Metformin in Diabetic Patients with Heart Failure: Safe and Effective

Current Cardiovascular Risk Reports

Volumn 7, Issue 6, 2013, Pages 417-422

  Ekeruo, Ijeoma Ananaba ^a   Solhpour, Amirreza ^a   Taegtmeyer, Heinrich ^a  

^a UNIVERSITY OF TEXAS MEDICAL SCHOOL   (United States)

Author keywords

Anti diabetic drugs; Heart failure; Type 2 diabetes mellitus

Indexed keywords

CYCLIC AMP DEPENDENT PROTEIN KINASE; GLUCOSE; GLUCOSE 6 PHOSPHATE; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE KINASE; MAMMALIAN TARGET OF RAPAMYCIN; METFORMIN; MYOCYTE ENHANCER FACTOR 2; PHENFORMIN; TRANSFORMING GROWTH FACTOR BETA1;

CONGESTIVE HEART FAILURE; DIABETES MELLITUS; DIABETIC CARDIOMYOPATHY; DRUG EFFICACY; DRUG SAFETY; HEART FAILURE; HUMAN; LACTIC ACIDOSIS; NONHUMAN; REVIEW;

EID: 84887532029     PISSN: 19329520     EISSN: 19329563     Source Type: Journal    
DOI: 10.1007/s12170-013-0355-4     Document Type: Review

References (55)

