REVIEW URRENT C OPINION
The cardiovascular effects of metformin: lost in translation? Niels P. Riksen a,b and Cornelis J. Tack a
Purpose of review In overweight patients with diabetes, treatment with metformin improves cardiovascular outcomes. This observation has fuelled the hypothesis that metformin has direct cardiovascular protective properties over and above glucose lowering. Here, we discuss the various cardiovascular effects of metformin observed in preclinical studies and recent clinical trials in patients, which fail to reproduce these findings. Recent findings Laboratory studies suggest that metformin limits atherosclerosis. Also, metformin consistently limits myocardial infarct size and reduces postinfarction remodeling in rodents. Confirmation of these effects in patients, however, appears difficult. In nondiabetic patients, metformin does not reduce carotid intima media thickness. In myocardial infarction patients, the effects of metformin on infarct size are inconclusive, but these studies suffer from methodological shortcomings. Finally, chronic administration of metformin does not affect postinfarction cardiac remodeling in nondiabetic patients. Summary Although recent trials in nondiabetic patients could not confirm direct effects of metformin on atherosclerosis and cardiac remodeling, an acute cardioprotective effect of metformin cannot be excluded yet. We might have to consider, though, that the beneficial effect of metformin on cardiovascular prognosis in patients with diabetes is due to its effects on glucose metabolism and body weight rather than due to pleiotropic direct cardiovascular effects. Keywords atherosclerosis, infarct size, metformin, remodeling, translation
INTRODUCTION The cardiovascular complications of atherosclerosis are a leading cause of morbidity and mortality worldwide. In the past decades, the short-term and long-term mortality after a myocardial infarction has steadily decreased for both men and women [1]. This decreased mortality is paralleled, however, by an increased incidence and prevalence of chronic heart failure, which occurs in approximately 20–40% of patients after a myocardial infarction [2]. The outcome after a myocardial infarction is dictated mainly by the infarct size and adverse postinfarction remodeling of the myocardium. The global burden of cardiovascular disease can thus be decreased by pharmacological interventions, targeting several pathological processes, including risk factors for atherosclerosis, the atherosclerotic inflammation of the vessel wall itself, ischemiareperfusion injury of the myocardium following coronary occlusion, and postinfarction remodeling. In 1998, the United Kingdom Prospective Diabetes Study (UKPDS) [3] reported that overweight www.co-lipidology.com
patients with type 2 diabetes mellitus who were treated with an intensive blood glucose lowering policy with metformin had a lower all-cause mortality and fewer myocardial infarctions than patients treated with diet only. Moreover, all-cause mortality was reduced more in the metformintreated patients than in patients receiving intensive treatment with sulfonylurea derivates or insulin, despite similar glycemic control. This seminal finding has fuelled hypotheses that metformin has direct beneficial cardiovascular effects. Indeed, subsequent studies in many animal models showed that metformin potently limits myocardial a
Department of Internal Medicine and bPharmacology-Toxicology, Radboud university medical center, Nijmegen, the Netherlands Correspondence to Niels P. Riksen, MD, PhD, Head division of Vascular Medicine, Department of Internal Medicine 463, Radboudumc, PO Box 9101, 6500 HB Nijmegen, the Netherlands. Tel: +31 24 3618819; fax: +31 24 3614214; e-mail: [email protected] Curr Opin Lipidol 2014, 25:446–451 DOI:10.1097/MOL.0000000000000128 Volume 25 Number 6 December 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
The cardiovascular effects of metformin Riksen and Tack
KEY POINTS Because metformin reduces mortality in patients with type 2 diabetes, it has been suggested that metformin can limit atherosclerosis, myocardial ischemiareperfusion injury, and postinfarction remodeling, independent from its glucose-lowering action. Although metformin has antiatherosclerotic effects in some preclinical studies, metformin does not reduce IMT in nondiabetic patients with coronary heart disease. Long-term administration of metformin reduces cardiac remodeling in several murine models of heart failure, but in nondiabetic patients suffering a myocardial infarction, metformin treatment after the infarction does not improve cardiac function. In murine models of myocardial infarction, acute administration of metformin before reperfusion consistently reduces infarct size, but this cardioprotective effect has not yet been investigated in well designed patient studies. Up till now, the beneficial cardiovascular effects of metformin that have been observed in preclinical studies cannot be translated into a cardiovascular benefit in nondiabetic patients with cardiovascular disease, although a direct cardioprotective effect of metformin has not yet been investigated in patients in well designed studies.
ischemia-reperfusion injury and postinfarction remodeling, as previously reviewed in this journal [4]. In contrast, in the past year, several prospective randomized trials failed to confirm any cardiovascular benefit of metformin in healthy individuals and in nondiabetic patients with cardiovascular disease [5 ,6 ,7 ]. In the current review, we will critically explore why the translation of the beneficial cardiovascular effects of metformin as observed in preclinical studies to patients with cardiovascular disease seems to fail. &
&&
&&
EPIDEMIOLOGICAL EVIDENCE OF SUPERIOR CARDIOVASCULAR EFFECTS OF METFORMIN In the UKPDS study [3], overweight patients with type 2 diabetes mellitus were randomized to receive metformin (n ¼ 342), chlorpropamide (n ¼ 265), glibenclamide (n ¼ 277), insulin (n ¼ 409), or diet alone. Metformin treatment reduced all-cause mortality by 36% compared with diet alone, which was also superior to the alternative treatment groups. In addition, the relative risk of an acute myocardial infarction was 0.61 (95% confidence interval, 0.41–0.89) in the metformin group compared with diet alone, versus 0.79 (95% confidence interval,
0.60–1.05) in the alternative treatment groups. There was no statistically significant difference between the metformin-treated group and the group receiving alternative glucose-lowering treatment [3]. More recently, metformin was compared with glipizide in 304 Chinese patients with coronary artery disease and type 2 diabetes. Approximately 65% of patients were treated with a statin at baseline. After 3 years of follow-up, despite a similar reduction in HbA1c, metformin reduced the incidence of cardiovascular events compared with glipizide, extending the observations of the UKPDS to a high-risk diabetic population [3,8 ]. Intriguingly, in a subset of patients of the UKPDS 34 paper [3] the addition of metformin to sulfonylurea-treated patients was associated with a two-fold increase in diabetes-related death. In both randomized controlled trials (RCTs), treatment with metformin was associated with a decreased body weight compared with the control groups with insulin and/or sulfonylurea derivatives. Meta-analyses on RCTs with metformin that also included trials in patients without diabetes mellitus [9] and trials dealing with metformin as an add-on therapy and metformin withdrawal [10] do not report on a cardiovascular benefit of metformin treatment compared with alternative glucose-lowering regimens. Altogether, some doubt still remains whether metformin has a direct beneficial effect on cardiovascular disease, particularly in nondiabetic patients in the context of modern cardiovascular risk intervention (e.g., use of statins). &
