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

In clinical practice, injectable glucagon-like peptide-1 (GLP-1) receptor agonists for obesity treatment appear less effective than in clinical trials, largely due to early discontinuation and low maintenance dosing, according to a study published in Obesity.¹

Cleveland Clinic’s retrospective cohort study of 7881 adults with obesity found that while semaglutide and tirzepatide can support meaningful weight loss and improve glycemic control in patients with prediabetes, real-world outcomes were weaker than those seen in randomized trials. One year after initiating therapy, patients who maintained treatment lost an average of 11.9% of their body weight. However, those who discontinued treatment early (within 3 months) lost only 3.6%, and those who discontinued late (within 3 to 12 months) lost 6.8% on average. In contrast, patients who remained on high maintenance doses lost the most: 13.7% with semaglutide and 18.0% with tirzepatide.

Patients on high maintenance dosing who did not discontinue treatment saw greater weight loss with tirzepatide than semaglutide. | Image credit: MKPhoto – stock.adobe.com

“Our study shows that patients treated for obesity with semaglutide or trizepatide lost less weight on average in a regular clinical setting compared to what is observed in randomized clinical trials,” Hamlet Gasoyan, PhD, lead study author and researcher at Cleveland Clinic’s Center for Value-Based Care Research, said in a news release.² “According to our data, this could be explained by higher rates of discontinuation and lower maintenance dosages used in clinical practice, compared to randomized clinical trial settings.”

Cleveland Clinic researchers analyzed electronic health record data from its sites in Ohio and Florida.¹ Patients included in the study had a body mass index (BMI) over 30 kg/m² or over 27 kg/m² with related comorbidities and initiated semaglutide or tirzepatide therapy between 2021 and 2023. Participants with type 2 diabetes were excluded to isolate obesity-specific effects.

The researchers also evaluated changes in hemoglobin A_1c levels among 895 participants with prediabetes and found that 482 (53.9%) of them converted to normoglycemia at 1 year. Of those patients:

• 56 discontinued treatment early
• 102 discontinued late
• 324 did not discontinue treatment

Thirty patients with prediabetes ended up developing type 2 diabetes, including 11 who discontinued GLP-1 treatment early, 11 who discontinued late, and 8 who never discontinued (P < .001).

Multivariable analysis found that patients were more likely to achieve at least 10% weight loss if they did not discontinue treatment or discontinued late, were on a high-dose regimen, were prescribed tirzepatide rather than semaglutide, and were female. The specific reasons for discontinuation were not deeply explored in this study, nor did it measure participation in other lifestyle interventions like nutritional counseling. Gasoyan told The American Journal of Managed Care^® (AJMC^®) that a follow-up study is underway looking at reasons for discontinuation in a randomly selected sample of patients.

Hamlet Gasoyan, PhD

Image credit: Cleveland Clinic

“In that second study that is currently under peer review, nearly half discontinued therapy due to high cost or insurance-related barriers, while side effects and medication shortages were also common reasons for discontinuation,” Gasoyan told AJMC. “The most commonly reported side effects were gastrointestinal. To our knowledge, this will be the first study to quantify the specific reasons for discontinuation of these medications for the treatment of obesity in clinical practice.”

AJMC also asked him how lower maintenance dosing patterns observed in the real world may be influenced by reimbursement policies or prior authorization requirements in the US, which he said is worth looking at in future research.

“It is worth noting that some of the patients with low dosages discontinued the treatment early (when the medication dosage is supposed to be titrated up), so they would not have had the chance to reach the recommended maintenance dosage because of treatment discontinuation,” he said.

Despite the attenuated weight loss outcomes, one finding that surprised the research team was that patients who discontinued therapy did not experience the rapid weight regain often seen in trial settings. Their weight remained relatively stable, which may reflect engagement in alternative weight-loss efforts post-discontinuation.

“This is in contrast to what has been observed after medication discontinuation at the end of randomized trials,” the researchers wrote. “Future studies are needed to understand this discrepancy, in particular, what additional weight management efforts patients might pursue in real-world settings.”

References

1. 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). Published online June 10, 2025. doi:10.1002/oby.24331
2. Cleveland Clinic research finds injectable medications for obesity produce smaller weight loss in a real-world setting, compared to randomized clinical trials. Cleveland Clinic. News release. June 10, 2025. Accessed June 10, 2025. https://newsroom.clevelandclinic.org/2025/06/10/cleveland-clinic-research-finds-injectable-medications-for-obesity-produce-smaller-weight-loss-in-a-real-world-setting-compared-to-randomized-clinical-trials