EASO recommends semaglutide and tirzepatide as first-line treatment for obesity

Semaglutide or tirzepatide should be the first line treatment for people living with obesity and most of its complications, according to a framework for the pharmacological treatment of obesity and its complications from the European Association for the Study of Obesity (EASO), published in the journal Nature.

Figure 1: Treatment algorithm from the EASO for individuals with obesity. The treatment algorithm is based on the presence or absence of relevant obesity-related medical conditions. The algorithm is grounded in scientific evidence available up to 31 January 2025. Obesity management medications are listed in order of efficacy. Medications with equivalent or comparable efficacy are listed in the same position. Asterisks indicate that the available number of trials for this category limits the reliability of the analysis performed and clinical judgment is recommended. Color coding reflects statistical significance: blue shading indicates statistically significant effects; gray shading denotes obesity medications tested without significant effects. CVD, cardiovascular disease; KOA, knee osteoarthritis; Naltr-Bupr, naltrexone–bupropion; Phen-Topir, phentermine–topiramate.

The number of medications available to treat obesity and its complications has been steadily increasing in recent years and is expected to continue growing, offering clinicians a wider selection of agents with distinct modes of action to be used alongside lifestyle interventions.

As different medications vary in their efficacy for total weight loss and their effects on obesity-related complications, personalised therapy based on individual patient characteristics has become both feasible and necessary.

In this new algorithm for obesity management medication (Figure 1), the authors used the presence or absence of obesity-related complications as the primary factor to guide the strategy for selecting the treatment. Each individual medication was therefore evaluated based on its effectiveness in promoting total weight loss, its impact on complications, and its safety profile.

The paper’s authors are an international team of obesity experts led by the co-chairs of the EASO Obesity Management Working Group, who are Dr Andreea Ciudin, Vall d'Hebron University Hospital, Autonomous University Barcelona, Barcelona, Spain; Professor Barbara McGowan, Guys & St Thomas's Hospital NHS Foundation Trust, London, UK; and a team including EASO President Professor Volkan Yumuk, Istanbul University-Cerrahpaşa, Cerrahpaşa Medical Faculty, Istanbul, Turkey, and colleagues.

"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," explained Professor McGowan. "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."

Although still relatively recently approved for obesity treatment, the evidence base for both semaglutide (a glucagon-like peptide-1 [GLP-1] receptor agonist) and tirzepatide (a dual gastric inhibitory polypeptide [GIP] and GLP-1 receptor agonist) has been building rapidly.

When looking at complications, the authors separated their analysis aligned with the conceptual distinction between fat mass disease (more prone to mechanical complications) and sick fat disease (more prone to immunological and metabolic complications). But, regardless of this distinction, again semaglutide and/or tirzepatide were the first-line recommendations in each case.

For so-called fat mass diseases, tirzepatide is the first line treatment recommended for people living with obesity and obstructive sleep apnoea (OSA), although this is based on only one randomised clinical trial (RCT) at present.

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

In the sick-fat disease category, four diseases were analysed (due to the evidence available at the time) - prediabetes and type 2 diabetes; cardiovascular disease; heart failure; and metabolic dysfunction associated steatotic liver disease (MASH).

For people living with obesity, prediabetes, and type 2 diabetes, tirzepatide and semaglutide should be prescribed as first-choice medications and liraglutide and naltrexone–bupropion as second-line treatments in individuals with obesity and abnormal blood sugar profiles.

For people living with obesity and cardiovascular disease, the authors' meta-analysis has shown a significant reduction in the incidence of major adverse cardiovascular events (MACE) in individuals with previous cardiovascular events treated with semaglutide, and therefore recommend semaglutide as the first line treatment.

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

For people living with obesity and MASH, at present, the authors recommend the use of tirzepatide as first line treatment, but note the Phase III ESSENCE trial, not included in the present algorithm because it was published after January, 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.

The authors also note the complex economic considerations, different in each national context, that these new medications, including semaglutide and tirzepatide, collectively known as incretins, are causing but say that "the cost of not treating obesity and adipose tissue dysfunction at early stages, thus enabling the progression to complications and end-organ damage , should be weighed equally in health policy and clinical decision-making."

"It is important to note that most medications have not been specifically evaluated for the treatment of individual complications, resulting in gaps in our understanding of their full therapeutic potential. Although some benefits may be inferred based on the degree of total body weight loss, given the well-documented positive effect of total weight loss on various complications, direct evidence for many conditions remains limited,” the authors stated. “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."

"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," said co-first author, Dr Ciudin. "Although no treatment algorithm can replace the nuanced clinical judgment required for such comprehensive assessments, this tool can serve to support therapeutic decision-making in obesity. This new class of GLP-1 agonists and GIP/GLP-1 dual agonists is completely transforming care of obesity and its complications."

Volkan Yumuk

The authors concluded that based on the results of clinical trials included in the traditional and network meta-analyses, 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 medications can be considered, including liraglutide, naltrexone–bupropion, and phentermine-topiramate.

"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,” concluded Professor Yumuk.

The findings were reported in the paper, ‘Framework for the pharmacological treatment of obesity and its complications from the European Association for the Study of Obesity (EASO)’, published in Nature Medicine. To access this paper, please click here