STEP-8

Background

Prior to STEP-8, comparisons of Semaglutide 2.4 mg and Liraglutide 3.0 mg relied on cross-trial inference. STEP-8 was designed as the direct randomised head-to-head comparison at their respective licensed weight-management doses. ^[1]

Study design

Randomised, open-label with double-dummy placebo for the alternate regimen, active-controlled Phase 3 trial. Participants received either once-weekly subcutaneous Semaglutide 2.4 mg plus daily placebo or once-daily subcutaneous Liraglutide 3.0 mg plus weekly placebo, both with lifestyle intervention, for 68 weeks.

Population

338 adults with a body-mass index of at least 30, or at least 27 with a weight-related coexisting condition, without diabetes.

Intervention

Once-weekly subcutaneous Semaglutide titrated to 2.4 mg maintenance dose plus lifestyle intervention.

Comparator

Once-daily subcutaneous Liraglutide titrated to 3.0 mg maintenance dose plus lifestyle intervention.

Primary endpoints

Percent change in body weight from baseline to week 68 (Semaglutide vs Liraglutide).

Secondary endpoints

Proportions achieving ≥5%, ≥10%, ≥15% and ≥20% weight reduction; treatment discontinuation, tolerability, waist circumference and cardiometabolic parameters.

Key findings

• Mean change in body weight was approximately −15.8% with Semaglutide 2.4 mg versus approximately −6.4% with Liraglutide 3.0 mg at week 68.
• A substantially greater proportion of Semaglutide-treated participants achieved ≥10%, ≥15% and ≥20% weight reduction.
• Gastrointestinal adverse events were common in both arms and predominated during titration.
• Trial discontinuation for adverse events was numerically higher with Liraglutide than with Semaglutide.

Mechanistic significance

• Consistent with pharmacokinetic differences (weekly Semaglutide vs daily Liraglutide) and reported potency differences at the GLP-1 receptor.
• Provides the first randomised, direct comparison used across the literature to contextualise dual-agonist (Tirzepatide, SURPASS-2) and triple-agonist (Retatrutide) head-to-head signals.

Limitations

Research context

STEP-8 is the reference head-to-head Semaglutide-vs-Liraglutide dataset in the incretin agonist literature and complements SURPASS-2 (Tirzepatide-vs-Semaglutide in type 2 diabetes) as a bridge between mono-, dual- and triple-agonist comparative evidence.