Real-World Weight Loss With GLP-1s Falls Short of Trial Results: Daily Dose

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On June 12, 2025, we reported on a study published in the journal Obesity that characterized changes in body weight and HbA1c through 12 months by obesity pharmacotherapy discontinuation status.

The study

Researchers analyzed electronic health records from Cleveland Clinic facilities in Ohio and Florida and identified 7881 adults with overweight or obesity without type 2 diabetes who initiated injectable semaglutide or tirzepatide between 2021 and 2023. The population included 6109 participants who received semaglutide and 1772 who received tirzepatide, with mean age 51.3 years, baseline weight 112.2 kg, and body mass index (BMI) of 39.7 kg/m². They 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).

The findings

One year after initiating therapy, participants 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, individuals who remained on high maintenance doses lost the most: 13.7% with semaglutide and 18.0% with tirzepatide, according to the results.

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).

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.

Authors' comments

"Our findings could inform the decisions of health care providers and their patients on the role of treatment discontinuation and maintenance dosage in achieving clinically meaningful weight loss."

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