Skip to main content
SpringerLink
Log in

Cardioprotection by Metformin: Beneficial Effects Beyond Glucose Reduction

  • Review Article
  • Published:
American Journal of Cardiovascular Drugs Aims and scope Submit manuscript

Abstract

Metformin is a biguanide that is widely used as an insulin-sparing agent to treat diabetes. When compared with the general population, diabetics are twice as likely to die from fatal myocardial infarction and congestive heart failure (CHF). There has been a significant concern regarding the use of metformin in patients with CHF because of their higher tendency to develop lactic acidosis. However, large epidemiological trials have reported better cardiovascular prognosis with metformin compared to other glucose-lowering agents among diabetics. Additionally, metformin has reduced the risk of reinfarction and all-cause mortality in patients with coronary artery disease and CHF, respectively. The protection against cardiovascular diseases appears to be independent of the anti-hyperglycemic effects of metformin. These effects are mediated through an increase in 5′ adenosine monophosphate-activated protein kinase (AMPK) phosphorylation and by increased phosphorylation of endothelial nitric oxide synthase (eNOS) in cardiomyocytes with an increased production of nitric oxide (NO). Metformin preconditions the heart against ischemia-reperfusion injury and may improve myocardial remodeling after an ischemic insult. The preponderance of evidence currently suggests that metformin is safe in patients with CHF, prompting the Food and Drug Administration to remove CHF as a contraindication from the package insert of all generic metformin preparations. In this narrative, along with a limited meta-analysis of available studies, we have reviewed the pleiotropic (non-glucose-lowering) effects of metformin that potentially contribute to its cardioprotective properties. Additionally, we have reviewed issues surrounding the safety of metformin in patients with cardiac diseases.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Padwal R, Majumdar SR, Johnson JA, Varney J, McAlister FA. A systematic review of drug therapy to delay or prevent type 2 diabetes. Diabetes Care. 2005;28(3):736–44.

    Article  PubMed  CAS  Google Scholar 

  2. Kannel WB, Hjortland M, Castelli WP. Role of diabetes in congestive heart failure: the Framingham study. Am J Cardiol. 1974;34(1):29–34.

    Article  PubMed  CAS  Google Scholar 

  3. Nichols GA, Hillier TA, Erbey JR, Brown JB. Congestive heart failure in type 2 diabetes: prevalence, incidence, and risk factors. Diabetes Care. 2001;24(9):1614–9.

    Article  PubMed  CAS  Google Scholar 

  4. Stratton IM, Adler AI, Neil HA, Matthews DR, Manley SE, Cull CA, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ. 2000;321(7258):405–12.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Yamaguchi A, Ino T, Adachi H, Murata S, Kamio H, Okada M, et al. Left ventricular volume predicts postoperative course in patients with ischemic cardiomyopathy. Ann Thorac Surg. 1998;65(2):434–8.

    Article  PubMed  CAS  Google Scholar 

  6. Iribarren C, Karter AJ, Go AS, Ferrara A, Liu JY, Sidney S, et al. Glycemic control and heart failure among adult patients with diabetes. Circulation. 2001;103(22):2668–73.

    Article  PubMed  CAS  Google Scholar 

  7. Fonarow GC. Approach to the management of diabetic patients with heart failure: role of thiazolidinediones. Am Heart J. 2004;148(4):551–8.

    Article  PubMed  CAS  Google Scholar 

  8. Masoudi FA, Wang Y, Inzucchi SE, Setaro JF, Havranek EP, Foody JM, et al. Metformin and thiazolidinedione use in Medicare patients with heart failure. JAMA. 2003;290(1):81–5.

    Article  PubMed  CAS  Google Scholar 

  9. UK Prospective Diabetes Study (UKPDS). Group Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet. 1998;352(9131):854–65.

    Article  Google Scholar 

  10. Abbasi F, Chu JW, McLaughlin T, Lamendola C, Leary ET, Reaven GM. Effect of metformin treatment on multiple cardiovascular disease risk factors in patients with type 2 diabetes mellitus. Metabolism. 2004;53(2):159–64.

