#EASD2025: Exploring semaglutide for post-bariatric surgery weight regain

TouchENDOCRINOLOGY coverage from EASD 2025:

At the EASD 2025 congress (Vienna, Austria; 15–19 September), Dr Janine Makarondis presented the BARI-STEP trial (NCT05073835), the first randomized, placebo-controlled trial evaluating the efficacy and safety of once-weekly semaglutide 2.4 mg in adults experiencing weight gain or suboptimal weight loss after gastric bypass or sleeve gastrectomy. The trial demonstrated clinically significant weight reduction, alongside improvements in cardiometabolic health, with a safety profile consistent with previous studies.

In this interview, Dr Makarondis discusses the rationale behind using semaglutide in this unique patient population, the design and key findings of BARI-STEP, and the implications for clinical practice and future research in post-bariatric obesity management.

Q. Semaglutide is already widely studied in obesity management. Could you explain its mechanism of action and why it was considered a promising candidate for patients with recurrent weight gain or suboptimal weight loss after bariatric surgery?

Semaglutide is a GLP-1 receptor agonist, and it has already been extensively studied. It is increasingly used in clinical practice and has significantly weight management strategies. GLP-1 is a gut hormone released in response to eating. It signals to the brain that we’ve eaten, generating a feeling of satiety and helping regulate appetite. Beyond the brain, GLP-1 also acts on the pancreas and the heart; therefore GLP-1 receptor agonists can improve insulin sensitivity, work as an effective treatment for diabetes, and reduce cardiovascular risk.

People who have had bariatric surgery are a unique group because their GLP-1 levels are often high after surgery, which is thought to contribute to the initial weight loss. Early studies with GLP-1 receptor agonists, like liraglutide, focused on post-surgical patients with low GLP-1 levels, since low levels were linked to suboptimal weight loss or weight regain. Those studies showed these patients responded well, suggesting GLP-1 receptor agonists could be effective even in this population.

For the BARI-STEP trial, we included patients with either low weight loss or weight regain, regardless of GLP-1 levels, allowing us to explore whether semaglutide’s effects were consistent across the post-bariatric surgery population. Importantly, this is a patient group that historically had limited treatment options, often facing stigma and few effective therapies, so it was crucial to explore whether semaglutide could help them.

Q. Could you briefly outline the design of the BARI-STEP trial, including the patient population, eligibility criteria, and how the intervention was delivered alongside lifestyle intervention?

BARI-STEP was a randomized, double-blind, placebo-controlled trial comparing semaglutide 2.4 mg weekly (the weight management dose) with a volume- and packaging-matched placebo. Participants also received a structured lifestyle intervention delivered by dietitians trained in behaviour change and exercise guidance.

The lifestyle programme aimed for a 500-calorie daily energy deficit, incorporating not only aerobic exercise but also resistance training to preserve muscle mass, as we monitored body composition throughout the trial.

The treatment period was 68 weeks, starting with a 16-week dose escalation to reach 2.4 mg, followed by a 6-week off-treatment washout period.

Q. What were the primary and secondary endpoints of the study, and how well were they achieved in terms of efficacy and safety?

The primary endpoint was percentage body weight change over 68 weeks compared with placebo. Semaglutide led to an 18.04% reduction in body weight, and when adjusted for procedure type, diabetes status, and baseline characteristics, the estimated treatment difference versus placebo was 19.4%.

Secondary endpoints included safety, categorical weight loss, cardiometabolic outcomes, body composition, and quality of life. The safety profile was consistent with what’s already known about semaglutide, with gastrointestinal side effects, primarily nausea and reduced appetite, being the most commonly reported. There were no significant differences in serious adverse events between groups.

Regarding categorical weight loss, 85% of semaglutide-treated participants lost more than 10% of their body weight, and 47% lost more than 20%, which are highly clinically significant results.

Q. The results show a substantial weight reduction with semaglutide compared with placebo. How do you see these findings shaping the treatment paradigm for patients struggling with weight regain following metabolic/bariatric surgery?

These findings strengthen the evidence that GLP-1 receptor agonists are safe, well-tolerated, and highly effective in post-bariatric surgery patients who haven’t achieved their desired weight outcomes. While we can’t yet conclude whether these drugs are more effective in this population compared with the general obesity population, the results show that they can be a valuable and effective treatment option, improving both weight and overall health. Emerging real-world data and other trials with GLP-1 receptor agonists further support this as a novel indication.

Q. What unanswered questions remain, and what further studies are needed to refine the role of GLP-1 receptor agonists like semaglutide in this post-bariatric surgery population?

There’s still much to learn. One key question is whether GLP-1 receptor agonists are more effective in post-bariatric surgery patients than in the general population, and if so, why. Interestingly, the number of non-responders in these trials has been very small, raising questions about what drives response variability in this population.

Looking ahead, research should focus on optimizing treatment combinations, as multiple highly effective therapies now exist for obesity. We need to understand how best to select and combine treatments over a patient’s lifespan, recognizing obesity as a chronic disease requiring ongoing management.