Background Sodium-glucose co-transporter 2 (SGLT2) inhibitors are a novel class of antidiabetics proven to reduce blood pressure, blood glucose and body weight. However, the long term safety implications of these agents remain unclear.

Purpose This systematic review aimed to evaluate the available clinical trial evidence pertaining to long term cardiovascular (CV) safety of SGLT2 inhibitors.

Material and methods The databases EMBASE (1980–April 2015) and MEDLINE (1948–April 2015) were searched. Search terms included ‘SGLT2 inhibitors’, ‘Canagliflozin’, ‘Dapagliflozin’, ‘Empagliflozin’, ‘cardiovascular’, ‘safety’, ‘myocardial infarction’, ‘stroke’ and ‘cardiovascular death’. Randomised controlled trials assessing CV safety of SGLT2 inhibitors compared with placebo or anti-diabetic medications were included. Two investigators independently extracted study data (study design, duration, population, interventions and CV safety outcomes), and completed risk of bias assessments (sequence generation, allocation concealment, blinding, incomplete outcome data, or selective outcome reporting and other biases). Outcomes included CV death, myocardial infarction and stroke.

Results A total of 455 studies were identified in the electronic search and 14 from other sources. 31 studies remained after screening titles and abstracts, with 16 randomised clinical trials included after full text review. All studies reported at least one of the pre-defined outcomes (CV death, myocardial infarction and stroke). 12 cases of non-fatal myocardial infarction or stroke and 14 CV deaths were observed in SGLT2 inhibitor groups versus 1 case of angina and 5 CV deaths in comparator groups. Risk of bias assessment showed mixed results, with overall quality assessments deemed unclear for 5 of 16 studies (31.3%).

Conclusion Findings showed CV outcomes do occur in patients taking SGLT2 inhibitors yet the clinical significance remains unclear. These results can be considered hypothesis generating, as studies were limited by inadequate power and/or follow-up time. Future studies are needed to further assess the efficacy and safety profiles of these new agents before they become widely adopted in clinical practice.

No conflict of interest.