    Article  PubMed  CAS  Google Scholar 

  11. Kirpichnikov D, McFarlane SI, Sowers JR. Metformin: an update. Ann Intern Med. 2002;137(1):25–33.

    Article  PubMed  CAS  Google Scholar 

  12. Gundewar S, Calvert JW, Jha S, Toedt-Pingel I, Ji SY, Nunez D, et al. Activation of AMP-activated protein kinase by metformin improves left ventricular function and survival in heart failure. Circ Res. 2009;104(3):403–11.

    Article  PubMed  CAS  Google Scholar 

  13. Schaper J, Froede R, Hein S, Buck A, Hashizume H, Speiser B, et al. Impairment of the myocardial ultrastructure and changes of the cytoskeleton in dilated cardiomyopathy. Circulation. 1991;83(2):504–14.

    Article  PubMed  CAS  Google Scholar 

  14. Sabbah HN, Sharov V, Riddle JM, Kono T, Lesch M, Goldstein S. Mitochondrial abnormalities in myocardium of dogs with chronic heart failure. J Mol Cell Cardiol. 1992;24(11):1333–47.

    Article  PubMed  CAS  Google Scholar 

  15. Ning XH, Zhang J, Liu J, Ye Y, Chen SH, From AH, et al. Signaling and expression for mitochondrial membrane proteins during left ventricular remodeling and contractile failure after myocardial infarction. J Am Coll Cardiol. 2000;36(1):282–7.

    Article  PubMed  CAS  Google Scholar 

  16. Sasaki H, Asanuma H, Fujita M, Takahama H, Wakeno M, Ito S, et al. Metformin prevents progression of heart failure in dogs: role of AMP-activated protein kinase. Circulation. 2009;119(19):2568–77.

    Article  PubMed  CAS  Google Scholar 

  17. Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, et al. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Investig. 2001;108(8):1167–74.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Bertrand L, Ginion A, Beauloye C, Hebert AD, Guigas B, Hue L, et al. AMPK activation restores the stimulation of glucose uptake in an in vitro model of insulin-resistant cardiomyocytes via the activation of protein kinase B. Am J Physiol Heart Circ Physiol. 2006;291(1):H239–50.

    Article  PubMed  CAS  Google Scholar 

  19. Zhang L, He H, Balschi JA. Metformin and phenformin activate AMP-activated protein kinase in the heart by increasing cytosolic AMP concentration. Am J Physiol Heart Circ Physiol. 2007;293(1):H457–66.

    Article  PubMed  CAS  Google Scholar 

  20. Kahn BB, Alquier T, Carling D, Hardie DG. AMP-activated protein kinase: ancient energy gauge provides clues to modern understanding of metabolism. Cell Metab. 2005;1(1):15–25.

    Article  PubMed  CAS  Google Scholar 

  21. Hardie DG. AMP-activated protein kinase: the guardian of cardiac energy status. J Clin Investig. 2004;114(4):465–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Calvert JW, Gundewar S, Jha S, Greer JJ, Bestermann WH, Tian R, et al. Acute metformin therapy confers cardioprotection against myocardial infarction via AMPK-eNOS-mediated signaling. Diabetes. 2008;57(3):696–705.

    Article  PubMed  CAS  Google Scholar 

  23. Gonon AT, Widegren U, Bulhak A, Salehzadeh F, Persson J, Sjoquist PO, et al. Adiponectin protects against myocardial ischaemia-reperfusion injury via AMP-activated protein kinase, Akt, and nitric oxide. Cardiovasc Res. 2008;78(1):116–22.

    Article  PubMed  CAS  Google Scholar 

  24. Russell RR 3rd, Li J, Coven DL, Pypaert M, Zechner C, Palmeri M, et al. AMP-activated protein kinase mediates ischemic glucose uptake and prevents postischemic cardiac dysfunction, apoptosis, and injury. J Clin Investig. 2004;114(4):495–503.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Tian R, Musi N, D’Agostino J, Hirshman MF, Goodyear LJ. Increased adenosine monophosphate-activated protein kinase activity in rat hearts with pressure-overload hypertrophy. Circulation. 2001;104(14):1664–9.

