Metformin: still the sweet spot for CV protection in diabetes?

Metformin remains the first-line drug treatment for type 2 diabetes (T2D) in most guidelines not only because it achieves significant reduction in HbA1c but also because of a wealth of clinical experience regarding its safety and observational data that has shown that metformin use is associated with lower mortality rates when compared to sulphonylureas or insulin. Recently other diabetes drugs, particularly SGLT2 inhibitors (SGLT2i) and GLP1 receptor agonists (GLP1RA), have attracted considerable attention for their cardioprotective benefits reported in cardiovascular outcome trials (CVOTs). Randomised control trials on these newer drugs are on a larger scale but have shorter follow-up than UKPDS, the main study supporting metformin use. In a recent change to the European Society of Cardiology guidelines, metformin was replaced by SGLT2i and GLP1RA as first-line for T2D with atherosclerotic cardiovascular disease, whereas American Diabetes Association and UK-wide guidelines maintain metformin as first choice drug pharmacotherapy for all T2D. A definitive evidence-base for prioritisation of these drugs is currently missing because there are no head-to-head clinical trial data. Without such trials being forthcoming, innovative, pragmatic and low-cost 'real-world' trial approaches based on electronic health records may need to be harnessed to determine the correct priority, combinations of drugs and/or identify-specific patient populations most likely to benefit from each one.