METFORMIN AND ATHEROSCLEROSIS Already more than 30 years ago, metformin was reported to reduce aortic and coronary atherosclerotic lesion formation induced by a high-fat diet in animal models [11]. Theoretically, this effect can be due do a beneficial effect of metformin on cardiovascular risk factors or due to a direct effect on the process of atherosclerosis itself. Body weight is an important risk factor for the development of atherosclerosis, and metformin consistently reduces body weight in patients with diabetes mellitus [3,8 ]. With regard to plasma lipids, many studies have reported that metformin reduces plasma triglycerides and plasma LDL and increases plasma HDL [12]. A meta-analysis of RCTs suggests that metformin has no intrinsic effect on HDL-cholesterol and triglycerides in patients with type 2 diabetes, but does reduce LDL-cholesterol independent of its hypoglycemic effect, although this effect was small [13]. More recent RCTs with a longer follow-up duration, however, did not show any effects of metformin treatment on plasma lipid concentration [7 ,8 ]. In addition to the effects on body weight and plasma
0957-9672 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
&
&&
www.co-lipidology.com
&
447
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Therapy and clinical trials
lipids, several studies have reported that metformin can lower blood pressure and can have beneficial effects on platelet aggregation and hypercoagulability in insulin-resistant individuals, but these studies were generally small and with a short follow-up period (reviewed in [12,14]). Inflammation of the vessel wall plays a critical role in the initiation, progression, and destabilization of atherosclerotic plaques, with a central role for monocytes and monocyte-derived macrophages [15]. Recent studies have reported that metformin can improve the prognosis in the setting of severe systemic inflammation. In a mouse model of endotoxemia, metformin reduces circulating proinflammatory cytokines and improves survival [16]. In isolated macrophages, this inhibition of proinflammatory cytokine release was mediated by activation of adenosine monophosphate-activated protein kinase (AMPK). Also in patients with type 2 diabetes admitted to the ICU, preadmission use of metformin appeared to be associated with a 20% reduction in mortality [17]. More relevant to the process of atherosclerosis, metformin in relevant concentrations suppresses oxidative stress, macrophage inflammatory activation (human leukocyte antigen type DR expression), and foam cell formation in cultured human blood-derived macrophages via AMPK activation [18]. In an artificial murine model of neointima formation induced by balloon injury, the administration of metformin markedly attenuated neointimal hyperplasia through inhibition of vascular smooth muscle cell proliferation, migration, and inflammation [19]. Do these preclinical findings indeed translate to a similar clinical in-vivo effect, so does metformin reduce atherosclerosis in patients? In a small study in patients with the metabolic syndrome, a 1-year treatment with 850 mg metformin once daily significantly reduced intima-media thickness (IMT) [20]. Based on the above-mentioned preclinical effects of metformin and the small patient study, the Carotid Atherosclerosis: MEtformin for insulin ResistAnce (CAMERA) trial was designed to investigate the effects of an 18-month period of metformin administration (850 mg twice daily) on carotid IMT in patients with a high cardiovascular risk [7 ]. This RCT enrolled nondiabetic patients with coronary heart disease and a large waist circumference who used statins for secondary prevention. After 18 months of treatment, there was no significant effect on carotid IMT. Patients taking metformin had a lower body weight, lower HbA1c, plasma insulin, and plasma tissue plasminogen activator levels compared with those taking placebo, but there were no significant differences for total cholesterol, HDL-cholesterol, non-HDL-cholesterol, &&
448
www.co-lipidology.com
triglycerides, high-sensitivity C-reactive protein, or fasting glucose levels. The most important difference with previous RCTs that reported a cardiovascular benefit of metformin was that the patients in the CAMERA study did not have diabetes and were all treated with statins.
DIRECT CARDIOPROTECTIVE EFFECTS OF METFORMIN The prognosis for patients after an acute myocardial infarction is dictated, among others, by the infarct size. Early reperfusion of the culprit coronary artery is the most effective strategy to limit myocardial infarct size. Paradoxically, reperfusion can in itself also induce myocardial injury and cardiomyocyte death, a phenomenon that has been termed ‘lethal reperfusion injury’ [21]. Driven by a better understanding of the pathophysiological mechanisms underlying ischemia-reperfusion injury, many drugs have been identified in preclinical studies that can limit myocardial infarct size [22]. For some drugs, including cyclosporin [23] and exenatide [24], an infarct size-limiting effect has also been demonstrated in patients suffering from an acute myocardial infarction in small RCTs. Approximately 10 preclinical studies in animal models of myocardial infarction have reported that the treatment with metformin can potently limit myocardial infarct size. These studies have been discussed in detail in a previous review on this topic [4]. In summary, the administration of a single dose of metformin either before ischemia or at the onset of reperfusion limits myocardial size in nondiabetic and diabetic rats and mice. More recently, also chronic administration of metformin in the drinking water appeared to confer cardioprotection in diabetic and nondiabetic rats [25]. Several intracellular signaling cascades contribute to the infarct size-limiting effect of metformin. First, there is a rapid activation of AMPK in myocardial tissue by metformin and the cardioprotective effect is abolished in cardiac-specific AMPKa2 dominate-negative transgenic mice [26]. In addition, increased intracellular formation of the endogenous nucleoside adenosine and subsequent adenosine receptor stimulation contributes to the cardioprotective effect of metformin [27]. Finally, metformin has been shown to prevent opening of the mitochondrial permeability transition pore at the moment of reperfusion, which is a well known cardioprotective mechanism [28]. In addition to limiting infarct size, the chronic administration of metformin, commenced before ischemia or immediately following reperfusion, also limits postinfarction myocardial remodeling in mice and rats [29,30]. Again, this was associated Volume 25 Number 6 December 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
The cardiovascular effects of metformin Riksen and Tack
with increased myocardial phosphorylation of AMPK and endothelial nitric oxide synthase and was abolished in cardiac-specific AMPKa2 dominate-negative transgenic mice. In the past year, several clinical studies have been performed that aimed to translate these promising preclinical effects of metformin on infarct size and remodeling to the clinical arena. Lexis et al. [31] retrospectively analyzed all consecutive patients presenting with an ST-elevation myocardial infarction in their center over the period 2004–2010. In their cohort, 677 patients had diabetes mellitus, of whom 189 were treated with metformin. Interestingly, treatment with metformin was associated with a smaller myocardial infarct size, estimated by peak plasma concentrations of creatine kinase and troponin-T, compared with nonmetformin using diabetic patients. It is probable that in most patients in this cohort, a relevant circulating metformin concentration was present at the moment of coronary occlusion, which resembles the preclinical studies on chronic metformin administration [25]. Although promising, the retrospective design of this study will probably have introduced bias, such as a difference in comedication or in duration of diabetes between the two groups of diabetic patients. Using a prospective randomized crossover open, blinded-endpoint design in healthy nondiabetic individuals, we investigated the effect of metformin treatment (500 mg three times a day for 3 days) on forearm ischemia-reperfusion injury [5 ]. In this study, forearm flow-mediated dilation before and after 20 min of forearm ischemia and reperfusion was used as a well validated surrogate for endothelial ischemia-reperfusion injury, as described previously [32,33]. In this study, metformin did not protect against endothelial ischemiareperfusion injury. In another open labeled randomized trial, the effect of metformin on myocardial ischemia-reperfusion injury was explored in patients with the metabolic syndrome who were scheduled for elective percutaneous coronary intervention (PCI) for stable or unstable angina [34]. Patients (n ¼ 152) were pretreated with metformin 250 mg three times daily for 7 days before the intervention. Blood was drawn 8 h and 24 h postintervention for the determination of creatine kinase-MB and troponin-I. Postprocedural myocardial injury, defined as a postprocedural elevation of these biomarkers, occurred more frequently in the control group than in the metformin group. In addition, mean postprocedural peak values of these biomarkers were lower in the metformin-treated group. Moreover, at 1 year of follow-up, the combined endpoint of post-PCI myocardial infarction, myocardial infarction after PCI hospitalization, target &
