Hypertension in Diabetes

Epidemiology

There is a growing pandemic of diabetes and its complications throughout the world, related in part to improved living conditions and increasing rates of obesity. This unfortunate trend is seen even in developing countries. The WHO now recognizes obesity as the #1 unaddressed public health problem facing the world.1

BP and diabetic complications

The UKPDS showed that blood pressure control has more impact on reducing complications of type 2 diabetes than glycemic control. Hypertension, as a treatment gap, presents the greatest opportunity for reducing complications of diabetes. The UKPDS trial revealed a linear reduction in all diabetic complications as systolic blood pressure was reduced.2 (Level 3). See Figure 1.

Review of RCTs of BP control in diabetes

SHEP - therapy with a thiazide diuretic in elderly patients with hypertension lowered the risk of cardiovascular events. The absolute effect was even twice as great in the diabetic subgroup.3 (Level 1)

SystEur - therapy with a long acting dihydropyridine calcium channel blocker lowered the risk of cardiovascular endpoints in elderly patients with systolic hypertension. The beneficial effect was almost three times greater in the diabetic subgroup.4 (Level 1)

HOT - aggressive blood pressure lowering (diastolic 80) based on a long acting dihydropyridine calcium channel blocker lowered complication rates in essential hypertension, but the beneficial effect was only seen in the diabetic subgroup.5 (Level 1)

UKPDS - aggressive BP lowering (diastolic 83 vs 87) with either an ACE inhibitor or Beta blocker lowered all complications of diabetes.6 There was no advantage to the ACE inhibitor over the beta blocker in this study, suggesting the beneficial effect of ACE inhibition in type 2 diabetes is related primarily to BP lowering. (Level 1)

CAPPP - in a planned subgroup analysis of the diabetic arm of this trial of captopril vs diuretic/BBlocker in essential hypertension, all cause mortality and cardiovascular events were significantly lower in the ACE inhibitor arm despite equivalent BP control.7 (Level 1)

FACET/ABCD remain problematic studies, but patients treated with combination therapy had the best outcomes.8 (Level 3)

New Guidelines for Target BP Control in Diabetics (Level 4)

WHO 19999 Lower diastolic < 80 in diabetics, < 125/75 if nephropathy and > 1g/day proteinuria. Leaves choice of antihypertensive agent open to physician.

British Guidelines 199910 Goal BP for all diabetics < 140/80. Target BP < 125/75 if renal disease and proteinuria > 1 gram/day. Recommends initial therapy with thiazide diuretic in all situations.

National Kidney Foundation Guidelines 2000 Begin therapy with ACE inhibitor and diuretic combination therapy. Target BP < 130/85, but in the presence of diabetic nephropathy target < 130/80.11

Canadian Guidelines 200112 Goal BP for all diabetics < 130/80. With established nephropathy and > 1 gram proteinuria/day target blood pressure < 125/75. The new Canadian guidelines state that ACE inhibitors, ARBs, diuretics, and calcium channel blockers could all be considered as first line agents in treating diabetic hypertension depending on the clinical situation.

There is no agreement among the guidelines as to which antihypertensive drug class should be utilized first, but all four sets of guidelines recommend lower blood pressure targets for diabetics.

Beyond BP control

Micro Hope - The diabetic subgroup of HOPE (40% of the study population) had a similar reduction in cardiovascular mortality as seen in the general HOPE population. (Level 1) The treatment arm had significant lower BP at the study end, making it difficult to ascertain the exact mechanism of cardioprotection seen with Ramipril. There was no reduction in ESRD in the Ramipril group, however the number of cases of ESRD in both arms was low.13 The CAPPP study did show a significant benefit of captopril vs diuretic/BBlocker on all cause mortality and all cardiovascular events, despite indentical BP control.

ARB trials - Therapy with ARBs in both early (microalbuminuria with normal renal function) and overt nephropathy (dipstick proteinuria and elevated creatinine) reduced the progression of diabetic nephropathy to ESRD, despite nearly identical blood pressure control in the control arms.14 15 16 (Level 1) In a head to head trials between an ACE inhibitor and an ARB, there was no difference in BP reduction or albumin excretion rate.17

Whether there will be a differential effect on the incidence of cardiovascular disease or ESRD between ACE inhibitors and ARBs remains uncertain. However, it appears clear now that blockade of the renin angiotensin system has a beneficial effect independent of BP control alone.

