Comparative Efficacy and Safety of Tirzepatide Versus Dulaglutide in Patients with Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis.
This systematic review and meta-analysis (PRISMA 2020, PROSPERO-registered) pooled three randomized controlled trials (N = 13,590 adults with type 2 diabetes) comparing once-weekly tirzepatide — a dual GIP/GLP-1 receptor agonist — against dulaglutide (a GLP-1 receptor agonist) over at least 26 weeks. The primary safety outcome was overall adverse event incidence, which the study found did not differ significantly between treatments (RR 1.04; moderate-certainty evidence). However, discontinuation due to adverse events was consistently higher with tirzepatide (RR 1.32; high-certainty evidence), suggesting a tolerability-persistence trade-off. Glycemic target achievement (HbA1c) was population-dependent: tirzepatide showed consistent benefit at the primary threshold in treatment-naïve patients receiving lower-dose dulaglutide, while the advantage narrowed in patients with established cardiovascular disease on higher-dose dulaglutide; heterogeneity was extreme at the strictest threshold. Weight-loss threshold achievement favored tirzepatide, though evidence certainty was very low due to substantial heterogeneity. Serious adverse events did not differ significantly. Key limitations include only three included trials, high heterogeneity for several outcomes, and restricted generalizability across patient subgroups. GRADE certainty ranged from very low to high across outcomes.
Why this grade: Although based on RCTs in humans and PROSPERO-registered, the pooled analysis includes only three trials with substantial heterogeneity across several key outcomes, limiting overall certainty to moderate despite high-certainty evidence for one individual outcome.
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]; I 2 = 36%; moderate-certainty evidence). Discontinuation due to adverse events was consistently higher with tirzepatide (RR 1.32 [1.20-1.45]; I 2 = 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 2 = 0%; p 2 = 92%), limiting confidence in any pooled summary estimate; the greatest instability occurred at the strictest threshold (HbA1c 2 = 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]; I 2 = 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 ( 2 = 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.
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