Real-World Use of GLP-1s Yields Less Weight Loss Than Clinical Trials

A Cleveland Clinic study found that real-world weight loss outcomes with semaglutide and tirzepatide were less pronounced than in clinical trials, with average weight loss at one year being 11.9% for those who maintained treatment, while early discontinuation resulted in only 3.6% weight loss; patients on high maintenance doses of semaglutide and tirzepatide experienced 13.7% and 18.0% weight loss, respectively. The study, which excluded patients with type 2 diabetes, attributed the difference to higher discontinuation rates and lower maintenance dosages in clinical practice, with cost and insurance barriers being key factors for discontinuation, though patients who discontinued did not experience rapid weight regain.

Analysis

A Cleveland Clinic retrospective study of 7881 adults with obesity reveals a notable disparity between the efficacy of GLP-1 receptor agonists, semaglutide and tirzepatide, in real-world clinical settings versus controlled clinical trials. While patients maintaining treatment for one year achieved an average body weight loss of 11.9%, this is below trial benchmarks. Early discontinuation (within 3 months) resulted in only 3.6% weight loss, and late discontinuation (3-12 months) yielded 6.8%. Significantly, patients on high maintenance doses experienced more substantial weight loss, with 13.7% for semaglutide and a superior 18.0% for tirzepatide. The study, which excluded type 2 diabetes patients, attributes the attenuated outcomes to higher real-world discontinuation rates and lower maintenance dosages. A follow-up study indicates that nearly half of discontinuations stem from cost or insurance-related barriers, with side effects and medication shortages also contributing. Despite these challenges, an unexpected finding was that patients discontinuing therapy did not exhibit the rapid weight regain commonly observed in trial settings, suggesting potential engagement in other weight management efforts. Furthermore, among 895 participants with prediabetes, 53.9% achieved normoglycemia at one year, underscoring the metabolic benefits beyond weight loss, even with real-world adherence challenges.

Key Decisions for Investors

• Investors should scrutinize manufacturers' strategies for improving patient adherence and navigating cost and insurance hurdles, as these factors significantly impact the realization of GLP-1 drugs' market potential for obesity.
• The observed superior real-world efficacy of tirzepatide at high maintenance doses compared to semaglutide (18.0% vs 13.7% weight loss) suggests potential for market share shifts and warrants close monitoring of comparative pricing and payer access.
• The unexpected stability in weight post-discontinuation in real-world settings, contrasting with trial data, could influence long-term treatment paradigms and persistency assumptions; further research into this phenomenon is critical for refining market models.
• Given that real-world weight loss outcomes and adherence appear lower than in clinical trials, investors may need to adopt a more cautious outlook on peak sales forecasts for this drug class, factoring in challenges like discontinuation rates and sub-optimal dosing.