Pitfalls in blockade of the Renin Angiotensin System

Blockade of the RAS is desirable in order to achieve the reductions in cardiovascular complications and nephropathy seen in RCTs of these agents in diabetes. They are extremely well tolerated in an ambulatory, closely supervised population studied in large multi center trials. Unfortunately, use of these drugs in patients who are less stable, such as those with acute heart failure, dehydration, or advanced renal failure can lead to acute renal failure and/or hyperkalemia, which may require temporary withdrawal of the ACE inhibitor or ARB. It is sometimes possible to reintroduce these agents once the patient has stabilized. If this is not successful, it should be remembered that aggressive blood pressure control with other commonly used antihypertensive drug classes is also effective in reducing complications of diabetes. According to the American Diabetes Association, the achievement of the target blood pressure goal with a regimen that does not produce burdensome side effects and is at reasonable cost to the patient is probably more important than the specific drug strategy.18

Combination Therapy

Combination therapy was required in both the UKPDS and the HOT Study to achieve the lower blood pressure values associated with reduction in complications.19 Combination therapy may be difficult in practice for several reasons: cost, compliance, and drug interactions. Combining multiple antihypertensive drug classes in a single pill is becoming increasing popular, and can help control drug costs and improve patient compliance. Be wary of combining water soluble beta blockers and non dihydropyridine calcium channel blockers in patients with significant renal insufficiency, as these drugs can accumulate and interact to cause significant bradycardia. The use of combination therapy with ACE inhibitors and ARBs is promising. The combination of the two drug classes in the CALM study20 led to further blood pressure reductions and reductions in proteinuria than either drug alone, although long term studies with harder endpoints are lacking.

Refractory Hypertension

Most cases of refractory hypertension referred to a hypertension specialty clinic will respond to therapy with a combination of 4 antihypertensive drug classes including full dose thiazide diuretic (25 mg daily).21 (Level 3) This illustrates the importance of compliance, combination therapy, and adequate diuresis in controlling hypertension. Patients with diabetic nephropathy often have a volume component to their blood pressure. Restriction of sodium in the diet is of paramount importance, and use of a loop diuretic is increasingly necessary as renal function declines.

Cost-effectiveness

More aggressive blood pressure lowering is not only cost effective, but should actually be cost neutral in the first 5 years. (Level 3) After 5 years, economic models project significant cost savings because of reduced hospitalizations for diabetic complications.22

Conclusions

The vast majority of type 2 diabetics have associated hypertension that is usually poorly controlled. Aggressive blood pressure lowering in this high-risk population is associated with a reduction in all diabetic complications, including cardiovascular and micro vascular disease. This almost always requires combination therapy with most of the commonly used antihypertensive drug classes, all of which have been shown in RCTs to reduce diabetic complications. Blockade of the renin angiotensin system is particularly effective in reducing nephropathy and cardiovascular disease, and the evidence from the most recent ARB trials reveals that the nephroprotective effect of these drugs is clearly independent of BP control. The most common causes of refractory hypertension are not enough drug classes utilized, noncompliance, and inadequate diuretic therapy. More aggressive treatment of hypertension in diabetics appears to be very cost-effective. Given the growing pandemic of diabetes and its complications, more attention to strict BP control in this population will be required in order to reduce the burden of disease on individuals and society.

- Thomas Hewlett

Thanks to Dr. Tim Dean, Dalhousie University Medical School, Halifax, Nova Scotia, for reviewing the draft copy of his article. Also thanks to Dr. Deborah Zwicker, Endocronologist and Dr. R.P. Baillie, Cardiologist at the Cape Breton Regional Hospital for their review of the manuscript.

  1. American Journal of Kidney Diseases,Vol 34, No 5 (November), 1999: pp 795-808. End-Stage Renal Failure in Type 2 Diabetes: A Medical Catastrophe ofWorldwide Dimensions
     
  2. Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): prospective observational study. AU - Adler AI; Stratton IM; Neil HA; Yudkin JS; Matthews DR; Cull CA; Wright AD; Turner RC; Holman RR. BMJ 2000 Aug 12;321(7258):412-9
  3. JAMA 1996 Dec 18;276(23):1886-92. 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. Curb JD, Pressel SL, Cutler JA, Savage PJ, Applegate WB, Black H, Camel G, Davis BR, Frost PH, Gonzalez N, Guthrie G, Oberman A, Rutan GH, Stamler J.
     
  4. J Nephrol 2000 May-Jun;13(3):232-7. Effects of antihypertensive treatment on endpoints in the diabetic patients randomized in the Systolic Hypertension in Europe (Syst-Eur) trial. Birkenhager WH, Staessen JA, Gasowski J, de Leeuw PW.
     
