Cardiovascular Protection by Metformin: Latest Advances in Basic and Clinical Research Free

Metformin (1,1-dimethylbiguanide hydrochloride) is a synthetic analog of the naturally occurring guanidine compound found in G. officinalis, a plant used in herbal-based traditional medicine. Metformin was first used as an antihyperglycemic agent by the French physician Jean Sterne in 1957 and approved by the US Food and Drug Administration (FDA) in 1995 for treating type 2 diabetes [1]. Due to its well-established efficacy in reducing blood glucose and improving insulin sensitivity as well as its favorable safety profile and affordability, metformin has become one of the most commonly used antidiabetic drugs worldwide. Metformin also remains the first-line medication to achieve and maintain the glycemic goal in type 2 diabetics [2], though other drugs (e.g., SGLT2 inhibitors) are preferred for cardiorenal risk reduction in high-risk patients with type 2 diabetes, as recently recommended by guidelines from the USA [2]. and Europe [3].

In addition to its glucose-lowering efficacy, metformin’s other beneficial effects have also been recognized, especially from studies in preclinical models, over the past 2 decades. Among the most notable effects is its protection against diverse cardiovascular disorders and related metabolic abnormalities, including dyslipidemias, obesity, inflammation, and oxidative stress (reviewed in [4, 5]). In line with findings from preclinical studies, multiple recent clinical trials have also suggested a cardiovascular protective efficacy for metformin in both diabetic patients and individuals without diabetes. Moreover, some latest studies have revealed additional novel molecular targets of metformin’s cardiovascular protection (see below). These novel findings provide important insights into the molecular mechanisms of metformin’s cardioprotective action, thereby expanding the foundation for further clinical trials to conclusively establish its efficacy in the management of specific cardiovascular disorders. Accordingly, in this article, we provide a concise review of recent cutting-edge findings on metformin’s cardiovascular protection reported in influential journals. Via focusing on latest cutting-edge discoveries rather than surveying all research findings reported in the literature, this mini-review would facilitate understanding of metformin’s novel mechanisms of cardiovascular protection and stimulate critical thinking on future basic and clinical research directions.

Beneficial effects of metformin, at clinically relevant doses, have been demonstrated in various animal models of cardiovascular disorders, especially atherosclerosis, myocardial injury, and heart failure (HF) [4, 5]. This section first provides an overview of the current understanding of the molecular mechanisms by which metformin protects against atherosclerosis, myocardial injury, and left ventricular (LV) dysfunction/HF. It then focuses on discussing newly discovered novel molecular targets of metformin’s cardiovascular protection, reported from comprehensive mechanistic studies.

Atherosclerosis involves the interplay of multiple factors, including endothelial cell dysfunction, infiltration of inflammatory cells and lipoprotein particles, as well as proliferation and migration of vascular smooth muscle cells (VSMC), among others. The resulting atherosclerotic lesions are typically asymmetric focal thickenings of the innermost layer of the artery, the intima. They consist of cells, connective-tissue elements, lipids, and debris. Instability or rupture of the plaques causes thrombus formation, leading to ischemic injury, such as a myocardial infarction if a coronary artery is occluded by the thrombus [6]. Atherosclerosis is the chief cause of coronary artery disease (CAD) and stroke, and is responsible for about 75% of total cardiovascular deaths [7]. As such, prevention and treatment of atherosclerosis is an important component of cardiovascular medicine.

Substantial preclinical studies over the past 2 decades have identified multiple molecular mechanisms underlying metformin’s atheroprotective effects. These include: (1) activation of adenosine monophosphate-activated kinase (AMPK) as a general mechanism of metformin’s atheroprotection both in vitro and in vivo; (2) inhibition of inflammatory responses in endothelial cells and macrophages, 2 cell types critically involved in atherogenesis; and (3) suppression of oxidative stress in vascular cells [4, 5]. Although AMPK is widely considered a major target of metformin, how activation of AMPK causes beneficial effects on atherogenesis and the detailed signaling cascades involved remain unclear [4, 5]. Recently, multiple novel targets have been identified that underlie metformin’s atheroprotective effects. Among them, most notable are the AMPK-dependent autophagy axis and the AMPK-independent mitochondrial reactive oxygen species (ROS)-mediated proinflammatory pathway (Fig. 1).

