Metformin for cardiovascular disease: promise still unproven
Authors: Chris P H Lexis, Iwan C C van der Horst
Journal: The Lancet Diabetes & Endocrinology (2013)

The role of metformin in cardiovascular disease is under investigation. Aside from its established use for patients with type 2 diabetes, metformin is thought to be beneficial for cardiovascular disease, although solid evidence is lacking. The alleged protective effects of metformin in cardiovascular disease seem at least partly unrelated to its effects on glucose metabolism. The investigators of the Carotid Atherosclerosis: MEtformin for insulin ResistAnce (CAMERA) study1Preiss D Lloyd SM Ford I et al.Metformin for non-diabetic patients with coronary heart disease (the CAMERA study): a randomised controlled trial.Lancet Diabet & Endocrinol. 2013; (published online Nov 7.)http://dx.doi.org/10.1016/S2213-8587(13)70152-9Google Scholar investigated the effect of metformin on carotid intima-media thickness (cIMT) in a double-blind randomised controlled trial of 173 patients with proven coronary heart disease, but without diabetes. After 18 months, cIMT progression did not differ significantly between metformin and placebo groups (slope difference 0·007 mm per year, 95% CI −0·006 to 0·020; p=0·29) The investigators did report a reduction in HbA1c or insulin concentrations in patients assigned to metformin compared with those assigned to placebo. Patients in the study had coronary heart disease and were therefore treated according to current guidelines, with all patients taking statins. Thus, the window of opportunity for improving atherosclerosis as measured by cIMT was small. The study was powered to detect a difference in cIMT between the metformin and control groups of 0·021 mm after 18 months. This difference was partly based on the study of Meaney and colleagues2Meaney E Vela A Samaniego V et al.Metformin, arterial function, intima-media thickness and nitroxidation in metabolic syndrome: the mefisto study.Clin Exp Pharmacol Physiol. 2008; 35: 895-903Crossref PubMed Scopus (74) Google Scholar in which 40 patients with features of metabolic syndrome were either treated with metformin or received no additional treatment. After 12 months, patients in the metformin group had a greater reduction of cIMT than in the control group (−0·1 mm, p=0·04 vs −0·02 mm, p=not significant). By contrast with patients in CAMERA, patients in the study by Meaney and colleagues2Meaney E Vela A Samaniego V et al.Metformin, arterial function, intima-media thickness and nitroxidation in metabolic syndrome: the mefisto study.Clin Exp Pharmacol Physiol. 2008; 35: 895-903Crossref PubMed Scopus (74) Google Scholar had higher baseline LDL-cholesterol, and data for use of statins were not presented, so the potential for cIMT reduction was probably greater. Katakami and colleagues3Katakami N Yamasaki Y Hayaishi-Okano R et al.Metformin or gliclazide, rather than glibenclamide, attenuate progression of carotid intima-media thickness in subjects with type 2 diabetes.Diabetalogia. 2004; 47: 1906-1913Crossref PubMed Scopus (103) Google Scholar also studied the effect of metformin on cIMT. They assessed 118 patients with type 2 diabetes treated with glibenclamide over 3 years. Addition of metformin was associated with less progression of cIMT compared with placebo (0·003 mm vs 0·064 mm; p<0·0001). However, few patients (n=29) were taking statins. The studies by Meaney and colleagues and Katakami and colleagues show that metformin might reduce progression of cIMT in the absence of statin treatment. The CAMERA study shows that the effect of metformin—in addition to current best treatment, including statins—on cIMT is probably small or negligible. In two upcoming trials, the Copenhagen Insulin and Metformin Therapy trial (CIMT; NCT00657943) and the REducing with MetfOrmin Vascular Adverse Lesions in type 1 diabetes trial (REMOVAL; NCT01483560), the effect of metformin on cIMT will be assessed in 500 patients with type 1 diabetes and 950 patients with type 2 diabetes in whom statin use will be monitored, respectively.4Lundby Christensen L Almdal T Boesgaard T et al.CIMT Trial GroupStudy rationale and design of the CIMT trial: the Copenhagen Insulin and Metformin Therapy trial.Diabetes Obes Metab. 