Skip to main content
SpringerLink
Log in

The Effect of Antihypertensive Agents on New-Onset Diabetes Mellitus

Time to Amend the Guidelines?

  • Current Opinion
  • Published:
American Journal of Cardiovascular Drugs Aims and scope Submit manuscript

Abstract

Recent large hypertension trials have shown great differences in incidence of new-onset diabetes mellitus among patients receiving different antihypertensive drug therapies. The incidence of diabetes is unchanged or increased by the use of thiazide diuretics and β-adrenoceptor antagonists (β-blockers) and unchanged or decreased by ACE inhibitors, calcium channel blockers (CCBs), and angiotensin II type 1 receptor antagonists (angiotensin receptor blockers). Recent results from ASCOT (Anglo-Scandinavian Cardiac Outcomes Trial) showed superiority of the ‘new’ combination of CCBs and ACE inhibitors over the ‘old’ or ‘conventional’ combination of β-blockers and diuretics. In this review, the results from some of the large hypertension trials are discussed, and the hypotheses on how different antihypertensive drug regimens can affect glucose homeostasis are considered. The question now is whether the results from these recent trials should affect the choice of antihypertensive treatment, particularly for special groups. However, the key goal is still to reduce BP, and this usually requires combinations of drugs.

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
Table I

Similar content being viewed by others

References

  1. Ford ES, Abbasi F, Reaven GM. Prevalence of insulin resistance and the metabolic syndrome with alternative definitions of impaired fasting glucose. Atherosclerosis 2005 Jul; 181 (1): 143–8.

    Article  PubMed  CAS  Google Scholar 

  2. International Diabetes Federation. IDF worldwide definition of the metabolic syndrome [online]. Available from URL: http://www.idf.org/home/index.cfm?node=1429 [Accessed 2006 May 5].

  3. Isomaa B, Almgren P, Tuomi T, et al. Cardiovascular morbidity and mortality associated with the metabolic syndrome. Diabetes Care 2001 Apr; 24 (4): 683–9.

    Article  PubMed  CAS  Google Scholar 

  4. DeFronzo RA, Ferrannini E. Insulin resistance: a multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease. Diabetes Care 1991 Mar; 14 (3): 173–94.

    Article  PubMed  CAS  Google Scholar 

  5. Sowers JR. Insulin resistance and hypertension. Am J Physiol Heart Circ Physiol 2004 May; 286 (5): H1597–1602.

    Article  PubMed  CAS  Google Scholar 

  6. Wheatcroft SB, Williams IL, Shah AM, et al. Pathophysiological implications of insulin resistance on vascular endothelial function. Diabet Med 2003 Apr; 20 (4): 255–68.

    Article  PubMed  CAS  Google Scholar 

  7. Stevens VJ, Obarzanek E, Cook NR, et al. Long-term weight loss and changes in blood pressure: results of the Trials of Hypertension Prevention, phase II. Ann Intern Med 2001 Jan 2; 134 (1): 1–11.

    PubMed  CAS  Google Scholar 

  8. Leiter LA, Abbott D, Campbell NR, et al. Lifestyle modifications to prevent and control hypertension. 2. Recommendations on obesity and weight loss. Canadian Hypertension Society, Canadian Coalition for High Blood Pressure Prevention and Control, Laboratory Centre for Disease Control at Health Canada, Heart and Stroke Foundation of Canada. CMAJ 1999 May 4; 160 (9 Suppl.): S7–12.

    PubMed  CAS  Google Scholar 

  9. Xin X, He J, Frontini MG, et al. Effects of alcohol reduction on blood pressure: a meta-analysis of randomized controlled trials. Hypertension 2001 Nov; 38 (5): 1112–7.

    Article  PubMed  CAS  Google Scholar 

  10. Sacks FM, Svetkey LP, Vollmer WM, et al. Effects on blood pressure of reduced dietary sodium and the Dietary Approaches to Stop Hypertension (DASH) diet. DASH-Sodium Collaborative Research Group. N Engl J Med 2001 Jan 4; 344 (1): 3–10.

    CAS  Google Scholar 

  11. He J, Whelton PK. What is the role of dietary sodium and potassium in hypertension and target organ injury? Am J Med Sci 1999 Mar; 317 (3): 152–9.

    Article  PubMed  CAS  Google Scholar 

  12. Ebrahim S, Smith GD. Lowering blood pressure: a systematic review of sustained effects of non-pharmacological interventions. J Public Health Med 1998 Dec; 20 (4): 441–8.

    Article  PubMed  CAS  Google Scholar 

  13. 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 Feb 8; 334 (6): 374–81.

