@article{99607c33ddca4c838b6309d0c0519d1c,
title = "Development and validation of optimal phenomapping methods to estimate long-term atherosclerotic cardiovascular disease risk in patients with type 2 diabetes",
abstract = "AIMS/HYPOTHESIS: Type 2 diabetes is a heterogeneous disease process with variable trajectories of CVD risk. We aimed to evaluate four phenomapping strategies and their ability to stratify CVD risk in individuals with type 2 diabetes and to identify subgroups who may benefit from specific therapies.METHODS: Participants with type 2 diabetes and free of baseline CVD in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial were included in this study (N = 6466). Clustering using Gaussian mixture models, latent class analysis, finite mixture models (FMMs) and principal component analysis was compared. Clustering variables included demographics, medical and social history, laboratory values and diabetes complications. The interaction between the phenogroup and intensive glycaemic, combination lipid and intensive BP therapy for the risk of the primary outcome (composite of fatal myocardial infarction, non-fatal myocardial infarction or unstable angina) was evaluated using adjusted Cox models. The phenomapping strategies were independently assessed in an external validation cohort (Look Action for Health in Diabetes [Look AHEAD] trial: n = 4211; and Bypass Angioplasty Revascularisation Investigation 2 Diabetes [BARI 2D] trial: n = 1495).RESULTS: Over 9.1 years of follow-up, 789 (12.2%) participants had a primary outcome event. FMM phenomapping with three phenogroups was the best-performing clustering strategy in both the derivation and validation cohorts as determined by Bayesian information criterion, Dunn index and improvement in model discrimination. Phenogroup 1 (n = 663, 10.3%) had the highest burden of comorbidities and diabetes complications, phenogroup 2 (n = 2388, 36.9%) had an intermediate comorbidity burden and lowest diabetes complications, and phenogroup 3 (n = 3415, 52.8%) had the fewest comorbidities and intermediate burden of diabetes complications. Significant interactions were observed between phenogroups and treatment interventions including intensive glycaemic control (p-interaction = 0.042) and combination lipid therapy (p-interaction < 0.001) in the ACCORD, intensive lifestyle intervention (p-interaction = 0.002) in the Look AHEAD and early coronary revascularisation (p-interaction = 0.003) in the BARI 2D trial cohorts for the risk of the primary composite outcome. Favourable reduction in the risk of the primary composite outcome with these interventions was noted in low-risk participants of phenogroup 3 but not in other phenogroups. Compared with phenogroup 3, phenogroup 1 participants were more likely to have severe/symptomatic hypoglycaemic events and medication non-adherence on follow-up in the ACCORD and Look AHEAD trial cohorts.CONCLUSIONS/INTERPRETATION: Clustering using FMMs was the optimal phenomapping strategy to identify replicable subgroups of patients with type 2 diabetes with distinct clinical characteristics, CVD risk and response to therapies.",
keywords = "Atherosclerotic cardiovascular disease, Cardiovascular disease, Epidemiology, Machine learning, Risk factors, Risk prediction, Type 2 diabetes",
author = "Segar, {Matthew W.} and Patel, {Kershaw V.} and Muthiah Vaduganathan and Caughey, {Melissa C.} and Jaeger, {Byron C.} and Mujeeb Basit and Duwayne Willett and Javed Butler and Sengupta, {Partho P.} and Wang, {Thomas J.} and McGuire, {Darren K.} and Ambarish Pandey",
note = "Funding Information: The authors thank the participants, study investigators and staff from the ACCORD, Look AHEAD and BARI 2D trials. MV serves on advisory boards for Amgen, AstraZeneca, Baxter Healthcare, Bayer AG and Boehringer Ingelheim; and participates on clinical endpoint committees for studies sponsored by Novartis and the NIH. JB is a consultant for Abbott, Amgen, Array, Astra Zeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squib, CVRx, G3 Pharmaceutical, Impulse Dynamics, Innolife, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, NovoNordisk, Relypsa and Vifor. DKM reports honoraria for trial leadership from Astra Zeneca, Sanofi Aventis, Janssen, Boehringer Ingelheim, Merck & Co, Pfizer, Novo Nordisk, Lexicon, Eisai, GlaxoSmithKline and Esperion; and honoraria for consulting for Astra Zeneca, Sanofi Aventis, Lilly US, Astra Zeneca, Boehringer Ingelheim, Merck & Co, Pfizer, Novo Nordisk and Metavant. AP has served on the advisory board of Roche Diagnostics and has received research support from the Gilead Sciences Research Scholar Program and Applied Therapeutics. The other authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work. Funding Information: MV serves on advisory boards for Amgen, AstraZeneca, Baxter Healthcare, Bayer AG and Boehringer Ingelheim; and participates on clinical endpoint committees for studies sponsored by Novartis and the NIH. JB is a consultant for Abbott, Amgen, Array, Astra Zeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squib, CVRx, G3 Pharmaceutical, Impulse Dynamics, Innolife, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, NovoNordisk, Relypsa and Vifor. DKM reports honoraria for trial leadership from Astra Zeneca, Sanofi Aventis, Janssen, Boehringer Ingelheim, Merck & Co, Pfizer, Novo Nordisk, Lexicon, Eisai, GlaxoSmithKline and Esperion; and honoraria for consulting for Astra Zeneca, Sanofi Aventis, Lilly US, Astra Zeneca, Boehringer Ingelheim, Merck & Co, Pfizer, Novo Nordisk and Metavant. AP has served on the advisory board of Roche Diagnostics and has received research support from the Gilead Sciences Research Scholar Program and Applied Therapeutics. The other authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work. Funding Information: MV is supported by the KL2/Catalyst Medical Research Investigator Training award from Harvard Catalyst (NIH/NCATS Award UL 1TR002541). KVP is supported by the National Heart, Lung, and Blood Institute T32 postdoctoral training grant (5T32HL125247-03). DW is supported by the National Center for Advancing Translational Sciences. AP is funded by the Texas Health Resources Clinical Research Scholarship, the Gilead Sciences Research Scholar Program, the National Institute of Aging GEMSSTAR Grant (1R03AG067960-01), and Applied Therapeutics. The study sponsor/funder was not involved in the design of the study; the collection, analysis and interpretation of data; writing the report; and did not impose any restrictions regarding the publication of the report. Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.",
year = "2021",
month = jul,
doi = "10.1007/s00125-021-05426-2",
language = "English (US)",
volume = "64",
pages = "1583--1594",
journal = "Diabetologia",
issn = "0012-186X",
publisher = "Springer Verlag",
number = "7",
}