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Use of Metformin in Diseases of Aging

  • Pharmacologic Treatment of Type 2 Diabetes (A Vella, Section Editor)
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Abstract

Metformin is the most commonly prescribed medication for type 2 diabetes (T2DM) in the world. It has primacy in the treatment of this disease because of its safety record and also because of evidence for reduction in the risk of cardiovascular events. Evidence has accumulated indicating that metformin is safe in people with stage 3 chronic kidney disease (CKD-3). It is estimated that roughly one-quarter of people with CKD-3 and T2DM in the United States (well over 1 million) are ineligible for metformin treatment because of elevated serum creatinine levels. This could be overcome if a scheme, perhaps based on pharmacokinetic studies, could be developed to prescribe reduced doses of metformin in these individuals. There is also substantial evidence from epidemiologic studies to indicate that metformin may not only be safe, but may actually benefit people with heart failure (HF). Prospective, randomized trials of the use of metformin in HF are needed to investigate this possibility.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. Stamler J, Vaccaro O, Neaton JD, Wentworth D. Diabetes, other risk factors, and 12-yr cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial. Diabetes Care. 1993;16:434–44.

    CAS  PubMed  Google Scholar 

  2. Gu K, Cowie CC, Harris MI. Mortality in adults with and without diabetes in a national cohort of the U.S. population, 1971-1993. Diabetes Care. 1998;21:1138–45.

    CAS  PubMed  Google Scholar 

  3. Haffner SM. Epidemiology of insulin resistance and its relation to coronary artery disease. Am J Cardiol. 1999;84:11J–4.

    CAS  PubMed  Google Scholar 

  4. Lakatta EG, Levy D. Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises: Part I: aging arteries: a “set up” for vascular disease. Circulation. 2003;107:139–46.

    PubMed  Google Scholar 

  5. Huang ES, Liu JY, Moffet HH, John PM, Karter AJ. Glycemic control, complications, and death in older diabetic patients: the diabetes and aging study. Diabetes Care. 2011;34:1329–36.

    PubMed Central  PubMed  Google Scholar 

  6. Werner E, Bell J. CCXIV. The preparation of methylguanidine, and of ββ-dimethylguanidine by the interaction of dicyandiamide, and methylammonium and dimethylammonium chlorides, respectively. J Chem Soc Trans. 1922;121:1790–4.

    CAS  Google Scholar 

  7. Banting F, Best C. The internal secretion of the pancreas. J Lab Clin Med. 1922;125:251–66.

    Google Scholar 

  8. Nathan DM, Buse JB, Davidson MB, Heine RJ, Holman RR, Sherwin R, et al. Management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2006;29:1963–72.

    PubMed  Google Scholar 

  9. Home PD. Impact of the UKPDS—an overview. Diabetic Med. 2008;25 Suppl 2:2–8.

    PubMed  Google Scholar 

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

  11. Holman R, Paul S, Bethel M, Matthews D, Neil H. Ten-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359:1577–89.

    CAS  PubMed  Google Scholar 

  12. Roussel R, Travert F, Pasquet B, Wilson PWF, Smith Jr SC, Goto S, et al. Reduction of atherothrombosis for continued health Registry I: metformin use and mortality among patients with diabetes and atherothrombosis. Arch Intern Med. 2010;170:1892–9. This is an epidemiological study in ~20,000 patients with type 2 diabetes and cardiovascular disease. In the study, metformin therapy was associated with a 31 % lower mortality from heart failure and a 24 % lower all-cause mortality.

  13. Klip A, Leiter LA. Cellular mechanism of action of metformin. Diabetes Care. 1990;13:696–704.

    CAS  PubMed  Google Scholar 

  14. DeFronzo RA. Pharmacologic therapy for type 2 diabetes mellitus. Ann Int Med. 1999;131:281–303.

    CAS  PubMed  Google Scholar 

  15. Perriello G, Misericordia P, Volpi E, Santucci A, Santucci C, Ferrannini E, et al. Acute antihyperglycemic mechanisms of metformin in NIDDM. Evidence for suppression of lipid oxidation and hepatic glucose production. Diabetes. 1994;43:920–8.