    Article  PubMed  CAS  Google Scholar 

  26. Shibata R, Ouchi N, Ito M, Kihara S, Shiojima I, Pimentel DR, et al. Adiponectin-mediated modulation of hypertrophic signals in the heart. Nat Med. 2004;10(12):1384–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Liao Y, Takashima S, Maeda N, Ouchi N, Komamura K, Shimomura I, et al. Exacerbation of heart failure in adiponectin-deficient mice due to impaired regulation of AMPK and glucose metabolism. Cardiovasc Res. 2005;67(4):705–13.

    Article  PubMed  CAS  Google Scholar 

  28. Baron SJ, Li J, Russell RR 3rd, Neumann D, Miller EJ, Tuerk R, et al. Dual mechanisms regulating AMPK kinase action in the ischemic heart. Circ Res. 2005;96(3):337–45.

    Article  PubMed  CAS  Google Scholar 

  29. Musi N, Fujii N, Hirshman MF, Ekberg I, Froberg S, Ljungqvist O, et al. AMP-activated protein kinase (AMPK) is activated in muscle of subjects with type 2 diabetes during exercise. Diabetes. 2001;50(5):921–7.

    Article  PubMed  CAS  Google Scholar 

  30. Mount PF, Kemp BE, Power DA. Regulation of endothelial and myocardial NO synthesis by multi-site eNOS phosphorylation. J Mol Cell Cardiol. 2007;42(2):271–9.

    Article  PubMed  CAS  Google Scholar 

  31. Woods A, Azzout-Marniche D, Foretz M, Stein SC, Lemarchand P, Ferre P, et al. Characterization of the role of AMP-activated protein kinase in the regulation of glucose-activated gene expression using constitutively active and dominant negative forms of the kinase. Mol Cell Biol. 2000;20(18):6704–11.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Zong H, Ren JM, Young LH, Pypaert M, Mu J, Birnbaum MJ, et al. AMP kinase is required for mitochondrial biogenesis in skeletal muscle in response to chronic energy deprivation. Proc Natl Acad Sci USA. 2002;99(25):15983–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Xing Y, Musi N, Fujii N, Zou L, Luptak I, Hirshman MF, et al. Glucose metabolism and energy homeostasis in mouse hearts overexpressing dominant negative alpha2 subunit of AMP-activated protein kinase. J Biol Chem. 2003;278(31):28372–7.

    Article  PubMed  CAS  Google Scholar 

  34. Sag D, Carling D, Stout RD, Suttles J. Adenosine 5’-monophosphate-activated protein kinase promotes macrophage polarization to an anti-inflammatory functional phenotype. J Immunol. 2008;181(12):8633–41.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Verma S, McNeill JH. Metformin improves cardiac function in isolated streptozotocin-diabetic rat hearts. Am J Physiol. 1994;266(2 Pt 2):H714–9.

    PubMed  CAS  Google Scholar 

  36. Legtenberg RJ, Houston RJ, Oeseburg B, Smits P. Metformin improves cardiac functional recovery after ischemia in rats. Horm Metab Res. 2002;34(4):182–5.

    Article  PubMed  CAS  Google Scholar 

  37. Xiao H, Ma X, Feng W, Fu Y, Lu Z, Xu M, et al. Metformin attenuates cardiac fibrosis by inhibiting the TGFbeta1-Smad3 signalling pathway. Cardiovasc Res. 2010;87(3):504–13.

    Article  PubMed  CAS  Google Scholar 

  38. Davis BJ, Xie Z, Viollet B, Zou MH. 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. Diabetes. 2006;55(2):496–505.

    Article  PubMed  CAS  Google Scholar 

  39. Chen ZP, Mitchelhill KI, Michell BJ, Stapleton D, Rodriguez-Crespo I, Witters LA, et al. AMP-activated protein kinase phosphorylation of endothelial NO synthase. FEBS Lett. 1999;443(3):285–9.

