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Antihypertensive agents, insulin sensitivity, and new-onset diabetes

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Abstract

The effects of the antihypertensive drugs on carbohydrate metabolism and the development of diabetes have been a major research field for more than two decades. Many clinical studies have investigated the effects of the antihypertensive classes on insulin sensitivity and glycemic control, whereas several observational studies and large outcome trials have examined associations of antihypertensive agents with diabetes incidence. In general, thiazide diuretics and conventional β blockers decrease insulin sensitivity and increase new-onset diabetes, whereas angiotensin-converting enzyme inhibitors, calcium channel blockers, and angiotensin II receptor blockers have neutral or beneficial effects on these parameters. However, several issues in this field, such as the specific properties of newer agents and the relationship of adverse metabolic outcomes and cardiovascular risk, remain to be fully elucidated. This article presents and evaluates the current knowledge in this important area.

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References and Recommended Reading

  1. Hajjar I, Kotchen TA: Trends in prevalence, awareness, treatment, and control of hypertension in the United States, 1988–2000. JAMA 2003, 290:199–206.

    Article  PubMed  Google Scholar 

  2. Sarafidis PA, McFarlane SI, Bakris GL: Gender disparity in outcomes of care and management for diabetes and the metabolic syndrome. Curr Diab Rep 2006, 6:219–224.

    Article  PubMed  Google Scholar 

  3. Bakris GL: The importance of blood pressure control in the patient with diabetes. Am J Med 2004, 116(suppl 5A):30S–38S.

    Article  PubMed  Google Scholar 

  4. Sarafidis PA, Nilsson PM: The metabolic syndrome: a glance at its history. J Hypertens 2006, 24:621–626.

    Article  PubMed  CAS  Google Scholar 

  5. National Diabetes Information Clearinghouse: Diabetes Statistics. Bethesda, MD: National Institutes of Health, NIH publication 02-3892; 2000.

    Google Scholar 

  6. Gress TW, Nieto FJ, Shahar E, et al.: Hypertension and antihypertensive therapy as risk factors for type 2 diabetes mellitus. Atherosclerosis Risk in Communities Study. N Engl J Med 2000, 342:905–912.

    Article  PubMed  CAS  Google Scholar 

  7. McFarlane SI, Banerji M, Sowers JR: Insulin resistance and cardiovascular disease. J Clin Endocrinol Metab 2001, 86:713–718.

    Article  PubMed  CAS  Google Scholar 

  8. Beck-Nielsen H, Groop LC: Metabolic and genetic characterization of prediabetic states. Sequence of events leading to non-insulin-dependent diabetes mellitus. J Clin Invest 1994, 94:1714–1721.

    PubMed  CAS  Google Scholar 

  9. Sarafidis PA, Lasaridis AN: Actions of peroxisome proliferatoractivated receptors-gamma agonists explaining a possible blood pressure-lowering effect. Am J Hypertens 2006, 19:646–653.

    Article  PubMed  CAS  Google Scholar 

  10. Sarafidis PA, Bakris GL: Antihypertensive therapy and the risk of new-onset diabetes. Diabetes Care 2006, 29:1167–1169.

    Article  PubMed  CAS  Google Scholar 

  11. Lithell HO: Effect of antihypertensive drugs on insulin, glucose, and lipid metabolism. Diabetes Care 1991, 14:203–209.

    Article  PubMed  CAS  Google Scholar 

  12. Pollare T, Lithell H, Berne C: A comparison of the effects of hydrochlorothiazide and captopril on glucose and lipid metabolism in patients with hypertension. N Engl J Med 1989, 321:868–873.

    Article  PubMed  CAS  Google Scholar 

  13. Lind L, Berne C, Pollare T, Lithell H: Metabolic effects of anti-hypertensive treatment with nifedipine or furosemide: a double-blind, cross-over study. J Hum Hypertens 1995, 9:137–141.

    PubMed  CAS  Google Scholar 

  14. Prince MJ, Stuart CA, Padia M, et al.: Metabolic effects of hydrochlorothiazide and enalapril during treatment of the hypertensive diabetic patient. Enalapril for hypertensive diabetics. Arch Intern Med 1988, 148:2363–2368.

