Journal of Atherosclerosis Prevention and Treatment – JAPT Submission: 19.07.2022, Acceptance: 11.08.2022 Review article J Atherosclerosis Prev Treat. 2022 May-Aug;13(2):67–73 Metformin and type 2 diabetes in the era of cardiovascular outcome trials; A narrative review Konstantinos Kitsios, Christina-Maria Trakatelli, Maria Sarigianni, Anastasia Kyriazidou, Fotios Aroutsidis, Konstantinos Mastrogiannis, Vasilios Kotsis 3 rd Department Of Internal Medicine, Aristotle University of Thessaloniki, Papageorgiou General Hospital, Thessaloniki, Greece Corresponding author: Konstantinos Kitsios 57 A. Papandreou Str, 55132, Kalamaria, Thessaloniki, Greece Tel.: +30 6977295744 E-mail: kitsios_k@yahoo.gr doi.: 10.53590/japt.02.1035 ABSTRACT Metformin has been for many years the first-line pharmaceutic treatment for most patients with type 2 dia- betes. However, new classes of antidiabetic agents with proven cardiorenal benefits beyond glycemic control challenge metformin’s predominance. The hypoglycemic effect of metformin is mediated in liver by inhibiting gluconeogenesis and improving insulin sensitivity and in intestines by reducing glucose absorption, increas- ing incretins and altering intestinal microbiome. After decades of use metformin has been proved to be one of the most potent, safe and cost-effective medications for the treatment of type 2 diabetes. Several other pleiotropic actions of metformin in inflammation pathways suggest a potential cardioprotective role. This hypothesis has been tested in a few randomized trials and in more observational studies and metanalyses with controversial results. Given the lack of robust evidence for the cardioprotective effect of metformin compared to the newer antidiabetic agents, current treatment algorithms are under scrutiny. Ongoing randomized clinical trials comparing metformin to placebo are expected to elucidate the effect of metformin on specific cardiovascular and renal outcomes. KEY WORDS: Metformin, type 2 diabetes, cardiovascular risk, cardiovascular outcome, renal outcome, CVOTs INTRODUCTION Metformin has been for decades the first-line treatment for most of the drug naïve patients with type 2 diabetes not achieving their glycemic target with diet and lifestyle modification alone. However, within the recent years, new classes of antidiabetic drugs with proven cardiorenal benefits beyond their hypoglycemic effect have emerged. Tested extensively in Cardiovascular Outcome randomized placebo-controlled Trials (CVOTs) these new factors chal- lenge metformin’s predominance in the treatment of diabetes 1 . The aim of this review is a critical reappraisal of current data for the cardiovascular and renal safety of metformin and for potential additional cardiovascular benefits from its use.