Systematic review of precision subclassification of type 2 diabetes

Heterogeneity in type 2 diabetes presentation, progression and treatment has the potential for precision medicine interventions that can enhance care and outcomes for affected individuals. We undertook a systematic review to ascertain whether strategies to subclassify type 2 diabetes are associated with improved clinical outcomes, show reproducibility and have high quality evidence. We reviewed publications that deployed simple subclassification using clinical features, biomarkers, imaging or other routinely available parameters or complex subclassification approaches that used machine learning and/or genomic data. We found that simple stratification approaches, for example, stratification based on age, body mass index or lipid profiles, had been widely used, but no strategy had been replicated and many lacked association with meaningful outcomes. Complex stratification using clustering of simple clinical data with and without genetic data did show reproducible subtypes of diabetes that had been associated with outcomes such as cardiovascular disease and/or mortality. Both approaches require a higher grade of evidence but support the premise that type 2 diabetes can be subclassified into meaningful groups. More studies are needed to test these subclassifications in more diverse ancestries and prove that they are amenable to interventions. ### Competing Interest Statement All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: no support from any organisation for the submitted work; SM has investigator initiated funding from DexCom and serves on the Board of Trustees for the Diabetes Research & Wellness Foundation (UK); RW declares lecture fees from Novo Nordisk, Sanofi and Eli Lilly. He served on an advisory board for Akcea Therapeutics, Daiichi Sankyo, Sanofi, Eli Lilly, and NovoNordisk; SJC reports a close family member employed by a Johnson & Johnson company; RHS reports fees from Novo Nordisk and Amgen; LKB has received consulting honoraria from Bayer, Novo Nordisk, Sanofi, Lilly, and Xeris; WHHS reported as Advisor and/or Speaker for AstraZeneca, Bayer HealthCare, Boehringer Ingelheim Pharmaceuticals., Daiichi-Sankyo, Eli Lilly and Company, Merck Sharp & Dohme, Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals, Novo Nordisk, Pfizer, Sanofi-Aventis, Takeda Pharmaceutical Company; MG has served on an advisory board for Nestle Health Science; ES is a Deputy Editor of Diabetes Care and a member of the editorial board of Diabetologia and receives payments from Wolters Kluwer for chapters and laboratory monographs in UpToDate on measurements of glycemic control and screening tests for type 2 diabetes; JCF has received speaking honoraria from AstraZeneca and Novo Nordisk for scientific talks over which he had full control of content; JM reports Academic Associate for Quest Inc. Diagnostics R & D; MU reports an unpaid collaborator with AstraZeneca. All other authors have no disclosures. ### Funding Statement No specific funding was received to undertake this body of work. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This is a systematic review of published manuscripts and all data are available in the manuscripts included in this analysis. No additional data was sought. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present work are contained in the manuscript