Hypertension and Diabetes Mellitus

European Cardiology Review, 2006;2(1):1-7

There has been an increase in the prevalence of diabetes mellitus over the past 40 years, both in the US and worldwide. The worldwide prevalence of diabetes in 2000 was approximately 2.8% and is estimated to grow to 4.4% by 2030. This translates to a projected rise of diabetes from 171 million in 2000 to well over 350 million in 2030. 1 The epidemic of diabetes will continue to rise as there is growing prevalence of obesity in children, which predisposes to diabetes.2 There is considerable evidence for an increased prevalence of hypertension in diabetic persons.3 In a large prospective cohort study that included 12,550 adults, the development of type 2 diabetes was almost 2.5 times as likely in persons with hypertension than in their normotensive counterparts.3,4 Similarly, evidence points to increased prevalence of hypertension in diabetic persons.3,5 Moreover, each pathophysiological disease entity serves to exacerbate the other.3,6 Both hypertension and diabetes predisposes to the development of cardiovascular disease (CVD) and renal disease.7,8 Subjects with diabetes are at about 60% increased risk of early mortality.8,9 The age-adjusted relative risk of death due to cardiovascular events in persons with type 2 diabetes is three-fold higher than in the general population. The presence of hypertension in diabetic patients substantially increases the risks of coronary heart disease, stroke, nephropathy and retinopathy.5,10,11 Indeed, when hypertension coexists with diabetes, the risk of CVD is increased by 75%, which further contributes to the overall morbidity and mortality of an already high-risk population.5,12 Generally, hypertension in type 2 diabetic persons clusters with other CVD risk factors such as microalbuminuria, central obesity, insulin resistance, dyslipidaemia, hypercoagulation, increased inflammation and left ventricular hypertrophy.5 This clustering risk factor in diabetic patients ultimately results in the development of CVD, which is the major cause of premature mortality in patients with type 2 diabetes.

Pathophysiology of Hypertension in the Diabetic Patient

Epidemiologic studies provide evidence for co-existence of hypertension and diabetes and possibly point towards a common genetic and environmental factor promoting both diabetes and hypertension. Similarly, clustering of hypertension, insulin resistance or frank type 2 diabetes, hyperlipidaemia and central obesity have been documented in several populations.13 Insulin resistance, increased tissue inflammation and reactive oxygen species (ROS) production resulting in endothelial dysfunction, increased tissue renin– angiotensin–aldosterone system (RAAS) and increased sympathetic nervous system (SNS) activity have all been implicated in this complex pathophysiology of diabetes and hypertension.

  1. Wild S, Roglic G, Green A, Sicree R, King H, “Global Prevalence of Diabetes: Estimates for the year 2000 and projections for 2030”, Diabetes Care (2004);27(5): pp. 1,047–1,053.
  2. Pinhas-Hamiel O, Zeitler P, “The global spread of type 2 diabetes mellitus in children and adolescents”, J. Pediatr. (2005);146(5): pp. 693–700.
  3. National High Blood Pressure Education Program Working Group report on hypertension in diabetes, Hypertension (1994);23(2): pp. 145–158.
  4. Gress T W, Nieto F J, Shahar E, Wofford M R, Brancati F L, “The Atherosclerosis Risk in Communities S. Hypertension and Antihypertensive Therapy as Risk Factors for Type 2 Diabetes Mellitus”, N. Engl. J. Med. (2000);342(13): pp. 905–912.
  5. Sowers J R, Epstein M, Frohlich E D, “Diabetes, hypertension, and cardiovascular disease: an update”, Hypertension (2001);37(4): pp. 1,053–1,059.
  6. Sowers J R, Epstein M, “Diabetes mellitus and associated hypertension, vascular disease, and nephropathy. An update”, Hypertension (1995);26(6 Pt 1): pp. 869–879.
  7. Sowers J R, “Treatment of hypertension in patients with diabetes”, Arch. Intern. Med. (2004);164(17): pp. 1,850–1,857.
  8. El-Atat F, McFarlane S I, Sowers J R, “Diabetes, hypertension, and cardiovascular derangements: pathophysiology and management”, Curr. Hypertens. Rep. (2004);6(3): pp. 215–223.
  9. Miettinen H, Lehto S, Salomaa V, Mahonen M, Niemela M, Haffner S M et al., “Impact of diabetes on mortality after the first myocardial infarction. The FINMONICA Myocardial Infarction Register Study Group”, Diabetes Care (1998);21(1): pp. 69–75.
