Treatment effect heterogeneity following type 2 diabetes treatment with GLP1-receptor agonists and SGLT2-inhibitors: a systematic review
Katherine Young, Eram Haider McInnes, Robert Massey, Anna R. Kahkoska, Scott J. Pilla, Sridharan Raghavan, Maggie A. Stanislawski, Deirdre K. Tobias, Andrew McGovern, Adem Y. Dawed, Angus G. Jones, Ewan R. Pearson, John Dennis, ADA/EASD PDMI, Deirdre K. Tobias, Jordi Merino, Abrar Ahmad, Catherine Aiken, Jamie L. Benham, Dhanasekaran Bodhini, Amy L. Clark, Kevin Colclough, Rosa Corcoy, Sara J. Cromer, Daisy Duan, Jamie L. Felton, Ellen C. Francis, Pieter Gillard, Véronique Gingras, Romy Gaillard, Eram Haider, Alice E. Hughes, Jennifer M. Iklé, Laura M. Jacobsen, Jarno L. T. Kettunen, Raymond J. Kreienkamp, Lee‐Ling Lim, Jonna M. E. Männistö, Robert Massey, Niamh‐Maire Mclennan, Rachel G. Miller, Mario Luca Morieri, Jasper Most, Rochelle N. Naylor, Bige Özkan, Kashyap Patel, Scott J. Pilla, Katsiaryna Prystupa, Sridaran Raghaven, Mary R. Rooney, Martin Schön, Zhila Semnani‐Azad, Magdalena Sevilla-González, Pernille Svalastoga, Wubet Worku Takele, Claudia H.T. Tam, Anne Cathrine B. Thuesen, Mustafa Tosur, Amelia S. Wallace, Caroline C. Wang, Jessie J. Wong, Jennifer M. Yamamoto, Katherine Young, Chloé Amouyal, Mette K. Andersen, Maxine P. Bonham, Mingling Chen, Feifei Cheng, Tinashe Chikowore, Sian C. Chivers, Christoffer Clemmensen, Dana Dabelea, Adem Y. Dawed, Aaron J. Deutsch, Laura T. Dickens, Linda A. DiMeglio, Monika Dudenhöffer‐Pfeifer, Carmella Evans‐Molina, María Mercè Fernández-Balsells, Hugo Fitipaldi, Stephanie L. Fitzpatrick, Stephen E. Gitelman, Mark O. Goodarzi, Jessica A. Grieger, Marta Guasch‐Ferré, Nahal Habibi, Torben Hansen, Chuiguo Huang, Arianna Harris-Kawano, Heba M. Ismail, Benjamin Hoag, Randi K. Johnson, Angus G. Jones, Robert W. Koivula, Aaron Leong, Gloria K. W. Leung, Ingrid Libman, Kai Liu, S. Alice Long, William L. Lowe
Abstract
BACKGROUND: A precision medicine approach in type 2 diabetes requires the identification of clinical and biological features that are reproducibly associated with differences in clinical outcomes with specific anti-hyperglycaemic therapies. Robust evidence of such treatment effect heterogeneity could support more individualized clinical decisions on optimal type 2 diabetes therapy. METHODS: We performed a pre-registered systematic review of meta-analysis studies, randomized control trials, and observational studies evaluating clinical and biological features associated with heterogenous treatment effects for SGLT2-inhibitor and GLP1-receptor agonist therapies, considering glycaemic, cardiovascular, and renal outcomes. After screening 5,686 studies, we included 101 studies of SGLT2-inhibitors and 75 studies of GLP1-receptor agonists in the final systematic review. RESULTS: Here we show that the majority of included papers have methodological limitations precluding robust assessment of treatment effect heterogeneity. For SGLT2-inhibitors, multiple observational studies suggest lower renal function as a predictor of lesser glycaemic response, while markers of reduced insulin secretion predict lesser glycaemic response with GLP1-receptor agonists. For both therapies, multiple post-hoc analyses of randomized control trials (including trial meta-analysis) identify minimal clinically relevant treatment effect heterogeneity for cardiovascular and renal outcomes. CONCLUSIONS: Current evidence on treatment effect heterogeneity for SGLT2-inhibitor and GLP1-receptor agonist therapies is limited, likely reflecting the methodological limitations of published studies. Robust and appropriately powered studies are required to understand type 2 diabetes treatment effect heterogeneity and evaluate the potential for precision medicine to inform future clinical care.