Effects of antidiabetic drugs on mortality risks in individuals with type 2 diabetes: A prospective cohort study of UK Biobank participants

Abstract: medRxiv preprint doi: https://doi.org/10.1101/2023.05.19.23290214; this version posted May 19, 2023. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license . 1 Effects of antidiabetic drugs on mortality risks in individuals with type 2 diabetes: 2 A prospective cohort study of UK Biobank participants 3 Elisa Araldi1-2, Catherine R. Jutzeler 3, Michael Ristow 1,4* 4 5 6 7 8 9 10 11 12 13 14 15 1 Energy Metabolism Laboratory, Institute of Translational Medicine, Swiss Federal Institute of Technology (ETH) Zürich, Schwerzenbach, CH-8603, Switzerland; 2Center for Thrombosis and Hemostasis and Preventive Cardiology and Preventive Medicine, Center for Cardiology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, D-55131, Germany; 3 Biomedical Data Science Lab, Institute of Translational Medicine, Swiss Federal Institute of Technology (ETH) Zürich, Zürich, CH-8008, Switzerland; 4Institute of Experimental Endocrinology, Charité Universitätsmedizin Berlin, Humboldt University, Berlin, D-10117, Germany 16 Abstract 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 Objective: To investigate the mortality risk linked to prescription of different anti-diabetic medication classes. Design: Prospective population-based study. Setting: UK Biobank. Participants: 410 389 of the 502 536 participants in UK Biobank with covariate data, clinical and prescription records were included in the analyses, 43 610 of which had been diagnosed type 2 diabetes (T2D). A nearest neighbour covariate matching (NNCM) algorithm based on covariates with relevant effects on survival was applied to match cohorts of anti-diabetic medication class users to minimally differing control cohorts, either with a T2D diagnosis or without. Kaplan Meier estimates and Cox proportional models were used to evaluate survival differences and hazard ratio between drug classes and controls. Main outcome measures: All-cause mortality and causes of death. Results : 13667 (3.3%) individuals died during a median of 12.2 years of follow-up. After applying NNCM, participants with T2D on metformin (average hazard ratio 0.39, 95% confidence interval 0.31 to 0.49) or SGLT2I (average hazard ratio 0.58, 95% confidence interval 0.36 to 0.93) have an increased survival probability compared to matched individuals with T2D. When compared to matched individuals without T2D, the survival probability of individuals with T2D increases only if prescribed SGLT2I (average hazard ratio 0.31, 95% confidence interval 0.19 to 0.51). NNCMbased analysis of matched individuals with T2D on both SGLT2I and metformin versus metformin only reveals increased survival in the presence of SGLT2I (average hazard ratio 0.29, 95% confidence interval 0.09 to 0.91), also when compared to matched identical individuals without T2D (average hazard ratio 0.05, 95% confidence interval 0.01 to 0.19). All the other anti-diabetic drugs analyzed are either detrimental in prolonging lifespan (insulin, thiazolidinediones, and sulfonylureas), or have no effect (DPP4 inhibitors and GLP1 receptor agonists). Conclusion: The use of the current first-line anti-diabetic treatment, metformin, or sodiumglucose cotransporter 2 inhibitors (SGLT2I) increases the survival probability compared to matched..