Introduction: As 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 methods: Using 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] or ischaemic stroke [IS] requiring hospitalisation and CV death), severe renal disease, and all-cause mortality. Results: Mean follow-up was 2.3 years (SGLTi cohort) and 2.1 years (comparison cohort). Mean age was 60.4 years (SGLTi cohort) and 60.4 years (comparison cohort). SGLT2i new users were associated with a reduced risk of the CV composite (HR 0.75, 95% CI: 0.61 to 0.93), severe renal disease (HR 0.55, 95% CI: 0.46 to 0.67), and all-cause mortality (HR 0.56, 95% CI: 0.49 to 0.63), with risk reductions similar irrespective of baseline CKD. Reduced risks were seen for IS (HR 0.51, 95% CI: 0.36 to 0.74) but not MI (HR 0.98, 95% CI: 0.74 to 1.28). Results were consistent in sensitivity analyses. Conclusions: In 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.

AG-P, MES and LAGR work for CEIFE, which has received research funding from Bayer AG. LAGR also declares honoraria for attendance at advisory board meetings for Bayer. DV is an employee of Bayer. ML has received research grants from Eli Lilly and Novonordisk and been a paid consultant or received honoraria from Astra Zeneca, Boehringer Ingelheim, Eli Lilly and Novonordisk.

The study was funded by Bayer AG

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 Independent Scientific Research Committee for IQVIA Medical Research Data-UK (IMRD-UK) gave ethical approval for this work

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 and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.

Yes

All data produced in the present study are available upon reasonable request to the authors