    Article  PubMed  CAS  Google Scholar 

  15. Harper R, Ennis CN, Sheridan B, et al.: Effects of low dose versus conventional dose thiazide diuretic on insulin action in essential hypertension. BMJ 1994, 309:226–230.

    PubMed  CAS  Google Scholar 

  16. Harper R, Ennis CN, Heaney AP, 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  PubMed  CAS  Google Scholar 

  17. Grassi G, Seravalle G, Dell’Oro R, et al.: Comparative effects of candesartan and hydrochlorothiazide on blood pressure, insulin sensitivity, and sympathetic drive in obese hypertensive individuals: results of the CROSS study. J Hypertens 2003, 21:1761–1769.

    Article  PubMed  CAS  Google Scholar 

  18. Hunter SJ, Wiggam MI, Ennis CN, et al.: Comparison of effects of captopril used either alone or in combination with a thiazide diuretic on insulin action in hypertensive type 2 diabetic patients: a double-blind crossover study. Diabet Med 1999, 16:482–487.

    Article  PubMed  CAS  Google Scholar 

  19. Sarafidis PA, Bakris GL: Do the metabolic effects of beta blockers make them leading or supporting antihypertensive agents in the treatment of hypertension? J Clin Hypertens (Greenwich) 2006, 8:351–356.

    Article  CAS  Google Scholar 

  20. Lithell H, Pollare T, Vessby B: Metabolic effects of pindolol and propranolol in a double-blind cross-over study in hypertensive patients. Blood Press 1992, 1:92–101.

    PubMed  CAS  Google Scholar 

  21. Pollare T, Lithell H, Morlin C, et al.: Metabolic effects of diltiazem and atenolol: results from a randomized, double-blind study with parallel groups. J Hypertens 1989, 7:551–559.

    Article  PubMed  CAS  Google Scholar 

  22. Pollare T, Lithell H, Selinus I, Berne C: Sensitivity to insulin during treatment with atenolol and metoprolol: a randomised, double blind study of effects on carbohydrate and lipoprotein metabolism in hypertensive patients. BMJ 1989, 298:1152–1157.

    Article  PubMed  CAS  Google Scholar 

  23. Haenni A, Lithell H: Treatment with a beta-blocker with beta 2-agonism improves glucose and lipid metabolism in essential hypertension. Metabolism 1994, 43:455–461.

    Article  PubMed  CAS  Google Scholar 

  24. Malminiemi K: Association between serum lipids, glucose tolerance, and insulin sensitivity during 12 months of celiprolol treatment. Cardiovasc Drugs Ther 1995, 9:295–304.

    Article  PubMed  CAS  Google Scholar 

  25. Jacob S, Rett K, Wicklmayr M, et al.: Differential effect of chronic treatment with two beta-blocking agents on insulin sensitivity: the carvedilol-metoprolol study. J Hypertens 1996, 14:489–494.

    Article  PubMed  CAS  Google Scholar 

  26. Giugliano D, Acampora R, Marfella R, et al.: Metabolic and cardiovascular effects of carvedilol and atenolol in non-insulindependent diabetes mellitus and hypertension. A randomized, controlled trial. Ann Intern Med 1997, 126:955–959.

    PubMed  CAS  Google Scholar 

  27. Bakris GL, Fonseca V, Katholi RE, et al.: Metabolic effects of carvedilol vs metoprolol in patients with type 2 diabetes mellitus and hypertension: a randomized controlled trial. JAMA 2004, 292:2227–2236.

    Article  PubMed  CAS  Google Scholar 

  28. Mason RP, Kalinowski L, Jacob RF, et al.: Nebivolol reduces nitroxidative stress and restores nitric oxide bioavailability in endothelium of black Americans. Circulation 2005, 112:3795–3801.

    Article  PubMed  CAS  Google Scholar 

  29. Poirier L, Cleroux J, Nadeau A, Lacourciere Y: Effects of nebivolol and atenolol on insulin sensitivity and haemodynamics in hypertensive patients. J Hypertens 2001, 19:1429–1435.

