A Review of Incretin Therapies Approved and in Late-Stage Development for Overweight and Obesity Management

Abstract

Objective: To review clinical trial data for incretin therapies that are approved or in late-stage development for overweight or obesity management, along with clinical implications of these therapies and future directions.

Methods: We searched for clinical trials involving incretin therapies studied specifically for overweight or obesity management in ClinicalTrials.gov and PubMed from registry inception through December 2023.

Results: Glucagon-like peptide-1 (GLP-1) receptor agonism, alone and in combination with glucose-dependent insulinotropic polypeptide (GIP) receptor agonism or glucagon agonism, leads to significant weight reduction in people with overweight or obesity. Newer incretin therapies have demonstrated weight reduction between 15% to 25%, far outpacing non-incretin therapies for weight management and achieving levels of weight loss that may prevent weight-related complications. However, the discontinuation of incretin therapies is associated with weight regain. The main side effects of incretin therapies are transient, mild-to-moderate gastrointestinal side effects - nausea, diarrhea, constipation, and vomiting - that commonly occur in the first 4 to 8 weeks of treatment. There is a rich late-stage pipeline of incretin therapies for weight management, consisting of oral GLP-1 receptor agonists, dual GLP-1/GIP receptor agonists, dual GLP-1/glucagon receptor agonists, triple GLP-1/GIP/glucagon receptor agonists, and combination therapies with nonincretin drugs.

Conclusion: Newer incretin therapies for weight management have the potential to improve the treatment for overweight and obesity, the treatment and prevention of weight-related complications, and the individualization of weight management. Ensuring that these therapies are accessible - and that treatment with them is consistent and sustainable - is necessary to translate findings from trials into the real world.

Keywords: glucagon-like peptide-1 (GLP-1); glucose-dependent insulinotropic polypeptide (GIP); incretin analog; semaglutide; tirzepatide; weight loss.