Autophagy is a crucial cellular system for removal of aggregated proteins and damaged organelles, and dysregulated autophagy has been implicated in many disease processes, including cardiovascular disorders [8‒10]. It is known that metformin suppresses atherosclerosis in animal models via AMPK activation [11, 12]. Recently, Robichaud et al. [13] reported a novel AMPK/autophagy-dependent mechanism underlying metformin’s protection against atherosclerosis in a mouse model. They found that autophagy-mediated cholesterol efflux is markedly reduced in VSMC-derived foam cells compared with macrophage-derived foam cells in atherosclerotic lesions. While macrophage-derived foam cells continue to possess functional autophagy in advanced atherosclerosis, VSMC-derived foam cells basally exhibit defective autophagy early in atherogenesis that persists over time. Notably, treatment with metformin improves autophagy-mediated cholesterol efflux in VSMC-derived foams cells, but not in macrophage-derived foam cells [13]. Mechanistically, in VSMC-derived foam cells, metformin causes activation of autophagy (via AMPK activation) which in turn augments ABCG1-mediated efflux of cholesterol to high-density lipoprotein particles. In contrast, in macrophage-derived foam cells, metformin does not activate autophagy due to the fact that autophagy is already maximally induced by lipid loading in these cells. These findings suggest that the basally defective autophagy (impaired autophagosome biogenesis and lysosome functionality) in VSMC-derived foam cells can be reversed, at least partly, by metformin. As VSMC-derived foam cells are the predominant foam cell type in advanced atherosclerotic plaques [14], the above findings point to a feasibility to retard atherosclerosis progression through targeted delivery of metformin to VSMC-derived foam cells in atherosclerotic lesions.

Both complexes I and IV of the mitochondrial electron transport chain (METC) are potential targets of metformin action in reducing hepatic glucose production [4, 15]. While complex I inhibition is believed to cause increased adenosine monophosphate levels and the subsequent activation of AMPK [4], inhibition of complex IV by metformin alters cellular redox state and reduces glucose production independent of AMPK activation [15]. Likewise, an AMPK-independent, METC-mediated pathway has been identified to underlie metformin’s protection against air particulate matter (PM)-induced thrombosis in mice [16]. Mechanistically, urban PM promotes arterial thrombosis via stimulating interleukin-6 (IL-6) production from alveolar macrophages in mice. Treatment of mice with metformin or exposure of murine or human alveolar macrophages to metformin prevents the PM-induced generation of METC-ROS. This METC-derived ROS production is required for the opening of calcium release-activated channels and the subsequent release of IL-6. Notably, targeted genetic deletion of METC or calcium release-activated channels in alveolar macrophages in mice prevents PM-induced acceleration of arterial thrombosis [16]. Hence, the above findings reveal a novel AMPK-independent, mitochondrial ROS-mediated signaling pathway on which metformin targets to exert its protection against vascular thrombosis. As air PM is an important cause of human atherosclerotic cardiovascular diseases [17], identification of the above novel mechanism provides a unique avenue for using metformin or related compounds to intervene air pollution-mediated cardiovascular injury.

As noted earlier, occlusion of coronary arteries due to atherosclerotic lesions and thrombosis is the predominant pathophysiological mechanism of myocardial infarction. On the other hand, prolonged diabetes also causes a specific form of myocardial injury – diabetic cardiomyopathy. In addition, many drugs, especially cancer chemotherapeutic agents, can cause direct damage to myocardium, commonly referred to as drug-induced cardiotoxicity. Regardless of the initial causes, progression of myocardial injury via pathological tissue remodeling (e.g., fibrosis and tissue hypertrophy) results in ventricular dysfunction and HF [7]. Hence, intervention of myocardial injury and adverse cardiac tissue remodeling represents an effective strategy for reducing cardiovascular morbidity and mortality.

