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

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). NNCM-based 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 sodium-glucose cotransporter 2 inhibitors (SGLT2I) increases the survival probability compared to matched individuals with diabetes using other anti-diabetic drugs. Only individuals on SGLT2I experience increased survival when compared to individuals without T2D. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement UK Biobank was established by the Wellcome Trust, Medical Research Council, Department of Health, Scottish government, and Northwest Regional Development Agency. It has also had funding from the Welsh assembly government and the British Heart Foundation. The analyses in this study were funded by the Swiss National Science Foundation (31003A\_176127 and 310030\_204511 to M.R., PZ00P3_186101 to C.R.J.), the ETH Career Seed Grant (1-007724 SEED-11 to E.A.), and the Holcim Stiftung (to E.A.). ### 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: The current study is using data from the UK Biobank. UK Biobank has obtained ethics approval from the North West Multi-Centre Research Ethics Committee (approval number: 11/NW/0382) and has obtained informed consent from all participants. 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 study are available upon reasonable request to the authors.