    Article  PubMed  CAS  Google Scholar 

  40. Morrow VA, Foufelle F, Connell JM, Petrie JR, Gould GW, Salt IP. Direct activation of AMP-activated protein kinase stimulates nitric-oxide synthesis in human aortic endothelial cells. J Biol Chem. 2003;278(34):31629–39.

    Article  PubMed  CAS  Google Scholar 

  41. Massion PB, Pelat M, Belge C, Balligand JL. Regulation of the mammalian heart function by nitric oxide. Comp Biochem Physiol A Mol Integr Physiol. 2005;142(2):144–50.

    Article  PubMed  CAS  Google Scholar 

  42. Lefer AM. Attenuation of myocardial ischemia-reperfusion injury with nitric oxide replacement therapy. Ann Thorac Surg. 1995;60(3):847–51.

    Article  PubMed  CAS  Google Scholar 

  43. Deussen A, Stappert M, Schafer S, Kelm M. Quantification of extracellular and intracellular adenosine production: understanding the transmembranous concentration gradient. Circulation. 1999;99(15):2041–7.

    Article  PubMed  CAS  Google Scholar 

  44. Liem DA, van den Doel MA, de Zeeuw S, Verdouw PD, Duncker DJ. Role of adenosine in ischemic preconditioning in rats depends critically on the duration of the stimulus and involves both A(1) and A(3) receptors. Cardiovasc Res. 2001;51(4):701–8.

    Article  PubMed  CAS  Google Scholar 

  45. Kin H, Zatta AJ, Lofye MT, Amerson BS, Halkos ME, Kerendi F, et al. Postconditioning reduces infarct size via adenosine receptor activation by endogenous adenosine. Cardiovasc Res. 2005;67(1):124–33.

    Article  PubMed  CAS  Google Scholar 

  46. Deussen A. Metabolic flux rates of adenosine in the heart. Naunyn Schmiedebergs Arch Pharmacol. 2000;362(4–5):351–63.

    Article  PubMed  CAS  Google Scholar 

  47. Peart JN, Headrick JP. Adenosinergic cardioprotection: multiple receptors, multiple pathways. Pharmacol Ther. 2007;114(2):208–21.

    Article  PubMed  CAS  Google Scholar 

  48. Solskov L, Lofgren B, Kristiansen SB, Jessen N, Pold R, Nielsen TT, et al. Metformin induces cardioprotection against ischaemia/reperfusion injury in the rat heart 24 hours after administration. Basic Clin Pharmacol Toxicol. 2008;103(1):82–7.

    Article  PubMed  CAS  Google Scholar 

  49. Bhamra GS, Hausenloy DJ, Davidson SM, Carr RD, Paiva M, Wynne AM, et al. Metformin protects the ischemic heart by the Akt-mediated inhibition of mitochondrial permeability transition pore opening. Basic Res Cardiol. 2008;103(3):274–84.

    Article  PubMed  CAS  Google Scholar 

  50. Paiva M, Riksen NP, Davidson SM, Hausenloy DJ, Monteiro P, Goncalves L, et al. Metformin prevents myocardial reperfusion injury by activating the adenosine receptor. J Cardiovasc Pharmacol. 2009;53(5):373–8.

    Article  PubMed  CAS  Google Scholar 

  51. Yin M, van der Horst IC, van Melle JP, Qian C, van Gilst WH, Sillje HH, et al. Metformin improves cardiac function in a nondiabetic rat model of post-MI heart failure. Am J Physiol Heart Circ Physiol. 2011;301(2):H459–68.

    Article  PubMed  CAS  Google Scholar 

  52. Soraya H, Rameshrad M, Mokarizadeh A, Garjani AR. Metformin attenuates myocardial remodeling and neutrophil recruitment after myocardial infarction in rat. BioImpacts 2015;5(1), 3–8. https://doi.org/10.15171/bi.2015.02.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Kitchen WH, Rickards AL, Ford GW, Doyle LW, Kelly E, Ryan MM. Selective improvement in cognitive test scores of extremely low birthweight infants aged between 2 and 5 years. Aust Paediatr J. 1989;25(5):288–91.