    Article  PubMed  CAS  Google Scholar 

  14. Padwal R, Laupacis A. Antihypertensive therapy and incidence of type 2 diabetes: a systematic review. Diabetes Care 2004 Jan; 27 (1): 247–55.

    Article  PubMed  Google Scholar 

  15. 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 Mar 30; 342 (13): 905–12.

    CAS  Google Scholar 

  16. Aksnes TA, Reims HM, Kjeldsen SE, et al. Antihypertensive treatment and new-onset diabetes mellitus. Curr Hypertens Rep 2005 Aug; 7 (4): 298–303.

    Article  PubMed  CAS  Google Scholar 

  17. 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). JAMA 2002 Dec 18; 288 (23): 2981–2997.

  18. 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 Jul 29; 356 (9227): 366–72.

    Article  PubMed  CAS  Google Scholar 

  19. 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 Jun 19; 363 (9426): 2022–31.

    Article  PubMed  CAS  Google Scholar 

  20. Verdecchia P, Reboldi G, Angeli F, et al. Adverse prognostic significance of new diabetes in treated hypertensive subjects. Hypertension 2004 May; 43 (5): 963–9.

    Article  PubMed  CAS  Google Scholar 

  21. Kostis JB, Wilson AC, Freudenberger RS, et al. Long-term effect of diuretic-based therapy on fatal outcomes in subjects with isolated hypertension with and without diabetes. Am J Cardiol 2005 Jan 1; 95 (1): 29–35.

    Article  PubMed  CAS  Google Scholar 

  22. Zimmet P, Alberti KG, Shaw J. Global and societal implications of the diabetes epidemic. Nature 2001 Dec 13; 414 (6865): 782–7.

    Article  PubMed  CAS  Google Scholar 

  23. Padwal R, Mamdani M, Alter DA, et al. Antihypertensive therapy and incidence of type 2 diabetes in an elderly cohort. Diabetes Care 2004 Oct; 27 (10): 2458–63.

    Article  PubMed  Google Scholar 

  24. 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 Sep 6; 362 (9386): 759–66.

    Article  PubMed  CAS  Google Scholar 

  25. Yusuf S, Gerstein H, Hoogwerf B, et al. Ramipril and the development of diabetes. JAMA 2001 Oct 17; 286 (15): 1882–5.

    Article  PubMed  CAS  Google Scholar 

  26. 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 May; 21 (5): 875–86.

    Article  PubMed  CAS  Google Scholar 

  27. Vermes E, Ducharme A, Bourassa MG, et al. Enalapril reduces the incidence of diabetes in patients with chronic heart failure: insight from the Studies Of Left Ventricular Dysfunction (SOLVD). Circulation 2003 Mar 11; 107 (9): 1291–6.

    Article  PubMed  CAS  Google Scholar 

  28. Braunwald E, Domanski MJ, Fowler SE, et al. Angiotensin-converting-enzyme inhibition in stable coronary artery disease. N Engl J Med 2004 Nov 11; 351 (20): 2058–68.

    Article  PubMed  CAS  Google Scholar 

  29. 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 Aug; 21 (8): 1563–74.

    Article  PubMed  CAS  Google Scholar 

  30. 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. Am J Hypertens 2003 May; 16 (5 Suppl. 1): A11.

  31. Niklason A, Hedner T, Niskanen L, et al. Development of diabetes is retarded by ACE inhibition in hypertensive patients: a subanalysis of the Captopril Prevention Project (CAPPP). J Hypertens 2004 Mar; 22 (3): 645–52.

    Article  PubMed  CAS  Google Scholar 

  32. Lindholm LH, Ibsen H, Borch-Johnsen K, et al. Risk of new-onset diabetes in the Losartan Intervention For Endpoint reduction in hypertension study. J Hypertens 2002 Sep; 20 (9): 1879–86.

    Article  PubMed  CAS  Google Scholar 

  33. 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 Nov 20; 354 (9192): 1751–6.

    Article  PubMed  CAS  Google Scholar 

  34. 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 Sep 10; 366 (9489): 895–906.

    Article  PubMed  Google Scholar 

  35. 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 Dec 3; 290 (21): 2805–16.

    CAS  Google Scholar 

  36. 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 Jul 29; 356 (9227): 359–65.

    Article  PubMed  CAS  Google Scholar 

  37. Diabetes mellitus: report of a WHO study group. World Health Organ Tech Rep Ser 1985; 727: 1–113.

    Google Scholar 

  38. Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med 1998 Jul; 15 (7): 539–53.

    CAS  Google Scholar 

  39. Gerstein HC, Yusuf S, Holman R, et al. Rationale, design and recruitment characteristics of a large, simple international trial of diabetes prevention: the DREAM trial. Diabetologia 2004 Sep; 47 (9): 1519–27.

