Does background metformin therapy influence the cardiovascular outcomes with SGLT-2 inhibitors in type 2 diabetes?

Metformin has been recommended as a first-line antidiabetic drug (ADD) for all patients with type 2 diabetes even in the presence of high cardiovascular (CV) risk by American Diabetes Association. In contrast, European Society of Cardiology recommends either a sodium-glucose co-transporter-2 inhibitors (SGLT-2i) or a glucagon-like peptide-1 receptor agonists as a first-line ADD, in presence of high CV risk. While this discordant recommendation has created a debate, we sought to find whether background metformin therapy influences the CV outcomes with SGLT-2i. We pooled the hazard ratio and 95% confidence interval of three-point composite major adverse cardiovascular events (3P-MACE) of 3 CV outcome trials (CVOTs) from the subgroup analysis based on outcomes with or without background metformin therapy. Subsequently, we conducted a meta-analysis by applying the inverse variance-weighted averages of pooled logarithmic hazard ratio, using a random-effects analysis. While this meta-analysis found a significant reduction in 3P-MACE with SGLT-2i without background metformin therapy (N = 7,233; HR 0.79; 95% CI, 0.69-0.90; p < 0.01; I² = 0.0%), no significant reduction in 3P-MACE was observed with SGLT-2i in presence of background metformin therapy (N = 27,081; HR 0.94; 95% CI, 0.86-1.02; p = 0.13; I² = 0.0%) with a significant P_heterogenity of 0.03 between the two groups. Similar finding was observed from the pooled results from 4 CVOTs. This may suggest that background metformin therapy may undermine the 3P-MACE benefit of SGLT-2i. However, no such interaction was observed in a recent meta-analysis of SGLT-2i, with or without background metformin therapy. Future research is warranted to understand the CV interaction of metformin with SGLT-2i.