    PubMed  CAS  Google Scholar 

  54. Hausenloy DJ, Duchen MR, Yellon DM. Inhibiting mitochondrial permeability transition pore opening at reperfusion protects against ischaemia-reperfusion injury. Cardiovasc Res. 2003;60(3):617–25.

    Article  PubMed  CAS  Google Scholar 

  55. Cittadini A, Napoli R, Monti MG, Rea D, Longobardi S, Netti PA, et al. Metformin prevents the development of chronic heart failure in the SHHF rat model. Diabetes. 2012;61(4):944–53.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Dhahri W, Roussel E, Drolet M, Gascon S, Sarrhini O, Russeau J, et al. Metformin reduces left ventricular eccentric re-modeling in experimental volume overload in the rat. Clin Exp Cardiol. 2012;3(11):28.

  57. Benes J, Kazdova L, Drahota Z, Houstek J, Medrikova D, Kopecky J, et al. Effect of metformin therapy on cardiac function and survival in a volume-overload model of heart failure in rats. Clin Sci (Lond). 2011;121(1):29–41.

    Article  PubMed  CAS  Google Scholar 

  58. Cameron AR, Morrison VL, Levin D, Mohan M, Forteath C, Beall C, et al. Anti-inflammatory effects of metformin irrespective of diabetes status. Circ Res. 2016;119(5):652–65.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Saisho Y. Metformin and inflammation: its potential beyond glucose-lowering effect. Endocr Metab Immune Disord Drug Targets. 2015;15(3):196–205.

    Article  PubMed  CAS  Google Scholar 

  60. Kannel WB, McGee DL. Diabetes and cardiovascular disease. The Framingham study. JAMA. 1979;241(19):2035–8.

    Article  PubMed  CAS  Google Scholar 

  61. He J, Ogden LG, Bazzano LA, Vupputuri S, Loria C, Whelton PK. Risk factors for congestive heart failure in US men and women: NHANES I epidemiologic follow-up study. Arch Intern Med. 2001;161(7):996–1002.

    Article  PubMed  CAS  Google Scholar 

  62. Beckman JA, Creager MA, Libby P. Diabetes and atherosclerosis: epidemiology, pathophysiology, and management. JAMA. 2002;287(19):2570–81.

    Article  PubMed  CAS  Google Scholar 

  63. Reaven GM, Lithell H, Landsberg L. Hypertension and associated metabolic abnormalities–the role of insulin resistance and the sympathoadrenal system. N Engl J Med. 1996;334(6):374–81.

    Article  PubMed  CAS  Google Scholar 

  64. Coats AJ, Anker SD. Insulin resistance in chronic heart failure. J Cardiovasc Pharmacol. 2000;35(7 Suppl 4):S9–14.

    Article  PubMed  CAS  Google Scholar 

  65. Wong AK, Symon R, AlZadjali MA, Ang DS, Ogston S, Choy A, et al. The effect of metformin on insulin resistance and exercise parameters in patients with heart failure. Eur J Heart Fail. 2012;14(11):1303–10.

    Article  PubMed  CAS  Google Scholar 

  66. Nichols GA, Koro CE, Gullion CM, Ephross SA, Brown JB. The incidence of congestive heart failure associated with antidiabetic therapies. Diabetes Metab Res Rev. 2005;21(1):51–7.

    Article  PubMed  CAS  Google Scholar 

  67. Masoudi FA, Inzucchi SE, Wang Y, Havranek EP, Foody JM, Krumholz HM. Thiazolidinediones, metformin, and outcomes in older patients with diabetes and heart failure: an observational study. Circulation. 2005;111(5):583–90.

    Article  PubMed  CAS  Google Scholar 

  68. Romero SP, Andrey JL, Garcia-Egido A, Escobar MA, Perez V, Corzo R, et al. Metformin therapy and prognosis of patients with heart failure and new-onset diabetes mellitus. A propensity-matched study in the community. Int J Cardiol. 2013;167(4):1206–16. https://doi.org/10.1016/j.ijcard.2012.03.134.

