Aims: STEP 1 investigated the GLP-1 analogue, subcutaneous semaglutide, for weight management in adults with overweight or obesity.
Methods: This was a randomised, double-blind, placebo-controlled, phase 3 trial (NCT03548935) of adults with a body mass index (BMI) ≥30kg/m2 or ≥27kg/m2 with ≥1 weight-related comorbidity, without type 2 diabetes. Patients were randomised 2:1 to 68 weeks’ treatment with once-weekly subcutaneous semaglutide 2.4mg or placebo, adjunct to lifestyle intervention. Co-primary endpoints were percentage change in body weight and weight loss ≥5%. Two estimands were defined: treatment policy and trial product; results are presented for the treatment-policy estimand, unless stated otherwise. P-values for parameters marked with # were not controlled for multiplicity.
Results: 1961 randomised participants (mean age 46 years, body weight 105.3kg, BMI 37.9kg/m2; 74.1% female) were included. Mean body weight change from baseline to week 68 was −14.9% (semaglutide) vs −2.4% (placebo) (estimated treatment difference [ETD]: −12.4%; 95% CI: −13.4, −11.5; p<0.0001). Similar results were obtained with the trial product estimand:#–16.9% (semaglutide) vs –2.4% (placebo) (ETD: –14.4%; 95% CI: –15.3, –13.6; p<0.0001). Participants were more likely to achieve weight loss ≥5%, ≥10%, ≥15% and ≥20%# with semaglutide vs placebo (86.4% vs 31.5%, 69.1% vs 12.0%, 50.5% vs 4.9% and 32.0% vs 1.7%, respectively; p<0.0001 for all). Greater improvements were seen with semaglutide vs placebo in waist circumference, BMI#, systolic and diastolic# blood pressure, glycated haemoglobin#, fasting plasma glucose#, C‑reactive protein#, fasting lipid profile# and self-reported physical functioning (p<0.05 for all). No new safety signals with semaglutide were observed.
Conclusions: In overweight or obese adults, once-weekly subcutaneous semaglutide 2.4mg plus lifestyle intervention induced a mean weight loss of ~15% by week 68. Clinically beneficial weight loss ≥10% was achieved by over two-thirds of participants and ≥20% by one-third of participants, along with associated improvements in cardiometabolic risk factors and physical functioning.