Combination Therapy for Hypertension and Renal Disease in Diabetics as Compared to Non-Diabetics

  • George L. Bakris


More than 75% of individuals with diabetes, microalbuminuria and hypertension require two or more antihypertensive medications to attain the currently recommended level of arterial pressure control, i.e., <130/80 mmHg [1–3]. To achieve this blood pressure goal, it is common to add a medication whose antihypertensive action potentiates the initially selected drug [4,5]. To further improve compliance and reduce drug side effect profiles, fixed-dose combinations of antihypertensive drugs with complementary modes of action have been recently developed. These medications combine a lower dose of two different antihypertensive drugs that, in a fixed dose combination, reduce arterial pressure to a greater extent than either alone. The history of various fixed-dose antihypertensive drug combinations is shown in table 55-1. The evolution of fixed-dose combination antihypertensive therapy is beyond the scope of this chapter. The reader, however, is referred to a recent review on the topic [5]. This chapter will focus on the available animal and clinical evidence of specific antihypertensive medications, either alone or combined, that have demonstrated efficacy for reducing arterial pressure and slowing the progression of diabetic renal disease. This will primarily, but not exclusively, include the angiotensin converting enzyme (ACE) inhibitors and calcium channel blockers (CCBs).


Diabetic Nephropathy Angiotensin Converting Enzyme Angiotensin Converting Enzyme Inhibitor Diabetic Renal Disease Comparable Blood Pressure 
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  1. 1.
    National High Blood Pressure Education Program Working Group on Hypertension and Renal Disease. 1995 Update of the working group reports on chronic renal failure and renovascular hypertension. Arch Intern Med 1996; in press.Google Scholar
  2. 2.
    Bakris GL. Pathogenesis of hypertension in diabetes. Diabetes Reviews 1995; 3: 460–476.Google Scholar
  3. 3.
    Nelson RG, Knowler WC, Pettitt DJ, Bennett PH. »Kidney diseases in diabetes.« In Diabetes In America National Institutes of Health, Pub. No. 95-1468, 2nd ed., 1995; pp 349-400.Google Scholar
  4. 4.
    Waeber B, Brunner HR. Main objectives and new aspects of combination treatment of hypertension. J Hypertens 1995; 13: S15–S19.CrossRefGoogle Scholar
  5. 5.
    Epstein M and Bakris GL. Newer approaches to antihypertensive therapy using fixed dose combination therapy: Future perspectives. Arch Intern Med., In press.Google Scholar
  6. 6.
    Griffin KA, Picken MM and Bidani AK. Deleterious effects of calcium channel blockade on pressure transmission and glomerular injury in rat remnant kidneys. J Clin Invest 1995; 96: 793–800.PubMedCentralPubMedCrossRefGoogle Scholar
  7. 7.
    Kilaru P and Bakris GL. ACE inhibition or calcium-channel blockade: Renal implications of combination therapy versus a single agent. J Cardiovasc Pharmacol 1996; in press.Google Scholar
  8. 8.
    Bakris GL, Walsh MF, Sowers JR. »Endothelium, mesangium interactions: Role of insulin-like growth factors.« In Endocrinology of the Vasculature, Sowers JR, ed. New Jersey, Humana Press Inc. 1996; pp 341–356.CrossRefGoogle Scholar
  9. 9.
    Bakris GL and Smith AC. Long term effects of two different calcium channel blockers on albuminuria and glomerular sieving. J Am Soc Nephrol 1996; in press.Google Scholar
  10. 10.
    Bakris GL. Microalbuminuria: Prognostic Implications. Curr Opinion Nephrol Hypertens 1996; 5: 219–233.CrossRefGoogle Scholar
  11. 11.
    Bakris GL, Mehler P, and Schrier R. »Hypertension and Diabetes.« In Diseases of the Kidney, Chapter 54, 6th ed., Schrier RW, Gottschalk CW, eds. Little Brown and Company, 1996: pp 1281-1328.Google Scholar
  12. 12.
    Bakris GL and Williams B. ACE inhibitors and calcium antagonists alone or combined: Is there a difference on progression of diabetic renal disease. J Hypertens 1995; 13: Suppl. 2: S95–S101.CrossRefGoogle Scholar
  13. 13.
    Steffes MW, Osterby R, Chavers B, and Mauer SM. Mesangial expansion as a central mechanism for loss of kidney function in diabetic patients. Diabetes 1989; 38: 1077–1081.PubMedCrossRefGoogle Scholar