lesion revascularization, and death occurred more frequently in the control group (22 versus 6 patients in the metformin group), but this difference was primarily due to the difference in the occurrence of post-PCI myocardial infarction. Finally, Lexis et al. [6 ] in the Glycometabolic Intervention as Adjunct to Primary Percutaneous Coronary Intervention in ST-Segment Elevation Myocardial Infarction (GIPS) III trial focused on the presumed beneficial effects of metformin on postinfarction remodeling. This double-blind randomized controlled study was designed to determine whether metformin preserves left ventricular function after STEMI in patients without diabetes. A total of 380 patients were randomized to either metformin (500 mg bid) or placebo for 4 months. The first dose was administered at a median of 102 min after PCI. Metformin did not affect the primary endpoint of left ventricular function (measured with MRI), nor the circulating levels of n-terminal pro-brain natriuretic peptide. The authors conclude that, on the basis of their results, it is unlikely that metformin will have a relevant impact on long-term outcome after ST-elevation myocardial infarction in patients without diabetes. &&
POTENTIALLY DELETERIOUS CARDIOVASCULAR EFFECTS OF METFORMIN As a counterweight to all purported beneficial cardiovascular effects of metformin, Habib et al. [35 ,36] recently suggested that AMPK activation by metformin might also have adverse cardiovascular effects in patients with an acute myocardial infarction. These adverse effects can be predicted from the well known effect of metformin on AMPK and on the mammalian target of rapamycin (mTOR). AMPK is an evolutionary highly conserved energy sensor that orchestrates cell proliferation, growth, and survival. Among others, AMPK inhibits the rapamycin sensitive mTOR (mTORC1), which is essential for cell proliferation and growth. Moreover, it has recently been established that metformin can also directly inhibit mTOR independent from AMPK activation [37]. In the context of atherosclerosis, mTOR inhibition might have antiatherosclerotic effects by inhibiting vascular smooth muscle cells proliferation and by triggering autophagy of plaque macrophages [38]. It is now well established that local application of mTOR inhibitors on coronary stents reduces restenosis rates. In contrast, the use of drug-eluting stents is associated with an increased risk of delayed stent thrombosis, particularly in patients with diabetes. Late stent thrombosis has been associated with impaired endothelialization [39]. In a rabbit model,
0957-9672 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
&
www.co-lipidology.com
449
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Therapy and clinical trials
oral administration of metformin has now been shown to further impair endothelialization of mTOR-eluting stents. In vitro, however, these antiproliferative effects of metformin could only be observed at concentrations that are significantly higher than concentrations obtained in patients who are treated with metformin, which casts doubt on the clinical relevance of this observation [35 ]. &
robust study design and convincingly showed that metformin does not affect postinfarction remodeling in nondiabetic patients. In this study, however, a relevant plasma concentration of metformin was obtained on average 4 h after PCI. Therefore, a direct effect of metformin on ischemia-reperfusion injury cannot be excluded by this study. Moreover, a potential beneficial effect of metformin might have been offset by the detrimental effect of metformin on endothelialization of drug-eluting stents [35 ]. In conclusion, despite the recent negative findings in patients with cardiovascular disease, current results do not exclude a potential acute beneficial effect of metformin on myocardial ischemia-reperfusion injury, and a well designed, prospective trial is warranted to investigate this possibility. Moreover, these studies do not exclude any beneficial cardiovascular effects in patients with diabetes. We have recently finished a double-blind RCT in which patients without diabetes scheduled for coronary artery bypass grafting were treated with metformin or placebo for 3 days until the operation. In this design, an effective plasma metformin concentration is present at the moment of myocardial ischemia and reperfusion. The results of this study will be available shortly (NCT01438723). If metformin does not limit myocardial ischemia-reperfusion injury in this study, we might have to reconsider whether the beneficial cardiovascular effects of metformin observed in the UKPDS are due to glucose lowering and weight loss rather than due to alternative direct cardiovascular protective effects. &
CONCLUSION After the reported beneficial effects of metformin on cardiovascular endpoint in patients with diabetes, several preclinical studies have investigated the direct effects of metformin on atherosclerosis, ischemiareperfusion injury, and remodeling. These preclinical studies strongly suggest that metformin can attenuate the process of atherosclerosis and consistently demonstrate that metformin can limit myocardial infarct size and postinfarction remodeling in diabetic and nondiabetic rodents. Given the fact that the drug is extremely cheap and has proven its long-term safety, metformin is thus an attractive candidate to treat patients with atherosclerosis at a high risk of coronary artery occlusion. The fact that two recent RCTs failed to demonstrate any beneficial effect of metformin on atherosclerosis and postinfarction remodeling in nondiabetic patients has tempered the enthusiasm about a role for metformin in the prevention of cardiovascular disease [6 ,7 ]. What is the reason for this apparent failure to translate preclinical results into clinical practice and do these negative studies definitely close the book on a cardioprotective role for metformin? In general, it is important to realize that many promising treatment strategies fail translation from animal experiments into patient care, both in the area of atherosclerosis as well as in the area of cardioprotection [40,41]. Animal studies often have suboptimal study designs, the animals used are mostly young healthy animals without comorbidities and comedication, and animal (patho)physiology can differ from the human situation. In this regard, the patients in the study by Preiss et al. [7 ] were all treated with statins, which might have limited the ability of metformin to reduce carotid IMT. Because they only included patients without diabetes, their results do not exclude that metformin has antiatherosclerotic properties in patients with diabetes. The direct effect of metformin on myocardial ischemia-reperfusion injury has only been investigated in studies with a suboptimal study design [31], in studies with surrogate endpoints of ischemia-reperfusion injury [5 ], or in an open-label study with mild ischemia-reperfusion injury during elective PCI [34]. The study by Lexis et al. [6 ] had a &&
&&
Acknowledgements N.P.R. is recipient of a Clinical Fellowship of the Netherlands Organisation for Health Research and Development (ZonMw) and a Dr Dekker grant of the Netherlands Heart Foundation. N.P.R. has served on a Scientific Advisory Board of AstraZeneca, which is unrelated to the topic of this paper. C.J.T. has received research grants from NovoNordisk and has been consultant for NovoNordisk, Bristol Myers Squibb/AstraZeneca, MSD, Johnson & Johnson, and Takeda.
&&
Conflicts of interest There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest
&
&&
450
www.co-lipidology.com
1. Nauta ST, Deckers JW, van Domburg RT, Akkerhuis KM. Sex-related trends in mortality in hospitalized men and women after myocardial infarction between 1985 and 2008: equal benefit for women and men. Circulation 2012; 126:2184–2189.
