Cardiovascular and Renal Outcomes among Patients with Type 2 Diabetes using SGLT2 Inhibitors added to Metformin: A Population-Based Cohort Study from the United Kingdom

IntroductionAs large numbers of patients with type 2 diabetes receive treatment with a sodium-glucose co-transporter-2 inhibitor (SGLT2i), we investigated whether the cardio-renal preventative effects found in clinical trials are also seen in clinical practice where patient characteristics and adherence to treatment differs. Research design and methodsUsing UK primary care electronic health records, we followed two cohorts of patients with type 2 diabetes prescribed metformin: SGLT2is (N=12,978) and a matched comparator of patients not using a SGLT2i at the start of follow-up (N=44,286). Independent follow-ups were performed to identify the study outcomes - Cox regression to estimate adjusted hazard ratios (HRs) for the study outcomes: cardiovascular (CV) composite outcome (comprising non-fatal myocardial infarction [MI]/ischaemic stroke [IS] requiring hospitalisation and CV death), severe renal disease, and all-cause mortality. ResultsMean follow-up was 2.3 years (SGLTi cohort) and 2.1 years (comparison cohort). Mean age was 60.4 years (SD {+/-}10.2, SGLTi cohort) and 60.4 years (SD {+/-} 10.0, comparison cohort). SGLT2i new users were associated with a reduced risk of the CV composite (HR 0.75, 95% CI: 0.61-0.93), severe renal disease (HR 0.55, 95% CI: 0.46- 0.67), and all-cause mortality (HR 0.56, 95% CI: 0.49-0.63), with risk reductions similar irrespective of baseline CKD. Reduced risks were seen for IS (HR 0.51, 95% CI: 0.36-0.74) but not MI (HR 0.98, 95% CI: 0.74-1.28). Results were consistent in sensitivity analyses. ConclusionsIn this population-based study, SGLT2is were associated with significant CV, renal and survival benefits among individuals with type 2 diabetes on metformin; the CV benefit was driven by a reduced risk of ischaemic stroke. What is already known on this topic?O_LIIn randomized controlled trials (RCTs), sodium-glucose co-transporter-2 inhibitors (SGLT2is) and have shown good efficacy in reducing the risk of adverse cardiovascular (CV) and renal events in patients with type 2 diabetes. C_LIO_LIThese benefits of SGLT2is have also been seen in observational studies, but have shown uncertainty around the evidence for benefits on myocardial infarction (MI). C_LIO_LIRCTs and observational studies differ in the characteristics of patients studied and in their adherence to treatment. C_LI What this study adds?O_LIIn this matched retrospective cohort study among patients with type 2 diabetes using metformin, those who started an SGLT2i had significantly reduced risks of all-cause mortality (44% risk reduction), severe renal disease (50% risk reduction), a CV composite outcome (non-fatal MI/ischaemic stroke requiring hospitalisation/CV death; 25% risk reduction) and ischaemic stroke (49 risk reduction) compared with those who didnt start a SGLT2i; however, the risk of non-fatal MI was not significantly different between groups. C_LIO_LIThese findings indicate that the beneficial effects on CV disease seen in trials are driven by a reduced risk of ischaemic stroke. C_LI How this study might affect research, practice or policyO_LIThese results confirm that the benefits of SGLT2i in patients with type 2 diabetes observed in clinical trials are applicable to real-world settings, thereby supporting an increasing role of SGLT2i in diabetes care. C_LI