Metformin: evidence from preclinical and clinical studies for potential novel applications in cardiovascular disease

ABSTRACT

Introduction

For a long time, metformin has been the first-line treatment for glycemic control in type 2 diabetes; however, the results of recent cardiovascular outcome trials of sodium-glucose co-transporter 2 inhibitors and glucagon-like peptide 1 receptor agonists have caused many to question metformin’s position in the guidelines. Although there are several plausible mechanisms by which metformin might have beneficial cardiovascular effects, for example, its anti-inflammatory effects and metabolic properties, and numerous observational data suggesting improved cardiovascular outcomes with metformin use, the main randomized clinical trial data for metformin was published over 20 years ago. Nevertheless, the overwhelming majority of participants in contemporary type 2 diabetes trials were prescribed metformin.

Areas covered

In this review, we will summarize the potential mechanisms of cardiovascular benefit with metformin, before discussing clinical data in individuals with or without diabetes.

Expert opinion

Metformin may have some cardiovascular benefit in patients with and without diabetes, however the majority of clinical trials were small and are before the use SGLT2 inhibitors and GLP1-RAs. Larger contemporary randomized trials, with metformin evaluating its cardiovascular benefit are warranted.

KEYWORDS:

• Cardiovascular disease
• diabetes
• heart failure
• metformin
• inflammation

Article highlights

• Metformin is currently still recommended as the first-line pharmacological treatment for management of hyperglycemia in type 2 diabetes despite recent trials showing the cardiovascular benefits of newer agents, such as sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide 1 receptor agonists.

• The main randomized trial evidence showing clinical outcome benefit with metformin in type 2 diabetes comes from an older, comparatively small trial.

• Metformin has a number of plausible potential mechanisms of cardiovascular benefit beyond its glycemic effects including anti-inflammatory effects and reductions in oxidative stress, body weight and blood pressure.

• Metformin may also have beneficial effects in individuals without type 2 diabetes.

• There is a need for contemporary evidence from large randomized trials to ascertain the cardiovascular benefits of metformin and clarify its position in clinical guidelines.

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This manuscript was supported by Tenovus Scotland under Grant T20/58.