Metformin’s action on the cardiovascular system

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Ischemic heart disease (IHD) remains the leading cause of death in the patients with T2D [72]. Importantly, the UKPDS longitudinal trial demonstrated that metformin reduced by 42% the diabetes-related death (9-63, p=0.017), and by 36% all-cause mortality (9-55, p=0.011). Interestingly, in this study, metformin was used as a primary prevention and its beneficial effect was rapidly observed after a median duration of the study of 10.7 years [3]. This conclusion has been replicated in other clinical or epidemiological studies [73, 74]. Thus, the use of metformin as the first-line antidiabetic treatment in T2D patients was not only justified by the antihyperglycemic effect of the drug but also by the reduction of the mortality rate in this population. The mechanisms of such beneficial effect are not clearly understood but data accumulated concerning some potential mechanisms of metformin action in heart including the promotion of myocardial preconditioning, the reduction of cardiomyocytes apoptosis during ischemia, the adaptation of cardiomyocytes metabolism during ischemia or the protection against the development of heart failure.

Experimental evidence suggests that metformin reduces cardiac ischemia/reperfusion injury. Indeed, Yin et al. showed that metformin treatment improves cardiac function (preserved left ventricular ejection fraction) and reduces the infarct size after a myocardial infarction in Sprague-Dawley rats [75]. By contrast with sham-operated rats, the metformin group was less insulin resistant and has altered myocardial AMPK phosphorylation status during cardiac remodeling. Myocardial preconditionning is now recognized as a protective mechanism that allows reducing the infarct size and the consequent risk of heart failure. Induction of such mechanism has been demonstrated in a model of rats with neonatal streptozotocin T2D treated or not by metformin 3 days prior to an ischemia-reperfusion of the heart [76]. In this study, metformin induced preconditionning was supported by a reduction of the infarct size in the treated group.

Cardioplegic-induced hypoxia/reoxygenation (H/R) injury results in cardiomyocytic apoptosis. In cardiomyocytes, metformin attenuated the production of proapoptotic proteins, increased the antiapoptotic proteins and reduced the percentage of apoptotic cardiomyocytes [77]. This effect was correlated with an activation of AMPK and reproduced by AICAR, another AMPK activator. Another property of metformin (which seemed fundamental to reduce the risk of heart failure) is the adaptation of cardiac metabolism during myocardial ischemic condition. The healthy heart gets 60-90% of its energy for oxidative phosphorylation from fatty acid oxidation [78]. The failing heart has been demonstrated to shift toward an increased glucose uptake and utilization [79]. Because utilization of fatty acid costs more oxygen per unit of ATP generated than glucose, the promotion of a metabolic shift from fatty acids oxidation to glucose utilization may improve ventricular performance and slow the progression of heart dysfunction [78, 79]. Thus, in a volume-overload model of heart failure in rats (aortocaval fistula), Benes et al. demonstrated that metformin normalized serum NEFAs, and modified the cardiac lipid/glucose oxidation ratio, suggesting a metabolic adaptation induced by the drug [80].

