Abstract
Type 2 diabetes mellitus (T2DM) is a worldwide major health burden and heart failure (HF) is the most common cardiovascular (CV) complication in affected patients. Therefore, identifying the best pharmacological approach for glycemic control, which is also useful to prevent and ameliorate the prognosis of HF, represents a crucial issue. Currently, the choice is between the new drugs sodium/glucose co-transporter 2 inhibitors that have consistently shown in large CV outcome trials (CVOTs) to reduce the risk of HF-related outcomes in T2DM, and metformin, an old medicament that might end up relegated to the background while exerting interesting protective effects on multiple organs among which include heart failure. When compared with other antihyperglycemic medications, metformin has been demonstrated to be safe and to lower morbidity and mortality for HF, even if these results are difficult to interpret as they emerged mainly from observational studies. Meta-analyses of randomized controlled clinical trials have not produced positive results on the risk or clinical course of HF and sadly, large CV outcome trials are lacking. The point of force of metformin with respect to new diabetic drugs is the amount of data from experimental investigations that, for more than twenty years, still continues to provide mechanistic explanations of the several favorable actions in heart failure such as, the improvement of the myocardial energy metabolic status by modulation of glucose and lipid metabolism, the attenuation of oxidative stress and inflammation, and the inhibition of myocardial cell apoptosis, leading to reduced cardiac remodeling and preserved left ventricular function. In the hope that specific large-scale trials will be carried out to definitively establish the metformin benefit in terms of HF failure outcomes, we reviewed the literature in this field, summarizing the available evidence from experimental and clinical studies reporting on effects in heart metabolism, function, and structure, and the prominent pathophysiological mechanisms involved.
Highlights
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The suspicion arose that background metformin therapy may obscure the CV benefits of SGLT2-Is, an interpretation that should be done with extreme caution as it is right to do for results from post hoc subgroup analyses [22]
A large number of people suffer from concomitant diabetes and heart failure (HF) and there will be even more in near future
Summary
The medicinal properties of metformin (dimethyl biguanide), an antihyperglycemic drug introduced in Europe in 1957 and registered about thirty years later in the US, were already known in the Middle Ages when the French lilac Galega officinalis containing the active compound galegine (isoamylene guanidine), was used to treat people with intense urination [1,2]. Data were accumulated until conclusive evidence revealed that the benefits of metformin use in diabetic patients with HF outweighed the potential risk [13,14] With this information, in 2006 the Food and Drug Administration (FDA) removed the absolute HF contraindication, acute or unstable congestive HF remained in the label’s warning section. The relative risk reduction in the composite of CV death or HF hospitalization in the CANVAS Program was 36% in metformin nonusers vs 12% in metformin users, with a nominally significant P interaction of 0.03 [21] Because of these results, the suspicion arose that background metformin therapy may obscure the CV benefits of SGLT2-Is, an interpretation that should be done with extreme caution as it is right to do for results from post hoc subgroup analyses [22]. We synthetized the available evidence from experimental and clinical studies reporting on metformin effects in heart metabolism, function, and structure, and the prominent pathophysiological mechanisms involved
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