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Meta-Analysis
. 2025 May 20;85(19):1858-1872.
doi: 10.1016/j.jacc.2025.03.516. Epub 2025 Mar 30.

Effects of Tirzepatide in Type 2 Diabetes: Individual Variation and Relationship to Cardiometabolic Outcomes

Arya Aminorroaya  1 , Evangelos K Oikonomou  1 , Dhruva Biswas  1 , Ania M Jastreboff  2 , Rohan Khera  3
Affiliations
Meta-Analysis

Effects of Tirzepatide in Type 2 Diabetes: Individual Variation and Relationship to Cardiometabolic Outcomes

Arya Aminorroaya et al. J Am Coll Cardiol. .

Abstract

Background: Tirzepatide-a dual GIP/GLP-1 receptor agonist-exerts pleiotropic effects on cardiometabolic health.

Objectives: The authors sought to investigate the efficacy of tirzepatide in improving different cardiometabolic risk factors across individuals and subpopulations.

Methods: Using an independent, global data-sharing and analytics platform, we performed an individual participant data meta-analysis by pooling data from 7 Phase 3 randomized clinical trials that compared tirzepatide with placebo or standard antihyperglycemic agents in individuals with type 2 diabetes. The study outcomes were the presence of a range of cardiometabolic abnormalities, representing components of metabolic syndrome (MetS) (elevated waist circumference, triglycerides, blood pressure, and fasting blood glucose, and decreased high-density lipoprotein cholesterol), as well as elevated body mass index and MetS (≥3 cardiometabolic abnormalities). Outcomes were modeled using mixed-effects models, with inverse probability weighting to account for study design differences.

Results: We included 7,805 participants with a weighted median age of 59 years (Q1-Q3: 51-66 years) and 43.2% women. Over a weighted median treatment duration of 41.0 weeks, tirzepatide reduced the odds of all cardiometabolic abnormalities, ranging from 34% reduction for the odds of decreased high-density lipoprotein cholesterol (OR: 0.66 [95% CI: 0.52-0.84]) to 96% reduction in the odds of elevated body mass index (OR: 0.04 [95% CI:0.02-0.08]), and 72% reduction for the odds of MetS (OR: 0.28 [95% CI: 0.24-0.33]). Tirzepatide's superior efficacy in resolving MetS was consistent across demographic and clinical subpopulations, with higher efficacy in age <65 years vs ≥65 years, and in individuals without vs with baseline use of sodium-glucose cotransporter 2 inhibitors (P for interaction = 0.008 and 0.009, respectively).

Conclusions: This pooled analysis suggests that tirzepatide may improve cardiometabolic abnormalities and resolve MetS in individuals with type 2 diabetes.

Keywords: diabetes mellitus type 2; heart disease risk factors; meta-analysis; randomized controlled trial; tirzepatide.

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Conflict of interest statement

Funding Support and Author Disclosures The authors acknowledge funding through the National Institutes of Health (NIH) under awards F32HL170592 (to Dr Oikonomou), R01DK099039, R01DK136623, R01DK134398 (to Dr Jastreboff), R01AG089981, R01HL167858, and K23HL153775 (to Dr Khera) and the Doris Duke Charitable Foundation under award 2022060 (to Dr Khera). The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Dr Oikonomou receives support from the National Heart, Lung, and Blood Institute of the National Institutes of Health (under award F32HL170592); is named as a coinventor in patent applications (18/813,882, 17/720,068, 63/508,315, 63/580,137, 63/619,241, 63/562,335) and granted patents (US12067714B2, US11948230B2); has been a consultant for Caristo Diagnostics Ltd and Ensight-AI, Inc; and has received royalty fees from technology licensed through the University of Oxford, outside this work. Drs Oikonomou and Khera are cofounders of Evidence2Health, a precision health platform to improve evidence-based cardiovascular care. Dr Jastreboff conducts multicenter trials with Amgen, Boehringer Ingelheim, Eli Lilly, Novo Nordisk, and Rhythm Pharmaceuticals; and serves on scientific advisory boards for Amgen, AstraZeneca, Biohaven, Boehringer Ingelheim, Eli Lilly, Intellihealth, Novo Nordisk, Pfizer, Regeneron Pharmaceuticals, Scholar Rock, Structure Therapeutics, Terns Pharmaceuticals, WeightWatchers, and Zealand Pharma. Dr Khera is an Associate Editor of JAMA; receives research support through Yale from Bristol Myers Squibb, Novo Nordisk, BridgeBio, and the Blavatnik Family Foundation; is a coinventor of U.S. Provisional Patent Applications WO2023230345A1, US20220336048A1, 63/346,610, 63/484,426, 63/508,315, 63/580,137, 63/606,203, 63/619,241, 63/562,335, and 18/813,882, all unrelated to the current work; and is an academic cofounder of Ensight-AI, Inc, an AI-ECG analytics company. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

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