What question did this study set out to answer?

To assess the protective effects of tirzepatide against cardiovascular and limb events in patients with type 2 diabetes at high risk.

January 10, 2026Diabetes Research and Clinical Practice0 citations

Major adverse cardiovascular and limb events caused by tirzepatide in patients with type 2 diabetes at high cardiovascular risk: A comparison with sitagliptin

YIYoshihiro IwasakiKansai Medical University TSTakenobu ShimadaInterventional Cardiology TKTakefumi KishimoriKansai Medical University

Key Result

Tirzepatide reduced the incidence of major adverse cardiovascular and limb events by 29% compared to sitagliptin in patients with type 2 diabetes at high cardiovascular risk (4.3% vs 6.1%, HR 0.70).

Key Points

To assess the protective effects of tirzepatide against cardiovascular and limb events in patients with type 2 diabetes at high risk.
Retrospective cohort study using the TriNetX global health research network.
Identified patients with type 2 diabetes starting tirzepatide or sitagliptin between January 2022 and December 2023.
Primary outcome was major adverse cardiovascular and limb events (MACLE) defined as a composite of MACE and MALE.
Applied propensity score matching to analyze outcomes.
After matching, 31,751 patients per group were analyzed.
Incidence of MACLE was lower with tirzepatide (4.3%) compared to sitagliptin (6.1%), with a hazard ratio (HR) of 0.70.
Tirzepatide also showed reduced risk for MACE (HR, 0.71) and MALE (HR, 0.39).
Significant reduction in major lower extremity amputation with tirzepatide (HR, 0.61).
Consistent benefits were observed across major subgroups.

Structured PICO

Does tirzepatide reduce major adverse cardiovascular and limb events in patients with type 2 diabetes compared to sitagliptin?

Population

63,502 adults (≥18 years) with type 2 diabetes (31,751 per group after propensity score matching), mean age 58.5-59.1 years, ~55% female, multinational (TriNetX global network across North America, South America, Europe, Middle East, Africa, Asia Pacific).

Intervention

Tirzepatide initiation

Comparator

Sitagliptin initiation (propensity score matched)

Outcome

1-year cumulative incidence of major adverse cardiovascular and limb events (MACLE), defined as a composite of all-cause death, acute myocardial infarction, stroke, and major lower limb amputationcomposite

In a large real-world cohort of patients with type 2 diabetes, initiation of tirzepatide was associated with a significantly lower 1-year risk of major adverse cardiovascular and limb events compared to sitagliptin.

Main Result

Absolute Event Rate: 0% vs 0%

Abstract

AIMS: To elucidate the overall protective effects of tirzepatide against atherosclerosis-related events, including cardiovascular and lower-extremity events. METHODS: We conducted a retrospective cohort study using the TriNetX global health research network to identify patients with type 2 diabetes (T2D) who initiated tirzepatide or sitagliptin between January 2022 and December 2023. The primary outcome was major adverse cardiovascular and limb events (MACLE), defined as the composite of major adverse cardiovascular events (MACE: all-cause death, myocardial infarction, and stroke) and major adverse limb events (MALE: all-cause death and major lower extremity amputation). Propensity score matching was applied. RESULTS: After matching, 31,751 patients per group were analyzed. At 1 year, the incidence of MACLE was lower with tirzepatide compared to that with sitagliptin (4.3 % vs. 6.1 %; hazard ratio (HR), 0.70; 95 % confidence interval (CI), 0.66-0.76; p < 0.001). Tirzepatide was also associated with a reduced risk of MACE (HR, 0.71; 95 % CI, 0.66-0.76), MALE (HR, 0.39; 95 % CI, 0.34-0.46), and major lower extremity amputation (HR, 0.61; 95 % CI, 0.44-0.84). Consistent benefits were observed across major subgroups. CONCLUSIONS: Tirzepatide was associated with a significantly lower risk of cardiovascular and limb events compared to sitagliptin in patients with T2D.

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