  14. 14.
    Anderson S, Rennke HG, Brenner BM. Nifedipine versus fosinopril in uninephrectomized diabetic rats. Kidney Int 1992; 41: 891–897.PubMedCrossRefGoogle Scholar
  15. 15.
    Ravid M, Lang R, Rachmani R, Lishner M. Long-term renoprotective effect of angiotensin-converting enzyme inhibition in non-insulin-dependent diabetes mellitus. Arch Intern Med 1996; 156: 286–289.PubMedCrossRefGoogle Scholar
  16. 16.
    Parving H, Hommel E, Nielsen M, Giese J. Effect of captopril on blood pressure and kidney function in normotensive insulin dependent diabetics with nephropathy. BMJ 1989; 299: 533–536.PubMedCrossRefGoogle Scholar
  17. 17.
    Bakris GL, Slataper R, Vicknair N, Sadler R. ACE inhibitor mediated reductions in renal size and microalbuminuria in normotensive, diabetic subjects. J Diabetic Compl 1994; 8: 2–6.CrossRefGoogle Scholar
  18. 18.
    Viberti GC, Mogensen CE, Groop L, Pauls JF for the European Microalbuminuria Captopril Study Group. Effect of captopril on progression to clinical proteinuria in patients with insulin-dependent diabetes mellitus and microalbuminuria. JAMA 1994; 271: 275–279.PubMedCrossRefGoogle Scholar
  19. 19.
    Sakamoto N. Effects of long-term enalapril treatment on persistent microalbuminuria in well-controlled hypertensive and normotensive NIDDM patients. Diabetes Care 1994; 17: 420–424.PubMedCrossRefGoogle Scholar
  20. 20.
    Slataper R, Vicknair N, Sadler R, Bakris GL. Comparative effects of different anti hypertensive treatments on progression of diabetic renal disease. Arch Intern Med 1993; 153: 973–980.PubMedCrossRefGoogle Scholar
  21. 21.
    Lebovitz HE, Wiegmann TB, Cnaan A. Renal protective effects of enalapril in hypertensive NIDDM: role of baseline albuminuria. Kidney Int 1994; 45: Suppl.: S150–S155.CrossRefGoogle Scholar
  22. 22.
    Lewis EJ, Hunsicker LG, Bain RP, Rohde RD for the Collaborative Study Group. The effect of angiotensin converting enzyme inhibition on diabetic nephropathy. N Engl J Med 1993; 329: 1456–1462.PubMedCrossRefGoogle Scholar
  23. 23.
    Gaber L, Walton C, Brown S, Bakris, GL. Effects of different antihypertensive treatments on morphologic progression of diabetic nephropathy in uninephrectomized dogs. Kidney Int 1994; 46: 161–169.PubMedCrossRefGoogle Scholar
  24. 24.
    Munter K, Hergenroder S, Jochims K, Kirchengast M. Individual and combined effects of verapamil or trandolapril on glomerular morphology and function in the stroke prone rat. J Am Soc Nephrol 1996; 7: 681–686.PubMedGoogle Scholar
  25. 25.
    Brown SA, Walton CL, Crawford P, Bakris GL. Long-term effects of different anti-hypertensive regimens on renal hemodynamics and proteinuria. Kidney Int 1993, 43: 1210–1218.PubMedCrossRefGoogle Scholar
  26. 26.
    Picken M, Griffin K, Bakris GL and Bidani A. Comparative effects of four different calcium antagonists on progression of renal disease in a remnant kidney model. J Am Soc Nephrol 1996; in press.Google Scholar
  27. 27.
    Griffin K, Picken M, Bakris GL, Bidani A. Calcium antagonists and the remnant kidney model: relative antihypertensive and glomeruloprotective efficacies. Abstract. Am J Hypertens 1996; 9: 38.CrossRefGoogle Scholar
  28. 28.
    Dworkin LD, Tolbert E, Recht PA, Hersch JC, Feiner H, Levin RI. Effects of amlodipine on glomerular filtration, growth and injury in experimental hypertension. Hypertension 1996; 27: 245–250.PubMedCrossRefGoogle Scholar
  29. 29.
    Jyothirmayi GN, Reddi AS. Effect of diltiazem on glomerular heparan sulfate and albuminuria in diabetic rats. Hypertension 1993; 21: 765–802.CrossRefGoogle Scholar
  30. 30.
    Andrawis NS, Abernathy DR. Effect of calcium antagonists on RNA synthesis of NIH 3T3 cells. Am J Med Sci 1993; 306: 137–140.PubMedCrossRefGoogle Scholar
  31. 31.
    Jyothirmayi GN, Alluru I, Reddi AS. Doxazosin prevents proteinuria and glomerular loss of heparan sulfate in diabetic rats. Hypertension 1996; 27: 1108–1114.PubMedCrossRefGoogle Scholar
  32. 32.
    Abbott K, Smith AC, Bakris GL. Effects of dihydropyridine calcium antagonists on albuminuria in diabetic subjects. J Clin Pharmacol 1996; 36: 274–279.PubMedCrossRefGoogle Scholar
