Novel therapeutic targets of metformin: metabolic syndrome and cardiovascular disease

Introduction: Metformin is a widely used drug in the treatment of type 2 diabetes mellitus (T2DM). However, it is becoming an attractive drug to manage patients with pre-diabetes and to possibly prevent cardiac remodeling and fibrosis and heart failure. Areas covered: In this review, we highlight the novel therapeutic targets of metformin with a special emphasis on cardiovascular disease. We discuss its key mechanisms of action and new signaling pathways that could partially account for its effect. Furthermore, metformin’s role in the management of patients with metabolic syndrome is debated, emphasizing its potential to prevent diabetic heart disease. On the other hand, intense research is ongoing to clarify if metformin will be a future drug to target ischemia-reperfusion injury in the setting of myocardial ischemia. Expert opinion: In the following years, one should look carefully at basic science results to successfully design and conduct clinical trials, emphasizing patients without full-blown T2DM, but who otherwise might have increased insulin resistance. Topics such as the prevention of cardiac fibrosis and heart failure with preserved ejection fraction, the attenuation of ischemia-reperfusion injury on an acute coronary syndrome and the post-myocardial infarction left ventricle remodeling surely deserve a special interest and should be faced as potential therapeutic targets for metformin.

[1]  A. Leite-Moreira,et al.  Diastolic dysfunction in the diabetic continuum: association with insulin resistance, metabolic syndrome and type 2 diabetes , 2015, Cardiovascular Diabetology.

[2]  Amanda N Haile,et al.  Supplemental Figure 1 , 2014 .

[3]  Alan D. Lopez,et al.  Global, regional, and national prevalence of overweight and obesity in children and adults during 1980–2013: a systematic analysis for the Global Burden of Disease Study 2013 , 2014, The Lancet.

[4]  V. Fuster Global burden of cardiovascular disease: time to implement feasible strategies and to monitor results. , 2014, Journal of the American College of Cardiology.

[5]  J. Tijssen,et al.  Effect of metformin on left ventricular function after acute myocardial infarction in patients without diabetes: the GIPS-III randomized clinical trial. , 2014, JAMA.

[6]  D. J. Veldhuisen,et al.  Chronic Metformin Treatment is Associated with Reduced Myocardial Infarct Size in Diabetic Patients with ST-segment Elevation Myocardial Infarction , 2014, Cardiovascular Drugs and Therapy.

[7]  A. Leite-Moreira,et al.  METformin in DIastolic Dysfunction of MEtabolic Syndrome (MET-DIME) Trial: Rationale and Study Design , 2014, Cardiovascular Drugs and Therapy.

[8]  G. Rena,et al.  Molecular mechanism of action of metformin: old or new insights? , 2013, Diabetologia.

[9]  H. Kwon,et al.  Adipokines Mediate Inflammation and Insulin Resistance , 2013, Front. Endocrinol..

[10]  Z. Fortes,et al.  Cardiac fibrosis and vascular remodeling are attenuated by metformin in obese rats. , 2013, International journal of cardiology.

[11]  R. Arena,et al.  Impact of obesity and the obesity paradox on prevalence and prognosis in heart failure. , 2013, JACC. Heart failure.

[12]  A. Luchner,et al.  Antidiabetic treatment restores adiponectin serum levels and APPL1 expression, but does not improve adiponectin-induced vasodilation and endothelial dysfunction in Zucker diabetic fatty rats , 2013, Cardiovascular Diabetology.

[13]  G. Rongen,et al.  Metformin Therapy in Diabetes: The Role of Cardioprotection , 2013, Current Atherosclerosis Reports.

[14]  C. Lang,et al.  Insulin sensitization therapy and the heart: focus on metformin and thiazolidinediones. , 2012, Heart failure clinics.

[15]  M. Pletcher,et al.  Metformin-based treatment for obesity-related hypertension: a randomized, double-blind, placebo-controlled trial , 2012, Journal of hypertension.

[16]  K. Nair,et al.  Effect of insulin sensitizer therapy on atherothrombotic and inflammatory profiles associated with insulin resistance. , 2012, Mayo Clinic proceedings.

[17]  K. Eckardt,et al.  Inflammation and metabolic dysfunction: links to cardiovascular diseases. , 2012, American journal of physiology. Heart and circulatory physiology.

