with semaglutide — thus, they recommended semaglutide as the first-line treatment.

For obesity and heart failure, the authors noted that more data are required, but current evidence suggests either tirzepatide or semaglutide should be considered first-line treatments.

For obesity and MASH, the authors recommend tirzepatide as first line-treatment for now, but noted the phase 3 ESSENCE trial, not included in the current algorithm because it was published after January 31, 2025, showed that semaglutide was associated with a significant improvement in MASH and liver fibrosis similar to tirzepatide. Thus, future updates to the algorithm are likely to include recommending semaglutide as a first-line treatment for people with obesity and MASH, according to the authors.

Summarizing the algorithm, the authors wrote, “It is important to note that most medications have not been specifically evaluated for the treatment of individual complications…[and] direct evidence for many conditions remains limited. Nevertheless, there is growing potential for medications to positively influence a broader range of complications, including chronic kidney disease, neurodegenerative disorders, polycystic ovary syndrome, certain cancers, and mental health conditions.”

That said, Ciudin and Barbara McGowan, MD, also a co-author of the paper and co-chair of the EASO Obesity Management Task Force, clarified that although semaglutide and tirzepatide are recommended as first-line drug treatments, “We do not recommend medication as the first-line intervention for weight management.”

“For most patients, lifestyle approaches should be the initial focus,” they told Medscape Medical News. “However, for patients in whom lifestyle interventions have not been successful, and where a healthcare professional has determined that pharmacotherapy is appropriate as an adjunct, the algorithm supports clinicians in navigating options and making evidence-based decisions to identify the most suitable medical treatment for each individual.”

Not Necessarily ‘Best’

Jamy Ard, MD, past president of The Obesity Society and co-director of the Wake Forest Baptist Health Weight Management Center in Winston-Salem, North Carolina, commented on the guidance for Medscape Medical News. “While semaglutide and tirzepatide have higher average treatment responses, this does not equate to being the best treatment option for an individual patient. There are some patients who may not get the treatment response they need or may be unable to tolerate the side effects of these treatments.”

“The evidence suggests patients can get effective treatment responses with a range of medications to which they may have access,” he said. “Studies have shown that the key to maximizing the effectiveness of any medication, including the earlier generation of obesity medications, is to tailor the treatment to the patient. Unfortunately, many patients in the US and elsewhere, may not be able to access tirzepatide or semaglutide, but that does not mean that treatment is out of reach.”

“Ultimately, deciding what the best treatment is for an individual patient should be based on a comprehensive evaluation and shared decision-making,” he concluded.

Ciudin reported receiving speaking fees from Astra Zeneca, Boehringer-Ingelheim, Eli-Lilly, Novo Nordisk, Sanofi, and Menarini; research grants from Eli Lilly, Novo Nordisk and Menarini; and being a member of the data monitoring committee of Boehringer Ingelheim. McGowan reported receiving speaker and/or advisory fees from Novo Nordisk, Eli-Lilly, Astra Zeneca, Janssen, Pfizer, and MSD, and a research grant from Novo Nordisk; she is a shareholder of Reset Health. Ard disclosed receiving research support from Lilly, Boehringer Ingelheim, KVKTech, WW, Novo Nordisk, Regeneron, Amgen; receiving consulting/advisory board fees from Eli Lilly, Novo Nordisk, Regeneron, Amgen, Zealand Pharma, Boehringer Ingelheim; and memberships in the International Food Information Council- Assembly, The Obesity Society (President 2024), Roundtable on Obesity Solutions, American Society for Nutrition, and the American Society for Nutrition Foundation-Board of Trustees Executive Committee.

Marilynn Larkin, MA, is an award-winning medical writer and editor whose work has appeared in numerous publications, including Medscape Medical News and its sister publication MDedge, The Lancet (where she was a contributing editor), and Reuters Health.