Volume 25 Number 6 December 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
The cardiovascular effects of metformin Riksen and Tack 2. Velagaleti RS, Pencina MJ, Murabito JM, et al. Long-term trends in the incidence of heart failure after myocardial infarction. Circulation 2008; 118:2057–2062. 3. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive bloodglucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998; 352:854–865. 4. El Messaoudi SE, Rongen GA, de Boer RA, Riksen NP. The cardioprotective effects of metformin. Curr Opin Lipidol 2011; 22:445–453. 5. El Messaoudi S, Schreuder TH, Kengen RD, et al. Impact of metformin on & endothelial ischemia-reperfusion injury in humans in vivo: a prospective randomized open, blinded-endpoint study. PLoS One 2014; 9:e96062. RCT in healthy nondiabetic individuals showing that metformin does not limit endothelial ischemia-reperfusion injury in the brachial artery. 6. Lexis CP, van der Horst IC, Lipsic E, et al. Effect of metformin on left ventricular && function after acute myocardial infarction in patients without diabetes: the GIPS-III randomized clinical trial. JAMA 2014; 311:1526–1535. RCT in nondiabetic patients with an acute myocardial infarction reporting that 4 month of metformin treatment, started immediately after PCI, does not result in an improved left ventricular ejection fraction. 7. Preiss D, Lloyd SM, Ford I, et al. Metformin for nondiabetic patients with && coronary heart disease (the CAMERA study): a randomised controlled trial. Lancet Diab Endocrinol 2014; 2:116–124. RCT in nondiabetic patients with coronary artery disease showing that 18-month treatment with metformin does not reduce carotid IMT. 8. Hong J, Zhang Y, Lai S, et al. Effects of metformin versus glipizide on & cardiovascular outcomes in patients with type 2 diabetes and coronary artery disease. Diabetes Care 2013; 36:1304–1311. RCT in diabetic patients with coronary artery disease demonstrating that treatment for 3 years with metformin reduced the incidence of major cardiovascular events compared with glipizide. 9. Lamanna C, Monami M, Marchionni N, Mannucci E. Effect of metformin on cardiovascular events and mortality: a meta-analysis of randomized clinical trials. Diab Obes Metab 2011; 13:221–228. 10. Boussageon R, Supper I, Bejan-Angoulvant T, et al. Reappraisal of metformin efficacy in the treatment of type 2 diabetes: a meta-analysis of randomised controlled trials. PLoS Med 2012; 9:e1001204. 11. Marquie G. Metformin action on lipid metabolism in lesions of experimental aortic atherosclerosis of rabbits. Atherosclerosis 1983; 47:7–17. 12. El Messaoudi S, Rongen GA, Riksen NP. Metformin therapy in diabetes: the role of cardioprotection. Curr Atheroscler Rep 2013; 15:314. 13. Wulffele MG, Kooy A, de Zeeuw D, et al. The effect of metformin on blood pressure, plasma cholesterol and triglycerides in type 2 diabetes mellitus: a systematic review. J Intern Med 2004; 256:1–14. 14. Kirpichnikov D, McFarlane SI, Sowers JR. Metformin: an update. Ann Intern Med 2002; 137:25–33. 15. Bekkering S, Joosten LA, van der Meer JW, et al. Trained innate immunity and atherosclerosis. Curr Opin Lipidol 2013; 24:487–492. 16. Tsoyi K, Jang HJ, Nizamutdinova IT, et al. Metformin inhibits HMGB1 release in LPS-treated RAW 264.7 cells and increases survival rate of endotoxaemic mice. Br J Pharmacol 2011; 162:1498–1508. 17. Christiansen CF, Johansen MB, Christensen S, et al. Preadmission metformin use and mortality among intensive care patients with diabetes: a cohort study. Crit Care 2013; 17:R192. 18. Wan X, Huo Y, Johns M, et al. 5’-AMP-activated protein kinase-activating transcription factor 1 cascade modulates human monocyte-derived macrophages to atheroprotective functions in response to heme or metformin. Arterioscler Thromb Vasc Biol 2013; 33:2470–2480. 19. Lu J, Ji J, Meng H, et al. The protective effect and underlying mechanism of metformin on neointima formation in fructose-induced insulin resistant rats. Cardiovasc Diabetol 2013; 12:58. 20. Meaney E, Vela A, Samaniego V, et al. Metformin, arterial function, intimamedia thickness and nitroxidation in metabolic syndrome: the mefisto study. Clin Exp Pharmacol Physiol 2008; 35:895–903. 21. Frohlich GM, Meier P, White SK, et al. Myocardial reperfusion injury: looking beyond primary PCI. Eur Heart J 2013; 34:1714–1722.
22. Riksen NP, Smits P, Rongen GA. Ischaemic preconditioning: from molecular characterization to clinical application. Part II. Neth J Med 2004; 62:409– 423. 23. Piot C, Croisille P, Staat P, et al. Effect of cyclosporine on reperfusion injury in acute myocardial infarction. N Engl J Med 2008; 359:473–481. 24. Lonborg J, Kelbaek H, Vejlstrup N, et al. Exenatide reduces final infarct size in patients with ST-segment-elevation myocardial infarction and short-duration of ischemia. Circ Cardiovasc Interv 2012; 5:288–295. 25. Whittington HJ, Hall AR, McLaughlin CP, et al. Chronic metformin associated cardioprotection against infarction: not just a glucose lowering phenomenon. Cardiovasc Drugs Ther 2013; 27:5–16. 26. Calvert JW, Gundewar S, Jha S, et al. Acute metformin therapy confers cardioprotection against myocardial infarction via AMPK-eNOS-mediated signaling. Diabetes 2008; 57:696–705. 27. Paiva M, Riksen NP, Davidson SM, et al. Metformin prevents myocardial reperfusion injury by activating the adenosine receptor. J Cardiovasc Pharmacol 2009; 53:373–378. 28. Bhamra GS, Hausenloy DJ, Davidson SM, et al. Metformin protects the ischemic heart by the Akt-mediated inhibition of mitochondrial permeability transition pore opening. Basic Res Cardiol 2008; 103:274–284. 29. Yin M, van der Horst IC, van Melle JP, et al. Metformin improves cardiac function in a nondiabetic rat model of post-MI heart failure. Am J Physiol Heart Circ Physiol 2011; 301:H459–H468. 30. Gundewar S, Calvert JW, Jha S, et al. Activation of AMP-activated protein kinase by metformin improves left ventricular function and survival in heart failure. Circ Res 2009; 104:403–411. 31. Lexis CP, Wieringa WG, Hiemstra B, et al. Chronic metformin treatment is associated with reduced myocardial infarct size in diabetic patients with ST-segment elevation myocardial infarction. Cardiovasc Drugs Ther 2014; 28:163–171. 32. van den Munckhof I, Riksen N, Seeger JP, et al. Aging attenuates the protective effect of ischemic preconditioning against endothelial ischemiareperfusion injury in humans. Am J Physiol Heart Circ Physiol 2013; 304: H1727–1732. 33. Loukogeorgakis SP, Panagiotidou AT, Broadhead MW, et al. Remote Ischemic Preconditioning Provides Early and Late Protection Against Endothelial Ischemia-Reperfusion Injury in Humans: Role of the Autonomic Nervous System. J Am Coll Cardiol 2005; 46:450–456. 34. Li J, Xu JP, Zhao XZ, et al. Protective effect of metformin on myocardial injury in metabolic syndrome patients following percutaneous coronary intervention. Cardiology 2014; 127:133–139. 35. Habib A, Karmali V, Polavarapu R, et al. Metformin impairs vascular endothelial & recovery after stent placement in the setting of locally eluted mammalian target of rapamycin inhibitors via S6 kinase-dependent inhibition of cell proliferation. J Am Coll Cardiol 2013; 61:971–980. Experimental study in rabbits showing that metformin impairs endothelialization of zotarolimus-eluting stents. 36. Habib A, Karmali V, Polavarapu R, et al. Metformin impairs endothelialization after placement of newer generation drug eluting stents. Atherosclerosis 2013; 229:385–387. 37. Liu X, Chhipa RR, Pooya S, et al. Discrete mechanisms of mTOR and cell cycle regulation by AMPK agonists independent of AMPK. Proc Natl Acad Sci U S A 2014; 111:E435–444. 38. Martinet W, De Loof H, De Meyer GR. mTOR inhibition: a promising strategy for stabilization of atherosclerotic plaques. Atherosclerosis 2014; 233:601– 607. 39. Finn AV, Joner M, Nakazawa G, et al. Pathological correlates of late drugeluting stent thrombosis: strut coverage as a marker of endothelialization. Circulation 2007; 115:2435–2441. 40. Hausenloy DJ, Baxter G, Bell R, et al. Translating novel strategies for cardioprotection: the Hatter Workshop Recommendations. Basic Res Cardiol 2010; 105:677–686. 41. van der Worp HB, Howells DW, Sena ES, et al. Can animal models of disease reliably inform human studies? PLoS Med 2010; 7:e1000245.