Metformin, at clinically relevant doses, has been shown to exert beneficial effects in various forms of myocardial injury, including myocardial ischemic injury [18], diabetic cardiomyopathy [19], cardiotoxicity [20], and ventricular dysfunction/HF [21, 22]. While activation of AMPK and the consequent suppression of inflammation and oxidative stress have been shown to be a primary mechanism by which metformin protects against myocardial pathologies [4, 5], detailed signaling cascades only begin to be delineated recently. These include sirtuin-mediated signaling and an autophagy-dependent pathway (Fig. 2).

Sirtuins are a family of signaling proteins involved in metabolic regulation, and mammalian sirtuins include 7 members, namely, Sirt 1–7. Sirtuins are also protective molecules in metabolic and aging-related pathologies, including cardiovascular disorders [23]. An early study by Tang et al. showed that Sirt2 represses aging-related and stress-induced cardiac hypertrophy in mice, at least in part, by maintaining signaling through the liver kinase B1 (LKB1)/AMPK pathway. Notably, the authors further demonstrated that Sirt2-knockout attenuates metformin-induced activation of AMPK signaling and, consequently, the protective effects of metformin on cardiac hypertrophy in mice [24]. Likewise, Sirt3/AMPK activation by metformin has been shown to normalize pulmonary hypertension associated with HF with preserved ejection fraction in rats [25].

Using a mouse model of salt-induced hepatic inflammation and accompanied hypertension and myocardial damage, Gao et al. [26] recently discovered a novel mechanism, involving Nrf2-regulated Sirt3 expression, in metformin’s myocardial protection. Specifically, Gao et al. showed that persistent hepatic steatosis and inflammation are critical for hypertension and myocardial injury (including LV dysfunction) in response to long-term high-salt diet in mice. The high-salt diet increases acetylated histone 3 lysine 27 (H3K27ac) on Sirt3 promoter in hepatocytes, thus inhibiting the binding of Nrf2, and results in the sustained inhibition of Sirt3 expression. Notably, the study demonstrated that treatment with metformin ameliorates high-salt diet-induced hepatic inflammation and myocardial damage. Mechanistically, metformin activation of AMPK decreases H3K27ac level on Sirt3 promoter and thereby increases Nrf2 binding ability to activate Sirt3 expression. This Nrf2-augmented Sirt3 expression is critical for metformin’s myocardial protection [25]. Hence, the study by Gao et al. identifies activation of the AMPK/Sirt3/Nrf2 axis as an important mechanism of metformin’s protection against cardiovascular injury resulting from high-salt diet-induced persistent hepatic inflammation. The study also for the first time demonstrates an important role for Nrf2 signaling in metformin’s cardiovascular protection. As Nrf2 is the central transcriptional activator of cytoprotective genes (especially antioxidative and anti-inflammatory genes) [27], further elucidation of the role of Nrf2 signaling in metformin’s action is warranted.

The above novel findings suggest that both Sirt2 and Sirt3 may mediate, at least partly, metformin-induced AMPK activation and myocardial protection. These findings further strengthen the notion that sirtuins are intrinsic myocardial protective factors, and pharmacological activation of these molecules may represent an important strategy for myocardial protection in settings of ischemic heart disease and HF. Further delineation of metformin-activated, sirtuin-mediated signaling cascades will advance the development of sirtuin-based pharmacotherapy for ischemic heart disease and HF, two major contributors to global burden of diseases [7]. In this context, activation of sirtuin signaling has recently been implicated also in myocardial protection of sodium-glucose cotransporter 2 (SGLT2) inhibitors [28]. SGLT2 inhibitors show an efficacy in treating HF with either reduced ejection fraction or preserved ejection fraction in multiple recent clinical trials [29‒32], and some (e.g., dapagliflozin and empagliflozin) have been approved by the US FDA for the treatment of HF. Likewise, activation of sirtuin signaling by metformin may be an important molecular mechanism underlying its potential efficacy in treating HF.

