What is the clinical evidence from this study?

Study design: Observational. Population: Type 2 Diabetes (n=19006). Intervention: Triglycerides (TG) vs. Lower triglycerides. Primary outcome: Coronary heart disease (CHD) in women (OR 3.2, 95% CI 1.2-8.3, p=2.3x10-13).

What does this research mean for the field?

Triglycerides have a causal, sex-specific effect on atherosclerotic cardiovascular disease in individuals with type 2 diabetes, conferring a significantly greater risk in women than in men. Novelty: ClaimNovelty.CONFIRMATORY. Consensus alignment: ConsensusAlignment.NEUTRAL.

What question did this study set out to answer?

This research aims to explore the causal relationship between triglycerides and atherosclerotic cardiovascular disease risk in men and women with type 2 diabetes.

June 7, 2026

2262-P: Mendelian Randomization Supports Sex-Specific Effects of Triglycerides on Atherosclerotic Cardiovascular Disease in Type 2 Diabetes

Resultado clave

Genetically predicted triglyceride levels were associated with a significantly greater risk of coronary heart disease in women (OR 3.2; 95% CI 1.2-8.3) compared to men (OR 0.6; 95% CI 0.2-1.4).

Puntos clave

This research aims to explore the causal relationship between triglycerides and atherosclerotic cardiovascular disease risk in men and women with type 2 diabetes.
Included 9740 men and 9266 women with type 2 diabetes from the eMERGE Network
Conducted sex-specific GWAS controlling for various factors
Performed Mendelian Randomization using significant SNPs to assess associations with ASCVD traits.
Identified 269 significant SNPs associated with median triglycerides, with 104 shared and others sex-specific.
Demonstrated stronger associations between triglycerides and ASCVD outcomes in women (OR for CHD 3.2, IS 7.6, HS 3.2) compared to men (OR for CHD 0.6, IS 0.5, HS 1.7).
Statistical significance was confirmed with p-values indicating strong differences between genders.

Diseño del estudio

Tipo

Observational (n=19,006)

Multicéntrico

Sí

PICO estructurado

Does genetically predicted triglyceride concentration differentially affect the risk of atherosclerotic cardiovascular disease in men versus women with type 2 diabetes?

Población

19,006 participants with type 2 diabetes and at least one statin prescription from the eMERGE Network.

Exposición

Genetically predicted median triglyceride (TG) concentration (Mendelian Randomization exposure)

Resultado

Coronary heart disease (CHD), ischemic stroke (IS), and hemorrhagic stroke (HS)hard clinical

Genetically predicted triglycerides are associated with a significantly greater risk of atherosclerotic cardiovascular disease in women with type 2 diabetes compared to men.

Resultado numérico

Odds Ratio: 3.2 (95% CI 1.2–8.3)

valor p: p=2.3x10-13

Resumen

Introduction and Objective: Hypertriglyceridemia may explain higher atherosclerotic cardiovascular disease (ASCVD) risk in women with type 2 diabetes (T2D) than men. We examined the causal relationship between triglycerides (TG) and ASCVD in men (M) and women (W) with T2D. Methods: We included participants with T2D from the Electronic Medical Records and Genomics (eMERGE) Network, who had ≥1 TG and BMI measurement and ≥1 statin prescription (nM=9740, nw=9266). We conducted sex-specific GWAS for median TG concentration, coronary heart disease (CHD), ischemic stroke (IS), and hemorrhagic stroke (HS), respectively. In our GWAS, we controlled BMI, age, statin use, race, collection site, and genetic principal components. We used the significant single nucleotide polymorphisms (SNPs) from our TG GWAS (p 5x10-8) to perform inverse variance weighted Mendelian Randomization (MR) with TG value as the exposure and the other ASCVD traits as outcomes. We then calculated sex-stratified odds ratios (ORs) per standard deviation increment (σ=96mg/dL) for our outcomes and tested for differences between ORs using z-tests. Results: Our sex-specific GWAS identified 269 significant SNPs associated with median TG values. Of these, 104 were shared, 129 were males only, and 36 were females only. MRs showed sex differential associations between TG and CHD (OR and 95% CI M: 0.6 0.2, 1.4, W: 3.2 1.2, 8.3), IS (M:0.5 0.2, 1.2, W: 7.6 2.9, 20.0), and HS (M: 1.7 0.7, 4.0, W: 3.2 1.2, 8.3). The ORs were significantly stronger in females (pairwise z-tests for CHD p=2.3x10-13, IS p=1.4x10-57, and HS p=2.3x10-3, respectively). Conclusion: We found sex differential TG SNPs and sex differential associations between TG and ASCVD in people with T2D. TG is associated with greater ASCVD risk in women than men with T2D. Disclosure J. Irizarry Ayala: None. Y. Lu: None. D.R. Crosslin: None. Y. Yoshida: None. Funding American Diabetes Association (7-23-JDFWH-10), National Institute of General Medical Sciences of the National Institutes of Health (1P20GM152305), Administrative Supplement of the Louisiana Clinical & Translational Science Center (U54 GM104940)

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