Summary: In a pre-specified patient-reported outcomes analysis of the four 68-week STEP Phase 3a trials, semaglutide 2.4 mg weekly was superior to placebo on physical functioning. A meaningful within-person improvement on SF-36v2 Physical Functioning was reached by 39.8% versus 24.1% in STEP 1 (p<0.0001), and on IWQOL-Lite-CT Physical Function by 51.8% versus 28.3% in STEP 1 (p<0.0001).
PICO Summary
| Element | Detail |
|---|---|
| Population | Adults with overweight or obesity enrolled in the STEP 1-4 Phase 3a, 68-week, double-blind, multinational randomized controlled trials; this report is a pre-specified analysis of weight- and health-related quality-of-life patient-reported outcomes. |
| Intervention | Semaglutide 2.4 mg once weekly subcutaneously, with physical functioning as a confirmatory secondary endpoint (IWQOL-Lite-CT in STEP 1 and 2; SF-36v2 in STEP 1-4). |
| Comparison | Matched placebo once weekly within each parent trial. |
| Outcome | Superiority for physical functioning was confirmed for semaglutide over placebo (IWQOL-Lite-CT in STEP 1 and 2; SF-36v2 in STEP 1, 2 and 4). Proportions reaching the meaningful within-person change threshold at Week 68, semaglutide versus placebo: IWQOL-Lite-CT Physical Function STEP 1 51.8% vs 28.3% (p<0.0001), STEP 2 39.6% vs 29.5% (p=0.0083); SF-36v2 Physical Functioning STEP 1 39.8% vs 24.1% (p<0.0001), STEP 2 41.0% vs 27.3% (p=0.0005), STEP 4 18.0% vs 6.6% (p<0.0001). All other IWQOL-Lite-CT and SF-36v2 scores were numerically improved with semaglutide except SF-36v2 Role Emotional in STEP 2. No 95% confidence intervals, absolute risk reduction or number needed to treat were reported in the abstract. |
Semaglutide 2.4 mg and Physical Functioning
Pre-specified PRO analysis · STEP 1-4 RCTs · 68 weeks
Across the four 68-week STEP trials, semaglutide 2.4 mg was superior to placebo for physical functioning, with more patients reaching a meaningful within-person improvement on both a generic (SF-36v2) and a weight-specific (IWQOL-Lite-CT) measure.
Expert Commentary
This pre-specified secondary analysis supports a genuine, statistically robust signal that semaglutide 2.4 mg improves self-reported physical functioning beyond weight change alone, with superiority formally confirmed under the trials’ testing hierarchy rather than rested on exploratory comparisons. The two complementary instruments, a weight-specific measure and a generic health survey, were moved in the same direction, which strengthens confidence that the finding reflects a real patient-felt benefit and not an artefact of a single questionnaire. The verdict is that the claim of improved physical functioning is supported. The principal limitation that should temper enthusiasm is that the analysis was funded by the manufacturer and several authors are company employees, and the report presents the proportion of patients crossing a meaningful-change threshold without accompanying confidence intervals, absolute differences or number needed to treat, so the magnitude of benefit at the individual level is harder to weigh. The effect was also notably smaller in STEP 4, a withdrawal-design trial, which is a useful reminder that benefit appears tied to continued treatment. Can I use this with my patients? Yes, for an adult with obesity who is already a candidate for semaglutide, these data are reassuring that meaningful gains in physical functioning are plausible alongside weight loss. Independent, non-industry replication reporting absolute effect sizes would be welcome.
References
Rubino D, Bjorner JB, Rathor N, Sharma AM, von Huth Smith L, Wharton S, Wadden T, Zeuthen N, Kolotkin RL. Effect of semaglutide 2.4 mg on physical functioning and weight- and health-related quality of life in adults with overweight or obesity: Patient-reported outcomes from the STEP 1-4 trials. Diabetes Obes Metab. 2024;26(7):2945-2955. doi:10.1111/dom.15620