    CAS  PubMed  Google Scholar 

  16. Scheen AJ. Clinical pharmacokinetics of metformin. Clin Pharmacokinet. 1996;30:359–71.

    CAS  PubMed  Google Scholar 

  17. Scarpello JH, Hodgson E, Howlett HC. Effect of metformin on bile salt circulation and intestinal motility in type 2 diabetes mellitus. Diabetic Med. 1998;15:651–6.

    CAS  PubMed  Google Scholar 

  18. 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;13:1–8.

    CAS  PubMed  Google Scholar 

  19. 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;333:541–9.

    CAS  PubMed  Google Scholar 

  20. Stumvoll M, Nurjhan N, Perriello G, Dailey G, Gerich JE. Metabolic effects of metformin in non-insulin-dependent diabetes mellitus. N Engl J Med. 1995;333:550–4.

    CAS  PubMed  Google Scholar 

  21. Makimattila S, Nikkila K, Yki-Jarvinen H. Causes of weight gain during insulin therapy with and without metformin in patients with Type II diabetes mellitus. Diabetologia. 1999;42:406–12.

    CAS  PubMed  Google Scholar 

  22. Willi SM, Martin K, Datko FM, Brant BP. Treatment of type 2 diabetes in childhood using a very-low-calorie diet. Diabetes Care. 2004;27:348–53.

    PubMed  Google Scholar 

  23. Kelley DE, Wing R, Buonocore C, Sturis J, Polonsky K, Fitzsimmons M. Relative effects of calorie restriction and weight loss in noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab. 1993;77:1287–93.

    CAS  PubMed  Google Scholar 

  24. Williamson DF, Thompson TJ, Thun M, Flanders D, Pamuk E, Byers T. Intentional weight loss and mortality among overweight individuals with diabetes. Diabetes Care. 2000;23:1499–504.

    CAS  PubMed  Google Scholar 

  25. Sobel BE, Frye R, Detre KM. Bypass Angioplasty Revascularization Investigation 2 Diabetes T: burgeoning dilemmas in the management of diabetes and cardiovascular disease: rationale for the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) Trial. Circulation. 2003;107:636–42.

    PubMed  Google Scholar 

  26. Chu NV, Kong APS, Kim DD, Armstrong D, Baxi S, Deutsch R, et al. Differential effects of metformin and troglitazone on cardiovascular risk factors in patients with type 2 diabetes. Diabetes Care. 2002;25:542–9.

    CAS  PubMed  Google Scholar 

  27. Miles JM, Wooldridge D, Grellner WJ, Windsor S, Isley WL, Klein S, et al. Nocturnal and postprandial free fatty acid kinetics in normal and type 2 diabetic subjects: effects of insulin sensitization therapy. Diabetes. 2003;52:675–81.

    CAS  PubMed  Google Scholar 

  28. Fendri S, Debussche X, Puy H, Vincent O, Marcelli JM, Dubreuil A, et al. Metformin effects on peripheral sensitivity to insulin in nondiabetic obese subjects. Diabete Metab. 1993;19:245–9.

    CAS  PubMed  Google Scholar 

  29. Pentikainen PJ, Neuvonen PJ, Penttila A. Pharmacokinetics of metformin after intravenous and oral administration to man. Eur J Clin Pharmacol. 1979;16:195–202.

    CAS  PubMed  Google Scholar 

  30. Proctor WR, Bourdet DL, Thakker DR. Mechanisms underlying saturable intestinal absorption of metformin. Drug Metab Dispos. 2008;36:1650–8.

    CAS  PubMed  Google Scholar 

  31. Sirtori CR, Franceschini G, Galli-Kienle M, Cighetti G, Galli G, Bondioli A, et al. Disposition of metformin (N, N-dimethylbiguanide) in man. Clin Pharmacol Ther. 1978;24:683–93.

    CAS  PubMed  Google Scholar 

  32. Rule A, Amer H, Cornell L, Taler S, Cosio F, Kremers W, et al. The association between age and nephrosclerosis on renal biopsy among healthy adults. Ann Int Med. 2010;152:561–7.

    PubMed Central  PubMed  Google Scholar 

  33. Wetzels J, Kiemeney L, Swinkels D, Willems H, den Heijer M. Age- and gender-specific reference values of estimated GFR in Caucasians: the Nijmegen Biomedical Study. Kidney Int. 2007;72:632–7.

