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Effect of eplerenone on insulin action in essential hypertension: a randomised, controlled, crossover study

Journal of Human Hypertension volume 28, pages 575–578 (2014)Cite this article

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Abstract

An association exists between hyperaldosteronism, hypertension and impaired insulin action. Eplerenone is a selective mineralocorticoid receptor antagonist; however, little is known about its effects on insulin action. The aim of this study was to determine the effect of eplerenone on insulin action in hypertensive adults, using the hyperinsulinaemic euglycaemic clamp. A randomised, controlled, double-blind, crossover design was employed. After a 6-week washout period, hypertensive, non-diabetic patients were treated with either eplerenone 25 mg twice daily or doxazosin 2 mg twice daily for 12 weeks. After each treatment period, insulin action was assessed by a hyperinsulinaemic euglycaemic clamp, with isotope dilution methodology. After washout, treatment groups were crossed over. Fifteen patients completed the study. There were no differences in fasting glucose, or fasting insulin between treatment with eplerenone or doxazosin. The measure of overall insulin sensitivity, exogenous glucose infusion rates during the last 30 min of the clamp, was similar with both treatments; 23.4 (3.9) μmol kg−1 min−1 after eplerenone and 23.3 (3.6) μmol kg−1 min−1 after doxazosin (P=0.83). Isotopically determined fasting endogenous glucose production rates were similar after both treatments (eplerenone 9.4 (0.6) μmol kg−1 min−1 vs doxazosin 10.6 (0.7) μmol kg−1 min−1). There was a trend for lower endogenous glucose production rates during hyperinsulinaemia following eplerenone compared with doxazosin (2.0 (0.8) μmol kg−1 min−1 vs 4.1 (0.9) μmol kg−1 min−1). There was no difference in insulin stimulated peripheral glucose utilisation rates after treatment with eplerenone or doxazosin (25.4 (3.6) μmol kg−1 min−1 vs 27.0 (3.9) μmol kg−1 min−1). This study gives reassuring evidence of the neutral effect of eplerenone on insulin action in hypertensive, non-diabetic patients.

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References

  1. Wiggam IM, Hunter SJ, Atkinson AB, Ennis CN, Henry JS, Browne JN et al. Captopril does not improve insulin action in essential hypertension: a double-blind placebo controlled study. J Hypertens 1998; 16: 103–109.

    Article  Google Scholar 

  2. Goossens GH, Blaak EE, Schiffers PM, Saris WHM, van Baak MA . Effect of short-term ACE inhibitor treatment on peripheral insulin sensitivity in obese insulin-resistant subjects. Diabetologia 2006; 49: 3009–3016.

    Article  CAS  Google Scholar 

  3. Gress TW, Nieto FJ, Shahar E, Wofford MR, Brancati FL . Hypertension and antihypertensive therapy as risk factors for type 2 diabetes mellitus. New Engl J Med 2000; 342: 905–912.

    Article  CAS  Google Scholar 

  4. Petrie JR, Morris AD, Ueda S, Small M, Donnell R, Connell JMC et al. Trandolapril does not improve insulin sensitivity in patients with hypertension and type 2 diabetes: A double-blind, placebo-controlled crossover trial. J Clin Endocrinol Metab 2000; 85: 1882–1889.

    CAS  PubMed  Google Scholar 

  5. Galletti F, Strazzullo P, Capaldo B, Fabris F, Ferrara LA, Gloriosa N et al. Controlled study of the effect of angiotension converting enzyme inhibiton versus calcium-entry blockade on insulin sensitivity in overweight hypertensive patients: Trandolapril Itatlian Study (TRIS). J Hypertens 1999; 17: 439–445.

    Article  CAS  Google Scholar 

  6. Mori Y, Tanaka T, Matsuura K, Yokoyama J, Utsunomiya K . Influence of telmisartan on insulin response after glucose loading in obese patients with hypertension: ARB trial of hypertension in obese patients with hyperinsulinemia assessed by oral glucose tolerance test (ATHLETE). Adv Ther 2011; 28: 698–706.