0957-9672 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-lipidology.com
451
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
The cardiovascular effects of metformin: lost in translation? Niels P. Riksen a,b and Cornelis J. Tack a
Purpose of review In overweight patients with diabetes, treatment with metformin improves cardiovascular outcomes. This observation has fuelled the hypothesis that metformin has direct cardiovascular protective properties over and above glucose lowering. Here, we discuss the various cardiovascular effects of metformin observed in preclinical studies and recent clinical trials in patients, which fail to reproduce these findings. Recent findings Laboratory studies suggest that metformin limits atherosclerosis. Also, metformin consistently limits myocardial infarct size and reduces postinfarction remodeling in rodents. Confirmation of these effects in patients, however, appears difficult. In nondiabetic patients, metformin does not reduce carotid intima media thickness. In myocardial infarction patients, the effects of metformin on infarct size are inconclusive, but these studies suffer from methodological shortcomings. Finally, chronic administration of metformin does not affect postinfarction cardiac remodeling in nondiabetic patients. Summary Although recent trials in nondiabetic patients could not confirm direct effects of metformin on atherosclerosis and cardiac remodeling, an acute cardioprotective effect of metformin cannot be excluded yet. We might have to consider, though, that the beneficial effect of metformin on cardiovascular prognosis in patients with diabetes is due to its effects on glucose metabolism and body weight rather than due to pleiotropic direct cardiovascular effects. Keywords atherosclerosis, infarct size, metformin, remodeling, translation
INTRODUCTION The cardiovascular complications of atherosclerosis are a leading cause of morbidity and mortality worldwide. In the past decades, the short-term and long-term mortality after a myocardial infarction has steadily decreased for both men and women [1]. This decreased mortality is paralleled, however, by an increased incidence and prevalence of chronic heart failure, which occurs in approximately 20–40% of patients after a myocardial infarction [2]. The outcome after a myocardial infarction is dictated mainly by the infarct size and adverse postinfarction remodeling of the myocardium. The global burden of cardiovascular disease can thus be decreased by pharmacological interventions, targeting several pathological processes, including risk factors for atherosclerosis, the atherosclerotic inflammation of the vessel wall itself, ischemiareperfusion injury of the myocardium following coronary occlusion, and postinfarction remodeling. In 1998, the United Kingdom Prospective Diabetes Study (UKPDS) [3] reported that overweight www.co-lipidology.com
patients with type 2 diabetes mellitus who were treated with an intensive blood glucose lowering policy with metformin had a lower all-cause mortality and fewer myocardial infarctions than patients treated with diet only. Moreover, all-cause mortality was reduced more in the metformintreated patients than in patients receiving intensive treatment with sulfonylurea derivates or insulin, despite similar glycemic control. This seminal finding has fuelled hypotheses that metformin has direct beneficial cardiovascular effects. Indeed, subsequent studies in many animal models showed that metformin potently limits myocardial a
Department of Internal Medicine and bPharmacology-Toxicology, Radboud university medical center, Nijmegen, the Netherlands Correspondence to Niels P. Riksen, MD, PhD, Head division of Vascular Medicine, Department of Internal Medicine 463, Radboudumc, PO Box 9101, 6500 HB Nijmegen, the Netherlands. Tel: +31 24 3618819; fax: +31 24 3614214; e-mail: [email protected] Curr Opin Lipidol 2014, 25:446–451 DOI:10.1097/MOL.0000000000000128 Volume 25 Number 6 December 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
The cardiovascular effects of metformin Riksen and Tack
KEY POINTS Because metformin reduces mortality in patients with type 2 diabetes, it has been suggested that metformin can limit atherosclerosis, myocardial ischemiareperfusion injury, and postinfarction remodeling, independent from its glucose-lowering action. Although metformin has antiatherosclerotic effects in some preclinical studies, metformin does not reduce IMT in nondiabetic patients with coronary heart disease. Long-term administration of metformin reduces cardiac remodeling in several murine models of heart failure, but in nondiabetic patients suffering a myocardial infarction, metformin treatment after the infarction does not improve cardiac function. In murine models of myocardial infarction, acute administration of metformin before reperfusion consistently reduces infarct size, but this cardioprotective effect has not yet been investigated in well designed patient studies. Up till now, the beneficial cardiovascular effects of metformin that have been observed in preclinical studies cannot be translated into a cardiovascular benefit in nondiabetic patients with cardiovascular disease, although a direct cardioprotective effect of metformin has not yet been investigated in patients in well designed studies.
ischemia-reperfusion injury and postinfarction remodeling, as previously reviewed in this journal [4]. In contrast, in the past year, several prospective randomized trials failed to confirm any cardiovascular benefit of metformin in healthy individuals and in nondiabetic patients with cardiovascular disease [5 ,6 ,7 ]. In the current review, we will critically explore why the translation of the beneficial cardiovascular effects of metformin as observed in preclinical studies to patients with cardiovascular disease seems to fail. &
&&
&&
EPIDEMIOLOGICAL EVIDENCE OF SUPERIOR CARDIOVASCULAR EFFECTS OF METFORMIN In the UKPDS study [3], overweight patients with type 2 diabetes mellitus were randomized to receive metformin (n ¼ 342), chlorpropamide (n ¼ 265), glibenclamide (n ¼ 277), insulin (n ¼ 409), or diet alone. Metformin treatment reduced all-cause mortality by 36% compared with diet alone, which was also superior to the alternative treatment groups. In addition, the relative risk of an acute myocardial infarction was 0.61 (95% confidence interval, 0.41–0.89) in the metformin group compared with diet alone, versus 0.79 (95% confidence interval,
0.60–1.05) in the alternative treatment groups. There was no statistically significant difference between the metformin-treated group and the group receiving alternative glucose-lowering treatment [3]. More recently, metformin was compared with glipizide in 304 Chinese patients with coronary artery disease and type 2 diabetes. Approximately 65% of patients were treated with a statin at baseline. After 3 years of follow-up, despite a similar reduction in HbA1c, metformin reduced the incidence of cardiovascular events compared with glipizide, extending the observations of the UKPDS to a high-risk diabetic population [3,8 ]. Intriguingly, in a subset of patients of the UKPDS 34 paper [3] the addition of metformin to sulfonylurea-treated patients was associated with a two-fold increase in diabetes-related death. In both randomized controlled trials (RCTs), treatment with metformin was associated with a decreased body weight compared with the control groups with insulin and/or sulfonylurea derivatives. Meta-analyses on RCTs with metformin that also included trials in patients without diabetes mellitus [9] and trials dealing with metformin as an add-on therapy and metformin withdrawal [10] do not report on a cardiovascular benefit of metformin treatment compared with alternative glucose-lowering regimens. Altogether, some doubt still remains whether metformin has a direct beneficial effect on cardiovascular disease, particularly in nondiabetic patients in the context of modern cardiovascular risk intervention (e.g., use of statins). &