  69. Eurich DT, Majumdar SR, McAlister FA, Tsuyuki RT, Johnson JA. Improved clinical outcomes associated with metformin in patients with diabetes and heart failure. Diabetes Care. 2005;28(10):2345–51.

    Article  PubMed  CAS  Google Scholar 

  70. Shah DD, Fonarow GC, Horwich TB. Metformin therapy and outcomes in patients with advanced systolic heart failure and diabetes. J Card Fail. 2010;16(3):200–6.

    Article  PubMed  CAS  Google Scholar 

  71. Evans JM, Doney AS, AlZadjali MA, Ogston SA, Petrie JR, Morris AD, et al. Effect of metformin on mortality in patients with heart failure and type 2 diabetes mellitus. Am J Cardiol. 2010;106(7):1006–10.

    Article  PubMed  CAS  Google Scholar 

  72. Eurich DT, McAlister FA, Blackburn DF, Majumdar SR, Tsuyuki RT, Varney J, et al. Benefits and harms of antidiabetic agents in patients with diabetes and heart failure: systematic review. BMJ. 2007;335(7618):497.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  73. Inzucchi SE, Masoudi FA, Wang Y, Kosiborod M, Foody JM, Setaro JF, et al. Insulin-sensitizing antihyperglycemic drugs and mortality after acute myocardial infarction: insights from the National Heart Care Project. Diabetes Care. 2005;28(7):1680–9.

    Article  PubMed  CAS  Google Scholar 

  74. Aguilar D, Chan W, Bozkurt B, Ramasubbu K, Deswal A. Metformin use and mortality in ambulatory patients with diabetes and heart failure. Circ Heart Fail. 2011;4(1):53–8.

    Article  PubMed  CAS  Google Scholar 

  75. Andersson C, Olesen JB, Hansen PR, Weeke P, Norgaard ML, Jorgensen CH, et al. Metformin treatment is associated with a low risk of mortality in diabetic patients with heart failure: a retrospective nationwide cohort study. Diabetologia. 2010;53(12):2546–53.

    Article  PubMed  CAS  Google Scholar 

  76. Norhammar A, Lindback J, Ryden L, Wallentin L, Stenestrand U. Improved but still high short- and long-term mortality rates after myocardial infarction in patients with diabetes mellitus: a time-trend report from the Swedish Register of Information and Knowledge about Swedish Heart Intensive Care Admission. Heart. 2007;93(12):1577–83.

    Article  PubMed  PubMed Central  Google Scholar 

  77. Bartnik M, Ryden L, Ferrari R, Malmberg K, Pyorala K, Simoons M, et al. The prevalence of abnormal glucose regulation in patients with coronary artery disease across Europe. The Euro Heart Survey on diabetes and the heart. Eur Heart J. 2004;25(21):1880–90.

    Article  PubMed  CAS  Google Scholar 

  78. Roussel R, Travert F, Pasquet B, Wilson PW, Smith SC Jr, Goto S, et al. Metformin use and mortality among patients with diabetes and atherothrombosis. Arch Intern Med. 2010;170(21):1892–9.

    Article  PubMed  CAS  Google Scholar 

  79. Ekstrom N, Schioler L, Svensson AM, Eeg-Olofsson K, Miao Jonasson J, Zethelius B, et al. Effectiveness and safety of metformin in 51 675 patients with type 2 diabetes and different levels of renal function: a cohort study from the Swedish National Diabetes Register. BMJ Open. 2012;2(4):e001076. https://doi.org/10.1136/bmjopen-2012-001076.

    Article  PubMed  PubMed Central  Google Scholar 

  80. Claesen M, Gillard P, De Smet F, Callens M, De Moor B, Mathieu C. Mortality in individuals treated with glucose-lowering agents: a large, controlled cohort study. J Clin Endocrinol Metab. 2016;101(2):461–9.

    Article  PubMed  CAS  Google Scholar 

  81. Cusi K, Consoli A, DeFronzo RA. Metabolic effects of metformin on glucose and lactate metabolism in noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab. 1996;81(11):4059–67.