  10. Bakris G, Williams M, Dworkin L, Elliott W, Epstein M, Toto R et al., “Preserving renal function in adults with hypertension and diabetes: A consensus approach”, Journal of Kidney Diseases (2000);36(3): p. 646.
  11. Sowers J R, Haffner S, “Treatment of cardiovascular and renal risk factors in the diabetic hypertensive”, Hypertension (2002);40(6): pp. 781–788.
  12. Adler A I, Stratton I M, Neil H A W, Yudkin J S, Matthews D R, Cull C A et al., “Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): prospective observational study”, BMJ (2000);321(7,258): pp. 412–419.
  13. Reaven G M, “Banting lecture 1988. Role of insulin resistance in human disease”, Diabetes (1988);37(12): pp. 1,595–1,607.
  14. Lind L, Berne C, Lithell H, “Prevalence of insulin resistance in essential hypertension”, J. Hypertens. (1995);13(12 Pt 1): pp. 1,457–1,462.
  15. Sechi L A, Melis A, Tedde R, “Insulin hypersecretion: a distinctive feature between essential and secondary hypertension”, Metabolism (1992);41(11): pp. 1,261–1,266.
  16. Sowers J R, Bakris G L, “Antihypertensive Therapy and the Risk of Type 2 Diabetes Mellitus”, N. Engl. J. Med. (2000);342(13): pp. 969–970.
  17. Richey J M, Ader M, Moore D, Bergman R N, “Angiotensin II induces insulin resistance independent of changes in interstitial insulin”, Am. J. Physiol. Endocrinol. Metab. (1999);277(5): pp. E920–926.
  18. Ogihara T, Asano T, Ando K, Chiba Y, Sakoda H, Anai M et al., “Angiotensin II-Induced Insulin Resistance Is Associated With Enhanced Insulin Signaling”, Hypertension (2002);40(6): pp. 872–879.
  19. Brenner B M, Cooper M E, de Zeeuw D, Keane W F, Mitch W E, Parving H-H et al., “Effects of Losartan on Renal and Cardiovascular Outcomes in Patients with Type 2 Diabetes and Nephropathy”, N. Engl. J. Med. (2001);345(12): pp. 861–869.
  20. Sowers J R, “Insulin resistance and hypertension”, Am. J. Physiol. Heart Circ. Physiol. (2004);286(5):H pp. 1,597–1,602.
  21. Sloniger J A, Saengsirisuwan V, Diehl C J, Dokken B B, Lailerd N, Lemieux A M et al., “Defective insulin signaling in skeletal muscle of the hypertensive TG(mREN2)27 rat”, Am. J. Physiol. Endocrinol. Metab. (2005);288(6): pp. E1,074–1,081.
  22. Blendea M C, Jacobs D, Stump C S, McFarlane S I, Ogrin C, Bahtyiar G et al., “Abrogation of oxidative stress improves insulin sensitivity in the Ren-2 rat model of tissue angiotensin II overexpression”, Am. J. Physiol. Endocrinol. Metab. (2005);288(2): pp. E353–359.
  23. Scheen A J, “Renin-angiotensin system inhibition prevents type 2 diabetes mellitus. Part 1. A meta-analysis of randomised clinical trials”, Diabetes Metab. (2004);30(6): pp. 487–496.
  24. Niklason A, Hedner T, Niskanen L, Lanke J, “Development of diabetes is retarded by ACE inhibition in hypertensive patients—a subanalysis of the Captopril Prevention Project (CAPPP)”, J. Hypertens. (2004);22(3): pp. 645–652.
  25. Kjeldsen S E, Westheim A S, Os I, “Prevention of cardiovascular events and diabetes with angiotensin-receptor blockers in hypertension: LIFE, SCOPE, and VALUE”, Curr. Hypertens. Rep. (2005);7(3): pp. 155–157.
  26. Sowers J R, “Hypertension in Type II Diabetes: Update on Therapy”, J. Clin. Hypertens. (Greenwich) (1999);1(1): pp. 41–47.
  27. McFarlane S I, Sowers J R, “Cardiovascular endocrinology 1: aldosterone function in diabetes mellitus: effects on cardiovascular and renal disease”, J. Clin. Endocrinol. Metab. (2003);88(2): pp. 516–523.
  28. Pitt B, Zannad F, Remme W J, Cody R, Castaigne A, Perez A et al., “The Effect of Spironolactone on Morbidity and Mortality in Patients with Severe Heart Failure”, N. Engl. J. Med. (1999);341(10): pp. 709–717.