METFORMIN AND ATHEROSCLEROSIS Already more than 30 years ago, metformin was reported to reduce aortic and coronary atherosclerotic lesion formation induced by a high-fat diet in animal models [11]. Theoretically, this effect can be due do a beneficial effect of metformin on cardiovascular risk factors or due to a direct effect on the process of atherosclerosis itself. Body weight is an important risk factor for the development of atherosclerosis, and metformin consistently reduces body weight in patients with diabetes mellitus [3,8 ]. With regard to plasma lipids, many studies have reported that metformin reduces plasma triglycerides and plasma LDL and increases plasma HDL [12]. A meta-analysis of RCTs suggests that metformin has no intrinsic effect on HDL-cholesterol and triglycerides in patients with type 2 diabetes, but does reduce LDL-cholesterol independent of its hypoglycemic effect, although this effect was small [13]. More recent RCTs with a longer follow-up duration, however, did not show any effects of metformin treatment on plasma lipid concentration [7 ,8 ]. In addition to the effects on body weight and plasma
0957-9672 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
&
&&
www.co-lipidology.com
&
447
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Therapy and clinical trials
lipids, several studies have reported that metformin can lower blood pressure and can have beneficial effects on platelet aggregation and hypercoagulability in insulin-resistant individuals, but these studies were generally small and with a short follow-up period (reviewed in [12,14]). Inflammation of the vessel wall plays a critical role in the initiation, progression, and destabilization of atherosclerotic plaques, with a central role for monocytes and monocyte-derived macrophages [15]. Recent studies have reported that metformin can improve the prognosis in the setting of severe systemic inflammation. In a mouse model of endotoxemia, metformin reduces circulating proinflammatory cytokines and improves survival [16]. In isolated macrophages, this inhibition of proinflammatory cytokine release was mediated by activation of adenosine monophosphate-activated protein kinase (AMPK). Also in patients with type 2 diabetes admitted to the ICU, preadmission use of metformin appeared to be associated with a 20% reduction in mortality [17]. More relevant to the process of atherosclerosis, metformin in relevant concentrations suppresses oxidative stress, macrophage inflammatory activation (human leukocyte antigen type DR expression), and foam cell formation in cultured human blood-derived macrophages via AMPK activation [18]. In an artificial murine model of neointima formation induced by balloon injury, the administration of metformin markedly attenuated neointimal hyperplasia through inhibition of vascular smooth muscle cell proliferation, migration, and inflammation [19]. Do these preclinical findings indeed translate to a similar clinical in-vivo effect, so does metformin reduce atherosclerosis in patients? In a small study in patients with the metabolic syndrome, a 1-year treatment with 850 mg metformin once daily significantly reduced intima-media thickness (IMT) [20]. Based on the above-mentioned preclinical effects of metformin and the small patient study, the Carotid Atherosclerosis: MEtformin for insulin ResistAnce (CAMERA) trial was designed to investigate the effects of an 18-month period of metformin administration (850 mg twice daily) on carotid IMT in patients with a high cardiovascular risk [7 ]. This RCT enrolled nondiabetic patients with coronary heart disease and a large waist circumference who used statins for secondary prevention. After 18 months of treatment, there was no significant effect on carotid IMT. Patients taking metformin had a lower body weight, lower HbA1c, plasma insulin, and plasma tissue plasminogen activator levels compared with those taking placebo, but there were no significant differences for total cholesterol, HDL-cholesterol, non-HDL-cholesterol, &&
448
www.co-lipidology.com
triglycerides, high-sensitivity C-reactive protein, or fasting glucose levels. The most important difference with previous RCTs that reported a cardiovascular benefit of metformin was that the patients in the CAMERA study did not have diabetes and were all treated with statins.
DIRECT CARDIOPROTECTIVE EFFECTS OF METFORMIN The prognosis for patients after an acute myocardial infarction is dictated, among others, by the infarct size. Early reperfusion of the culprit coronary artery is the most effective strategy to limit myocardial infarct size. Paradoxically, reperfusion can in itself also induce myocardial injury and cardiomyocyte death, a phenomenon that has been termed ‘lethal reperfusion injury’ [21]. Driven by a better understanding of the pathophysiological mechanisms underlying ischemia-reperfusion injury, many drugs have been identified in preclinical studies that can limit myocardial infarct size [22]. For some drugs, including cyclosporin [23] and exenatide [24], an infarct size-limiting effect has also been demonstrated in patients suffering from an acute myocardial infarction in small RCTs. Approximately 10 preclinical studies in animal models of myocardial infarction have reported that the treatment with metformin can potently limit myocardial infarct size. These studies have been discussed in detail in a previous review on this topic [4]. In summary, the administration of a single dose of metformin either before ischemia or at the onset of reperfusion limits myocardial size in nondiabetic and diabetic rats and mice. More recently, also chronic administration of metformin in the drinking water appeared to confer cardioprotection in diabetic and nondiabetic rats [25]. Several intracellular signaling cascades contribute to the infarct size-limiting effect of metformin. First, there is a rapid activation of AMPK in myocardial tissue by metformin and the cardioprotective effect is abolished in cardiac-specific AMPKa2 dominate-negative transgenic mice [26]. In addition, increased intracellular formation of the endogenous nucleoside adenosine and subsequent adenosine receptor stimulation contributes to the cardioprotective effect of metformin [27]. Finally, metformin has been shown to prevent opening of the mitochondrial permeability transition pore at the moment of reperfusion, which is a well known cardioprotective mechanism [28]. In addition to limiting infarct size, the chronic administration of metformin, commenced before ischemia or immediately following reperfusion, also limits postinfarction myocardial remodeling in mice and rats [29,30]. Again, this was associated Volume 25 Number 6 December 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
The cardiovascular effects of metformin Riksen and Tack
with increased myocardial phosphorylation of AMPK and endothelial nitric oxide synthase and was abolished in cardiac-specific AMPKa2 dominate-negative transgenic mice. In the past year, several clinical studies have been performed that aimed to translate these promising preclinical effects of metformin on infarct size and remodeling to the clinical arena. Lexis et al. [31] retrospectively analyzed all consecutive patients presenting with an ST-elevation myocardial infarction in their center over the period 2004–2010. In their cohort, 677 patients had diabetes mellitus, of whom 189 were treated with metformin. Interestingly, treatment with metformin was associated with a smaller myocardial infarct size, estimated by peak plasma concentrations of creatine kinase and troponin-T, compared with nonmetformin using diabetic patients. It is probable that in most patients in this cohort, a relevant circulating metformin concentration was present at the moment of coronary occlusion, which resembles the preclinical studies on chronic metformin administration [25]. Although promising, the retrospective design of this study will probably have introduced bias, such as a difference in comedication or in duration of diabetes between the two groups of diabetic patients. Using a prospective randomized crossover open, blinded-endpoint design in healthy nondiabetic individuals, we investigated the effect of metformin treatment (500 mg three times a day for 3 days) on forearm ischemia-reperfusion injury [5 ]. In this study, forearm flow-mediated dilation before and after 20 min of forearm ischemia and reperfusion was used as a well validated surrogate for endothelial ischemia-reperfusion injury, as described previously [32,33]. In this study, metformin did not protect against endothelial ischemiareperfusion injury. In another open labeled randomized trial, the effect of metformin on myocardial ischemia-reperfusion injury was explored in patients with the metabolic syndrome who were scheduled for elective percutaneous coronary intervention (PCI) for stable or unstable angina [34]. Patients (n ¼ 152) were pretreated with metformin 250 mg three times daily for 7 days before the intervention. Blood was drawn 8 h and 24 h postintervention for the determination of creatine kinase-MB and troponin-I. Postprocedural myocardial injury, defined as a postprocedural elevation of these biomarkers, occurred more frequently in the control group than in the metformin group. In addition, mean postprocedural peak values of these biomarkers were lower in the metformin-treated group. Moreover, at 1 year of follow-up, the combined endpoint of post-PCI myocardial infarction, myocardial infarction after PCI hospitalization, target &
