Precision subclassification of type 2 diabetes: a systematic review
Authors: Misra Shivani , Wagner Robert , Ozkan Bige , Schön Martin , Sevilla-Gonzalez Magdalena , Prystupa Katsiaryna , Wang Caroline C. , Kreienkamp Raymond J. , Cromer Sara J. , Rooney Mary R. , Duan Daisy , Thuesen Anne Cathrine Baun , Wallace Amelia S. , Leong Aaron , Deutsch Aaron J. , Andersen Mette K. , Billings Liana K. , Eckel Robert H. , Sheu Wayne Huey-Herng , Hansen Torben , Stefan Norbert , Goodarzi Mark O. , Ray Debashree , Selvin Elizabeth , Florez Jose C. ,   ADA/EASD PMDI, Tobias Deirdre K. , Merino Jordi , Ahmad Abrar , Aiken Catherine , Benham Jamie L. , Bodhini Dhanasekaran , Clark Amy L. , Colclough Kevin , Corcoy Rosa , Cromer Sara J. , Felton Jamie L. , Francis Ellen C. , Gillard Pieter , Gingras Véronique , Gaillard Romy , Haider Eram , Hughes Alice , Ikle Jennifer M. , Jacobsen Laura M. , Kahkoska Anna R. , Kettunen Jarno L. T. , Kreienkamp Raymond J. , Lim Lee-Ling , Männistö Jonna M. E. , Massey Robert , Mclennan Niamh-Maire , Miller Rachel G. , Morieri Mario Luca , Most Jasper , Naylor Rochelle N. , Ozkan Bige , Patel Kashyap Amratlal , Pilla Scott J. , Raghaven Sridaran , Schön Martin , Semnani-Azad Zhila , Sevilla-Gonzalez Magdalena , Svalastoga Pernille , Takele Wubet Worku , Tam Claudia Ha-ting , Thuesen Anne Cathrine B. , Tosur Mustafa , Wang Caroline C. , Wong Jessie J. , Yamamoto Jennifer M. , Young Katherine , Amouyal Chloé , Bonham Maxine P. , Chen Mingling , Cheng Feifei , Chikowore Tinashe , Chivers Sian C. , Clemmensen Christoffer , Dabelea Dana , Dawed Adem Y. , Deutsch Aaron J. , Dickens Laura T. , DiMeglio Linda A. , Dudenhöffer-Pfeifer Monika , Evans-Molina Carmella , Fernández-Balsells María Mercè , Fitipaldi Hugo , Fitzpatrick Stephanie L. , Gitelman Stephen E. , Goodarzi Mark O. , Grieger Jessica A. , Guasch-Ferré Marta , Habibi Nahal , Huang Chuiguo , Harris-Kawano Arianna , Ismail Heba M. , Hoag Benjamin , Johnson Randi K. , Jones Angus G. , Koivula Robert W. , Leong Aaron , Leung Gloria K. W. , Libman Ingrid M. , Liu Kai , Long S. Alice , Lowe William L. , Morton Robert W. , Motala Ayesha A. , Onengut-Gumuscu Suna , Pankow James S. , Pathirana Maleesa , Pazmino Sofia , Perez Dianna , Petrie John R. , Powe Camille E. , Quinteros Alejandra , Jain Rashmi , Ried-Larsen Mathias , Saeed Zeb , Santhakumar Vanessa , Kanbour Sarah , Sarkar Sudipa , Monaco Gabriela S. F. , Scholtens Denise M. , Sheu Wayne Huey-Herng , Speake Cate , Stanislawski Maggie A. , Steenackers Nele , Steck Andrea K. , Stefan Norbert , Støy Julie , Taylor Rachael , Tye Sok Cin , Ukke Gebresilasea Gendisha , Urazbayeva Marzhan , Van der Schueren Bart , Vatier Camille , Wentworth John M. , Hannah Wesley , White Sara L. , Yu Gechang , Zhang Yingchai , Zhou Shao J. , Beltrand Jacques , Polak Michel , Aukrust Ingvild , de Franco Elisa , Flanagan Sarah E. , Maloney Kristin A. , McGovern Andrew , Molnes Janne , Nakabuye Mariam , Njølstad Pål Rasmus , Pomares-Millan Hugo , Provenzano Michele , Saint-Martin Cécile , Zhang Cuilin , Zhu Yeyi , Auh Sungyoung , de Souza Russell , Fawcett Andrea J. , Gruber Chandra , Mekonnen Eskedar Getie , Mixter Emily , Sherifali Diana , Eckel Robert H. , Nolan John J. , Philipson Louis H. , Brown Rebecca J. , Billings Liana K. , Boyle Kristen , Costacou Tina , Dennis John M. , Florez Jose C. , Gloyn Anna L. , Gomez Maria F. , Gottlieb Peter A. , Greeley Siri Atma W. , Griffin Kurt , Hattersley Andrew T. , Hirsch Irl B. , Hivert Marie-France , Hood Korey K. , Josefson Jami L. , Kwak Soo Heon , Laffel Lori M. , Lim Siew S. , Loos Ruth J. F. , Ma Ronald C. W. , Mathieu Chantal , Mathioudakis Nestoras , Meigs James B. , Misra Shivani , Mohan Viswanathan , Murphy Rinki , Oram Richard , Owen Katharine R. , Ozanne Susan E. , Pearson Ewan R. , Perng Wei , Pollin Toni I. , Pop-Busui Rodica , Pratley Richard E. , Redman Leanne M. , Redondo Maria J. , Reynolds Rebecca M. , Semple Robert K. , Sherr Jennifer L. , Sims Emily K. , Sweeting Arianne , Tuomi Tiinamaija , Udler Miriam S. , Vesco Kimberly K. , Vilsbøll Tina , Rich Stephen S. , Franks Paul W. , Meigs James B. , Udler Miriam S. 
Published: October 2023

Abstract
Background
Heterogeneity in type 2 diabetes presentation and progression suggests that precision medicine interventions could improve clinical outcomes. We undertook a systematic review to determine whether strategies to subclassify type 2 diabetes were associated with high quality evidence, reproducible results and improved outcomes for patients.

Methods
We searched PubMed and Embase for publications that used ‘simple subclassification’ approaches using simple categorisation of clinical characteristics, or ‘complex subclassification’ approaches which used machine learning or ‘omics approaches in people with established type 2 diabetes. We excluded other diabetes subtypes and those predicting incident type 2 diabetes. We assessed quality, reproducibility and clinical relevance of extracted full-text articles and qualitatively synthesised a summary of subclassification approaches.

Results
Here we show data from 51 studies that demonstrate many simple stratification approaches, but none have been replicated and many are not associated with meaningful clinical outcomes. Complex stratification was reviewed in 62 studies and produced reproducible subtypes of type 2 diabetes that are associated with outcomes. Both approaches require a higher grade of evidence but support the premise that type 2 diabetes can be subclassified into clinically meaningful subtypes.

Conclusion
Critical next steps toward clinical implementation are to test whether subtypes exist in more diverse ancestries and whether tailoring interventions to subtypes will improve outcomes.