American Diabetes Association
TECOS028_Supplementary_Content_11-2-20.pdf (739.45 kB)

Cluster Analysis of Cardiovascular Phenotypes in Patients With Type 2 Diabetes and Established Atherosclerotic Cardiovascular Disease: A Potential Approach to Precision Medicine

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posted on 2021-10-29, 19:41 authored by Abhinav Sharma, Yinggan Zheng, Justin A. Ezekowitz, Cynthia M. Westerhout, Jacob A. Udell, Shaun G. Goodman, Paul W. Armstrong, John B. Buse, Jennifer B. Green, Robert G. Josse, Keith D. Kaufman, Darren K. McGuire, Giuseppe Ambrosio, Lee-Ming Chuang, Renato D. Lopes, Eric D. Peterson, Rury R. Holman
Objective: Phenotypic heterogeneity among patients with type 2 diabetes mellitus (T2DM) and atherosclerotic cardiovascular disease (ASCVD) is ill defined. We used cluster analysis machine learning algorithms to identify phenotypes among trial participants with T2DM and ASCVD.

Research Design and Methods: We used data from the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) study (n=14,671), a cardiovascular outcome safety trial comparing sitagliptin with placebo in patients with T2DM and ASCVD (median follow-up 3.0 years). Cluster analysis using 40 baseline variables was conducted, with associations between clusters and the primary composite outcome (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina) assessed by Cox proportional hazards models. We replicated the results using the Exenatide Study of Cardiovascular Event Lowering (EXSCEL) trial.

Results: Four distinct phenotypes were identified: cluster I included Caucasian men with a high prevalence of coronary artery disease; cluster II included Asian patients with a low body mass index; cluster III included women with non-coronary ASCVD disease; and cluster IV included patients with heart failure and kidney dysfunction. The primary outcome occurred respectively in 11.6%, 8.6%, 10.3%, and 16.8% of patients in clusters I to IV. The crude difference in cardiovascular risk for the highest versus lowest risk cluster (cluster IV vs. II) was statistically significant (HR, 2.74; 95% CI, 2.29-3.29). Similar phenotypes and outcomes were identified in EXSCEL.

Conclusions: In patients with T2DM and ASCVD, cluster analysis identified four clinically distinct groups. Further cardiovascular phenotyping is warranted to inform patient care and optimize clinical trial designs.


The TECOS trial was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ. The EXSCEL trial was funded by Amylin Pharmaceuticals, a wholly owned subsidiary of AstraZeneca.


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