An early study in diabetic mice showed that decreased AMPK activity and subsequent reduction in cardiac autophagy are important events in the development of diabetic cardiomyopathy [19]. Notably, chronic AMPK activation by metformin prevents cardiomyopathy by upregulating autophagy activity in diabetic mice [19]. A recent study found that metformin also protects against carfilzomib-induced cardiotoxicity in mice via activating the AMPK/autophagy pathway [20]. Specifically, carfilzomib, a proteasome-inhibiting drug for treating refractory multiple myeloma, induces LV dysfunction by inhibition of the AMPK/autophagy pathway, and restoration by metformin of the suppressed AMPK/autophagy axis preserves LV function in mice [20]. More recently, Papanagnou et al. [33] demonstrated that activation of autophagy by metformin administration in flies treated with proteasome inhibitors reduces proteome instability, partially restores mitochondrial function, mitigates cardiotoxicity, and improves flies’ longevity. Discovery of autophagy activation as an important underlying mechanism of metformin’s cardiovascular protection has important implications for future clinical trials on common human diseases involving dysregulated autophagy. In this regard, downregulation of autophagy is increasingly recognized as a major mechanism of common human diseases as well as aging [34‒36].

Metformin’s beneficial effects in human cardiovascular diseases have been suggested in multiple observational cohort studies and randomized controlled trials (RCTs) over the past decades. Early clinical studies demonstrated a decreased cardiovascular mortality in type 2 diabetic patients following treatment with metformin as compared with other antidiabetic agents, such as sulfonylureas [37, 38]. As preclinical studies show cardiovascular protective effects of metformin independent of its glucose-lowering action and in nondiabetic animal models, recent clinical studies begin to determine the cardiovascular benefits of metformin in persons without type 2 diabetes. Indeed, over the past few years, findings from multiple clinical studies, including RCTs suggested an efficacy for metformin treatment in nondiabetic patients with established cardiovascular diseases or at increased risk of developing cardiovascular diseases. Notably, in line with findings from preclinical research, multiple clinical studies (although involving a relatively small number of participants) suggested a potential efficacy for metformin in improving metabolic status, sirtuin signaling, inflammatory profile, and cardiovascular performance in obese individuals with prediabetes as well as in prediabetic patients with acute myocardial infarction [39‒42]. This section discusses these clinical studies, focusing on the latest findings from good-quality RCTs reported in influential journals.

The established effectiveness of metformin in protecting against atherosclerosis in preclinical models has prompted clinical studies to determine if its atheroprotective action can translate into an efficacy in treating human atherosclerosis. An early small-scale RCT involving 33 nondiabetic women with angina showed that metformin treatment (0.5 g, twice daily) for 8 weeks improved vascular function and decreased myocardial ischemia [43]. However, a subsequent RCT (the CAMERA study) in 173 nondiabetic patients with coronary heart disease and on statin therapy did not show a significant effect of metformin treatment (850 mg, twice daily for 18 months) on carotid intima-media thickness (cIMT), a surrogate marker for atherosclerosis [44]. On the other hand, the CAMERA trial did show that metformin use significantly reduced all measures of adiposity, including body weight, body fat, body mass index (BMI), and waist circumference. Notably, the mean body weight loss in metformin group was 3.2 kg versus 0.0 kg in the placebo group at 18 months [44]. This finding, in line with observations in preclinical models, suggests that metformin improves the overall metabolic status and energy balance in nondiabetic patients with atherosclerotic CAD (ACAD).

