OBJECTIVES: Tirzepatide (5/10/15mg/week), liraglutide (3.0mg/day) and semaglutide (2.4mg/week) demonstrated their respective efficacy and safety versus placebo (adjunct to reduced-calorie diet and increased physical activity) in patients with obesity or overweight. No published randomized controlled trials (RCTs) compare tirzepatide versus semaglutide or liraglutide, and available indirect comparisons do not exclusively focus on these three treatments. This network meta-analysis (NMA) of RCTs compared the efficacy and safety of tirzepatide with semaglutide and liraglutide.

METHODS: Of 42 RCTs identified via a systematic literature review conducted in November 2023, six RCTs (SURMOUNT-1, STEP 1/5/8, O’Neil, SCALE Obesity and Prediabetes), had homogeneous baseline clinical characteristics and were included in a Bayesian random-effects NMA for efficacy (using efficacy estimand [patients remaining on randomized treatment for the study period, per the EMA definition]) and safety.

RESULTS: Versus liraglutide; tirzepatide 5/10/15mg demonstrated statistically improved total weight reduction (WR) (kg) (mean difference [MD]: -8.59/-14.65/-16.06), total WR (%), odds of ≥5% WR (odds ratio: 3.74/11.48/11.82) and ≥10%/≥15%/≥20% WR.

Versus semaglutide; tirzepatide 10/15mg demonstrated statistically improved total WR (kg) (MD: -4.85/-6.26) and odds of ≥20% WR, while total WR (%) and ≥5%/≥10%/≥15% WR showed no statistical differences. Tirzepatide 5 mg showed no statistical differences for most WR outcomes versus semaglutide.

For cardiometabolic outcomes, tirzepatide demonstrated statistically improved waist circumference and triglycerides versus liraglutide, and had similar lipids (HDL/LDL/total cholesterol), glycemic parameters (HbA1c/FPG) and blood pressure (SBP/DBP). Tirzepatide demonstrated comparable results in these cardiometabolic outcomes to semaglutide.

Tirzepatide had similar odds of safety outcomes (nausea/discontinuations/gastrointestinal AEs) to semaglutide and liraglutide.

CONCLUSIONS: All tirzepatide doses demonstrated statistically improved WR outcomes versus liraglutide; and similar or statistically improved WR outcomes versus semaglutide. Tirzepatide demonstrated a similar safety profile to liraglutide and semaglutide, and comparable or improved cardiometabolic outcomes. These NMA results suggest that tirzepatide is a strong alternative treatment for patients with obesity or overweight.