  29. Pitt B, 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”, N. Engl. J. Med. (2003);348(14): pp. 1,309–1,321.
  30. Modan M, Halkin H, “Hyperinsulinemia or increased sympathetic drive as links for obesity and hypertension”, Diabetes Care (1991);14(6): pp. 470–487.
  31. DeFronzo R A, Ferrannini E, “Insulin resistance. A multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease”, Diabetes Care (1991);14(3): pp. 173–194.
  32. DeFronzo R A, “The effect of insulin on renal sodium metabolism. A review with clinical implications”, Diabetologia (1981);21(3): pp. 165–171.
  33. Anderson E A, Hoffman R P, Balon T W, Sinkey C A, Mark A L, “Hyperinsulinemia produces both sympathetic neural activation and vasodilation in normal humans”, J. Clin. Invest. (1991);87(6): pp. 2,246–2,252.
  34. Berne C, Fagius J, Pollare T, Hjemdahl P, “The sympathetic response to euglycaemic hyperinsulinaemia. Evidence from microelectrode nerve recordings in healthy subjects”, Diabetologia (1992);35(9): pp. 873–879.
  35. Rowe J W, Young J B, Minaker K L, Stevens A L, Pallotta J, Landsberg L, “Effect of insulin and glucose infusions on sympathetic nervous system activity in normal man”, Diabetes (1981);30(3): pp. 219–225.
  36. Nickenig G, Roling J, Strehlow K, Schnabel P, Bohm M, “Insulin Induces Upregulation of Vascular AT1 Receptor Gene Expression by Posttranscriptional Mechanisms”, Circulation (1998);98(22): pp. 2,453–2,460.
  37. Westerbacka J, Vehkavaara S, Bergholm R, Wilkinson I, Cockcroft J, Yki-Jarvinen H, “Marked resistance of the ability of insulin to decrease arterial stiffness characterizes human obesity”, Diabetes (1999);48(4): pp. 821–827.
  38. Raji A, Seely E W, Bekins S A, Williams G H, Simonson D C, “Rosiglitazone improves insulin sensitivity and lowers blood pressure in hypertensive patients”, Diabetes Care (2003);26(1): pp. 172–178.
  39. Dengel D R, Hagberg J M, Pratley R E, Rogus E M, Goldberg A P, “Improvements in blood pressure, glucose metabolism, and lipoprotein lipids after aerobic exercise plus weight loss in obese, hypertensive middle-aged men”, Metabolism (1998);47(9): pp. 1,075–1,082.
  40. Wassertheil-Smoller S, Blaufox M D, Oberman A S, Langford H G, Davis B R, Wylie-Rosett J, “The Trial of Antihypertensive Interventions and Management (TAIM) study. Adequate weight loss, alone and combined with drug therapy in the treatment of mild hypertension”, Arch. Intern. Med. (1992);152(1): pp. 131–136.
  41. Sacks F M, Svetkey L P, Vollmer W M, Appel L J, Bray G A, Harsha D et al., “Effects on Blood Pressure of Reduced Dietary Sodium and the Dietary Approaches to Stop Hypertension (DASH) Diet”, N. Engl. J. Med. (2001);344(1): pp. 3–10.
  42. Halbert J A, Silagy C A, Finucane P, Withers R T, Hamdorf P A, “Exercise training and blood lipids in hyperlipidemic and normolipidemic adults: a meta-analysis of randomized, controlled trials”, Eur. J. Clin. Nutr. (1999);53(7): pp. 514–522.
  43. Whelton S P, Chin A, Xin X, He J, “Effect of Aerobic Exercise on Blood Pressure: A Meta-Analysis of Randomized, Controlled Trials”, Ann. Intern. Med. (2002);136(7): pp. 493–503.
  44. Whaley-Connell A, Sowers J R, “Hypertension management in type 2 diabetes mellitus: recommendations of the Joint National Committee VII”, Endocrinol. Metab. Clin. North Am. (2005);34(1): pp. 63–75.
  45. “Treatment of Hypertension in Adults With Diabetes”, Diabetes Care (2003);26(90,001): pp. 80S–82.
  46. Chobanian A V, Bakris G L, Black H R, Cushman W C, Green L A, Izzo J L, Jr et al., “The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: The JNC 7 Report”, JAMA (2003);289(19): pp. 2,560–2,571.
  47. Arauz-Pacheco C, Parrott M A, Raskin P, “The Treatment of Hypertension in Adult Patients With Diabetes”, Diabetes Care (2002);25(1): pp. 134–147.
