Sodium glucose cotransporter 2 inhibitors and risk of major adverse cardiovascular events: multi-database retrospective cohort study

Abstract

Objective: To compare the risk of cardiovascular events between sodium glucose cotransporter 2 (SGLT2) inhibitors and dipeptidyl peptidase-4 (DPP-4) inhibitors among people with type 2 diabetes in a real world context of clinical practice.

Design: Multi-database retrospective cohort study using a prevalent new user design with subsequent meta-analysis.

Setting: Canadian Network for Observational Drug Effect Studies (CNODES), with administrative healthcare databases from seven Canadian provinces and the United Kingdom, 2013-18.

Population: 209 867 new users of a SGLT2 inhibitor matched to 209 867 users of a DPP-4 inhibitor on time conditional propensity score and followed for a mean of 0.9 years.

Main outcome measures: The primary outcome was major adverse cardiovascular events (MACE, a composite of myocardial infarction, ischaemic stroke, or cardiovascular death). Secondary outcomes were the individual components of MACE, heart failure, and all cause mortality. Cox proportional hazards models were used to estimate site specific adjusted hazards ratios and 95% confidence intervals, comparing use of SGLT2 inhibitors with use of DPP-4 inhibitors in an as treated approach. Site specific results were pooled using random effects meta-analysis.

Results: Compared with DPP-4 inhibitors, SGLT2 inhibitors were associated with decreased risks of MACE (incidence rate per 1000 person years: 11.4 v 16.5; hazard ratio 0.76, 95% confidence interval 0.69 to 0.84), myocardial infarction (5.1 v 6.4; 0.82, 0.70 to 0.96), cardiovascular death (3.9 v 7.7; 0.60, 0.54 to 0.67), heart failure (3.1 v 7.7; 0.43, 0.37 to 0.51), and all cause mortality (8.7 v 17.3; 0.60, 0.54 to 0.67). SGLT2 inhibitors had more modest benefits for ischaemic stroke (2.6 v 3.5; 0.85, 0.72 to 1.01). Similar benefits for MACE were observed with canagliflozin (0.79, 0.66 to 0.94), dapagliflozin (0.73, 0.63 to 0.85), and empagliflozin (0.77, 0.68 to 0.87).

Conclusions: In this large observational study conducted in a real world clinical practice context, the short term use of SGLT2 inhibitors was associated with a decreased risk of cardiovascular events compared with the use of DPP-4 inhibitors.

Trial registration: ClinicalTrials.gov NCT03939624.

Conflict of interest statement

Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: SA-S received research grants from Pfizer and Merck for projects not involving SGLT2 inhibitors or DPP-4 inhibitors. SS has attended advisory meetings or received speaking fees from Atara, Boehringer-Ingelheim, Bristol-Myers-Squibb, Merck, and Pfizer; SS is on the scientific advisory board of the EMPRISE study of SGLT2 inhibitors conducted by Harvard University and funded by Boehringer-Ingelheim; no other relationships or activities that could appear to have influenced the submitted work.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Fig 1

Selection of study cohort. Numbers might not add up because site specific cells with a value of less than six were suppressed owing to privacy restrictions. Patients aged less than 19 years in Alberta and less than 66 years in Ontario were excluded. Patients were eligible to enter the study cohort a maximum of two times, first with a prescription for a dipeptidyl peptidase-4 (DPP-4) inhibitor and second time with a prescription for a sodium glucose cotransporter 2 (SGLT2) inhibitor

Fig 2

Cumulative incidence of major adverse cardiovascular events among users of sodium glucose cotransporter 2 (SGLT2) inhibitors and matched users of dipeptidyl peptidase-4 (DPP-4) inhibitors in Ontario and Quebec, the two largest study sites

Fig 3

Adjusted hazard ratios (95% confidence intervals) of major adverse cardiovascular events associated with use of sodium glucose cotransporter 2 (SGLT2) inhibitors compared with dipeptidyl peptidase-4 (DPP-4) inhibitors. Outcome models were adjusted for age (continuous), sex, diabetes duration (continuous), and 10ths of time conditional propensity score. CPRD=Clinical Practice Research Datalink

Fig 4

Cumulative incidence of hospital admission for heart failure among users of sodium glucose cotransporter 2 (SGLT2) inhibitors and matched users of dipeptidyl peptidase-4 (DPP-4) inhibitors in Ontario and Quebec, the two largest study sites

Fig 5

Adjusted hazard ratios (95% confidence intervals) of hospital admission for heart failure associated with use of sodium glucose cotransporter 2 (SGLT2) inhibitors compared with dipeptidyl peptidase-4 (DPP-4) inhibitors. Outcome models were adjusted for age (continuous), sex, diabetes duration (continuous), and 10ths of time conditional propensity score. CPRD=Clinical Practice Research Datalink