Background

Sodium–glucose co-transporter 2 inhibitors (SGLT2is) are licensed for the treatment of type 2 diabetes (T2D) and more recently for heart failure in those with and without diabetes.

In T2D, both canagliflozin and empagliflozin reduce major adverse cardiovascular events (MACE) but dapagliflozin does not. All three agents reduce heart failure in established diabetes and dapagliflozin reduces heart failure in those without diabetes. Furthermore, safety concerns have emerged, either during trials or through post-marketing surveillance, such as SGLT2i exposure possibly being associated with LLA, DKA, bone fracture and GMI.

For effectiveness, population-based pharmacoepidemiology studies can confirm and extend the findings of randomised controlled trials (RCTs) to broader populations not eligible for trial participation and explore safety, for which RCTs are not usually powered, in more detail.

Why carry out this study?

We did a pre-planned and registered, impartial systematic review asking: do the benefits of SGLT2is in T2D extend to those ineligible for RCT participation, and are safety concerns which arose during the trials (or in post-marketing) detected, in population-based observational pharmacoepidemiology studies? We considered and reported all clinical event-based outcomes for effectiveness and safety in studies which met our inclusion/exclusion criteria.

What was learned from the study?

A total of 37 population-based studies including adults (n = 1,300,184) with T2D were identified. These appear to confirm that SGLT2is in T2D appear safe from the CVD perspective, and may have associated benefit in primary as well as secondary CVD prevention, particularly in HF-associated events. However, SGLT2i exposure may be associated with an increased risk of GMI, LLA and DKA, although longer follow-up studies are needed.