  33. 33.
    Gilbert RE, Jerum G, Allen T, Hammond J, Cooper ME on behalf on Diabetic Nephropathy Study Group. Effect of different antihypertensive agents on normotensive microalbuminuria patients with IDDM and NIDDM. Abstract. J Am Soc Nephrol 1994; 5: 377.Google Scholar
  34. 34.
    Zucchelli P, Zuccala A, Borghi M, et al. Long term comparison between captopril and nifedipine in the progression of renal insufficiency. Kidney Int 1992; 42: 452–458.PubMedCrossRefGoogle Scholar
  35. 35.
    Velussi M, Brocco E, Frigato F, ZoUi M, Muollo B, Maioli M, Carraro A, Tonolo G, Fresu P, Cernigoi A, Fioretto P, Nosadini R. Effects of cilazapril and amlodipine on kidney function in hypertensive NIDDM patients. Diabetes 1996; 45: 216–222.PubMedCrossRefGoogle Scholar
  36. 36.
    Gansevoort RT, Sluiter WJ, Hemmelder MH, de Zeeuw D, de Jong PE. Antiproteinuric effect of blood pressure lowering agents: a meta-analysis of comparative trials. Nephrol Dial Transplant 1995; 10: 1963–1974.PubMedGoogle Scholar
  37. 37.
    Weidmann P, Scneider M, Bohlen L, et al. Therpeutic efficacy of different antihypertensive drugs in human diabetic nephropathy: An updated meta-analysis. Nephrol Dial Transpl 1995; 10: Suppl. 9: 39–45.Google Scholar
  38. 38.
    Maki DD, Ma JZ, Louis TA, Kasiske BL. Effect of antihypertensive agents on the kidney. Arch Intern Med 1995; 155: 1073–1082.PubMedCrossRefGoogle Scholar
  39. 39.
    Savage S, Johnson NN, Estacio RO. The ABCD (Appropriate Blood Pressure Control in Diabetes) trial: rationale and design of a trial of hypertension control (moderate or intensive) in type II diabetes. Online J Curr Clin Trials Doc. No. 1993; 104.Google Scholar
  40. 40.
    Bakris GL, Copley JB, Vicknair N, Sadler R, Leurgans S. Calcium channel blockers versus other antihypertensive therapies on progression of NIDDM associated nephropathy: Results of a six year study. Kidney Int 1996; in press.Google Scholar
  41. 41.
    Bakris GL, Copley JB, Vicknair N. Blood pressure reduction and progression of diabetic nephropathy in African-Americans: A five year follow-up study. J Am Soc Nephrol 1995; 6: 446A.Google Scholar
  42. 42.
    Wenzel RO, Helmchen U, Schoeppe W, Schwietzer G. Combination treatment of enalapril with nitrendipine in rats with renovascular hypertension. Hypertension 1994; 23: 114–122.PubMedCrossRefGoogle Scholar
  43. 43.
    Picken M, Griffin K, Bakris GL, Bidani A. Effects of a fixed dose combination of either amlodipine, benazapril or their combination on glomerulosclerosis and proteinuria. Kidney Int 1996; in press.Google Scholar
  44. 44.
    Smith AC, Kilaru P, Bakris GL Effects of a dihydropyridine calcium antagonist on proteinuria when added to NIDDM patients receiving an ACE inhibitor. Kidney Int 1996; in press.Google Scholar
  45. 45.
    Bakris GL, Weir MR, DeQuattro V, Rosendorff C, MacMahon G. Renal hemodynamic and antiproteinuric response to an ACE inhibitor, trandolopril or calcium antagonist, verapamil, alone or in fixed dose combination in patients with diabetic nephropathy: a randomized multicentered study. J Am Soc Nephrol 1996; in press.Google Scholar
  46. 46.
    Lash JP, Bakris GL. Effects of ACE inhibitors and calcium antagonists alone or combined on progression of diabetic nephropathy. Nephrol Dialysis Transpl 1995; 10: Suppl. 9: 56–62.Google Scholar
  47. 47.
    Yusuf S, Lessem J, Jha P, Lonn E. Primary and secondary prevention of myocardial infarction and strokes: an update of randomly allocated, controlled trials. J Hypertens 1993; 11: Suppl. 4: S61–S73.Google Scholar
  48. 48.
    Furberg CD, Psaty BM and Meyer JV. Dose-related increase in mortality in patients with coronary heart disease. Circulation 1995; 92: 1326–1331.PubMedCrossRefGoogle Scholar
  49. 49.
    Perna A, Remuzzi G. Abnormal permeability to proteins and glomerular lesions: a meta-analysis of experimental and human studies. Am J Kidney Dis 1996; 27: 34–41.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1996

Authors and Affiliations

  • George L. Bakris
    • 1
  1. 1.Rush University Hypertension Center, Rush-Presbyterian-St. Luke’s Medical CenterChicagoUSA

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