Direct comparison of the efficacy of two GLP-1RA on weight loss in overweight and obese adults
Effect of Weekly Subcutaneous Semaglutide vs Daily Liraglutide on Body Weight in Adults With Overweight or Obesity Without Diabetes: The STEP 8 Randomized Clinical Trial
Introduction and methods
Aim of the study
This study directly compared the efficacy two GLP-1RA, semaglutide and liraglutide, on weight loss, added to counseling for diet and physical activity, in adults with overweight or obesity without diabetes.
Eligible participants were ≥18 years old and had a BMI ≥30 or ≥27 with at least one weight-related comorbidity (hypertension, dyslipidemia, obstructive sleep apnea or CVD). People with diabetes, HbA1c ≥6.5% and self-reported body weight changes >5 kg within 90 days prior to screening were excluded.
A total of 338 participants were randomized in a 3:1:3:1 ratio to receive once-weekly subcutaneous semaglutide (2.4 mg, n=126), or matching placebo, or once-daily subcutaneous liraglutide (3.0 mg, n=127), or matching placebo for 68 weeks. Placebo groups were pooled (n=85). Due to dosing differences, assignment to semaglutide or liraglutide was not blinded. In contrast, assignment to active treatment or placebo was double-blinded.
Semaglutide was initiated at 0.25 mg and escalated to 2.4 mg over 16 weeks. If the target dose of 2.4 mg could not be tolerated, a maintenance dose of 1.7 mg was allowed. Liraglutide was initiated at 0.6 mg and escalated to 3.0 mg over 4 weeks. If a dose of 3.0 mg was not tolerated, liraglutide was discontinued. The treatment could be restarted.
All participants received counseling for diet and physical activity recommendations.
The primary outcome was percentage change in body weight from baseline to week 68 in the semaglutide versus liraglutide group. Confirmatory secondary endpoints included the proportion of participants in the semaglutide versus liraglutide group who achieved a weight loss of ≥10%, ≥15% and ≥20% by week 68.
Supportive secondary endpoints included comparisons versus the pooled placebo group and changes from baseline to week 68 in absolute body weight, waist circumference, blood pressure, fasting lipid concentrations, CRP, HbA1c, fasting plasma glucose, fasting serum insulin, glycemic status, and permanent discontinuations of study drug for semaglutide versus liraglutide.
Percentage change in body weight
- The mean percentage change in body weight from baseline at week 68 was -15.8% in the semaglutide group and -6.4% in the liraglutide group (difference: -9.4%, 95% CI -12.0 to -6.9, P<0.001).
Weight loss of ≥10%, ≥15% or ≥20%
- In the semaglutide group, 70.9%, 55.6% and 38.5% achieved a weight loss from baseline of ≥10%, ≥15% and ≥20%, respectively, at week 68. The corresponding percentages in the liraglutide group were 25.6%, 12.0%, and 6.0%.
- The odds of achieving a weight loss of ≥10%, ≥15% or ≥20% were significantly greater in the semaglutide group compared with the liraglutide group (≥10%: OR 6.3, 95% CI 3.5-11.2; ≥15%: OR 7.9%, 95% CI 4.1-15.4; ≥20%: OR 8.2, 95% CI 3.5-19.1; P<0.001 for all).
Other secondary outcomes
- Weight loss was significantly greater with semaglutide and liraglutide compared with placebo (semaglutide vs. placebo: difference -13.9%, 95% CI -16.7 to -11.0; liraglutide vs. placebo: difference -4.5%, 95% CI -7.3 to -1.7).
- At week 68, reductions of following measurements were significantly greater in the semaglutide group compared with the liraglutide group: Absolute body weight (difference -8.5 kg, 95% CI -11.2 to -5.7) waist circumference (difference -6.6 cm, 95% CI -9.1 to -4.2), total cholesterol (difference -7.0%, 95% CI -11.7% to -2.1%), VLDL (difference -11.0%, 95% CI -18.5% to -2.7%), triglycerides (difference -11.0%, 95% CI -18.9% to -2.2%), HbA1c (difference -0.2%, 95% CI -0.2 to -0.1), fasting plasma glucose (difference -3.9mg/dL, 95% CI -7.2 to -0.7), CRP (difference -37.2%, 95% CI -51.7% to -18.5%) and diastolic BP (-4.5 mmHg, 95% CI -7.1 to -1.9).
- The proportion of participants who permanently discontinued treatment was greatest in the liraglutide group (27.6%), followed by the placebo group (17.6%) and semaglutide group (13.5%).
- Adverse events (AEs) were common in all groups: 95.2% of participants reported AEs in the semaglutide group, 96.1% in the liraglutide group and 95.3% in the placebo group.
- The most frequently reported AEs were gastrointestinal disorders: 84.1% in the semaglutide group, 82.7% in the liraglutide group, and 55.3% in the placebo group. Gastrointestinal disorders were most frequently reported during or shortly after dose escalation.
- Serious AEs were reported by 7.9% of participants (n=10) in the semaglutide group, 11.0% (n=14) in the liraglutide group and 7.1% (n=6) in the placebo group.
- Permanent treatment discontinuations due to AEs occurred in 12.6% of participants (n=16) in the liraglutide group, 3.2% (n=4) in the semaglutide group and 3.5% (n=3) in the placebo group.
Treatment with once-weekly subcutaneous semaglutide compared with once-daily subcutaneous liraglutide, added to counseling for diet and physical activity, led to significantly greater weight loss at 68 weeks in adults with obesity or overweight without diabetes.