Use of Metformin and Cardiovascular Effects of New Classes of Glucose-Lowering Agents: A Meta-analysis of Cardiovascular Outcome Trials in Type 2 Diabetes
Abstract
Over the last two decades, the large majority of clinical guidelines on the treatment of hyperglycemia in subjects with type2diabeteshavesuggestedmetformin as the first-line glucose-lowering treatment alongside lifestyle changes to reach personalized glycemic targets. Recently, the European Society of Cardiology recommended using glucagon-like peptide 1 receptor agonists (GLP-1RA) or sodium–glucose cotransporter2 inhibitors (SGLT-2i) as first-line glucose-lowering therapy in subjects with type 2 diabetes at high or very high risk of cardiovascular disease, ahead of metformin treatment, to reduce cardiovascular events (1). Following the European Society of Cardiology guidelines, several analyses have investigated whether the cardiovascular effects ofGLP-1RA or SGLT-2i would differ in relation to the use of metformin. Some of these studies reported a “statistically significant” difference (i.e., interaction) in the cardiovascular effects of SGLT-2is, whereby subjects with metformin have a lower cardiovascular protection from SGLT-2i, leading to several hypotheses about the possible pharmacological mechanisms. Interpreting interaction results, however, may be difficult, as they suffer from well-known drawbacks, including limited statistical power (2). For overcoming this problem and identifying who may be most likely to benefit from a specific treatment, trial-specific interactions may be combined with a metaanalytical approach (3). In this study, we systematically investigated…
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