While it remains unclear why metformin failed to reduce the cIMT in the CAMERA study, concomitant statin therapy (a much more effective treatment of ACAD) might have diluted the effect of metformin. In addition, the trial period of 18 months might not be long enough. Nevertheless, the favorable effects of metformin on adiposity may improve the overall vascular function in patients with ACAD or at high risk for developing ACAD. Indeed, the Diabetes Prevention Program and Its Outcome Study (DPPOS) showed that long-term metformin treatment significantly reduced coronary artery calcium (CAC), a marker for subclinical coronary atherosclerosis [45]. DPPOS is a long-term interventional study in 3,234 individuals with prediabetes to determine the effects of lifestyle modification and metformin treatment. CAC was measured in 2,029 participants after an average of 14 years of follow-up. The study found that metformin use, but not lifestyle modification, resulted in a remarkable 41% reduction in the CAC severity compared with placebo in men. However, no benefit of metformin on CAC was found in women [45], and the biological basis for such gender dependence remains unknown.

More recently, the coronary atheroprotective effects of metformin was also investigated in a multicenter prospective study (the CODYCE study) [46]. The CODYCE study, involving 258 propensity-matched patients, was to determine the effects of metformin therapy on coronary endothelial dysfunction as well as markers for inflammation and oxidative stress in patients with stable angina and coronary artery stenosis. The study found that at 6, 12, and 24 months of follow-up, metformin treatment was associated with: (1) a marked reduction (29–60%) in the relative risk of the major adverse cardiac events (composite of cardiac death, myocardial infarction, and HF); (2) a significant improvement in coronary endothelial function (assessed by acetylcholine-mediated coronary vasodilation); and (3) significant decreases in markers of inflammation/oxidative stress including C-reactive protein, IL-1, IL-6, tumor necrosis factor-alpha, and nitrotyrosine (a marker of oxidative stress) [46]. Of note, the CODYCE study for the first time suggested that metformin use could suppress the overall inflammation and oxidative stress status of not only the cardiovascular system per se but also other body systems. This is because proinflammatory molecules (e.g., IL-1, IL-6, tumor necrosis factor-alpha) in the circulation distribute throughout the body, particularly to organs that are well-perfused, such as the lungs, brain, liver, and kidneys. This notion is supported by findings from a recent phase 2 RCT, showing that metformin treatment reduced metabolic complications and inflammation, as well as low-density lipoprotein (LDL) and cIMT in patients with inflammatory diseases on systemic glucocorticoid therapy [47].

Metformin is not recommended for treating patients with type 1 diabetes due to its lack of antihyperglycemic efficacy when added to standard insulin therapy. Recent clinical studies, especially the REMOVAL trial, however, showed an atheroprotective efficacy of metformin in type 1 diabetic patients [48, 49]. The REMOVAL study is a RCT in 493 adult patients (40 years and order) with long-standing type 1 diabetes (on standard insulin therapy) and at least 3 cardiovascular risk factors to determine the cardiovascular and metabolic effects of chronic metformin treatment (1 g, twice daily for 3 years) [48]. The trial showed that adding metformin to standard insulin therapy did not adequately improve glycemic control as defined by current guidelines. However, metformin use significantly reduced the maximal cIMT as well as body weight and blood LDL-cholesterol. In addition, renal glomerular filtration rate was also markedly improved by metformin. Of note, the participants are well treated with antihypertensive drugs and statins [48]. As the largest and longest RCT of metformin in patients with type 1 diabetes, the findings of the REMOVAL trial suggest that metformin may have a direct beneficial effect on atherosclerosis progression in type 1 diabetic patients, even in middle-aged individuals with long diabetes duration, who are well treated with antihypertensive drugs and statins. Likewise, a RCT in youth (12–21 years of age) with type 1 diabetes also demonstrated beneficial vascular effects of metformin, as evidenced by reduced cIMT, improved aortic dysfunction, and decreased BMI and fat mass [49]. These findings indicate that metformin’s atheroprotection in type 1 diabetic patients is age independent. As persons with type 1 diabetes are at increased risk of developing atherosclerotic cardiovascular diseases [50], early intervention with drugs having atheroprotective potential and favorable safety profile (like metformin) may greatly reduce cardiovascular morbidity and mortality in this patient population.

