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

Abstract

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.

Keywords: Diabetes Mellitus; Epidemiology; Pharmacology.

Figure 1. Flow chart of inclusion of patients in the study cohort. DPP-4i, dipeptidyl peptidase-4 inhibitor; SGLT-2i, sodium-glucose cotransporter-2 inhibitor.