Another new area of intense research is the possibility to use metformin in patients with a history of heart failure. Metformin is classically contraindicated in patients with heart failure because this condition increases the risk of lactic acidosis. Surprisingly, recent evidence suggests that this contraindication could be revised [81]. Indeed, metformin alone or in combination with sulfonylurea reduced the mortality and the morbidity in T2D patients with heart failure in comparison of sulfonylurea monotherapy [82-84]. This unexpected result has been found in the Reduction of Atherothrombosis for Continued Health (REACH) Registry which included 19691 T2D patients with established atherothrombosis [85]. The mortality rate was significantly lower in patients treated with metformin, including the ones in whom metformin use is not now recommended (history of congestive heart failure, patients older than 65 years and patients with an estimated creatinine clearance of 30 to 60 mL/min/1.73 m²). The cardiovascular protection in metformin-treated T2D patients seems not to be dependent of reduction in HbA1c level since it was not observed with other oral antidiabetic drugs [86], suggesting that metformin has specific properties on cardiovascular outcomes. Even if further studies are needed to better understand this specific point at the molecular level, some original mechanisms have already been proposed. Thus, dysregulated autophagy has been described as a key mechanism for the development of diabetic cardiomyopathy and heart failure. Interestingly, treatment with metformin restored impaired autophagy in OVE26 diabetic mice and prevented heart damage in this model [87]. This effect is probably dependent of cardiac AMPK activation since metformin is inefficient in cardiac-specific AMPK dominant-negative transgenic diabetic mice. In addition, Gundewar et al. demonstrated that metformin significantly improves left ventricular function and survival in a murine model of heart failure (myocardial ischemia induced by left coronary artery occlusion) [88]. The authors showed that metformin significantly improved myocardial cell mitochondrial respiration and ATP synthesis by an underlying mechanism requiring activation of AMPK and its downstream mediators, eNOS and PGC-1a [88]. Similar prevention of both heart failure and mortality by metformin was observed in a dog model of heart failure [89]. In this case, other AMPK activators such as AICAR have equivalent effects than those of metformin, suggesting that myocardial AMPK activation is also required. A large proportion of T2D patients have chronic high blood pressure, which is known to induce cardiac hypertrophy and fibrosis. Metformin inhibits cardiac hypertrophy in a rat model of pressure overload (transaortic constriction) via a reduction of angiotensin II-induced protein synthesis and enhanced phosphorylation of AMPK and eNOS, leading to subsequent increase in NO production. All of these effects were abolished by Compound C, a non-specific AMPK inhibitor [90].

Beyond its specific effects in heart, the reduction of mortality by metformin asked also the question of how endothelial dysfunction and atherogenesis could be prevented by the drug. Endothelial dysfunction, as characterized by an impairment of endothelium-dependent relaxation and reduced NO bioactivity, is the critical step for atherogenesis. In addition, vascular NO inhibits platelet aggregation and adhesion and can also reduce leucocytes adhesion to the vessel wall (see for review [91]). Schulz et al. have demonstrated that AMPK phosphorylates and activates eNOS in cultured endothelial cells, stimulates NO synthesis in response to several agonists and increases endothelium-dependent vasodilatation in animal model [92]. Taken together, such data suggested an anti-atherogenic role for the AMPK system. High glucose leads to endothelial ROS overproduction which promotes endothelial dysfunction. Metformin, decreased intracellular ROS production in aortic endothelial cells by inhibiting both NAD(P)H oxidase and the respiratory-chain complex 1 [93]. Furthermore, activated AMPK reduces hyperglycaemia-induced mitochondrial ROS production by induction of Mn-SOD and promotion of mitochondrial biogenesis through activation of the PGC-1a pathway in HUVEC [94]. Lastly, activated AMPK largely offsets the adverse effects of palmitate on endothelial superoxide production and NF-kB activation. Recently, two additional vascular target of metformin have been described: the advanced glycated end products (AGEs), the soluble intercellular cell-adhesion molecules (ICAMs) and the soluble vascular cell-adhesion molecules (VCAMs). AGEs are important contributors of diabetic complications by promoting cellular oxidative stress and inflammation. It has been reported that metformin can reduce AGE synthesis and their specific cell receptor expression independently of its anti-hyperglycemic effects [95]. Although done in vitro, this suggests that metformin can directly modulate the glycation process. In addition, excessive plasma levels of ICAM-1 and VCAM-1 are linked with an increase of cardiovascular events. Interestingly, as for AGE, metformin decreases ICAM-1 and VCAM-1 levels in T2D patients independently of its normoglycemic property [96]. These studies support the notion that activated AMPK has a beneficial effect on endothelial function by suppressing oxidative stress in endothelial cells [97]. Altogether, these data suggested that metformin has complex properties on endothelial functions, ROS production and cardiomyocytes functionality.