    CAS  PubMed  Google Scholar 

  34. Schaeffner E, Ebert N, Delanaye P, Frei U, Gaedeke J, Jakob O, et al. Two novel equations to estimate kidney function in persons aged 70 years or older. Ann Int Med. 2012;157:471–81.

    PubMed  Google Scholar 

  35. Grams M, Juraschek S, Selvin E, Foster M, Inker L, Eckfeldt J, et al. Trends in the prevalence of reduced GFR in the United States: a comparison of creatinine—and cystatin C-based estimates. Am J Kidney Dis. 2013;62:253–60.

    CAS  PubMed Central  PubMed  Google Scholar 

  36. Glassock RJ, Rule AD. The implications of anatomical and functional changes of the aging kidney: with an emphasis on the glomeruli. Kidney Int. 2012;82:270–7.

    PubMed Central  PubMed  Google Scholar 

  37. Wang X, Vrtiska TJ, Avula RT, Walters LR, Chakkera HA, Kremers WK, et al. Age, kidney function, and risk factors associate differently with cortical and medullary volumes of the kidney. Kidney Int. 2014;85:677-85.

    Google Scholar 

  38. Foley RN, Wang C, Collins AJ. Cardiovascular risk factor profiles and kidney function stage in the US general population: the NHANES III study. Mayo Clin Proc. 2005;80:1270–7.

    PubMed  Google Scholar 

  39. Koro CE, Lee BH, Bowlin SJ. Antidiabetic medication use and prevalence of chronic kidney disease among patients with type 2 diabetes mellitus in the United States. Clin Ther. 2009;31:2608–17.

    PubMed  Google Scholar 

  40. Coresh J, Astor BC, Greene T, Eknoyan G, Levey AS. Prevalence of chronic kidney disease and decreased kidney function in the adult US population: Third National Health and Nutrition Examination Survey. Am J Kidney Dis. 2003;41:1–12.

    PubMed  Google Scholar 

  41. Macisaac RJ, Jerums G. Diabetic kidney disease with and without albuminuria. Curr Op Neph Hypertens. 2011;20:246–57.

    CAS  Google Scholar 

  42. Howlett HC, Bailey CJ. A risk-benefit assessment of metformin in type 2 diabetes mellitus. Drug Saf. 1999;20:489–503.

    CAS  PubMed  Google Scholar 

  43. Warren RE, Strachan MWJ, Wild S, McKnight JA. Introducing estimated glomerular filtration rate (eGFR) into clinical practice in the UK: implications for the use of metformin. Diabetic Med. 2007;24:494–7.

    CAS  PubMed  Google Scholar 

  44. Earley A, Miskulin D, Lamb EJ, Levey AS, Uhlig K. Estimating equations for glomerular filtration rate in the era of creatinine standardization: a systematic review. Ann Int Med. 2012;156:785–95.

    PubMed  Google Scholar 

  45. Cohen R. The relative risks of different biguanides in the causation of lactic acidosis. Res Clin Forums. 1978;1:125–34.

    Google Scholar 

  46. Ekstrom N, Schioler L, Svensson A-M, Eeg-Olofsson K, 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:e001076. This study of over 50,000 people in the Swedish Diabetes. Registry includes >32,000 individuals on metformin and >4000 with CKD-3.It reports a hazard ratio of 0.85 for infection or acidosis and 0.87 for all-cause mortality vs other agents (both P <0.05).

    PubMed Central  PubMed  Google Scholar 

  47. Vasisht KP, Chen SC, Peng Y, Bakris GL. Limitations of metformin use in patients with kidney disease: are they warranted? Diabetes Obes Metab. 2010;12:1079–83.

    CAS  PubMed  Google Scholar 

  48. Nattrass M, Todd PG, Hinks L, Lloyd B, Alberti KG. Comparative effects of phenformin, metformin and glibenclamide on metabolic rhythms in maturity-onset diabetics. Diabetologia. 1977;13:145–52.

    CAS  PubMed  Google Scholar 

  49. Davis TM, Jackson D, Davis WA, Bruce DG, Chubb P. The relationship between metformin therapy and the fasting plasma lactate in type 2 diabetes: the Fremantle Diabetes Study. Brit J Clin Pharm. 2001;52:137–44.