    Article  PubMed  CAS  Google Scholar 

  40. NAVIGATOR information site [online]. Available from URL: http://www.bioportfolio.com/news/novartisl.htm [Accessed 2004 Oct 24].

  41. Teo K, Yusuf S, Sleight P, et al. Rationale, design, and baseline characteristics of 2 large, simple, randomized trials evaluating telmisartan, ramipril, and their combination in high-risk patients: the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial/Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease (ONTARGET/TRANSCEND) trials. Am Heart J 2004 Jul; 148 (1): 52–61.

    Article  PubMed  Google Scholar 

  42. Harris MI, Klein R, Welborn TA, et al. Onset of NIDDM occurs at least 4–7 yr before clinical diagnosis. Diabetes Care 1992 Jul; 15 (7): 815–9.

    Article  PubMed  CAS  Google Scholar 

  43. 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 Feb 13; 348 (7): 583–92.

    Article  PubMed  CAS  Google Scholar 

  44. Abuissa H, Jones PG, Marso SP, et al. Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers for prevention of type 2 diabetes. J Am Coll Cardiol 2005 Sep; 46 (5): 821–6.

    Article  PubMed  CAS  Google Scholar 

  45. Cheung BMY, Cheung GTY, Lauder IJ, et al. Meta-analysis of large outcome trials of angiotensin receptor blockers in hypertension. J Hum Hypertens 2006 Jan; 20 (1): 37–43.

    Article  PubMed  CAS  Google Scholar 

  46. Scheen AJ. Renin-angiotensin system inhibition prevents type 2 diabetes mellitus. Part 1. A meta-analysis of randiomised clinical trials. Diabetes Metab 2004 Dec; 30 (6): 487–96.

    CAS  Google Scholar 

  47. Henriksen EJ, Jacob S. Modulation of metabolic control by angiotensin converting enzyme (ACE) inhibition. J Cell Physiol 2003 Jul; 196 (1): 171–9.

    Article  PubMed  CAS  Google Scholar 

  48. Jacob S, Henriksen EJ, Fogt DL, et al. Effects of trandolapril and verapamil on glucose transport in insulin-resistant rat skeletal muscle. Metabolism 1996 May; 45 (5): 535–41.

    Article  PubMed  CAS  Google Scholar 

  49. Sharma AM, Janke J, Gorzelniak K, et al. Angiotensin blockade prevents type 2 diabetes by formation of fat cells. Hypertension 2002 Nov; 40 (5): 609–11.

    Article  PubMed  CAS  Google Scholar 

  50. Ferrannini E, Seghieri G, Muscelli E. Insulin and the renin-angiotensin-aldosterone system: influence of ACE inhibition. J Cardiovasc Pharmacol 1994; 24 Suppl. 3: S61–9.

    Article  PubMed  CAS  Google Scholar 

  51. Tikellis C, Wookey PJ, Candido R, et al. Improved islet morphology after blockade of the renin: angiotensin system in the ZDF rat. Diabetes 2004 Apr; 53 (4): 989–97.

    Article  PubMed  CAS  Google Scholar 

  52. Carlsson PO, Berne C, Jansson L. Angiotensin II and the endocrine pancreas: effects on islet blood flow and insulin secretion in rats. Diabetologia 1998 Feb; 41 (2): 127–33.

    Article  PubMed  CAS  Google Scholar 

  53. 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 May; 43 (5): 993–1002.

    Article  PubMed  CAS  Google Scholar 

  54. Pitre M, Gaudreault N, Santure M, et al. Isradipine and insulin sensitivity in hypertensive rats. Am J Physiol 1999 Jun; 276 (6 Pt 1): E1038–48.

    PubMed  CAS  Google Scholar 

  55. Trost BN, Weidmann P. Effects of calcium antagonists on glucose homeostasis and serum lipids in non-diabetic and diabetic subjects: a review. J Hypertens Suppl 1987 Dec; 5 (4): S81–104.

    Article  PubMed  CAS  Google Scholar 

  56. Hood S, Cannon J, Foo R, et al. Prevalence of primary hyperaldosteronism assessed by aldosterone/renin ratio and spironolactone testing. Clin Med 2005 Jan; 5 (1): 55–60.

    PubMed  Google Scholar 

  57. 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 Sep 28; 321 (13): 868–73.

    Article  PubMed  CAS  Google Scholar 

  58. Conn JW. Hypertension, the potassium ion and impaired carbohydrate tolerance. N Engl J Med 1965 Nov 18; 273 (21): 1135–43.