  48. Ravid M, Lang R, Rachmani R, Lishner M, “Long-term renoprotective effect of angiotensin-converting enzyme inhibition in non-insulin-dependent diabetes mellitus. A 7-year follow-up study”, Arch. Intern. Med. (1996);156(3): pp. 286–289.
  49. Bakris G L, Smith A C, Richardson D J, Hung E, Preston R, Goldberg R et al., “Impact of an ACE inhibitor and calcium antagonist on microalbuminuria and lipid subfractions in type 2 diabetes: a randomised, multi-centre pilot study”, J. Hum. Hypertens. (2002);16(3): pp. 185–191.
  50. Bakris G L, Weir M R, “Angiotensin-converting enzyme inhibitor-associated elevations in serum creatinine: is this a cause for concern?”, Arch. Intern. Med. (2000);160(5): pp. 685–693.
  51. Lindholm L H, Persson M, Alaupovic P, Carlberg B, Svensson A, Samuelsson O, “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(8): pp. 1,563–1,574.
  52. Pfeffer M A, Swedberg K, Granger C B, Held P, McMurray J J, Michelson E L et al., “Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme”, Lancet (2003);362(9,386): pp. 759–766.
  53. Lindholm L H, Ibsen H, Borch-Johnsen K, Olsen M H, Wachtell K, Dahlof B et al., “Risk of new-onset diabetes in the Losartan Intervention For Endpoint reduction in hypertension study”, J. Hypertens. (2002);20(9): pp. 1,879–1,886.
  54. Yusuf S, Pfeffer M A, Swedberg K, Granger C B, Held P, McMurray J J et al., “Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial”, Lancet (2003);362(9,386): pp. 777–781.
  55. Julius S, Kjeldsen S E, Weber M, Brunner H R, Ekman S, Hansson L 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(9,426): pp. 2,022–2,031.
  56. Yusuf S, “From the HOPE to the ONTARGET and the TRANSCEND studies: challenges in improving prognosis”, Am. J. Cardiol. (2002);89(2A): pp. 18A–25A; discussion pp. 25A–26A.
  57. Gerstein H C, Yusuf S, Holman R, Bosch J, Pogue J, “Rationale, design and recruitment characteristics of a large, simple international trial of diabetes prevention: the DREAM trial”, Diabetologia (2004);47(9): pp. 1,519–1,527.
  58. Califf R M, “Insulin resistance: a global epidemic in need of effective therapies”, Eur. Heart J. Suppl. (2003);5(suppl_C): pp. C13–18.
  59. Scheen A J, “Prevention of type 2 diabetes mellitus through inhibition of the Renin-Angiotensin system”, Drugs (2004);64(22): pp. 2,537–2,565.
  60. Group UKPDS, “Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38”, BMJ (1998);317(7,160): pp. 703–713.
  61. Group UKPDS, “Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39”, BMJ (1998);317(7160): pp. 713–720.
  62. Giugliano D, Acampora R, Marfella R, De Rosa N, Ziccardi P, Ragone R et al., “Metabolic and Cardiovascular Effects of Carvedilol and Atenolol in Non-Insulin-Dependent Diabetes Mellitus and Hypertension: A Randomized, Controlled Trial”, Ann. Intern. Med. (1997);126(12): pp. 955–959.
  63. “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);288(23): pp. 2,981–2,997.
  64. Curb J D, Pressel S L, Cutler J A, Savage P J, Applegate W B, Black H et al., “Effect of diuretic-based antihypertensive treatment on cardiovascular disease risk in older diabetic patients with isolated systolic hypertension”, Systolic Hypertension in the Elderly Program Cooperative Research Group, JAMA (1996);276(23): pp. 1,886–1,892.
  65. Birkenhager W H, Staessen J A, Gasowski J, de Leeuw P W, “Effects of antihypertensive treatment on endpoints in the diabetic patients randomized in the Systolic Hypertension in Europe (Syst-Eur) trial”, J. Nephrol. (2000);13(3): pp. 232–237.
  66. Hansson L, Zanchetti A, Carruthers S G, Dahlof B, Elmfeldt D, Julius S et al., “Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial”, HOT Study Group, Lancet (1998);351(9,118): pp. 1,755–1,762.
  67. Poulter N R, “Calcium antagonists and the diabetic patient: a response to recent controversies”, Am. J. Cardiol. (1998);82(9B): pp. 40R–41R.

Suggest a topic for future coverage