Treatment effect heterogeneity following type 2 diabetes treatment with GLP1-receptor agonists and SGLT2-inhibitors: a systematic review

Authors

Katherine G. Young, University of Exeter Medical School
Eram Haider McInnes, University of Dundee School of Medicine
Robert J. Massey, University of Dundee School of Medicine
Anna R. Kahkoska, Department of Nutrition
Scott J. Pilla, Johns Hopkins University School of Medicine
Sridharan Raghavan, U.S. Department of Veterans Affairs
Maggie A. Stanislawski, University of Colorado School of Medicine
Deirdre K. Tobias, Harvard T.H. Chan School of Public Health
Andrew P. McGovern, University of Exeter Medical School
Andrew P. McGovern, University of Exeter Medical School
Adem Y. Dawed, University of Dundee School of Medicine
Angus G. Jones, University of Exeter Medical School
Ewan R. Pearson, University of Dundee School of Medicine
Ewan R. Pearson, University of Dundee School of Medicine
John M. Dennis, University of Exeter Medical School
John M. Dennis, University of Exeter Medical School
Paul W. Franks, Harvard T.H. Chan School of Public Health
Stephen S. Rich, University of Virginia School of Medicine
Robert Wagner, Deutsches Diabetes-Zentrum
Tina Vilsbøll, Steno Diabetes Center Copenhagen
Kimberly K. Vesco, Kaiser Permanente Center for Health Research
Miriam S. Udler, Massachusetts General Hospital
Tiinamaija Tuomi, Helsinki University Hospital
Arianne Sweeting, Faculty of Medicine and Health
Emily K. Sims, Indiana University School of Medicine
Jennifer L. Sherr, Yale School of Medicine
Robert K. Semple, Edinburgh Medical School
Rebecca M. Reynolds, Edinburgh Medical School
Maria J. Redondo, Baylor College of Medicine
Leanne M. Redman, Pennington Biomedical Research Center
Richard E. Pratley, AdventHealth Translational Research Institute
Rodica Pop-Busui, University of Michigan Medical School
Toni I. Pollin, University of Maryland School of Medicine
Wei Perng, University of Colorado Anschutz Medical Campus

Document Type

Article

Publication Date

12-1-2023

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.

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