[18]  T. Marwick,et al.  Integrated backscatter as a fibrosis marker in the metabolic syndrome: association with biochemical evidence of fibrosis and left ventricular dysfunction. , 2012, European heart journal cardiovascular Imaging.

[19]  D. Hardie,et al.  AMPK: a nutrient and energy sensor that maintains energy homeostasis , 2012, Nature Reviews Molecular Cell Biology.

[20]  P. Netti,et al.  Metformin Prevents the Development of Chronic Heart Failure in the SHHF Rat Model , 2012, Diabetes.

[21]  S. Grundy Pre-diabetes, metabolic syndrome, and cardiovascular risk. , 2012, Journal of the American College of Cardiology.

[22]  J. G. Reyes-García,et al.  The effects of metformin on inflammatory mediators in obese adolescents with insulin resistance: controlled randomized clinical trial , 2012, Journal of pediatric endocrinology & metabolism : JPEM.

[23]  B. Stratmann,et al.  Heart in Diabetes: Not Only a Macrovascular Disease , 2011, Diabetes Care.

[24]  Shunichi Homma,et al.  Effect of obesity and overweight on left ventricular diastolic function: a community-based study in an elderly cohort. , 2011, Journal of the American College of Cardiology.

[25]  C. Buechler,et al.  Globular and full-length adiponectin induce NO-dependent vasodilation in resistance arteries of Zucker lean but not Zucker diabetic fatty rats. , 2011, American journal of hypertension.

[26]  Fengjuan Yao,et al.  Metformin attenuates ventricular hypertrophy by activating the AMP‐activated protein kinase–endothelial nitric oxide synthase pathway in rats , 2011, Clinical and experimental pharmacology & physiology.

[27]  A. Beck‐Sickinger,et al.  Molecular mechanisms of signal transduction via adiponectin and adiponectin receptors , 2010, Biological chemistry.

[28]  Yi Zhu,et al.  Metformin attenuates cardiac fibrosis by inhibiting the TGFbeta1-Smad3 signalling pathway. , 2010, Cardiovascular research.

[29]  C. Jellis,et al.  Assessment of nonischemic myocardial fibrosis. , 2010, Journal of the American College of Cardiology.

[30]  B. Viollet,et al.  Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state. , 2010, The Journal of clinical investigation.

[31]  S. Hawley,et al.  Use of Cells Expressing γ Subunit Variants to Identify Diverse Mechanisms of AMPK Activation , 2010, Cell metabolism.

[32]  M. Ludgate,et al.  Metformin reduces arterial stiffness and improves endothelial function in young women with polycystic ovary syndrome: a randomized, placebo-controlled, crossover trial. , 2009, The Journal of clinical endocrinology and metabolism.

[33]  M. Takeuchi,et al.  Subclinical left ventricular dysfunction in asymptomatic diabetic patients assessed by two-dimensional speckle tracking echocardiography: correlation with diabetic duration. , 2009, European journal of echocardiography : the journal of the Working Group on Echocardiography of the European Society of Cardiology.

[34]  M. Mocanu,et al.  Metformin Prevents Myocardial Reperfusion Injury by Activating the Adenosine Receptor , 2009, Journal of cardiovascular pharmacology.

[35]  S. Jha,et al.  Activation of AMP-Activated Protein Kinase by Metformin Improves Left Ventricular Function and Survival in Heart Failure , 2009, Circulation research.

[36]  R. Sacco,et al.  Association between diabetes mellitus and left ventricular hypertrophy in a multiethnic population. , 2008, The American journal of cardiology.

[37]  G. Bhamra,et al.  Metformin protects the ischemic heart by the Akt-mediated inhibition of mitochondrial permeability transition pore opening , 2008, Basic Research in Cardiology.

[38]  R. Freeman,et al.  Leptin: Linking obesity, the metabolic syndrome, and cardiovascular disease , 2008, Current hypertension reports.

[39]  S. Jha,et al.  Acute Metformin Therapy Confers Cardioprotection Against Myocardial Infarction Via AMPK-eNOS–Mediated Signaling , 2008, Diabetes.

[40]  E. Salpeter,et al.  Meta-analysis: metformin treatment in persons at risk for diabetes mellitus. , 2008, The American journal of medicine.

