Efficacy and Safety of Tirzepatide Versus Dulaglutide in Type 2 Diabetes With or Without Established Atherosclerotic Cardiovascular Disease: A Network Meta‐Analysis of Randomized Clinical Trials

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Abstract
Background and Aim: This network meta‐analysis addresses the limited dose‐specific comparative evidence by evaluating different doses of tirzepatide (TZP) versus dulaglutide (DULA) for glycemic control, weight loss, and safety in type 2 diabetes mellitus (T2DM). Methods: Following PRISMA and Cochrane guidance, we searched major databases for RCTs comparing TZP and DULA in adults with T2DM. Efficacy outcomes included body weight change (Weeks 12 and 16) and mean HbA1c change (Weeks 12 and 24). Safety outcomes included mortality, cardiovascular events, and adverse events (AEs). SUCRA ranking was used and analysis performed in RStudio (v4.5.1). Results: Four RCTs comprising 14,348 participants contributed to a seven‐node network. However, Nicholls et al. 2025 had the majority of sample size ( n = 13,165). TZP 15 mg achieved the greatest reduction in body weight at Week 16 (mean difference [MD] vs. TZP 5 mg: −2.68 kg; 95% CI −4.98 to −0.38), while TZP 1 mg (MD: 4.39 kg; 95% CI 1.28 to 7.51) and DULA 0.75 mg (MD: 3.10 kg; 95% CI 0.25 to 5.96) were associated with smaller reductions relative to TZP 5 mg. TZP 15 mg also produced the largest HbA1c reduction at Week 24 (MD vs. TZP 5 mg: −0.40%; 95% CI −0.62 to −0.19), compared with TZP 10 mg (MD: −0.23%; 95% CI −0.44 to −0.02) and DULA 1.5 mg (MD: 0.67%; 95% CI 0.25 to 1.09). No significant differences were observed between treatments for all‐cause mortality or major cardiovascular events. Gastrointestinal AEs were more frequent with higher TZP doses, especially TZP 15 mg vs. TZP 5 mg for nausea, while serious AEs and severe hypoglycemia were similar across doses. Conclusion: Higher TZP doses potentially improve efficacy, while lower TZP/DULA doses enhance tolerability, supporting individualized T2DM care. However, these findings should be interpreted cautiously because several comparisons are indirect, many participants had not reached their maintenance dose, several safety outcomes were based on limited event counts, and significant inconsistency was observed for early body‐weight outcomes.

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