In summary, as illustrated in Figure 3, findings from multiple good-quality (though relatively small-scale) clinical studies strongly suggest an efficacy for metformin in improving the overall metabolic status and reducing atherosclerosis progression not only in type 2 diabetic patients but also in nondiabetic individuals, or persons with type 1 diabetes. These latest clinical findings are in line with the atheroprotective effects of metformin demonstrated in preclinical studies. These advances in both preclinical and clinical studies lay a foundation for designing large-scale RCTs to conclusively define the atheroprotective effects of metformin in specific patient populations. In this context, the VA-IMPACT trial with over 7,400 participants (currently in recruiting phase) is a multicenter, RCT to test the hypothesis that treatment with metformin, compared with placebo, reduces mortality and cardiovascular morbidity in patients with prediabetes and established atherosclerotic cardiovascular disease (https://clinicaltrials.gov/ct2/show/NCT02915198).

Although newer guidelines recommend usage of SGLT2 inhibitors in diabetic patients with HF [2], metformin remains the most commonly used antihyperglycemic agent [51]. Data, particularly from large-scale randomized clinical studies, on the impact of metformin in patients with HF are relatively lacking, possibly due to historical concerns about metformin-induced lactic acidosis in this patient population [52]. With increasing recognition of the cardiovascular protecting properties of alternative antidiabetic agents, interest in understanding the effects of metformin in HF has also grown.

Several observational studies have emerged over the past few years examining this relationship. In a retrospective cohort study by Khan et al. [53] of 5,852 diabetic patients naïve to metformin who were hospitalized for HF, metformin initiation was associated with improvements in 12-month clinical outcomes. In the study, patients who were newly prescribed metformin within 90 days of discharge demonstrated a 19% reduction in the risk of composite of all-cause mortality or HF hospitalization at 12 months. Notably, when stratified by LV ejection fraction (LVEF), this relationship was strictly driven by risk reduction among patients with LVEF >40% [53]. On the other hand, a prospective cohort study by Benes et al. [54] following 380 patients with diabetes and HF with reduced ejection fraction over an average of 3 years reported improved outcomes with metformin use. The authors found that diabetic patients on metformin demonstrated signs of more stable HF, including lower brain natriuretic peptide levels, lower mitral and tricuspid regurgitation severity, improved LV and right ventricular function, and usage of smaller doses of diuretics. Interestingly, patients on metformin had worse metabolic parameters, such as higher BMI, hemoglobin A1c, and increased insulin resistance. With regards to clinical outcomes, metformin-treated diabetic patients had increased survival compared to metformin-free counterparts. On subgroup analysis, the authors discovered improved outcomes regardless of HF severity or treatment. Furthermore, metformin treatment remained associated with improved outcomes even after adjustment for BMI, brain natriuretic peptide, and renal function, or after propensity score matching utilizing 81 pairs of patients [54].

Other observational studies, however, have not reported benefits of metformin in diabetic patients with HF. Bergmark et al. [55] conducted a post hoc analysis of 12,156 patients in the SAVOR-TIMI 53 trial to examine associations between metformin and clinical outcomes in diabetic patients with or without HF or kidney dysfunction. In subgroup analysis of 1,661 patients with HF, there was no significant association between metformin use and all-cause mortality. However, interpretation was limited by statistical power. With regards to the overall cohort, metformin use was associated with a 24% lower risk of all-cause mortality and a 32% lower risk of cardiovascular death but not the composite endpoint of cardiovascular death, myocardial infarction, or ischemic stroke [55].

Several recent RCTs have examined the impact of metformin on LV function and HF in patients without diabetes. In a study by Larsen et al. [56] 36 patients with HF with reduced ejection fraction and insulin resistance were randomized to metformin or placebo for 3 months, in addition to standard HF therapy, to determine the effects of metformin on myocardial efficiency expressed by the work metabolic index. Metformin usage resulted in a 20% relative efficiency increase, as well as a 17% reduction in myocardial oxygen consumption with preserved stroke work. Work metabolic index improvements were greater in patients with above-median plasma metformin levels. Thus, metformin was shown to have favorable effects on myocardial energetic parameters which possess prognostic value in patients with HF [57]. These effects were independent of glycemic and metabolic control. Of note, metformin use did not result in any changes to LVEF, global longitudinal strain, or LV mass, though conclusions on these endpoints were limited by statistical power. Furthermore, the study duration may have been too short to detect improvements in LV function [56].