    Article  PubMed  CAS  Google Scholar 

  30. Kaiser T, Heise T, Nosek L, et al.: Influence of nebivolol and enalapril on metabolic parameters and arterial stiffness in hypertensive type 2 diabetic patients. J Hypertens 2006, 24:1397–1403.

    Article  PubMed  CAS  Google Scholar 

  31. Sarafidis PA, Bakris GL: Metabolic effects of beta-blockers: importance of dissociating newer from conventional agents. J Hypertens 2007, 25:249–252.

    PubMed  CAS  Google Scholar 

  32. Jauch KW, Hartl W, Guenther B, et al.: Captopril enhances insulin responsiveness of forearm muscle tissue in noninsulin-dependent diabetes mellitus. Eur J Clin Invest 1987, 17:448–454.

    Article  PubMed  CAS  Google Scholar 

  33. Lefkos N, Efthimiadis A, Liatsis I, et al.: Hemodynamic and biochemical changes after chronic administration of cilazapril to hypertensive patients. Cardiology 1993, 82:249–258.

    PubMed  CAS  Google Scholar 

  34. Suzuki M, Ikebuchi M, Yokota C, et al.: Normalization of insulin resistance in non-obese essential hypertension by cilazapril treatment. Clin Exp Hypertens 1995, 17:1257–1268.

    PubMed  CAS  Google Scholar 

  35. Zebekakis P, Kopras A, Lasaridis AN, et al.: A comparative study of the effects of amlodipine and fosinopril on blood pressure and insulin sensitivity in hypertensive patients [abstract]. J Hypertens 2003, 21:S71.

    Google Scholar 

  36. Seghieri G, Yin W, Boni C, et al.: Effect of chronic ACE inhibition on glucose tolerance and insulin sensitivity in hypertensive type 2 diabetic patients. Diabet Med 1992, 9:732–738.

    PubMed  CAS  Google Scholar 

  37. Andersson PE, Lithell H: Metabolic effects of doxazosin and enalapril in hypertriglyceridemic, hypertensive men. Relationship to changes in skeletal muscle blood flow. Am J Hypertens 1996, 9:323–333.

    Article  PubMed  CAS  Google Scholar 

  38. Lender D, Arauz-Pacheco C, Breen L, et al.: A double blind comparison of the effects of amlodipine and enalapril on insulin sensitivity in hypertensive patients. Am J Hypertens 1999, 12:298–303.

    Article  PubMed  CAS  Google Scholar 

  39. Reneland R, Alvarez E, Andersson PE, et al.: Induction of insulin resistance by beta-blockade but not ACE-inhibition: long-term treatment with atenolol or trandolapril. J Hum Hypertens 2000, 14:175–180.

    Article  PubMed  CAS  Google Scholar 

  40. Koyama Y, Kodama K, Suzuki M, Harano Y: Improvement of insulin sensitivity by a long-acting nifedipine preparation (nifedipine-CR) in patients with essential hypertension. Am J Hypertens 2002, 15:927–931.

    Article  PubMed  CAS  Google Scholar 

  41. Sarafidis PA, Lasaridis AN, Hatzistavri L, et al.: The effect of telmisartan and lercanidipine on blood pressure and insulin resistance in hypertensive patients. Rev Clin Pharmacol Pharmacokinet (International Edition) 2004, 18:60–66.

    CAS  Google Scholar 

  42. Benndorf RA, Rudolph T, Appel D, et al.: Telmisartan improves insulin sensitivity in nondiabetic patients with essential hypertension. Metabolism 2006, 55:1159–1164.

    Article  PubMed  CAS  Google Scholar 

  43. Widimsky J, Sirotiakova J: Efficacy and tolerability of rilmenidine compared with isradipine in hypertensive patients with features of metabolic syndrome. Curr Med Res Opin 2006, 22:1287–1294.

    Article  PubMed  CAS  Google Scholar 

  44. Lind L, Berne C, Pollare T, Lithell H: Metabolic effects of isradipine as monotherapy or in combination with pindolol during long-term antihypertensive treatment. J Intern Med 1994, 236:37–42.