    CAS  PubMed Central  PubMed  Google Scholar 

  50. van der Meer RW, Rijzewijk LJ, de Jong HWAM, Lamb HJ, Lubberink M, Romijn JA, et al. Pioglitazone improves cardiac function and alters myocardial substrate metabolism without affecting cardiac triglyceride accumulation and high-energy phosphate metabolism in patients with well-controlled type 2 diabetes mellitus. Circulation. 2009;119:2069–77.

    PubMed  Google Scholar 

  51. 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:CD002967.

  52. Lalau JD, Lacroix C, Compagnon P, de Cagny B, Rigaud JP, Bleichner G, et al. Role of metformin accumulation in metformin-associated lactic acidosis. Diabetes Care. 1995;18:779–84.

    CAS  PubMed  Google Scholar 

  53. Galea M, Jelacin N, Bramham K, White I. Severe lactic acidosis and rhabdomyolysis following metformin and ramipril overdose. Brit J Anaesth. 2007;98:213–5.

    CAS  PubMed  Google Scholar 

  54. Miller DK, Brinson AJ, Catalano G, Catalano MC. Lactic acidosis, hypotension, and sensorineural hearing loss following intentional metformin overdose. Curr Drug Safety. 2011;6:346–9.

    CAS  Google Scholar 

  55. Perrone J, Phillips C, Gaieski D. Occult metformin toxicity in three patients with profound lactic acidosis. J Emerg Med. 2011;40:271–5.

    PubMed  Google Scholar 

  56. Rifkin SI, McFarren C, Juvvadi R, Weinstein SS. Prolonged hemodialysis for severe metformin intoxication. Ren Fail. 2011;33:459–61.

    PubMed  Google Scholar 

  57. Wills BK, Bryant SM, Buckley P, Seo B. Can acute overdose of metformin lead to lactic acidosis? Am J Emerg Med. 2010;28:857–61.

    PubMed  Google Scholar 

  58. Sambol NC, Chiang J, Lin ET, Goodman AM, Liu CY, Benet LZ, et al. Kidney function and age are both predictors of pharmacokinetics of metformin. J Clin Pharm. 1995;35:1094–102.

    CAS  Google Scholar 

  59. Bardin C, Nobecourt E, Larger E, Chast F, Treluyer J-M, Urien S. Population pharmacokinetics of metformin in obese and non-obese patients with type 2 diabetes mellitus. Eur J Clin Pharm. 2012;68:961–8.

    CAS  Google Scholar 

  60. Arias E, Anderson RN, Kung H-C, Murphy SL, Kochanek KD. Deaths: final data for 2001. Natl Vital Stat Rep. 2003;52:1–115.

    PubMed  Google Scholar 

  61. Owan TE, Hodge DO, Herges RM, Jacobsen SJ, Roger VL, Redfield MM. Trends in prevalence and outcome of heart failure with preserved ejection fraction. New Engl J Med. 2006;355:251–9.

    CAS  PubMed  Google Scholar 

  62. Chamberlain A, McNallan S, Dunlay S, Spertus J, Redfield M, Moser D, et al. Physical health status measures predict all-cause mortality in patients with heart failure. Circ Heart Fail. 2013;6:669–75.

    PubMed Central  PubMed  Google Scholar 

  63. Dunlay S, Gerber Y, Weston S, Killian J, Redfield M, Roger V. Prognostic value of biomarkers in heart failure: application of novel methods in the community. Circ Heart Fail. 2009;2:393–400.

    CAS  PubMed Central  PubMed  Google Scholar 

  64. Borlaug BA, Melenovsky V, Russell SD, Kessler K, Pacak K, Becker LC, et al. Impaired chronotropic and vasodilator reserves limit exercise capacity in patients with heart failure and a preserved ejection fraction. Circulation. 2006;114:2138–47.

    PubMed  Google Scholar 

  65. Mohammed S, Borlaug B, Roger V, Mirzoyev S, Rodeheffer R, Chirinos J, et al. Comorbidity and ventricular and vascular structure and function in heart failure with preserved ejection fraction: a community-based study. Circ Heart Fail. 2012;5:710–9.