In a previous RCT of metformin on LV hypertrophy (LVH), Mohan et al. [58] demonstrated improvements in LV mass indexed to height with metformin treatment, though this trial was not conducted in patients with HF. In this study of 68 patients with CAD and insulin resistance and/or prediabetes randomized to metformin or placebo for 12 months, metformin treatment resulted in a 1.37 g/m^1.7 reduction in LV mass index. Metformin treatment also reduced the concentration of thiobarbituric acid reactive substances, a marker of oxidative stress, which may partially explain the mechanism behind LVH regression. Changes to other LV functional parameters, such as LVEF, were not observed. However, as LVH is an important predictor of cardiovascular events [59], the study suggested that metformin may have a myocardial protective role [58].

A recent meta-analysis by Kamel et al. [60] of nine RCTs further examined the impact of metformin on LV mass and LV functional parameters in patients without diabetes, with five studies including patients with HF. The meta-analysis demonstrated that metformin use resulted in LVH regression by approximately 10 g/m² in nondiabetic patients after 12 months of use. Metformin use also resulted in mild improvements (2–3%) in LVEF, although this result was only statistically significant after removing one outlier study. On subgroup analysis, improvements in LVEF were observed only in patients who received >1,000 mg/day of metformin and patients with HF. Thus, Kamel et al. [60] demonstrated favorable myocardial effects of metformin in patients without diabetes, including those with HF.

In short, a few relatively small-scale RCTs have demonstrated beneficial effects of metformin on myocardial metabolic and functional parameters (Fig. 4). However, studies examining the impact of metformin on clinical outcomes in HF are largely limited to observational studies in patients with diabetes. Overall, these observational studies seem to suggest improved cardiovascular outcomes in patients treated with metformin. Randomized outcome trials are needed to further explore these findings, in patients both with and without diabetes. In addition, the relationship between LVEF phenotype and metformin usage remains unclear at this time, which also warrants further investigation.

Metformin remains one of the most commonly used antidiabetic drugs worldwide. In addition to its antihyperglycemic effects, its beneficial cardiovascular effects are increasingly recognized. Preclinical studies over the past 2 decades have demonstrated cardioprotective roles in atherosclerosis, myocardial injury, and HF. Recent preclinical studies have revealed novel targets underlying metformin’s effects, including activation of an AMPK/autophagy axis, suppression of mitochondrial ROS via an AMPK-independent pathway, and activation of sirtuin signaling. Clinical studies have corroborated metformin’s beneficial effects. Several RCTs have demonstrated a role for metformin in improving metabolic status and reducing atherosclerosis progression in diverse patient populations, including those with or without type 2 diabetes. A few RCTs have also demonstrated beneficial effects on cardiac metabolic and functional parameters, including in patients with HF.

Further preclinical studies are needed to elucidate the molecular mechanisms of metformin. Given metformin’s multitude of cardiovascular and metabolic benefits, recognizing its mechanism of action will broaden our knowledge of cardiovascular diseases and facilitate the development of future cardioprotective drugs or strategies. Concurrently, large-scale randomized trials are warranted to evaluate the cardiovascular outcomes of metformin use, especially in patients with a high risk of negative cardiovascular events and HF. In this regard, several randomized studies, such as the MET-HEFT [61], VA-IMPACT (https://clinicaltrials.gov/ct2/show/NCT02915198), and GLINT (https://www.dtu.ox.ac.uk/glint/) trials, are ongoing to address these knowledge gaps.

The authors have no relevant financial or non-financial interests to disclose.

There was no funding source.

Both Jason Z. Li and Y. Robert Li contributed to the review article topic conception, literature searching and analysis, and the writing of the manuscript. Both authors read and approved the final manuscript.