    Article  PubMed  CAS  Google Scholar 

  45. Pollare T, Lithell H, Selinus I, Berne C: Application of prazosin is associated with an increase of insulin sensitivity in obese patients with hypertension. Diabetologia 1988, 31:415–420.

    Article  PubMed  CAS  Google Scholar 

  46. Haenni A, Lithell H: Moxonidine improves insulin sensitivity in insulin-resistant hypertensives. J Hypertens Suppl 1999, 17:S29–S35.

    PubMed  CAS  Google Scholar 

  47. Kurtz TW: New treatment strategies for patients with hypertension and insulin resistance. Am J Med 2006, 119:S24–S30.

    Article  PubMed  CAS  Google Scholar 

  48. Benson SC, Pershadsingh HA, Ho CI, et al.: Identification of telmisartan as a unique angiotensin II receptor antagonist with selective PPARgamma-modulating activity. Hypertension 2004, 43:993–1002.

    Article  PubMed  CAS  Google Scholar 

  49. Sarafidis PA, Nilsson PM: The effects of thiazolidinediones on blood pressure levels: a systematic review. Blood Press 2006, 15:135–150.

    Article  PubMed  CAS  Google Scholar 

  50. Vitale C, Mercuro G, Castiglioni C, et al.: Metabolic effect of telmisartan and losartan in hypertensive patients with metabolic syndrome. Cardiovasc Diabetol 2005, 4:6.

    Article  PubMed  CAS  Google Scholar 

  51. Erbe DV, Gartrell K, Zhang YL, et al.: Molecular activation of PPARgamma by angiotensin II type 1-receptor antagonists. Vascul Pharmacol 2006, 45:154–162.

    Article  PubMed  CAS  Google Scholar 

  52. Taylor EN, Hu FB, Curhan GC: Antihypertensive medications and the risk of incident type 2 diabetes. Diabetes Care 2006, 29:1065–1070.

    Article  PubMed  CAS  Google Scholar 

  53. Hansson L, Lindholm LH, Niskanen L, et al.: Effect of angiotensin-converting-enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the Captopril Prevention Project (CAPPP) randomised trial. Lancet 1999, 353:611–616.

    Article  PubMed  CAS  Google Scholar 

  54. Brown MJ, Palmer CR, Castaigne A, et al.: Morbidity and mortality in patients randomised to double-blind treatment with a long-acting calcium-channel blocker or diuretic in the International Nifedipine GITS study: Intervention as a Goal in Hypertension Treatment (INSIGHT). Lancet 2000, 356:366–372.

    Article  PubMed  CAS  Google Scholar 

  55. Dahlof B, Devereux RB, Kjeldsen SE, et al.: Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 2002, 359:995–1003.

    Article  PubMed  CAS  Google Scholar 

  56. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) [no authors listed]. JAMA 2002, 288:2981–2997.

  57. Wing LM, Reid CM, Ryan P, et al.: A comparison of outcomes with angiotensin-converting enzyme inhibitors and diuretics for hypertension in the elderly. N Engl J Med 2003, 348:583–592.

    Article  PubMed  CAS  Google Scholar 

  58. Reid CM, Johnston CI, Ryan P, et al.: Diabetes and cardiovascular outcomes in elderly subjects treated with ACE-inhibitors or diuretics: findings from the 2nd Australian National Blood Pressure Study [abstract]. Am J Hypertens 2003, 16(suppl):11A.

    Article  Google Scholar 

  59. Pepine CJ, Handberg EM, Cooper-DeHoff RM, et al.: A calcium antagonist vs a non-calcium antagonist hypertension treatment strategy for patients with coronary artery disease. The International Verapamil-Trandolapril Study (INVEST): a randomized controlled trial. JAMA 2003, 290:2805–2816.

    Article  PubMed  CAS  Google Scholar 

  60. Dahlof B, Sever PS, Poulter NR, et al.: Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial. Lancet 2005, 366:895–906.

