Gülçin Türkmen SARIYILDIZ, Canan Çiçek DEMİR
The Journal of European Internal Medicine Professionals - 2026;4(3):105-112
Background: Tirzepatide, a dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, has shown large weight-loss efficacy across the phase 3 SURMOUNT program in adults with overweight or obesity, with and without type 2 diabetes (T2DM). Because these trials differ in population, design, and reported estimand, we synthesized them while keeping non-comparable designs and estimands separate. Methods: We searched PubMed, Embase, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov from database inception through [final search date] for randomized trials of tirzepatide in adults with overweight or obesity in whom body-weight change was a primary or co-primary endpoint. The primary meta-analysis pooled conventional placebo-controlled trials (tirzepatide 15 mg vs placebo) using the trials' directly reported between-group differences under the treatment-regimen estimand, with random-effects models (restricted maximum likelihood [REML] with modified Knapp-Hartung [mKH] confidence intervals). Enriched-design, efficacy-estimand, randomized-withdrawal, and active-comparator trials were analyzed separately or in sensitivity analyses. Risk of bias (RoB 2) and certainty (GRADE) were assessed. The review was not prospectively registered; analytic choices are reported as post hoc amendments. Results: Eight trials were included. In the primary contrast (tirzepatide 15 mg vs placebo; SURMOUNT-1, -2, -CN; 2,039 participants), the pooled mean difference in body weight was -14.8 percentage points (mKH 95% CI -23.0 to -6.7; I² = 94%); the estimate was smaller in the single T2DM trial than in the two non-diabetic trials. Sensitivity analyses adding the enriched-design SURMOUNT-3 (-16.3) or using the efficacy estimand with SURMOUNT-J (-17.8) were consistent in direction. Most tirzepatide-treated participants achieved clinically meaningful weight loss (model-based responder outcomes, summarized descriptively). In the single T2DM trial, HbA1c fell by 1.57 percentage points more than placebo (95% CI -1.76 to -1.37). Gastrointestinal adverse events (real participant counts) were more frequent with tirzepatide 15 mg than placebo but were mostly mild-moderate. The randomized-withdrawal trials (SURMOUNT-4, SURMOUNT-MAINTAIN) and the active-comparator trial (SURMOUNT-5, versus semaglutide), analyzed separately, supported maintained and greater weight loss, respectively. Conclusion: Among the placebo-controlled SURMOUNT trials, tirzepatide was associated with substantially greater weight reduction than placebo, with additional glycemic benefit in T2DM. Estimates varied by diabetes status, design, and estimand, and the evidence base is small, clinically heterogeneous, and entirely industry-sponsored; pooled estimates should be interpreted cautiously. Certainty was moderate for weight loss, high for HbA1c and for nausea and diarrhea, and moderate for vomiting.