    Article  PubMed  CAS  Google Scholar 

  59. 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 Jul 23; 309 (6949): 226–30.

    Article  PubMed  CAS  Google Scholar 

  60. Helderman JH, Elahi D, Andersen DK, et al. Prevention of the glucose intolerance of thiazide diuretics by maintenance of body potassium. Diabetes 1983 Feb; 32 (2): 106–11.

    Article  PubMed  CAS  Google Scholar 

  61. Shamiss A, Carroll J, Peleg E, et al. The effect of enalapril with and without hydrochlorothiazide on insulin sensitivity and other metabolic abnormalities of hypertensive patients with NIDDM. Am J Hypertens 1995 Mar; 8 (3): 276–81.

    Article  PubMed  CAS  Google Scholar 

  62. Cerasi E, Luft R, Efendic S. Effect of adrenergic blocking agents on insulin response to glucose infusion in man. Acta Endocrinol (Copenh) 1972 Feb; 69 (2): 335–46.

    CAS  Google Scholar 

  63. Jacob S, Rett K, Henriksen EJ. Antihypertensive therapy and insulin sensitivity: do we have to redefine the role of beta-blocking agents? Am J Hypertens 1998 Oct; 11 (10): 1258–65.

    Article  PubMed  CAS  Google Scholar 

  64. Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 2003 Dec; 42 (6): 1206–52.

    Article  PubMed  CAS  Google Scholar 

  65. Whitworth JA. 2003 World Health Organization (WHO)/International Society of Hypertension (ISH) statement on management of hypertension. J Hypertens 2003 Nov; 21 (11): 1983–92.

    Article  PubMed  Google Scholar 

  66. European Society of Hypertension. European Society of Cardiology guidelines for the management of arterial hypertension. J Hypertens 2003 Jun; 21 (6): 1011–53.

    Article  Google Scholar 

  67. Williams B, Poulter NR, Brown MJ, et al. Guidelines for management of hypertension: report of the fourth working party of the British Hypertension Society, 2004-BHS IV. J Hum Hypertens 2004 Mar; 18 (3): 139–85.

    Article  PubMed  CAS  Google Scholar 

  68. Sever P. The heterogeneity of hypertension: why doesn’t every patient respond to every antihypertensive drug? J Hum Hypertens 1995 Jul; 9 Suppl. 2: S33–6.

    PubMed  Google Scholar 

  69. Sagnella GA. Why is plasma renin activity lower in populations of African origin? J Hum Hypertens 2001 Jan; 15 (1): 17–25.

    Article  PubMed  CAS  Google Scholar 

  70. Opie LH, Schall R. Old antihypertensives and new diabetes. J Hypertens 2004 Aug; 22 (8): 1453–8.

    Article  PubMed  CAS  Google Scholar 

  71. NICE and BHS confirm review of hypertension guidelines [online]. Available from URL: http://www.nice.org.uk/page.aspx?.o=276966 [Accessed 2005 Oct 26].

  72. Kjeldsen SE, Reims H, Fagard R, et al. Hypertension. In: Camm AJ, L: uscher TF, Serruys P, editors. European Society of Cardiology textbook of cardiovascular medicine. 2005 ed. Oxford: Blackwell Publishing, 2005.

Download references

Acknowledgments

SE Kjelsen has received honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, Menarini, Merck & Co., Novartis, Pharmacia, Pfizer, and Sankyo; a grant from Merck & Co.; and royalties from Gylendal (Oslo, Norway) and Blood Pressure (Gottenburg, Sweden).

G Mancia has provided consultancies for drug companies producing all major antihypertensive drugs and has received honoraria for participation in scientific meetings sponsored by drug companies with subtypes of drugs (ACE inhibitors, ARBs, diuretics, calcium antagonists, β-blockers).

No sources of funding were used to assist in the conducting of this review.

Author information

Authors and Affiliations

  1. Department of Cardiology, Ullevaal University Hospital, Kirkeveien 166, Oslo, 0407, Norway

    Tonje Amb Aksnes & Sverre Erik Kjeldsen

  2. Clinica Medica, Ospedale S Gerardo, Universita di Milano-Bicocca, Monza, Italy

    Giuseppe Mancia

Authors
  1. Tonje Amb Aksnes
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sverre Erik Kjeldsen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Giuseppe Mancia
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tonje Amb Aksnes.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Aksnes, T.A., Kjeldsen, S.E. & Mancia, G. The Effect of Antihypertensive Agents on New-Onset Diabetes Mellitus. Am J Cardiovasc Drugs 6, 139–147 (2006). https://doi.org/10.2165/00129784-200606030-00001

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00129784-200606030-00001

Keywords

Search

Navigation