    PubMed Central  PubMed  Google Scholar 

  66. van Heerebeek L, Franssen C, Hamdani N, Verheugt F, Somsen G, Paulus WJ. Molecular and cellular basis for diastolic dysfunction. Circ Heart Fail. 2012;9:293–302.

    CAS  Google Scholar 

  67. Borlaug B, Redfield M, Melenovsky V, Kane G, Karon B, Jacobsen S, et al. Longitudinal changes in left ventricular stiffness: a community-based study. Circ Heart Fail. 2013;6:944–52.

    PubMed  Google Scholar 

  68. Nichols GA, Gullion CM, Koro CE, Ephross SA, Brown JB. The incidence of congestive heart failure in type 2 diabetes: an update. Diabetes Care. 2004;27:1879–84.

    PubMed  Google Scholar 

  69. De Groote P, Lamblin N, Mouquet F, Plichon D, McFadden E, Van Belle E, et al. Impact of diabetes mellitus on long-term survival in patients with congestive heart failure. Eur Heart J. 2004;25:656–62.

    PubMed  Google Scholar 

  70. Borlaug BA, Paulus WJ. Heart failure with preserved ejection fraction: pathophysiology, diagnosis, and treatment. Eur Heart J. 2011;32:670–9.

    PubMed Central  PubMed  Google Scholar 

  71. Diamant M, Lamb HJ, Groeneveld Y, Endert EL, Smit JWA, Bax JJ, et al. Diastolic dysfunction is associated with altered myocardial metabolism in asymptomatic normotensive patients with well-controlled type 2 diabetes mellitus. J Am Coll Cardiol. 2003;42:328–35.

    CAS  PubMed  Google Scholar 

  72. Smith CS, Bottomley PA, Schulman SP, Gerstenblith G, Weiss RG. Altered creatine kinase adenosine triphosphate kinetics in failing hypertrophied human myocardium. Circulation. 2006;114:1151–8.

    CAS  PubMed Central  PubMed  Google Scholar 

  73. Phan TT, Abozguia K, Nallur Shivu G, Mahadevan G, Ahmed I, Williams L, et al. Heart failure with preserved ejection fraction is characterized by dynamic impairment of active relaxation and contraction of the left ventricle on exercise and associated with myocardial energy deficiency. J Am Coll Cardiol. 2009;54:402–9.

    PubMed  Google Scholar 

  74. Lind M, Olsson M, Rosengren A, Svensson A-M, Bounias I, Gudbjornsdottir S. The relationship between glycaemic control and heart failure in 83,021 patients with type 2 diabetes. Diabetologia. 2012;55:2946–53.

    CAS  PubMed  Google Scholar 

  75. Nesto RW, Bell D, Bonow RO, Fonseca V, Grundy SM, Horton ES, et al. American Heart Association, American Diabetes Association: thiazolidinedione use, fluid retention, and congestive heart failure: a consensus statement from the American Heart Association and American Diabetes Association. Circulation. 2003;108:2941–8.

    PubMed  Google Scholar 

  76. 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;21:51–7.

    CAS  PubMed  Google Scholar 

  77. Yki-Jarvinen H, Ryysy L, Kauppila M, Kujansuu E, Lahti J, Marjanen T, et al. Effect of obesity on the response to insulin therapy in noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab. 1997;82:4037–43.

    CAS  PubMed  Google Scholar 

  78. Genev N, Lau I, Willey K, Molyneaux L, Xu Z, Zilkens R, et al. Does insulin therapy have a hypertensive effect in type 2 diabetes? J Cardiovasc Pharmacol. 1998;32:39–41.

    CAS  PubMed  Google Scholar 

  79. DeFronzo RA, Cooke CR, Andres R, Faloona GR, Davis PJ. The effect of insulin on renal handling of sodium, potassium, calcium, and phosphate in man. J Clin Invest. 1975;55:845–55.

    CAS  PubMed Central  PubMed  Google Scholar 

  80. 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;290:81–5.

    CAS  PubMed  Google Scholar 

  81. Liebl A. Challenges in optimal metabolic control of diabetes. Diabetes Metab Res Rev. 2002;18 Suppl 3:S36–41.

    PubMed  Google Scholar 

  82. Neumiller JJ, Setter SM. Pharmacologic management of the older patient with type 2 diabetes mellitus. Am J Ger Pharmacother. 2009;7:324–42.