1. Cowie CC, Rust KF, Byrd-Holt DD, Gregg EW, Ford ES, Geiss LS, et al. Prevalence of diabetes and high risk for diabetes using A1c criteria in the U. S. Population in 1988-2006. Diabetes Care. 2010;33(3): 562-8.
2. American Diabetes Association. Economic costs of diabetes in the U. S. in 2012. Diabetes Care. 2013;36(4): 1033-46.
3. 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.
4. Nissen SE. The rise and fall of rosiglitazone. Eur Heart J. 2010;31(7): 773-6.
5. 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. A retrospective cohort study that included 401 patients with DM and severe heart failure followed between 1994 and 2008. Although there was a trend to improvement of outcomes in the patients on metformin, the results were not statistically significant.
6. Khalaf KI, Taegtmeyer H. After Avandia: the use of Antidiabetic drugs in patients with heart failure. Tex Heart Inst J. 2012;39(2): 174-8.
7. Purcell IF, Poole-Wilson PA. Heart failure: why and how to define it? Eur J Heart Fail. 1999;1(1): 7-10.
8. Kannel WB, Hjortland M, Castelli WP. Role of diabetes in congestive heart failure: the Framingham study. Am J Cardiol. 1974;34(1): 29-34.
9. 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.
10. Bertoni AG, Tsai A, Kasper EK, Brancati FL. Diabetes and idiopathic cardiomyopathy: a nationwide case-control study. Diabetes Care. 2003;26(10): 2791-5.
11. 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.
12. Taegtmeyer H, McNulty P, Young ME. Adaptation and maladaptation of the heart in diabetes: part I: general concepts. Circulation. 2002;105(14): 1727-33.
13. Factor SM, Borczuk A, Charron MJ, Fein FS, van Hoeven KH, Sonnenblick EH. Myocardial alterations in diabetes and hypertension. Diabetes Res Clin Pract. 1996;31(Suppl): S133-42.
14. Devereux RB, Roman MJ, Paranicas M, O'Grady MJ, Lee ET, Welty TK, et al. Impact of diabetes on cardiac structure and function: the strong heart study. Circulation. 2000;101(19): 2271-6.
15. Hardin NJ. The myocardial and vascular pathology of diabetic cardiomyopathy. Coron Artery Dis. 1996;7(2): 99-108.
16. Dhalla NS, Liu X, Panagia V, Takeda N. Subcellular remodeling and heart dysfunction in chronic diabetes. Cardiovasc Res. 1998; 40(2): 239-47.
17. MacDonald MR, Petrie MC, Hawkins NM, Petrie JR, Fisher M, McKelvie R, et al. Diabetes, left ventricular systolic dysfunction, and chronic heart failure. Eur Heart J. 2008;29(10): 1224-40.
18. Razeghi P, Young ME, Cockrill TC, Frazier OH, Taegtmeyer H. Downregulation of myocardial myocyte enhancer factor 2c and myocyte enhancer factor 2c-regulated gene expression in diabetic patients with nonischemic heart failure. Circulation. 2002;106(4): 407-11.
19. Young ME, Yan J, Razeghi P, Cooksey RC, Guthrie PH, Stepkowski SM, McClain DA, Tian R, Taegtmeyer H. Proposed regulation of gene expression by glucose in rodent heart. Gene Regul Syst Bio. 2007;1: 1251-262.
20. Benbow A, Stewart M, Yeoman G. Thiazolidinediones for type 2 diabetes. All glitazones may exacerbate heart failure. BMJ. 2001;322(7280): 236.
21. Gerstein HC, Miller ME, Byington RP, Goff Jr DC, Bigger JT, Buse JB, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358(24): 2545-59.
22. Finfer S, Chittock DR, Su SY, Blair D, Foster D, Dhingra V, et al. Intensive versus conventional glucose control in critically ill patients. N Engl J Med. 2009;360(13): 1283-97.
23. Selvin E, Bolen S, Yeh HC, Wiley C, Wilson LM, Marinopoulos SS, et al. Cardiovascular outcomes in trials of oral diabetes medications: a systematic review. Arch Intern Med. 2008;168(19): 2070-80.
24. 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. 2010;4(1): 53-8. A multicenter retrospective cohort study that studied metformin use in ambulatory patients with DM and CHF. Here, metformin use was associated with a significantly lower rate of mortality. Surprisingly, in this study the effect of the use of metformin on the rate of hospitalizations was minimal.
25. Ingelsson E, Sundstrom J, Arnlov J, Zethelius B, Lind L. Insulin resistance and risk of congestive heart failure. JAMA. 2005;294(3): 334-41.
26. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med. 2007;356(24): 2457-71.
27. Khalaf KI, Taegtmeyer H. Insulin sensitizers and heart failure: an engine flooded with fuel. Curr Hypertens Rep. 2010;12(6): 399-401. A concise review of the literature, drawing special attention to the present difficulty in treating patients.
28. Brunton L, Chabner B, Knollman B. Goodman and Gillman's the pharmacological basis of therapeutics. New York: McGraw Hill Professional Publications; 2010.
29. Hardie G. AMPK: a target for drugs and natural products with effects on both diabetes and cancer. Diabetes. 2013;62(7): 2164-72.
30. Miller RA, Chu Q, Xie J, Foretz M, Viollet B, Birnbaum MJ. Biguanides suppress hepatic glucagon signalling by decreasing production of cyclic AMP. Nature. 2013;494(7436): 256-60.
31. Martin-Montalvo A, Mercken EM, Mitchell SJ, Palacios HH, Mote PL, Scheibye-Knudsen M, et al. Metformin improves healthspan and lifespan in mice. Nat Commun. 2013;4: 2192.
32. 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.
33. 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.
34. 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. A rodent animal study investigating cardioprotective effects of metformin. Specifically the role of metformin in decreasing cardiac fibrosis was investigated and a pathway was proposed.
35. 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.
36. Shimizu I, Minamino T, Toko H, Okada S, Ikeda H, Yasuda N, et al. Excessive cardiac insulin signaling exacerbates systolic dysfunction induced by pressure overload in rodents. J Clin Invest. 2010;120(5): 1506-14.
37. 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.
38. Russell 3rd RR, 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 Invest. 2004;114(4): 495-503.
39. Hausenloy DJ, Yellon DM. Reperfusion injury salvage kinase signalling: taking a risk for cardioprotection. Heart Fail Rev. 2007;12(3-4): 217-34.
40. Hausenloy DJ. Cardioprotection techniques: preconditioning, postconditioning and remote conditioning (basic science). Curr Pharm Des. 2013;19(25): 4544-63.
41. Hausenloy DJ, Yellon DM. Myocardial ischemia-reperfusion injury: a neglected therapeutic target. J Clin Invest. 2013;123(1): 92-100.
42. Cohn JN, Ferrari R, Sharpe N. Cardiac remodeling-concepts and clinical implications: a consensus paper from an international forum on cardiac remodeling. Behalf of an international forum on cardiac remodeling. J Am Coll Cardiol. 2000;35(3): 569-82.
43. Whittington HJ, Harding I, Stephenson CI, Bell R, Hausenloy DJ, Mocanu MM, et al. Cardioprotection in the aging, diabetic heart: The loss of protective akt signalling. Cardiovasc Res. 2013;99(4): 694-704.
44. Sen S, Kundu BK, Wu HC, Hashmi SS, Guthrie P, Locke LW, et al. Glucose regulation of load-induced mTOR signaling and ER stress in mammalian heart. J Am Heart Assoc. 2013;2(3): e004796. This study shows for the fist time that an intermediary metabolie (glucose 6-phosphate, G6P) regulates mTOR, the endoplasmic reticulum (ER) stress response and contratile efficiency in animal models and the failing human heart. Metformin improves contractile function by reducing G6P levels and ER stress.
45. Luft D, Schmulling RM, Eggstein M. Lactic acidosis in biguanide-treated diabetics: a review of 330 cases. Diabetologia. 1978;14(2): 75-87.
46. Chang CT, Chen YC, Fang JT, Huang CC. Metformin-associated lactic acidosis: case reports and literature review. J Nephrol. 2002;15(4): 398-402.
47. Sulkin TV, Bosman D, Krentz AJ. Contraindications to metformin therapy in patients with niddm. Diabetes Care. 1997;20(6): 925-8.
48. Misbin RI, Green L, Stadel BV, Gueriguian JL, Gubbi A, Fleming GA. Lactic acidosis in patients with diabetes treated with metformin. N Engl J Med. 1998;338(4): 265-6.
49. Eurich DT, Weir DL, Majumdar SR, Tsuyuki RT, Johnson JA, Tjosvold L, et al. Comparative safety and effectiveness of metformin in patients with diabetes mellitus and heart failure: systematic review of observational studies involving 34, 000 patients. Circ Heart Fail. 2013;6(3): 395-402.
50. 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.
51. 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. Longitudinal animal study where rats with hypertensive heart disease were treated with metformin and rosiglitazone. Metformin was associated with improved cardiac outcomes and decreased progression to heart failure.
52. 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.
53. Braunwald E, Bristow MR. Congestive heart failure: fifty years of progress. Circulation. 2000;102(20 Suppl 4): IV14-23.
54. Algahim MF, Sen S, Taegtmeyer H. Bariatric surgery to unload the stressed heart: a metabolic hypothesis. Am J Physiol Heart Circ Physiol. 2012;302(8): H1539-45.
55. Lavie CJ, Alpert MA, Arena R, Mehra MR, Milani RV, Ventura HO. Impact of obesity and the obesity paradox on prevalence and prognosis in heart failure. J Am Coll Cardiol HF. 2013;1(2): 93-102.