2009; 11: 315-322Crossref PubMed Scopus (25) Google Scholar We are interested to see whether these studies will show a beneficial effect of metformin in addition to statins. Proof-of-principle trials such as CAMERA are usually powered to assess markers thought to be reliable proxies for outcomes. Ideally, a strong causal relation exists between the surrogate endpoint and outcome. cIMT is an established marker for the diagnosis of atherosclerotic disease, and a surrogate approved by the US Food and Drug Administration. Conversely, little evidence exists of a direct association between improvement of cIMT and outcome. Moreover, the experimental evidence for a direct effect of metformin on cIMT is weak.5Stocker DJ Taylor AJ Langley RW Jezior MR Vigersky RA A randomized trial of the effects of rosiglitazone and metformin on inflammation and subclinical atherosclerosis in patients with type 2 diabetes.Am Heart J. 2007; 153: 445.e1-445.e6Summary Full Text Full Text PDF Scopus (90) Google Scholar Experimental evidence of an effect on myocardial function is more established: several studies show that metformin is associated with a reduced size of myocardial infarct.6Yin 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-H468Crossref PubMed Scopus (135) Google Scholar Furthermore, metformin exerts anti-thrombotic effects, which could explain the improved outcome in atherothrombotic disease.7Bailey CJ Metformin: effects on micro and macrovascular complications in type 2 diabetes.Cardiovasc Drugs Ther. 2008; 22: 215-224Crossref PubMed Scopus (99) Google Scholar Likewise, in a non-ischaemic experimental study of rats, metformin prevented heart failure and improved myocardial function, suggesting that metformin might even improve myocardial function irrespective of ischaemia.8Cittadini A Napoli R Monti MG et al.Metformin prevents the development of chronic heart failure in the SHHF rat model.Diabetes. 2012; 61: 944-953Crossref PubMed Scopus (97) Google Scholar In several retrospective analyses9Kao J Tobis J McClelland RL et al.Relation of metformin treatment to clinical events in diabetic patient undergoing percutaneous intervention.Am J Cardiol. 2004; 93: 1347-1350Summary Full Text Full Text PDF PubMed Scopus (95) Google Scholar, 10Roussel R Travert F Pasquet B et al.Metformin use and mortality among patients with diabetes and atherothrombosis.Arch Intern Med. 2010; 170: 1892-1899Crossref PubMed Scopus (301) Google Scholar of patients with diabetes with concomitant coronary artery disease and even heart failure, use of metformin was associated with improved survival independent of glycaemic control. Ongoing randomised, double-blind clinical trials such as the Metformin in CABG trial (MetCAB; NCT01438723) and the Glycometabolic Intervention as Adjunct to Primary Percutaneous Intervention in ST Elevation Myocardial Infarction Trial (GIPS-III; NCT01217307) will elucidate whether metformin can reduce myocardial infarct size, improve resilience to ischaemia, and improve left ventricular function after ischaemia-reperfusion injury. Like cIMT, the effect of metformin on myocardial function and infarct size is also a surrogate endpoint for clinical outcome. Whether the primary endpoint of CAMERA or secondary endpoints such as HbA1c best represent cardiovascular outcome is unclear. The definitive evidence for the role of metformin in non-diabetic cardiovascular disease will have to be provided by large randomised clinical trials powered for cardiovascular outcomes such as the Glucose Lowering In Non-diabetic hyperglycaemia Trial (GLINT; ISRCTN34875079), in which 12 000 patients with high cardiovascular risk and dysglycaemia but without diabetes, will be assigned to metformin or placebo for 5 years. Until then, the role of metformin for improving cardiovascular outcomes has promise, but is still largely unproven. CPHL and ICCH (principal) are investigators of the Glycometabolic Intervention as Adjunct to Primary Percutaneous Intervention in ST Elevation Myocardial Infarction trial (NCT01217307), of the effect of metformin on left ventricular function in patients without diabetes presenting with acute myocardial infarction. Metformin for non-diabetic patients with coronary heart disease (the CAMERA study): a randomised controlled trialMetformin had no effect on cIMT and little or no effect on several surrogate markers of cardiovascular disease in non-diabetic patients with high cardiovascular risk, taking statins. Further evidence is needed before metformin can be recommended for cardiovascular benefit in this population. Full-Text PDF Open Access