    Article  CAS  Google Scholar 

  7. Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 2003; 26 (Suppl 14): S5–S20.

  8. Giacchetti G, Sechi LA, Rilli S, Carey R . The renin–angiotensin–aldosterone system, glucose metabolism and diabetes. Trends Endocrin Metab 2005; 16: 120–126.

    Article  CAS  Google Scholar 

  9. Bentley-Lewis R, Adler GK, Perlstein T, Seely EW, Hopkins PN, Williams GH et al. Body mass index predicts aldosterone production in normotensive adults on a high salt diet. J Clin Endocrinol Metab 2007; 92 (11): 4472–4475.

    Article  CAS  Google Scholar 

  10. Garg R, Hurwitz S, Williams GH, Hopkins PN, Adler GK . Aldosterone production and insulin resistance in healthy adults. J Clin Endocrinol Metab 2010; 95 (4): 1986–1990.

    Article  CAS  Google Scholar 

  11. Catena C, Lapenna R, Baroselli S, Nadalini E, Colussi G-L, Novello M et al. Insulin sensitivity in patients with primary aldosteronism: a follow up study. J Clin Endocrinol Metab 2006; 91: 3457–3463.

    Article  CAS  Google Scholar 

  12. Pitt BP, Remme W, Zannad F, Neaton J, Martinez F, Roniker B et al. Eplerenone, a selective aldosterone blocker in patients with left ventricular dysfunction after myocardial infarction. New Engl J Med 2003; 348: 1309–1321.

    Article  CAS  Google Scholar 

  13. Zanad F, McMurray JJ, Krum H, van Veldhuisen DJ, Swedberg K, Shi H et al. Eplerenone in patients with systolic heart failure and mild symptoms. New Engl J Med 2011; 364 (1): 11–21.

    Article  Google Scholar 

  14. Guo C, Ricchiuti V, Lian BQ, Yao TM, Coutinho P, Romero JR et al. Mineralocoticoid receptor blockade reverses obesity-related changes in expressions of adiponectin, peroxisome proliferator-activated receptor-γ and pro-inflammatory adipokines. Circulation 2008; 117 (17): 2253–2261.

    Article  CAS  Google Scholar 

  15. Harper R, Ennis CN, Heany AP, Sheridan B, Gormley M, Atkinson AB et al. A comparison of the effects of low and conventional dose thiazide diuretic on insulin action in hypertensive patients with NIDDM. Diabetologia 1995; 38: 853–859.

    Article  CAS  Google Scholar 

  16. Courtney CH, McCance DR, Atkinson AB, Bassett J, Ennis CN, Sheridan B et al. Effect of the alpha-adrenergic blocker, doxazosin, on endothelial function and insulin action. Metabolism 2003; 52 (9): 1147–1152.

    Article  CAS  Google Scholar 

  17. Neely RD, Rooney DP, Atkinson AB, Sheridan B, Ennis CN, Trimble ER et al. Underestimation of glucose turnover determined using (6-3H) glucose tracer in non-steady state. The role of a tritiated tracer impurity. Diabetologia 1990; 33: 681–687.

    Article  CAS  Google Scholar 

  18. Harper R, Ennis CN, Sheridan B, Atkinson AB, Johnston GD, Bell PM . Effects of low dose versus conventional dose thiazide diuretic on insulin action in essential hypertension. BMJ 1994; 309: 226–230.

    Article  CAS  Google Scholar 

  19. Somogyi M . Determination of blood sugar. J Biol Chem 1945; 160: 69–73.

    CAS  Google Scholar 

  20. Steele R, Wall JS, DeBodo RC, Atlszuler N . Measurement of size and turnover rate of body glucose pool by the dilutional method. Am J Physiol 1956; 1987: 15–24.