    CAS  Google Scholar 

  83. Misbin RI, Green L, Stadel BV, Gueriguian JL, Gubbi A, Fleming GA. Lactic acidosis in patients with diabetes treated with metformin. New Engl J Med. 1998;338:265–6.

    CAS  PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  85. Inzucchi SE, Masoudi FA, McGuire DK. Metformin in heart failure. Diabetes Care. 2007;30:e129.

    PubMed  Google Scholar 

  86. Pantalone KM, Kattan MW, Yu C, Wells BJ, Arrigain S, Jain A, et al. The risk of developing coronary artery disease or congestive heart failure, and overall mortality, in type 2 diabetic patients receiving rosiglitazone, pioglitazone, metformin, or sulfonylureas: a retrospective analysis. Acta Diabetol. 2009;46:145–54.

    CAS  PubMed  Google Scholar 

  87. 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;28:2345–51.

    CAS  PubMed  Google Scholar 

  88. 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;111:583–90.

    CAS  PubMed  Google Scholar 

  89. Xie Z, Lau K, Eby B, Lozano P, He C, Pennington B, et al. Improvement of cardiac functions by chronic metformin treatment is associated with enhanced cardiac autophagy in diabetic OVE26 mice. Diabetes. 2011;60:1770–8. This study, conducted in rodents, suggests a biochemical basis (improvement in myocardial AMP-activated protein kinase) for improved outcomes in people with heart failure who are treated with metformin.

    CAS  PubMed Central  PubMed  Google Scholar 

  90. Pocock SJ, McMurray JJV, Dobson J, Yusuf S, Granger CB, Michelson EL, et al. Weight loss and mortality risk in patients with chronic heart failure in the candesartan in heart failure: assessment of reduction in mortality and morbidity (CHARM) program. Eur Heart J. 2008;29:2641–50.

    PubMed  Google Scholar 

  91. Wohlfahrt P, Redfield MM, Lopez-Jimenez F, Melenovsky V, Kane GC, Rodeheffer RJ, et al. Impact of general and central adiposity on ventricular-arterial aging in women and men. JACC Heart Fail. 2014; in press.

  92. Alpert MA, Terry BE, Mulekar M, Cohen MV, Massey CV, Fan TM, et al. Cardiac morphology and left ventricular function in normotensive morbidly obese patients with and without congestive heart failure, and effect of weight loss. Am J Cardiol. 1997;80:736–40.

    CAS  PubMed  Google Scholar 

  93. Mariotti R, Castrogiovanni F, Canale ML, Borelli G, Rondinini L. Weight loss and quality of life in chronic heart failure patients. J Cardiovasc Med. 2008;9:576–80.

    Google Scholar 

  94. Peterson LR, Herrero P, Schechtman KB, Racette SB, Waggoner AD, Kisrieva-Ware Z, et al. Effect of obesity and insulin resistance on myocardial substrate metabolism and efficiency in young women. Circulation. 2004;109:2191–6.

    PubMed  Google Scholar 

  95. Korvald C, Elvenes OP, Myrmel T. Myocardial substrate metabolism influences left ventricular energetics in vivo. Am J Physiol. 2000;278:H1345–51.

    CAS  Google Scholar 

  96. Lee J, Xu Y, Lu L, Bergman B, Leitner JW, Greyson C, et al. Multiple abnormalities of myocardial insulin signaling in a porcine model of diet-induced obesity. Am J Physiol. 2010;298:H310–9.

    CAS  Google Scholar 

  97. Alpert MA, Fraley MA, Birchem JA, Senkottaiyan N. Management of obesity cardiomyopathy. Expert Rev Cardiovasc Ther. 2005;3:225–30.

    PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  99. Borlaug BA, Nishimura RA, Sorajja P, Lam CSP, Redfield MM. Exercise hemodynamics enhance diagnosis of early heart failure with preserved ejection fraction. Circ Heart Fail. 2010;3:588–95.

    PubMed Central  PubMed  Google Scholar 

  100. Packer M. Role of the sympathetic nervous system in chronic heart failure. A historical and philosophical perspective. Circulation. 1990;82:I1–6.

