Metabolic Effects of Metformin in the Failing Heart

Abstract

Accumulating evidence shows that metformin is an insulin-sensitizing antidiabetic drug widely used in the treatment of type 2 diabetes mellitus (T2DM), which can exert favorable effects on cardiovascular risk and may be safely used in patients with heart failure (HF), and even able to reduce the incidence of HF and to reduce HF mortality. In failing hearts, metformin improves myocardial energy metabolic status through the activation of AMP (adenosine monophosphate)-activated protein kinase (AMPK) and the regulation of lipid and glucose metabolism. By increasing nitric oxide (NO) bioavailability, limiting interstitial fibrosis, reducing the deposition of advanced glycation end-products (AGEs), and inhibiting myocardial cell apoptosis metformin reduces cardiac remodeling and hypertrophy, and thereby preserves left ventricular systolic and diastolic functions. While a lot of preclinical and clinical studies showed the cardiovascular safety of metformin therapy in diabetic patients and HF, to confirm observed benefits, the specific large-scale trials configured for HF development in diabetic patients as a primary endpoints are necessary.

Metformin and Its Benefits for Various Diseases

“…Reports indicated that patients with diabetes account for almost one-third of heart failure cases (99). It has been shown that metformin improves the myocardial energy status through ameliorating cellular lipid and glucose metabolism via AMPK (100). Recently, a randomized controlled trial in patients with coronary artery disease without diabetes demonstrated that metformin significantly reduces left ventricular hypertrophy (LVH), one of the most powerful prognostic factors in coronary artery disease.…”

The Gut Microbiota and Its Implication in the Development of Atherosclerosis and Related Cardiovascular Diseases

“…Other examples of the relationships between microbiota and atherosclerosis are the administration of metformin and whole grains; metformin is a biguanide antidiabetic drug widely used in adults that have shown to exert positive effects to fight against CVD risk and that might be used safely in patients with heart failure and even reduce its occurrence or mortality, not only by direct effects [140], but also because of the possible effects produced through gut microbiota remodeling [141]. Also, the diet seems to be a potential therapy to diminish the risk of CVD since a study on a specific population of Danish adults showed that a diet abundant in whole grain compared to refined grain reduces body mass and systemic inflammation [142], which are risk factors to a bad prognosis of CVD.…”

The Role of AMPK Activation for Cardioprotection in Doxorubicin-Induced Cardiotoxicity

“…A more recent opinion, however, considers the risk of metformin in diabetic patients with heart failure as minimal and suggests that the cardioprotective benefit outweighs this risk [97]. Indeed, the metabolic and anti-fibrotic effects of metformin on the failing heart have been reviewed, encouraging large-scale clinical trials in diabetic patients with heart failure [98]. Moreover, metformin improves cardiac LVEF and survival in mice with ischaemiainduced heart failure [99].…”