lesion revascularization, and death occurred more frequently in the control group (22 versus 6 patients in the metformin group), but this difference was primarily due to the difference in the occurrence of post-PCI myocardial infarction. Finally, Lexis et al. [6 ] in the Glycometabolic Intervention as Adjunct to Primary Percutaneous Coronary Intervention in ST-Segment Elevation Myocardial Infarction (GIPS) III trial focused on the presumed beneficial effects of metformin on postinfarction remodeling. This double-blind randomized controlled study was designed to determine whether metformin preserves left ventricular function after STEMI in patients without diabetes. A total of 380 patients were randomized to either metformin (500 mg bid) or placebo for 4 months. The first dose was administered at a median of 102 min after PCI. Metformin did not affect the primary endpoint of left ventricular function (measured with MRI), nor the circulating levels of n-terminal pro-brain natriuretic peptide. The authors conclude that, on the basis of their results, it is unlikely that metformin will have a relevant impact on long-term outcome after ST-elevation myocardial infarction in patients without diabetes. &&
POTENTIALLY DELETERIOUS CARDIOVASCULAR EFFECTS OF METFORMIN As a counterweight to all purported beneficial cardiovascular effects of metformin, Habib et al. [35 ,36] recently suggested that AMPK activation by metformin might also have adverse cardiovascular effects in patients with an acute myocardial infarction. These adverse effects can be predicted from the well known effect of metformin on AMPK and on the mammalian target of rapamycin (mTOR). AMPK is an evolutionary highly conserved energy sensor that orchestrates cell proliferation, growth, and survival. Among others, AMPK inhibits the rapamycin sensitive mTOR (mTORC1), which is essential for cell proliferation and growth. Moreover, it has recently been established that metformin can also directly inhibit mTOR independent from AMPK activation [37]. In the context of atherosclerosis, mTOR inhibition might have antiatherosclerotic effects by inhibiting vascular smooth muscle cells proliferation and by triggering autophagy of plaque macrophages [38]. It is now well established that local application of mTOR inhibitors on coronary stents reduces restenosis rates. In contrast, the use of drug-eluting stents is associated with an increased risk of delayed stent thrombosis, particularly in patients with diabetes. Late stent thrombosis has been associated with impaired endothelialization [39]. In a rabbit model,
0957-9672 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
&
www.co-lipidology.com
449
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Therapy and clinical trials
oral administration of metformin has now been shown to further impair endothelialization of mTOR-eluting stents. In vitro, however, these antiproliferative effects of metformin could only be observed at concentrations that are significantly higher than concentrations obtained in patients who are treated with metformin, which casts doubt on the clinical relevance of this observation [35 ]. &
robust study design and convincingly showed that metformin does not affect postinfarction remodeling in nondiabetic patients. In this study, however, a relevant plasma concentration of metformin was obtained on average 4 h after PCI. Therefore, a direct effect of metformin on ischemia-reperfusion injury cannot be excluded by this study. Moreover, a potential beneficial effect of metformin might have been offset by the detrimental effect of metformin on endothelialization of drug-eluting stents [35 ]. In conclusion, despite the recent negative findings in patients with cardiovascular disease, current results do not exclude a potential acute beneficial effect of metformin on myocardial ischemia-reperfusion injury, and a well designed, prospective trial is warranted to investigate this possibility. Moreover, these studies do not exclude any beneficial cardiovascular effects in patients with diabetes. We have recently finished a double-blind RCT in which patients without diabetes scheduled for coronary artery bypass grafting were treated with metformin or placebo for 3 days until the operation. In this design, an effective plasma metformin concentration is present at the moment of myocardial ischemia and reperfusion. The results of this study will be available shortly (NCT01438723). If metformin does not limit myocardial ischemia-reperfusion injury in this study, we might have to reconsider whether the beneficial cardiovascular effects of metformin observed in the UKPDS are due to glucose lowering and weight loss rather than due to alternative direct cardiovascular protective effects. &
CONCLUSION After the reported beneficial effects of metformin on cardiovascular endpoint in patients with diabetes, several preclinical studies have investigated the direct effects of metformin on atherosclerosis, ischemiareperfusion injury, and remodeling. These preclinical studies strongly suggest that metformin can attenuate the process of atherosclerosis and consistently demonstrate that metformin can limit myocardial infarct size and postinfarction remodeling in diabetic and nondiabetic rodents. Given the fact that the drug is extremely cheap and has proven its long-term safety, metformin is thus an attractive candidate to treat patients with atherosclerosis at a high risk of coronary artery occlusion. The fact that two recent RCTs failed to demonstrate any beneficial effect of metformin on atherosclerosis and postinfarction remodeling in nondiabetic patients has tempered the enthusiasm about a role for metformin in the prevention of cardiovascular disease [6 ,7 ]. What is the reason for this apparent failure to translate preclinical results into clinical practice and do these negative studies definitely close the book on a cardioprotective role for metformin? In general, it is important to realize that many promising treatment strategies fail translation from animal experiments into patient care, both in the area of atherosclerosis as well as in the area of cardioprotection [40,41]. Animal studies often have suboptimal study designs, the animals used are mostly young healthy animals without comorbidities and comedication, and animal (patho)physiology can differ from the human situation. In this regard, the patients in the study by Preiss et al. [7 ] were all treated with statins, which might have limited the ability of metformin to reduce carotid IMT. Because they only included patients without diabetes, their results do not exclude that metformin has antiatherosclerotic properties in patients with diabetes. The direct effect of metformin on myocardial ischemia-reperfusion injury has only been investigated in studies with a suboptimal study design [31], in studies with surrogate endpoints of ischemia-reperfusion injury [5 ], or in an open-label study with mild ischemia-reperfusion injury during elective PCI [34]. The study by Lexis et al. [6 ] had a &&
&&
Acknowledgements N.P.R. is recipient of a Clinical Fellowship of the Netherlands Organisation for Health Research and Development (ZonMw) and a Dr Dekker grant of the Netherlands Heart Foundation. N.P.R. has served on a Scientific Advisory Board of AstraZeneca, which is unrelated to the topic of this paper. C.J.T. has received research grants from NovoNordisk and has been consultant for NovoNordisk, Bristol Myers Squibb/AstraZeneca, MSD, Johnson & Johnson, and Takeda.
&&
Conflicts of interest There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest
&
&&
450
www.co-lipidology.com
1. Nauta ST, Deckers JW, van Domburg RT, Akkerhuis KM. Sex-related trends in mortality in hospitalized men and women after myocardial infarction between 1985 and 2008: equal benefit for women and men. Circulation 2012; 126:2184–2189.
