Metformin therapy in patients with diabetes mellitus is associated with a reduced risk of vasculopathy and cardiovascular mortality after heart transplantation

Cardiac allograft vasculopathy (CAV) is a major cause of morbidity and mortality after heart transplantation (HT) and remains a major obstacle to the long-term success of HT. The International Society of Heart and Lung Transplantation (ISHLT) registry reports a high incidence of CAV after HT: up to 50% by 10 years post-transplant and ~ 30% by 5 years post-transplant [1, 2]. Perhaps the most important information to emerge from an analysis of the ISHLT statistics is that in the past two decades there has been only a minimal reduction in 5-year CAV—from 32 to 29% [1, 2]. CAV is a diffuse panarteritis with concentric, longitudinal intimal thickening of the epicardial coronary arteries. It likely involves the coronary microvasculature as well. While CAV is generally a diffuse process, it can manifest in ways similar to native coronary artery disease with focal stenosis. The pathogenesis is multifactorial and involves contributions from atherosclerotic mechanisms, ischemia–reperfusion injury, immune responses, and particular infections. Although improvements in both immunological and nonimmunological interventions have been achieved in the field of HT, they have barely impacted the natural history of CAV. As such, the 5-year survival for patients with CAV detected within 3 years of transplant has improved marginally from to 71 to 76% but remains lower than the 82% survival for recipients without CAV [2].

A common post-HT complication—and a major contributor to morbidity and mortality following HT—is the development of type 2 diabetes mellitus (T2DM), with 21% and 35% of survivors being affected within 1- and 5 years following HT, respectively. These patients are usually treated with metformin, one of the most commonly used anti-diabetes drugs worldwide and generally the initial oral agent of choice for patients with T2DM. The potential benefits of this drug include: anti-glycemic efficacy, potential for weight reduction, attenuation of metabolic syndrome, lipid lowering benefits, anti-inflammatory effects both alone [3] or in combination with other medications [4] and anti-neoplastic potential [5, 6]. It also could limit the expansion of abdominal aortic aneurysms [7]. Increasing evidence is also accumulating that metformin has potential as a treatment for cardiovascular disease, since lower cardiovascular-associated mortality and morbidity have been reported in non-HT patients treated with metformin [8‐12]. Thus, given the high prevalence of CAV and diabetes in HT patients and the favorable metabolic profile of metformin, we designed a study to investigate the association between metformin therapy and the incidence of CAV after HT.

The results of this investigation, designed to elucidate the influence of metformin on CAV, indicate that metformin therapy is independently associated with a reduced risk for CAV and combined endpoint of CAV or cardiovascular mortality. The importance of this study lies in the notion that CAV and diabetes are major confounders of mortality and morbidity after HT and therefore every effort should be made to reduce their burden. Thus, our findings could have major clinical implications for the treatment of HT patients, considering metformin treatment in patients with and without T2DM.

Although many strategies have been implemented to reduce CAV in HT recipients, in the past two decades there has not been any significant improvement in survival beyond 1 year, probably because the challenges in detecting and treating the processes underlying mortality, particularly those relevant to CAV, remain to be resolved [16]. It is currently held that the breakthroughs needed for CAV treatment will be derived from the growing understanding that CAV is initiated and propagated by both immunological and nonimmunological factors. With regard to the former, it is known that the traditional cardiovascular risk factors contribute to atherogenesis through enhancement of endothelial inflammation, leading to endothelial injury and fibroproliferative cellular responses [17]. Nonimmunological insults predisposing to CAV include vascular risk factors, and prominent among them is T2DM, frequently encountered in the post-HT course, with 21% and 35% of survivors being affected within 1 and 5 years following HT, respectively [18]. For the total cohort, approximately 40% of recipients were diagnosed with T2DM through the follow up.

Post-transplant diabetes is usually managed in accordance with the general guidelines for the treatment of T2DM in the general population [19, 20]. Metformin, the first-line oral agent used to treat patients with T2DM in the nontransplant population, has been shown to be safe for use in renal and cardiac transplant recipients [5]. By virtue of its potential non-hypoglycemic benefits, this therapy also appears to be the drug of choice for the HT population. These potential benefits include: attenuation of metabolic syndrome, cardiovascular protection, lipid-lowering benefits, neutral weight maintenance or potential weight reduction, and anti-neoplastic potential [5, 6, 21]. Furthermore, metformin is not metabolized by CYP3A4, and therefore there are no drug–drug interactions with immunosuppressive medications.

