SAT-722 - Tirzepatide 10 and 15 mg (SURMOUNT-1) vs Semaglutide 7.2 mg (STEP UP) in Adults With Obesity Without Type 2 Diabetes: An Indirect Treatment Comparison

Introduction:
Once-weekly (QW) injectable tirzepatide is a dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 (GLP-1) receptor agonist (RA). Injectable semaglutide is a GLP-1 RA, with the 2.4 mg QW dose demonstrating inferior outcomes head-to-head vs tirzepatide for weight management. With recent EMA and FDA approvals of semaglutide 7.2 mg QW, and no head-to-head data vs tirzepatide, this indirect treatment comparison (ITC) compared tirzepatide 10 and 15 mg to semaglutide 7.2 mg in adults with obesity without type 2 diabetes (T2D).

Methods:
A systematic literature review identified two studies to compare: SURMOUNT-1 (tirzepatide vs placebo) and STEP UP (semaglutide vs placebo). The ITC included adults with obesity (body mass index [BMI] ≥30 kg/m²) without T2D, using STEP UP whole population data and SURMOUNT-1 subgroup data at their primary timepoint, week 72. A heterogeneity assessment found differences in treatment effect modifiers (TEMs) % female (68.5% SURMOUNT-1; 73.7% STEP UP), % Hispanic/Latino (48.7%; 4.5%, respectively) and baseline BMI (38.5 kg/m2; 39.9 kg/m2, respectively) which were adjusted for by multi-level network meta-regression for weight-related outcomes. Bucher ITC was used for outcomes assumed to be unaffected by the TEMs: HbA1c (of interest as 40.9% and 37.6% of participants had prediabetes, respectively), discontinuation and safety outcomes. Efficacy outcomes were analysed separately for the efficacy (treatment adherence with no rescue therapy) and treatment regimen (regardless of adherence or rescue therapy) estimands, with discontinuation outcomes analysed in the safety population. Severe gastrointestinal adverse events (AEs) were too rare for an ITC ( < 2% of participants per arm).

Results:
In the treatment regimen estimand, tirzepatide 10 and 15 mg were associated with statistically greater reductions from baseline in weight (%) vs semaglutide 7.2 mg: mean difference (95% CI) for 10 mg -3.17 (-5.01, -1.40) and 15 mg -4.51 (-6.31, -2.80) – both trials’ primary endpoint. Tirzepatide 15 mg was associated with statistically greater odds of ≥20% weight reduction vs semaglutide 7.2 mg: odds ratio (95% CI) 3.54 (1.05, 11.05), while tirzepatide 10 mg was associated with no statistically significant difference: 2.46 (0.70, 7.75). Tirzepatide 10 and 15 mg were associated with no statistically significant difference in HbA1c (%) reduction and odds of treatment discontinuation due to AEs vs semaglutide 7.2 mg. Results were generally similar across estimands.

Conclusion:
In this ITC tirzepatide 10 and 15 mg were associated with improved or comparable weight-related outcomes, and comparable HbA1c reduction and discontinuation to semaglutide 7.2 mg. However, comparisons were not direct, and as only two trials were available and adjustment used aggregate trial-level modifiers, residual cross-trial confounding cannot be excluded.

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