Cardiovascular Effects of Metformin on Left Ventricular Hypertrophy in Nondiabetic Patients with Coronary Artery Disease

Abstract

Left ventricular hypertrophy (LVH) is highly prevalent in patients with coronary artery disease (CAD) irrespective, of blood pressure (BP) and is associated with an increased risk of all-cause mortality and cardiovascular events including myocardial infarction, heart failure, stroke and arrhythmias. Previous studies of mainly antihypertensive therapies have shown LVH to be a reversible risk factor. However, controlling BP is only partially effective as LVH persists in 20% of hypertensive patients who attain target BP. Therefore, novel ways of regressing LVH, independent of BP, in patients with CAD could reduce cardiovascular events and mortality in this patient group.

Apart from uncontrolled BP, insulin resistance (IR) and central obesity are implicated in the development of LVH. Metformin - an anti-diabetic drug, has been shown to reduce body weight and to improve insulin sensitivity, thus reducing IR. These properties of metformin may have the potential of regressing LVH. Additionally, metformin has complex multiple modes of actions involving both AMP-activated protein kinase (AMPK)-dependent and AMPK-independent mechanisms that is implicated in cardiac hypertrophy. Indeed, metformin has been shown to reduce cardiac hypertrophy in different animal models of hypertrophy. However, there has never been a clinical study to show that metformin is capable of regressing LVH.

In my PhD, I tested the hypothesis that metformin may regress LVH in patients who have CAD with insulin resistance and/or pre-diabetes.

The MET-REMODEL trial was a randomized, double-blinded, placebo controlled study of 68 patients without diabetes who had well controlled blood pressure and have CAD, LVH and IR and/or prediabetes. Study subjects were assigned to receive either metformin (2000mg/day) or placebo therapy, over a 12 month follow up period. LV mass was measured at baseline and 12 months using cardiac magnetic resonance imaging (CMR). Primary endpoint of this study was change in left ventricular mass indexed (LVMI) to height1.7 (LVMI); other endpoints were changes in left ventricular mass (LVM), changes in body weight, abdominal obesity (measured by MRI), endothelial function, BP and biomarkers of cardiac wall stress and fibrosis, inflammation and oxidative stress.

In this study, we demonstrated 2000 mg daily of metformin therapy over a 12-month treatment period significantly reduced LVMI, LVM, office systolic blood pressure (SBP), body weight and oxidative stress. In the modified intention-to-treat (mITT) analysis (n=63), metformin treatment significantly reduced LVMI (metformin -2.71 ± 2.31 g/m1.7 vs. placebo -1.34 ± 2.65 g/m1.7; P=0.033) and LVM (metformin -6.53 ± 5.59g vs. placebo -3.23 ± 6.32g; P=0.032). Metformin also significantly reduced other secondary study end points such as: body weight (P=0.001), sub-cutaneous adipose tissue (P=0.024), SBP (P=0.022) and concentration of thiobarbituric acid reactive substances (TBARs), a biomarker for oxidative stress (P=0.04). The per protocol analysis (n=56) also produced findings consistent with findings to mITT, but a more significant reduction of LVMI (P=0.005). The glycated haemoglobin A1C concentration and fasting insulin resistance index did not differ between study groups at the end of the study.

These results may suggest a potentially novel cardio-protective effect of metformin and raise the possibility of using metformin in patients without diabetes with CAD.

Although LVH is a good surrogate marker of cardiovascular outcome, definitive evidence for the cardio-protective role of metformin in non-diabetic cardiovascular disease will have to be provided by large randomized cardiovascular outcome clinical trials.

Date of Award	2019
Original language	English
Awarding Institution	University of Dundee
Sponsors	British Heart Foundation
Supervisor	Chim Lang (Supervisor) & Jacob George (Supervisor)