Comparative Efficacy and Safety of Tirzepatide Versus Dulaglutide in Patients with Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis

Background: Tirzepatide, a dual GIP/GLP-1 receptor agonist, demonstrates substantial glycemic and weight benefits versus GLP-1 receptor agonists in indirect comparisons, but direct comparative safety evidence versus dulaglutide remains limited. We evaluated comparative safety (primary outcome: overall adverse events) and efficacy. Methods: Following PRISMA 2020 (prospectively registered: PROSPERO CRD420251276594), we searched MEDLINE, Embase, Scopus, and CENTRAL (inception–31 December 2025) for randomized controlled trials (≥26 weeks) comparing once-weekly tirzepatide with dulaglutide in adults with type 2 diabetes. Three trials (N = 13,590 participants) were included. Dichotomous outcomes were pooled using random-effects models (risk ratios [RRs], 95% confidence intervals [CIs]). GRADE assessed certainty of evidence. Results: Overall adverse event incidence did not differ significantly (RR 1.04 [0.98–1.10]; I2 = 36%; moderate-certainty evidence). Discontinuation due to adverse events was consistently higher with tirzepatide (RR 1.32 [1.20–1.45]; I2 = 0%; high-certainty evidence), representing a 32% increased risk across all populations. Categorical HbA1c target achievement was analyzed in two trials; the third trial reported HbA1c as a continuous outcome only. At the primary threshold (HbA1c < 7.0%), tirzepatide was consistently superior with no heterogeneity (RR 1.48 [1.33–1.64]; I2 = 0%; p < 0.00001). Across all thresholds combined, heterogeneity was extreme (I2 = 92%), limiting confidence in any pooled summary estimate; the greatest instability occurred at the strictest threshold (HbA1c < 5.7%; I2 = 98%; p = 0.40). Tirzepatide showed greater HbA1c target attainment in treatment-naive patients receiving dulaglutide 0.75 mg, whereas the glycemic advantage was smaller in patients with established cardiovascular disease receiving dulaglutide 1.5 mg. Categorical weight-loss outcomes were analyzed in two trials; tirzepatide was associated with greater weight-loss threshold achievement (RR 8.80 [4.04–19.17]; very low-certainty evidence), although interpretation is limited by substantial heterogeneity and restricted generalizability. Serious adverse events were not significantly different (RR 0.82 [0.47–1.43]; I2 = 42%). Conclusions: Overall adverse events were similar between treatments, but tirzepatide consistently increased discontinuation risk, indicating a clinically important tolerability-persistence trade-off. Glycemic efficacy was highly population-dependent: benefits were consistent at the primary HbA1c target (<7.0%; I2 = 0%) in early-stage disease, whereas the advantage was smaller in long-standing disease with established cardiovascular disease. Tirzepatide may be favored when glycemic or weight efficacy is prioritized in earlier-stage disease, provided tolerability is proactively managed. Dulaglutide remains appropriate when persistence is threatened by tolerability concerns or cardiovascular risk reduction is the primary goal.