    PubMed  CAS  Google Scholar 

  82. DeFronzo RA, Goodman AM. Efficacy of metformin in patients with non-insulin-dependent diabetes mellitus. The Multicenter Metformin Study Group. N Engl J Med. 1995;333(9):541–9.

    Article  PubMed  CAS  Google Scholar 

  83. Wu MS, Johnston P, Sheu WH, Hollenbeck CB, Jeng CY, Goldfine ID, et al. Effect of metformin on carbohydrate and lipoprotein metabolism in NIDDM patients. Diabetes Care. 1990;13(1):1–8.

    Article  PubMed  CAS  Google Scholar 

  84. Mellbin LG, Malmberg K, Norhammar A, Wedel H, Ryden L. The impact of glucose lowering treatment on long-term prognosis in patients with type 2 diabetes and myocardial infarction: a report from the DIGAMI 2 trial. Eur Heart J. 2008;29(2):166–76.

    Article  PubMed  CAS  Google Scholar 

  85. Frye RL, August P, Brooks MM, Hardison RM, Kelsey SF, MacGregor JM, et al. A randomized trial of therapies for type 2 diabetes and coronary artery disease. N Engl J Med. 2009;360(24):2503–15.

    Article  PubMed  CAS  Google Scholar 

  86. Gerstein HC, Miller ME, Byington RP, Goff DC Jr, Bigger JT, Buse JB, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358(24):2545–59.

    Article  PubMed  CAS  Google Scholar 

  87. Preiss D, Lloyd SM, Ford I, McMurray JJ, Holman RR, Welsh P, et al. Metformin for non-diabetic patients with coronary heart disease (the CAMERA study): a randomised controlled trial. Lancet Diabetes Endocrinol. 2014;2(2):116–24.

    Article  PubMed  CAS  Google Scholar 

  88. Lexis CP, van der Horst IC, Lipsic E, Wieringa WG, de Boer RA, van den Heuvel AF, 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(15):1526–35.

    Article  PubMed  CAS  Google Scholar 

  89. Lamanna C, Monami M, Marchionni N, Mannucci E. Effect of metformin on cardiovascular events and mortality: a meta-analysis of randomized clinical trials. Diabetes Obes Metab. 2011;13(3):221–8.

    Article  PubMed  CAS  Google Scholar 

  90. Holstein A, Nahrwold D, Hinze S, Egberts EH. Contra-indications to metformin therapy are largely disregarded. Diabet Med. 1999;16(8):692–6.

    Article  PubMed  CAS  Google Scholar 

  91. Buse JB, DeFronzo RA, Rosenstock J, Kim T, Burns C, Skare S, et al. The primary glucose-lowering effect of metformin resides in the gut, not the circulation: results from short-term pharmacokinetic and 12-week dose-ranging studies. Diabetes Care. 2016;39(2):198–205.

    PubMed  CAS  Google Scholar 

  92. Sweileh WM. Contraindications to metformin therapy among patients with type 2 diabetes mellitus. Pharm World Sci. 2007;29(6):587–92.

    Article  PubMed  CAS  Google Scholar 

  93. Hung SC, Chang YK, Liu JS, Kuo KL, Chen YH, Hsu CC, et al. Metformin use and mortality in patients with advanced chronic kidney disease: national, retrospective, observational, cohort study. Lancet Diabetes Endocrinol. 2015;3(8):605–14.

    Article  PubMed  CAS  Google Scholar 

  94. Calabrese AT, Coley KC, DaPos SV, Swanson D, Rao RH. Evaluation of prescribing practices: risk of lactic acidosis with metformin therapy. Arch Intern Med. 2002;162(4):434–7.

    Article  PubMed  Google Scholar 

  95. Jones P, Yate P. Contraindications to use of metformin. Blanket banning of metformin two days before surgery may not be a good idea. BMJ. 2003;326(7392):762; author reply 762.

    Article  PubMed  PubMed Central  Google Scholar 

  96. Salpeter SR, Greyber E, Pasternak GA, Salpeter EE. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Cochrane Database Syst Rev. 2010;4:CD002967.

