High Discontinuation Rates of GLP-1 RA-Based Drugs Linked to Weight Loss Far Below Phase 3 Clinical Trials

A large retrospective cohort study of nearly 8,000 adults with overweight or obesity reveals that real-world weight loss outcomes with injectable semaglutide and tirzepatide fall significantly below the results achieved in pivotal phase 3 clinical trials, primarily as a result of higher discontinuation rates and lower maintenance dosing. Findings, published in the journal Obesity, showed that individuals lost an average of 8.7% of baseline body weight after 1 year of treatment, compared to the 14.9% to 20.9% weight reductions demonstrated in phase 3 clinical trials with the glucagon-like peptide-1 (GLP-1)-based receptor agonists.

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The study, conducted by Cleveland Clinic researchers, found that more than half of participants discontinued their medication within the first year—20.4% within 3 months and 32.0% between 3 and 12 months. Those who stopped treatment early achieved weight loss of only 3.6% from baseline, while participants who never discontinued lost 11.9% of their initial weight.

“Our analyses did not attempt to emulate a target trial but rather to describe these outcomes that were recorded in a regular clinical setting, with an emphasis on characterization by treatment discontinuation status,” the researchers advised.

Hamlet Gasoyan, PhD, assistant professor of medicine at the Cleveland Clinic, and colleagues analyzed electronic health records from Cleveland Clinic facilities in Ohio and Florida and identified 7,881 adults with overweight or obesity without type 2 diabetes who initiated injectable semaglutide or tirzepatide between 2021 and 2023. The population included 6,109 participants who received semaglutide and 1,772 who received tirzepatide, with mean age 51.3 years, baseline weight 112.2 kg, and body mass index (BMI) of 39.7 kg/m². Three-quarters were women, 78% identified as White, and 73.7% had private insurance.

The researchers defined treatment discontinuation as a gap greater than 90 days between prescription fills, classifying it as early (within 3 months) or late (3 to 12 months after initiation), according to the study.

FINDINGS

Gasoyan et al reported significant differences in weight loss based on medication persistence. Participants who discontinued semaglutide early lost only 3.6% of their weight, compared to 10.9% among those who continued treatment. For tirzepatide, early discontinuation resulted in 3.6% weight loss versus 15.3% for those who persisted.

Maintenance dosing proved equally significant. Most participants (80.8%) remained on low maintenance doses. Among participants who both continued treatment and achieved high maintenance dosing, weight loss approached clinical trial results: 13.7% with semaglutide and 18.0% with tirzepatide.

In multivariable analysis, participants who never discontinued treatment had 4.68 times higher odds of achieving 10% weight loss compared to early discontinuers (95% CI, 3.97-5.55), while late discontinuation resulted in 1.74 times higher odds (95% CI, 1.45-2.08). Tirzepatide users were nearly 2 and one-half times more likely to achieve a 10% reduction from baseline weight vs semaglutide users (OR 2.46; 95% CI, 2.16-2.80), and high-dose maintenance therapy increased the likelihood by nearly the same proportion (OR, 2.39; 95% CI, 2.08-2.75). Female sex independently predicted better outcomes with 1.86 times higher odds (95% CI: 1.62-2.13).

For participants with prediabetes at baseline, those who continued treatment achieved a mean 0.4% reduction in hemoglobin A1c levels, compared to 0.1% among early discontinuers (P <.001). More importantly, 67.9% of participants with prediabetes who maintained therapy achieved normal glucose levels at 1 year, compared to just 33.1% of early discontinuers.

The discontinuation rates substantially exceeded those in pivotal phase 3 trials, where 17.1% discontinued semaglutide and 14.3% to 16.4% stopped tirzepatide.

The authors acknowledged several limitations to the study including analysis of individuals from a single health system, potential misclassification due to medication shortages during the study period, and inability to capture lifestyle interventions or patient-specific discontinuation factors.

“As clinicians and policy makers pay closer attention to the issue of treatment discontinuation of these highly effective medications, relatively little real-world data are available on the relationship between discontinuation and long-term weight outcomes,” the authors noted. "High out-of-pocket costs, insurance coverage-related issues, adverse effects, and medication supply shortages could explain the higher discontinuation rates in this study compared to clinical trial settings, warranting future studies on determinants of novel [antiobesity medication] discontinuation,” they concluded.

Gasoyan H, Butsch WS, Schulte R, et al. Changes in weight and glycemic control following obesity treatment with semaglutide or tirzepatide by discontinuation status. Obesity (Silver Spring). 2025;1–11. doi:10.1002/oby.24331

Wilding JPH, Batterham RL, Calanna S, et al. Once-weekly semaglutide in adults with overweight or obesity. N Engl J Med. 2021; 384(11):989-1002. doi:10.1056/NEJMoa2032183

Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide once weekly for the treatment of obesity. N Engl J Med. 2022;387(3):205-216. doi:10.1056/NEJMoa2206038