    Article  PubMed  CAS  Google Scholar 

  61. Yusuf S, Sleight P, Pogue J, et al.: Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000, 342:145–153.

    Article  PubMed  CAS  Google Scholar 

  62. Pfeffer MA, Swedberg K, Granger CB, et al.: Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme. Lancet 2003, 362:759–766.

    Article  PubMed  CAS  Google Scholar 

  63. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP). SHEP Cooperative Research Group [no authors listed]. JAMA 1991, 265:3255–3264.

  64. Padwal R, Laupacis A: Antihypertensive therapy and incidence of type 2 diabetes: a systematic review. Diabetes Care 2004, 27:247–255.

    Article  PubMed  Google Scholar 

  65. Hansson L, Lindholm LH, Ekbom T, et al.: Randomised trial of old and new antihypertensive drugs in elderly patients: cardiovascular mortality and morbidity the Swedish Trial in Old Patients with Hypertension-2 study. Lancet 1999, 354:1751–1756.

    Article  PubMed  CAS  Google Scholar 

  66. Hansson L, Hedner T, Lund-Johansen P, et al.: Randomised trial of effects of calcium antagonists compared with diuretics and beta-blockers on cardiovascular morbidity and mortality in hypertension: the Nordic Diltiazem (NORDIL) study. Lancet 2000, 356:359–365.

    Article  PubMed  CAS  Google Scholar 

  67. Lithell H, Hansson L, Skoog I, et al.: The Study on Cognition and Prognosis in the Elderly (SCOPE): principal results of a randomized double-blind intervention trial. J Hypertens 2003, 21:875–886.

    Article  PubMed  CAS  Google Scholar 

  68. Wilhelmsen L, Berglund G, Elmfeldt D, et al.: Beta-blockers versus diuretics in hypertensive men: main results from the HAPPHY trial. J Hypertens 1987, 5:561–572.

    Article  PubMed  CAS  Google Scholar 

  69. Julius S, Kjeldsen SE, Weber M, et al.: Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial. Lancet 2004, 363:2022–2031.

    Article  PubMed  CAS  Google Scholar 

  70. Kjeldsen SE, Julius S, Mancia G, et al.: Effects of valsartan compared to amlodipine on preventing type 2 diabetes in high-risk hypertensive patients: the VALUE trial. J Hypertens 2006, 24:1405–1412.

    Article  PubMed  CAS  Google Scholar 

  71. Lindholm LH, Persson M, Alaupovic P, et al.: Metabolic outcome during 1 year in newly detected hypertensives: results of the Antihypertensive Treatment and Lipid Profile in a North of Sweden Efficacy Evaluation (ALPINE study). J Hypertens 2003, 21:1563–1574.

    Article  PubMed  CAS  Google Scholar 

  72. Bakris G, Molitch M, Hewkin A, et al.: Differences in glucose tolerance between fixed-dose antihypertensive drug combinations in people with metabolic syndrome. Diabetes Care 2006, 29:2592–2597.

    Article  PubMed  CAS  Google Scholar 

  73. Bosch J, Yusuf S, Gerstein HC, et al.: Effect of ramipril on the incidence of diabetes. N Engl J Med 2006, 355:1551–1562.

    Article  PubMed  Google Scholar 

  74. Verdecchia P, Reboldi G, Angeli F, et al.: Adverse prognostic significance of new diabetes in treated hypertensive subjects. Hypertension 2004, 43:963–969.

    Article  PubMed  CAS  Google Scholar 

  75. Kostis JB, Wilson AC, Freudenberger RS, et al.: Long-term effect of diuretic-based therapy on fatal outcomes in subjects with isolated systolic hypertension with and without diabetes. Am J Cardiol 2005, 95:29–35.

    Article  PubMed  CAS  Google Scholar 

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Correspondence to Pantelis A. Sarafidis MD, MSc, PhD.

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Sarafidis, P.A., McFarlane, S.I. & Bakris, G.L. Antihypertensive agents, insulin sensitivity, and new-onset diabetes. Curr Diab Rep 7, 191–199 (2007). https://doi.org/10.1007/s11892-007-0031-5

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