    CAS  PubMed  Google Scholar 

  101. Sverrisdottir YB, Rundqvist B, Johannsson G, Elam M. Sympathetic neural burst amplitude distribution: a more specific indicator of sympathoexcitation in human heart failure. Circulation. 2000;102:2076–81.

    CAS  PubMed  Google Scholar 

  102. Cohn JN, Levine TB, Olivari MT, Garberg V, Lura D, Francis GS, et al. Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure. New Engl J Med. 1984;311:819–23.

    CAS  PubMed  Google Scholar 

  103. Straznicky NE, Grima MT, Eikelis N, Nestel PJ, Dawood T, Schlaich MP, et al. The effects of weight loss vs weight loss maintenance on sympathetic nervous system activity and metabolic syndrome components. J Clin Endocrinol Metab. 2011;96:E503–8.

    CAS  PubMed  Google Scholar 

  104. Manzella D, Grella R, Esposito K, Giugliano D, Barbagallo M, Paolisso G. Blood pressure and cardiac autonomic nervous system in obese type 2 diabetic patients: effect of metformin administration. Am J Hypertens. 2004;17:223–7.

    CAS  PubMed  Google Scholar 

  105. DeBeck LD, Petersen SR, Jones KE, Stickland MK. Heart rate variability and muscle sympathetic nerve activity response to acute stress: the effect of breathing. Am J Physiol. 2010;299:R80–91.

    CAS  Google Scholar 

  106. Gudbjornsdottir S, Friberg P, Elam M, Attvall S, Lonnroth P, Wallin BG. The effect of metformin and insulin on sympathetic nerve activity, norepinephrine spillover and blood pressure in obese, insulin resistant, normoglycemic, hypertensive men. Blood Press. 1994;3:394–403.

    CAS  PubMed  Google Scholar 

  107. Patel JN, Eisenhofer G, Coppack SW, Miles JM. Norepinephrine spillover in forearm and subcutaneous adipose tissue before and after eating. J Clin Endocrinol Metab. 1999;84:2815–9.

    CAS  PubMed  Google Scholar 

  108. Kern W, Peters A, Born J, Fehm HL, Schultes B. Changes in blood pressure and plasma catecholamine levels during prolonged hyperinsulinemia. Metabolism. 2005;54:391–6.

    CAS  PubMed  Google Scholar 

  109. Jeppesen J, Zhou M, Chen Y, Reaven G. Effect of metformin on postprandial lipemia in patients with fairly to poorly controlled NIDDM. Diabetes Care. 1994;17:1093–9.

    CAS  PubMed  Google Scholar 

  110. Landsberg L. Feast or famine: the sympathetic nervous system response to nutrient intake. Cell Mol Neurobiol. 2006;26:497–508.

    CAS  PubMed  Google Scholar 

  111. Viljanen APM, Karmi A, Borra R, Parkka JP, Lepomaki V, Parkkola R, et al. Effect of caloric restriction on myocardial fatty acid uptake, left ventricular mass, and cardiac work in obese adults. Am J Cardiol. 2009;103:1721–6.

    CAS  PubMed  Google Scholar 

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Acknowledgments

Supported in part by grants from the USPHS (RO1 HL67933 and UL1 RR 24150) and the Mayo Foundation.

Compliance with Ethics Guidelines

ᅟ

Conflict of Interest

John M. Miles and Andrew D. Rule declare that they have no conflict of interest. Barry A. Borlaug has been a consultant for Merck, Amgen, GlaxoSmithKline, and Cardiokinetix. He has received grant support from Atcor Medical.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

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Authors and Affiliations

  1. Divisions of Endocrinology, Nephrology and Cardiovascular Diseases, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA

    John M. Miles, Andrew D. Rule & Barry A. Borlaug

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  1. John M. Miles
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  2. Andrew D. Rule
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  3. Barry A. Borlaug
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Correspondence to John M. Miles.

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This article is part of the Topical Collection on Pharmacologic Treatment of Type 2 Diabetes

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Miles, J.M., Rule, A.D. & Borlaug, B.A. Use of Metformin in Diseases of Aging. Curr Diab Rep 14, 490 (2014). https://doi.org/10.1007/s11892-014-0490-4

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  • DOI: https://doi.org/10.1007/s11892-014-0490-4

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