From Pleiotropic Mechanisms To Clinical Outcomes: Reevaluating Metformin’s Role In Cardiovascular Prevention

Abstract

Abstract
Background: Cardiovascular disease (CVD) remains the leading cause of morbidity and
mortality in patients with type 2 diabetes mellitus (T2DM) and metabolic syndrome. While
metformin has historically been the first-line pharmacotherapy for T2DM, its role is beingreassessed in the era of newer drug classes like SGLT-2 inhibitors and GLP-1 receptor
agonists, which have demonstrated significant cardiovascular benefits. This review aims to
evaluate the cardioprotective mechanisms of metformin, its clinical efficacy in reducing
major adverse cardiovascular events (MACE), and its comparative safety profile against other
antidiabetic agents in both mono- and combination therapies.
Methods: We conducted a comprehensive review of current literature, including landmark
randomized controlled trials (such as UKPDS and DPPOS), systematic reviews, and metaanalyses. The scope of the review encompasses the pharmacological properties of metformin,
its pleiotropic mechanisms of action (AMPK activation, reduction of oxidative stress and
inflammation, improvement of endothelial function), and its impact on hard cardiovascular
endpoints. We further analyzed real-world evidence comparing metformin with
sulfonylureas, DPP-4 inhibitors, SGLT-2 inhibitors, and GLP-1 receptor agonists in various
patient populations, including those with heart failure and chronic kidney disease.
Results: Metformin demonstrates significant cardioprotective potential through glycemicdependent and independent mechanisms, including the activation of the Nrf2 pathway,
inhibition of HMGB1-mediated inflammation, and modulation of the gut microbiota. Clinical
evidence confirms that metformin reduces the risk of myocardial infarction and all-cause
mortality in overweight patients with T2DM. However, in prediabetic populations (DPPOS
study), metformin did not significantly reduce MACE compared to placebo, potentially due
to effective concomitant management of cardiovascular risk factors. In comparative analyses,
metformin exhibits a superior safety profile to sulfonylureas, which are associated with
higher risks of hypoglycemia and cardiovascular events. While SGLT-2 inhibitors and GLP-1 receptor agonists offer distinct advantages in reducing heart failure hospitalizations and
stroke, respectively, metformin remains a crucial backbone for combination therapy,
enhancing glycemic durability and insulin sensitivity.
Conclusion: Metformin remains a cornerstone of T2DM management with a proven longterm safety profile and multifaceted cardioprotective effects. While newer agents provide
specific cardiovascular and renal benefits, metformin's ability to improve endothelial
function, reduce oxidative stress, and act synergistically in combination therapies justifies its
continued status as a first-line treatment. Future therapeutic strategies should focus on
personalized combination regimens that leverage metformin's unique mechanisms alongside
the cardiorenal benefits of newer drug classes.