@article{329cab9d6b8744a1811ff487d2e4c991,
title = "Cluster Analysis of Cardiovascular Phenotypes in Patients With Type 2 Diabetes and Established Atherosclerotic Cardiovascular Disease: A Potential Approach to Precision Medicine",
abstract = "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 BMI; cluster III included women with noncoronary 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 (hazard ratio 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.",
author = "Abhinav Sharma and Yinggan Zheng and Ezekowitz, {Justin A.} and Westerhout, {Cynthia M.} and Udell, {Jacob A.} and Goodman, {Shaun G.} and Armstrong, {Paul W.} and Buse, {John B.} and Green, {Jennifer B.} and Josse, {Robert G.} and Kaufman, {Keith D.} and McGuire, {Darren K.} and Giuseppe Ambrosio and Chuang, {Lee Ming} and Lopes, {Renato D.} and Peterson, {Eric D.} and Holman, {Rury R.}",
note = "Funding Information: Funding. The TECOS trial was funded by Merck Sharp & Dohme, a subsidiary of Merck & Co., Inc. The EXSCEL trial was funded by Amylin Pharmaceuticals, a wholly owned subsidiary of AstraZeneca. A.S. received support from the Fonds de Recherche Sant{\'e} Quebec Junior 1 Clinical Research Scholars program, Alberta Innovates Health Solutions, and the European Society of Cardiology Young Investigator Award. J.B.B. is supported by grants from the National Institutes of Health (UL1TR002489, U01DK098246, UC4DK108612, and U54DK118612), Patient-Centered Outcomes Research Institute, and American Diabetes Association. Duality of Interest. A.S. reports receiving support from Roche Diagnostics, Boehringer-Ingelheim, Novartis, and Takeda. J.A.E. has received research grant support and/or personal fees from Amgen, AstraZeneca, Bayer, Merck, Novartis, and Servier. J.A.U. has received support from Novartis (clinical trial site); received consultancy from Amgen, Boehringer Ingelheim, Eli Lilly and Company, Janssen, Merck, Novartis, Sanofi Pasteur; received honoraria from the Canadian Cardiovascular Society, Novartis (registry steering committee), and Servier. S.G.G. has received research grant support and/or personal fees from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly and Company, Fenix Group International, Ferring Pharmaceuticals, Glaxo-SmithKline, Janssen/Johnson & Johnson, Matrizyme, Merck, Novartis, Pfizer, Regeneron Pharmaceuticals, Sanofi, Servier, and Tenax Therapeutics. P.W.A. has received grants, personal fees, and nonfinancial support from Merck and grants from AstraZeneca. J.B.B.{\textquoteright}s contracted consulting fees and travel support for contracted activities are paid to the University of North Carolina by Adocia, AstraZeneca, Dance Biopharm, Dexcom, Eli Lilly and Company, Fractyl Health, GI Dynamics, Intarcia Therapeutics, Lexicon Pharmaceuticals, MannKind Corporation, Metavention, NovaTarg Therapeutics, Novo Nordisk, Orexigen Therapeutics, PhaseBio, Sanofi, Senseonics, vTv Therapeutics Inc, and Zafgen; he reports grant support from AstraZeneca, Eli Lilly and Company, Intarcia Therapeutics, Johnson & Johnson, Lexicon Pharmaceuticals, Medtronic, Novo Nordisk, Sanofi, Theracos, Tolerion, and vTv Therapeutics Inc; he is a consultant to Cirius Therapeutics Inc, CSL Behring, Mellitus Health, Neurimmune AG, Pendulum Therapeutics, and Stability Health; and holds stock/options in Mellitus Health, Pendulum Therapeutics, PhaseBio, and Stability Health. J.B.G. has received grants from AstraZeneca, Boehringer Ingelheim, Glax-oSmithKline, and Sanofi and personal fees from AstraZeneca, Merck, Boehringer-Ingelheim, and Novo Nordisk. R.G.J. has received grants or personal fees from Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, Janssen, and Merck. K.D.K. is an employee of Merck & Co., Inc., the manufacturer of sitagliptin, and owns stock and stock options in Merck & Co., Inc. D.K.M. has provided clinical trial leadership for Lilly USA, LLC, AstraZeneca, Sanofi Aventis, Janssen, Boehringer Ingelheim, Merck & Co, Novo Nordisk, Lexicon Pharmaceuticals, Eisai Co., Ltd., GlaxoSmithKline, and Esperion Therapeutics and consultancy for Afimmune, AstraZe-neca, Sanofi Aventis, Lilly USA, LLC, Boehringer Ingelheim, Merck & Co, Pfizer, Novo Nordisk, Applied Therapeutics, and Metavant Sciences. G.A. has served on an advisory board and speakers bureau for Merck. R.D.L. has received research support from Bristol-Myers Squibb and GlaxoSmithKline; and personal fees from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, Pfizer, and Portola Pharmaceuticals. E.D.P. has received grants from Jans-sen, Merck, Sanofi, AstraZeneca, Genentech, and Amgen; and has consulting associations with Janssen, Bayer, Merck, and Sanofi. R.R.H. has received grants and personal fees from Merck; grants from Bayer, AstraZeneca, and Bristol-Myers Squibb; personal fees from Amgen, Bayer, Intarcia Therapeutics, Novartis, and Novo Nordisk; and other support from GlaxoSmithKline, Janssen, and Takeda Pharmaceutical Company. No other potential conflicts of interest relevant to this article were reported. Author Contributions. A.S. conceived of the analysis, developed the analysis plan, and wrote the initial drafts of the manuscript. Y.Z. conducted the statistical analysis. J.A.E. provided critical review and edited the manuscript. C.M.W. supervised the statistical analysis plan development and statistical analysis. J.A.U. provided critical review and edited the manuscript. S.G.G. provided critical review and edited the manuscript. P.W.A. provided critical review and edited the manuscript. J.B.B. provided critical review and edited the manuscript. J.B.G. provided critical review and edited the manuscript. R.G.J. provided critical review and edited the manuscript. K.D.K. provided critical review and edited the manuscript. D.K.M. provided critical review and edited the manuscript. G.A. provided critical review and edited the manuscript. L.-M.C. provided critical review and edited the manuscript. R.D.L. provided critical review and edited the manuscript. E.D.P. provided critical review and edited the manuscript. R.R.H. provided critical review and edited the manuscript. A.S. and R.R.H. are the guarantors of this work and, as such, had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Prior Presentation. This study was presented at the European Society of Cardiology Congress, Munich, Germany, 25–29 August 2018. Publisher Copyright: {\textcopyright} 2021 by the American Diabetes Association.",
year = "2022",
month = jan,
doi = "10.2337/dc20-2806",
language = "English (US)",
volume = "45",
pages = "204--212",
journal = "Diabetes Care",
issn = "1935-5548",
publisher = "American Diabetes Association Inc.",
number = "1",
}