Objective: To compare the effects of individual SGLT2i on cardiovascular endpoints in patients with T2D using network meta-analysis (NMA).

Data Sources: PubMed, www.clinicaltrials.gov and the Cochrane Central Register of Controlled Trials up to August 12^th 2019.

Study Selection: We selected randomised controlled trials exploring the use of canagliflozin, dapagliflozin, empagliflozin or ertugliflozin in adults (≥ 18 years) with T2D. Comparators included placebo or any other active treatment. Only trials with a treatment duration ≥24 weeks were eligible. There were no restrictions regarding year of publication, sample size, background diabetes treatment, or dose of SGLT2i.

Data Extraction and Synthesis: Data extraction and quality assessment was performed by two independent reviewers following the PRISMA extension statement for reporting systematic reviews incorporating NMAs of health care interventions. Evidence was synthesised using NMA. A random effects model was applied.

Main Outcomes and Measures: Endpoints included cardiovascular mortality and worsening heart failure (HF).

Results: Fifty-two trials reporting on 60,950 patients were included. The overall quality of evidence was high. Empagliflozin and canagliflozin improved cardiovascular mortality, with empagliflozin being superior to other SGLT2i. Empagliflozin, canagliflozin and dapagliflozin similarly improved worsening HF. Sensitivity analyses including extension periods of trials or excluding studies with a treatment duration of <52 weeks confirmed the main results. Similar results were obtained when restricting mortality analyses to patients included in cardiovascular outcome trials.

Conclusions and Relevance: All SGLT2i improved cardiovascular endpoints with empagliflozin being superior to the other SGLT2i for cardiovascular mortality reduction. Empagliflozin, canagliflozin and dapagliflozin had similar effects on improving worsening HF. Prospective head-to-head comparisons would be needed to confirm these results (PROSPERO 151112).