[41]  Benjamin D. Levine,et al.  Cardiac Steatosis in Diabetes Mellitus: A 1H-Magnetic Resonance Spectroscopy Study , 2007, Circulation.

[42]  E. Abel,et al.  Diabetic cardiomyopathy revisited. , 2007, Circulation.

[43]  C. Rihal,et al.  Association of obesity with left ventricular remodeling and diastolic dysfunction in patients without coronary artery disease. , 2006, The American journal of cardiology.

[44]  Feng Liu,et al.  APPL1 binds to adiponectin receptors and mediates adiponectin signalling and function , 2006, Nature Cell Biology.

[45]  B. Viollet,et al.  Activation of the AMP-activated kinase by antidiabetes drug metformin stimulates nitric oxide synthesis in vivo by promoting the association of heat shock protein 90 and endothelial nitric oxide synthase. , 2006, Diabetes.

[46]  David V. Power,et al.  Standards of Medical Care in Diabetes: Response to position statement of the American Diabetes Association , 2006 .

[47]  Fernando Costa,et al.  Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. , 2005, Circulation.

[48]  A. Legrand,et al.  Metformin decreases intracellular production of reactive oxygen species in aortic endothelial cells. , 2005, Metabolism: clinical and experimental.

[49]  P. Scherer,et al.  Adiponectin – journey from an adipocyte secretory protein to biomarker of the metabolic syndrome , 2005, Journal of internal medicine.

[50]  D. Yellon,et al.  The mitochondrial permeability transition pore: its fundamental role in mediating cell death during ischaemia and reperfusion. , 2003, Journal of molecular and cellular cardiology.

[51]  D. Yellon,et al.  Myocardial Protection by Insulin at Reperfusion Requires Early Administration and Is Mediated via Akt and p70s6 Kinase Cell-Survival Signaling , 2001, Circulation research.

[52]  F. Maklady,et al.  Prevalence of diastolic dysfunction in normotensive, asymptomatic patients with well-controlled type 2 diabetes mellitus. , 2001, The American journal of cardiology.

[53]  M. Owen,et al.  Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. , 2000, The Biochemical journal.

[54]  D. Latchman,et al.  Insulin administered at reoxygenation exerts a cardioprotective effect in myocytes by a possible anti-apoptotic mechanism. , 2000, Journal of molecular and cellular cardiology.

[55]  K. Ohmori,et al.  Alteration in left ventricular diastolic filling and accumulation of myocardial collagen at insulin-resistant prediabetic stage of a type II diabetic rat model. , 2000, Circulation.

[56]  T Nakamura,et al.  Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. , 1999, Biochemical and biophysical research communications.

[57]  R. Holman,et al.  Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34) , 1998, The Lancet.

[58]  R. V. Sharma,et al.  Vascular effects of metformin. Possible mechanisms for its antihypertensive action in the spontaneously hypertensive rat. , 1996, American journal of hypertension.

[59]  B. Spiegelman,et al.  AdipoQ Is a Novel Adipose-specific Gene Dysregulated in Obesity (*) , 1996, The Journal of Biological Chemistry.

[60]  J. Yudkin,et al.  Effects of Metformin on Insulin Resistance, Risk Factors for Cardiovascular Disease, and Plasminogen Activator Inhibitor in NIDDM Subjects: A study of two ethnic groups , 1993, Diabetes Care.

[61]  K. Landin-Wilhelmsen Metformin and blood pressure , 1992, Journal of clinical pharmacy and therapeutics.

[62]  H. Gin,et al.  Study of the effect of metformin on platelet aggregation in insulin-dependent diabetics. , 1989, Diabetes research and clinical practice.

[63]  F. Ross,et al.  Use of Cells Expressing gamma Subunit Variants to Identify Diverse Mechanisms of AMPK Activation , 2010 .

[64]  H. Minuk,et al.  Metabolic syndrome. , 2005, Journal of insurance medicine.

[65]  R. Krauss,et al.  Diagnosis and management of the metabolic syndrome , 2005 .

[66]  F. Gao,et al.  Ischemia-Reperfusion : The Roles of PI 3-Kinase , Akt , and Endothelial Nitric Oxide Nitric Oxide Mediates the Antiapoptotic Effect of Insulin in Myocardial , 2002 .