Volume 25 Number 6 December 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
The cardiovascular effects of metformin Riksen and Tack 2. Velagaleti RS, Pencina MJ, Murabito JM, et al. Long-term trends in the incidence of heart failure after myocardial infarction. Circulation 2008; 118:2057–2062. 3. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive bloodglucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998; 352:854–865. 4. El Messaoudi SE, Rongen GA, de Boer RA, Riksen NP. The cardioprotective effects of metformin. Curr Opin Lipidol 2011; 22:445–453. 5. El Messaoudi S, Schreuder TH, Kengen RD, et al. Impact of metformin on & endothelial ischemia-reperfusion injury in humans in vivo: a prospective randomized open, blinded-endpoint study. PLoS One 2014; 9:e96062. RCT in healthy nondiabetic individuals showing that metformin does not limit endothelial ischemia-reperfusion injury in the brachial artery. 6. Lexis CP, van der Horst IC, Lipsic E, et al. Effect of metformin on left ventricular && function after acute myocardial infarction in patients without diabetes: the GIPS-III randomized clinical trial. JAMA 2014; 311:1526–1535. RCT in nondiabetic patients with an acute myocardial infarction reporting that 4 month of metformin treatment, started immediately after PCI, does not result in an improved left ventricular ejection fraction. 7. Preiss D, Lloyd SM, Ford I, et al. Metformin for nondiabetic patients with && coronary heart disease (the CAMERA study): a randomised controlled trial. Lancet Diab Endocrinol 2014; 2:116–124. RCT in nondiabetic patients with coronary artery disease showing that 18-month treatment with metformin does not reduce carotid IMT. 8. Hong J, Zhang Y, Lai S, et al. Effects of metformin versus glipizide on & cardiovascular outcomes in patients with type 2 diabetes and coronary artery disease. Diabetes Care 2013; 36:1304–1311. RCT in diabetic patients with coronary artery disease demonstrating that treatment for 3 years with metformin reduced the incidence of major cardiovascular events compared with glipizide. 9. Lamanna C, Monami M, Marchionni N, Mannucci E. Effect of metformin on cardiovascular events and mortality: a meta-analysis of randomized clinical trials. Diab Obes Metab 2011; 13:221–228. 10. Boussageon R, Supper I, Bejan-Angoulvant T, et al. Reappraisal of metformin efficacy in the treatment of type 2 diabetes: a meta-analysis of randomised controlled trials. PLoS Med 2012; 9:e1001204. 11. Marquie G. Metformin action on lipid metabolism in lesions of experimental aortic atherosclerosis of rabbits. Atherosclerosis 1983; 47:7–17. 12. El Messaoudi S, Rongen GA, Riksen NP. Metformin therapy in diabetes: the role of cardioprotection. Curr Atheroscler Rep 2013; 15:314. 13. Wulffele MG, Kooy A, de Zeeuw D, et al. The effect of metformin on blood pressure, plasma cholesterol and triglycerides in type 2 diabetes mellitus: a systematic review. J Intern Med 2004; 256:1–14. 14. Kirpichnikov D, McFarlane SI, Sowers JR. Metformin: an update. Ann Intern Med 2002; 137:25–33. 15. Bekkering S, Joosten LA, van der Meer JW, et al. Trained innate immunity and atherosclerosis. Curr Opin Lipidol 2013; 24:487–492. 16. Tsoyi K, Jang HJ, Nizamutdinova IT, et al. Metformin inhibits HMGB1 release in LPS-treated RAW 264.7 cells and increases survival rate of endotoxaemic mice. Br J Pharmacol 2011; 162:1498–1508. 17. Christiansen CF, Johansen MB, Christensen S, et al. Preadmission metformin use and mortality among intensive care patients with diabetes: a cohort study. Crit Care 2013; 17:R192. 18. Wan X, Huo Y, Johns M, et al. 5’-AMP-activated protein kinase-activating transcription factor 1 cascade modulates human monocyte-derived macrophages to atheroprotective functions in response to heme or metformin. Arterioscler Thromb Vasc Biol 2013; 33:2470–2480. 19. Lu J, Ji J, Meng H, et al. The protective effect and underlying mechanism of metformin on neointima formation in fructose-induced insulin resistant rats. Cardiovasc Diabetol 2013; 12:58. 20. Meaney E, Vela A, Samaniego V, et al. Metformin, arterial function, intimamedia thickness and nitroxidation in metabolic syndrome: the mefisto study. Clin Exp Pharmacol Physiol 2008; 35:895–903. 21. Frohlich GM, Meier P, White SK, et al. Myocardial reperfusion injury: looking beyond primary PCI. Eur Heart J 2013; 34:1714–1722.
22. Riksen NP, Smits P, Rongen GA. Ischaemic preconditioning: from molecular characterization to clinical application. Part II. Neth J Med 2004; 62:409– 423. 23. Piot C, Croisille P, Staat P, et al. Effect of cyclosporine on reperfusion injury in acute myocardial infarction. N Engl J Med 2008; 359:473–481. 24. Lonborg J, Kelbaek H, Vejlstrup N, et al. Exenatide reduces final infarct size in patients with ST-segment-elevation myocardial infarction and short-duration of ischemia. Circ Cardiovasc Interv 2012; 5:288–295. 25. Whittington HJ, Hall AR, McLaughlin CP, et al. Chronic metformin associated cardioprotection against infarction: not just a glucose lowering phenomenon. Cardiovasc Drugs Ther 2013; 27:5–16. 26. Calvert JW, Gundewar S, Jha S, et al. Acute metformin therapy confers cardioprotection against myocardial infarction via AMPK-eNOS-mediated signaling. Diabetes 2008; 57:696–705. 27. Paiva M, Riksen NP, Davidson SM, et al. Metformin prevents myocardial reperfusion injury by activating the adenosine receptor. J Cardiovasc Pharmacol 2009; 53:373–378. 28. Bhamra GS, Hausenloy DJ, Davidson SM, et al. Metformin protects the ischemic heart by the Akt-mediated inhibition of mitochondrial permeability transition pore opening. Basic Res Cardiol 2008; 103:274–284. 29. Yin M, van der Horst IC, van Melle JP, et al. Metformin improves cardiac function in a nondiabetic rat model of post-MI heart failure. Am J Physiol Heart Circ Physiol 2011; 301:H459–H468. 30. Gundewar S, Calvert JW, Jha S, et al. Activation of AMP-activated protein kinase by metformin improves left ventricular function and survival in heart failure. Circ Res 2009; 104:403–411. 31. Lexis CP, Wieringa WG, Hiemstra B, et al. Chronic metformin treatment is associated with reduced myocardial infarct size in diabetic patients with ST-segment elevation myocardial infarction. Cardiovasc Drugs Ther 2014; 28:163–171. 32. van den Munckhof I, Riksen N, Seeger JP, et al. Aging attenuates the protective effect of ischemic preconditioning against endothelial ischemiareperfusion injury in humans. Am J Physiol Heart Circ Physiol 2013; 304: H1727–1732. 33. Loukogeorgakis SP, Panagiotidou AT, Broadhead MW, et al. Remote Ischemic Preconditioning Provides Early and Late Protection Against Endothelial Ischemia-Reperfusion Injury in Humans: Role of the Autonomic Nervous System. J Am Coll Cardiol 2005; 46:450–456. 34. Li J, Xu JP, Zhao XZ, et al. Protective effect of metformin on myocardial injury in metabolic syndrome patients following percutaneous coronary intervention. Cardiology 2014; 127:133–139. 35. Habib A, Karmali V, Polavarapu R, et al. Metformin impairs vascular endothelial & recovery after stent placement in the setting of locally eluted mammalian target of rapamycin inhibitors via S6 kinase-dependent inhibition of cell proliferation. J Am Coll Cardiol 2013; 61:971–980. Experimental study in rabbits showing that metformin impairs endothelialization of zotarolimus-eluting stents. 36. Habib A, Karmali V, Polavarapu R, et al. Metformin impairs endothelialization after placement of newer generation drug eluting stents. Atherosclerosis 2013; 229:385–387. 37. Liu X, Chhipa RR, Pooya S, et al. Discrete mechanisms of mTOR and cell cycle regulation by AMPK agonists independent of AMPK. Proc Natl Acad Sci U S A 2014; 111:E435–444. 38. Martinet W, De Loof H, De Meyer GR. mTOR inhibition: a promising strategy for stabilization of atherosclerotic plaques. Atherosclerosis 2014; 233:601– 607. 39. Finn AV, Joner M, Nakazawa G, et al. Pathological correlates of late drugeluting stent thrombosis: strut coverage as a marker of endothelialization. Circulation 2007; 115:2435–2441. 40. Hausenloy DJ, Baxter G, Bell R, et al. Translating novel strategies for cardioprotection: the Hatter Workshop Recommendations. Basic Res Cardiol 2010; 105:677–686. 41. van der Worp HB, Howells DW, Sena ES, et al. Can animal models of disease reliably inform human studies? PLoS Med 2010; 7:e1000245.
0957-9672 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-lipidology.com
451
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