    Article  Google Scholar 

  21. DeBodo RC, Stelle R, Altszuler N, Dunn A, Bishop JS . Effects of insulin on hepatic glucose metabolism and glucose utilization by tissue. Diabetes 1963; 12: 16–30.

    Article  CAS  Google Scholar 

  22. Hills M, Armitage P . The two-period cross-over clinical trial. Br J Clin Pharmacol 1979; 8: 7–20.

    Article  CAS  Google Scholar 

  23. DeFronzo RA, Tobin JD, Andres R . Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol 1979; 237 (3): E214–E223.

    CAS  PubMed  Google Scholar 

  24. Chapman N, Dobson J, Wilson S, Dahlof B, Sever PS, Wedel H et al. Effect of spironolactone on blood pressure in subjects with resistant hypertension. Hypertension 2007; 49: 839–845.

    Article  CAS  Google Scholar 

  25. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. New Engl J Med 1999; 341: 709–717.

    Article  CAS  Google Scholar 

  26. Rossing K, Schjoedt KJ, Smidt UM, Boomsma F, Parving H-H . Beneficial effects of adding spironolactone to recommended antihypertensive treatment in diabetic nephropathy. Diabetes Care 2005; 28: 2106–2112.

    Article  CAS  Google Scholar 

  27. Sindelka G, Widimsky J, Haas T, Pazny M, Hilgertova J, Skrha J . Insulin action in primary hyperaldosteronsim before and after surgical or pharmacological treatment. Exp Clin Endocrinol Diabetes 2000; 108 (1): 21–25.

    CAS  Google Scholar 

  28. Davies JI, Band M, Morris A, Struthers AD . Spironolactone impairs endothelial function and heart rate variability in patients with type 2 diabetes. Diabetologia 2004; 47 (10): 1687–1694.

    Article  CAS  Google Scholar 

  29. Swaminathan K, Davies J, George J, Rajendra NS, Morris AD, Struthers AD . Spironolactone for poorly controlled hypertension in type 2 diabetes: conflicting effects on blood pressure, endothelial function, glycaemic control and hormonal profiles. Diabetologia 2008; 51 (5): 762–768.

    Article  CAS  Google Scholar 

  30. Yamaji M, Tsutamoto T, Kawahara C, Nishiyama K, Yamamoto T, Fujii M et al. Effect of eplerenone versus spironolactone on cortisol and haemoglobin A1c levels in patients with chronic heart failure. Am Heart J 2010; 160: 915–921.

    Article  CAS  Google Scholar 

  31. Preiss D, van Veldhuisen DJ, Sattar N, Krum H, Swedberg K, Shi H et al. Eplerenone and new-onset diabetes in patients with mild heart failure: results from the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF). Eu J Heart Fail 2012; 14: 909–915.

    Article  CAS  Google Scholar 

  32. Young WF . Primary aldosteronism; renaissance of a syndrome. Clin Endocrinol 2007; 66: 607–618.

    Article  CAS  Google Scholar 

  33. Milliez P, Girerd X, Plouin PF, Blacher J, Safar ME, Mourad JJ . Evidence for an increased rate of cardiovascular events in patients with primary aldosteronism. J Am Coll Cardiol 2005; 45 (8): 1243–1248.

    Article  CAS  Google Scholar 

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Acknowledgements

The research was funded by the Research and Development Office, Northern Ireland Health and Social Care Services Agency, Linenhall Street, Belfast.

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  1. Regional Centre for Endocrinology and Diabetes, Royal Victoria Hospital, Belfast, UK

    E M McMurray, I R Wallace, C Ennis, S J Hunter, A B Atkinson & P M Bell

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  1. E M McMurray
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Correspondence to E M McMurray.

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McMurray, E., Wallace, I., Ennis, C. et al. Effect of eplerenone on insulin action in essential hypertension: a randomised, controlled, crossover study. J Hum Hypertens 28, 575–578 (2014). https://doi.org/10.1038/jhh.2014.19

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