    Google Scholar 

  97. Cryer DR, Nicholas SP, Henry DH, Mills DJ, Stadel BV. Comparative outcomes study of metformin intervention versus conventional approach the COSMIC Approach Study. Diabetes Care. 2005;28(3):539–43.

    Article  PubMed  CAS  Google Scholar 

  98. Lalau JD, Race JM. Lactic acidosis in metformin therapy: searching for a link with metformin in reports of ‘metformin-associated lactic acidosis’. Diabetes Obes Metab. 2001;3(3):195–201.

    Article  PubMed  CAS  Google Scholar 

  99. Shenoy C. Metformin-associated lactic acidosis precipitated by acute renal failure. Am J Med Sci. 2006;331(1):55–7.

    Article  PubMed  Google Scholar 

  100. DePalo VA, Mailer K, Yoburn D, Crausman RS. Lactic acidosis. Lactic acidosis associated with metformin use in treatment of type 2 diabetes mellitus. Geriatrics. 2005;60(11):36, 9–41.

  101. Rachmani R, Slavachevski I, Levi Z, Zadok B, Kedar Y, Ravid M. Metformin in patients with type 2 diabetes mellitus: reconsideration of traditional contraindications. Eur J Intern Med. 2002;13(7):428.

    Article  PubMed  CAS  Google Scholar 

  102. Inzucchi SE, Masoudi FA, McGuire DK. Metformin in heart failure. Diabetes Care. 2007;30(12):e129.

    Article  PubMed  Google Scholar 

  103. Lalau JD, Race JM. Lactic acidosis in metformin-treated patients. Prognostic value of arterial lactate levels and plasma metformin concentrations. Drug Saf. 1999;20(4):377–84.

    Article  PubMed  CAS  Google Scholar 

  104. Lalau JD, Race JM. Lactic acidosis in metformin therapy. Drugs. 1999;58(Suppl 1):55–60 (discussion 75–82).

    Article  PubMed  CAS  Google Scholar 

  105. Tahrani AA, Varughese GI, Scarpello JH, Hanna FW. Metformin, heart failure, and lactic acidosis: is metformin absolutely contraindicated? BMJ. 2007;335(7618):508–12.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  106. Inzucchi SE, Masoudi FA, McGuire DK. Metformin therapy in patients with type 2 diabetes complicated by heart failure. Am Heart J. 2007;154(6):e45.

    Article  PubMed  Google Scholar 

  107. Khurana R, Malik IS. Metformin: safety in cardiac patients. Heart. 2010;96(2):99–102.

    PubMed  CAS  Google Scholar 

  108. Misbin RI. The phantom of lactic acidosis due to metformin in patients with diabetes. Diabetes Care. 2004;27(7):1791–3.

    Article  PubMed  Google Scholar 

  109. Lalau JD, Race JM. Metformin and lactic acidosis in diabetic humans. Diabetes Obes Metab. 2000;2(3):131–7.

    Article  PubMed  CAS  Google Scholar 

Download references

Funding

No external funding was used in the preparation of this manuscript.

Author information

Authors and Affiliations

  1. Carilion Roanoke Memorial Hospital, Roanoke, VA, 24014, USA

    Leon Varjabedian

  2. Department of Medicine, University at Buffalo, Buffalo, NY, 14203, USA

    Mohammad Bourji

  3. Department of Anesthesiology, University at Buffalo, 77 Goodell Street # 550, Buffalo, NY, 14203, USA

    Leili Pourafkari & Nader D. Nader

Authors
  1. Leon Varjabedian
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mohammad Bourji
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Leili Pourafkari
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Nader D. Nader
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Nader D. Nader.

Ethics declarations

Conflict of interest

Leon Varjabedian, Mohammad Bourji, Leili Pourafkari and Nader D. Nader declare that they have no conflict of interest that might be relevant to the contents of this manuscript.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Varjabedian, L., Bourji, M., Pourafkari, L. et al. Cardioprotection by Metformin: Beneficial Effects Beyond Glucose Reduction. Am J Cardiovasc Drugs 18, 181–193 (2018). https://doi.org/10.1007/s40256-018-0266-3

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40256-018-0266-3

Search

Navigation