Sodium-glucose cotransporter-2 inhibitors and the risk of all-cause mortality: a population-based cohort study using the UK Clinical Practice Research Datalink

Aim Sodium-glucose cotransporter-2 inhibitors (SGLT-2is) have a direct cardiac effect that is independent of their glucose-lowering renal effect. We investigated the relation between SGLT-2is and all-cause mortality compared with (1) dipeptidyl peptidase-4 inhibitors (DPP-4is) and (2) metformin monotherapy in type 2 diabetes among subjects with a diabetes duration of <5 years at cohort entry. Methods A cohort study was conducted among patients initiating a new antidiabetic drug class between January 2013 and September 2020 by extracting data from the UK Clinical Practice Research Datalink. The HR of all-cause mortality comparing (1) SGLT-2is versus DPP-4is in type 2 diabetes and (2) SGLT-2is versus metformin monotherapy among subjects with a diabetes duration of <5 years at cohort entry was calculated using Cox regression. Stratified analyses were performed according to sex and the presence of cardiovascular disease. Results The cohort consisted of 152 591 new users of antidiabetic drugs, with 15 125 SGLT-2i users, 31 896 DPP-4i users, 15 723 other second-line to third-line antidiabetic drug users and 89 847 first-line antidiabetic drug users at cohort entry. After adjusting for all relevant confounders, SGLT-2i use was associated with a reduced rate of all-cause mortality compared with metformin monotherapy (HR: 0.77, 95% CI: 0.64 to 0.93) or DPP4-i (HR: 0.57, 95% CI: 0.51 to 0.63). This reduced rate of all-cause mortality appeared to be independent of sex and cardiovascular disease. Conclusion Our findings suggest a reduced risk of all-cause mortality with SGLT-2is compared with DPP-4is or metformin monotherapy in type 2 diabetes among subjects with a diabetes duration of <5 years at cohort entry.