Various lines of evidence suggest that metformin has potential as a treatment for cardiovascular disease in both T2DM and non-T2DM patients. A landmark study of the cardiovascular benefits of metformin—the United Kingdom Prospective Diabetes Study (UKPDS) [22]—demonstrated that metformin reduces diabetes-associated deaths and all-cause mortality vs. any other conventional treatment [23]. Moreover, it shows synergistic effects with saxagliptin helping to improve endothelial dysfunction in early diabetes before macrovascular complications appear [24], protects the heart against hypertrophic and apoptotic remodeling after myocardial infarction [25] and is independently associated with a lower below-the-knee arterial calcification score [26]. Observational studies have also reported cardiovascular benefits in metformin users, especially in patients with T2DM and heart failure [27, 28].

Indications of cardiovascular benefits in metformin-treated T2DM patients have thus driven interest in repurposing metformin to treat cardiovascular disease, irrespective of diabetes status [29]. In non-diabetes patients who have cardiac syndrome X with normal coronary arteries but two consecutive positive exercise tolerance tests, an 8-week period of metformin treatment improved maximal ST-segment depression, Duke score, and chest pain incidence in comparison with placebo [9]. In the recently published prospective randomized control MET-REMODEL trial, metformin treatment of non-T2DM patients with coronary artery disease significantly reduced left ventricular mass index, left ventricular mass, systolic blood pressure, body weight and oxidative stress. As left ventricular hypertrophy is a good surrogate marker for cardiovascular outcome, that study did indeed indicate a cardioprotective role for metformin [30]. In addition, metformin usage was independently associated with lower coronary artery calcification scores in T2DM patients [31]. To the best of our knowledge, the current study is the first to investigate the effect of metformin on CAV in HT recipients.

The details of metformin’s cellular mechanism are yet to be elucidated definitively [29], but it is known that its fundamental mode of action is to reduce mitochondrial oxidative phosphorylation, thereby inducing energy stress [32] and inhibition of mitochondrial enzymes. While no detectable differential microRNA expression in non-atherosclerotic arteries of T2DM patients treated or untreated with metformin was found [33], it is known that mitochondrial suppression of oxidative phosphorylation activates AMP-activated protein kinase, selectively targeting redox control [34]. Importantly, it is also possible that the benefits of the drug in cardiovascular disease may be due to mechanisms distinct from its metabolic activity [29]. Metformin’s anti-inflammatory effects derive from its suppression of the nuclear factor κB (NF-κB) inflammatory signaling pathway [10, 35] and systemic inflammation markers. Metformin has also been found to suppress plasma cytokines—including the aging-associated cytokine, C–C motif chemokine ligand 11 (CCL11)—in patients with heart failure who do not have T2DM. It is known that blockade of CCL11 can suppress certain aspects of age-related cellular dysfunction.

The management of CAV currently remains limited and incomplete [36]. It is, however, well known that traditional atherosclerotic risk factors lead to CAV progression and, as such, the management of glycemia is thus of the utmost importance. Indeed, in keeping with this idea, we demonstrated that metformin therapy is independently associated with a significant reduction in the long-term risk for CAV and the combined end-point of CAV or cardiovascular mortality after HT.

There are several limitations to our study. First, there is the inherent limitation of observational trials that uncover associations but preclude the determination of cause-and-effect relationships. Second, our current practice does not include routine intravascular ultrasound assessment, which might be associated with underestimation of CAV. Third, this study was limited by being based on a single-center experience. Finally, the study sample was relatively small and not all possible confounders might have been recorded or taken into account. The present results will therefore require confirmation in larger cohorts and preferably with a prospective study design.

Based on metformin’s cardiac and metabolic benefits, consideration should be given to the clinical implications of metformin therapy for HT recipients, even those without T2DM (unless there are contraindications), with focus on the reduction of CAV—a major obstacle to the long-term success of HT. The role of metformin therapy for reduction of cardiovascular morbidity and mortality in HT patients must be further evaluated prospectively.