  5. 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. Hansson L; Zanchetti A; Carruthers SG; Dahlof B; Elmfeldt D; Julius S; Menard J; Rahn KH; Wedel H; Westerling S. Lancet 1998 Jun 13;351(9118):1755-62
     
  6. Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39. UK Prospective Diabetes Study Group. BMJ 1998 Sep 12;317(7160):713- 20
     
  7. Diabetes Care 24:2091Ð2096, 2001. Reduced Cardiovascular Morbidity and Mortality in Hypertensive Diabetic Patients on First-Line Therapy With an ACE Inhibitor Compared With a Diuretic/BlockerÐBased Treatment Regimen, A subanalysis of the Captopril Prevention Project. Leo Niskanen, Thomas Hedner, Lennart Hansson, Jan Lanke, Anders Niklason, for the CAPPP study group
     
  8. Am J Cardiol 1998 Nov 12;82(9B):15R-19R. Comorbidity of hypertension and diabetes: the fosinopril versus amlodipine cardiovascular events trial (FACET)
     
  9. Chalmers J et al. WHO-ISH Hypertension Guidelines Committee. 1999 World Health Organization - International Society of Hypertension Guidelines for the Management of Hypertension. J Hypertens, 1999, 17:151-185.
     
  10. Journal of Human Hypertension (1999) 13, 569Ð592. BHS GUIDELINES Guidelines for management of hypertension: report of the third working party of the British Hypertension Society. LE Ramsay, B Williams, GD Johnston, GA MacGregor, L Poston, JF Potter, NR Poulter and G Russell for the British Hypertension Society
     
  11. American Journal of Kidney Diseases,Vol 36, No 3 (September), 2000: pp 646-661. SPECIAL REPORT: Preserving Renal Function in AdultsWith Hypertension and Diabetes: A Consensus Approach George L. Bakris, MD, Mark Williams, MD, Lance Dworkin, MD, William J. Elliott, MD, PhD, Murray Epstein, MD, Robert Toto, MD, Katherine Tuttle, MD, Janice Douglas, MD, Willa Hsueh, MD, and James Sowers, MD for the National Kidney Foundation Hypertension and Diabetes Executive Committees Working Group
     
  12. The 2001 Canadian Hypertension Recommendations. What's new and what's old but still important. Canadian Hypertension Recommendations Working Group.
     
  13. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Heart Outcomes Prevention Evaluation Study Investigators. Lancet 2000 Jan 22;355(9200):253-9
     
  14. NEJM Volume 345:851-860 September 20, 2001 Number 12. Renoprotective Effect of the Angiotensin-Receptor Antagonist Irbesartan in Patients with Nephropathy Due to Type 2 Diabetes. Edmund J. Lewis, M.D., Lawrence G. Hunsicker, M.D., William R. Clarke, Ph.D., Tomas Berl, M.D., Marc A. Pohl, M.D., Julia B. Lewis, M.D., Eberhard Ritz, M.D., Robert C. Atkins, M.D., Richard Rohde, B.S., Itamar Raz, M.D., for the Collaborative Study Group.
     
  15. NEJM Volume 345:861-869 September 20, 2001 Number 12 Effects of Losartan on Renal and Cardiovascular Outcomes in Patients with Type 2 Diabetes and Nephropathy. Barry M. Brenner, M.D., Mark E. Cooper, M.D., Ph.D., Dick de Zeeuw, M.D., Ph.D., William F. Keane, M.D., William E. Mitch, M.D., Hans-Henrik Parving, M.D., Giuseppe Remuzzi, M.D., Steven M. Snapinn, Ph.D., Zhonxin Zhang, Ph.D., Shahnaz Shahinfar, M.D., for the RENAAL Study Investigators
     
  16. NEJM Volume 345:870-878 September 20, 2001 Number 12 The Effect of Irbesartan on the Development of Diabetic Nephropathy in Patients with Type 2 Diabetes. Hans-Henrik Parving, M.D., D.M.Sc., Hendrik Lehnert, M.D., Jens Brochner-Mortensen, M.D., D.M.Sc., Ramon Gomis, M.D., Steen Andersen, M.D., Peter Arner, M.D., D.M.Sc., for the Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria Study Group
     
  17. Kidney International 58 (2), 762-769. Long-term comparison of losartan and enalapril on kidney function in hypertensive type 2 diabetics with early nephropathy. Yves Lacourcière, André Bélanger, Chantal Godin, Jean-Pierre Hallé, Stuart Ross, Noël Wright, and Jean Marion
     
  18. Diabetes Care 25, 1 January, 2002
     
  19. SPECIAL REPORT: Preserving Renal Function in Adults With Hypertension and Diabetes: A Consensus Approach. George L. Bakris, MD, Mark Williams, MD, Lance Dworkin, MD, William J. Elliott, MD, PhD, Murray Epstein, MD, Robert Toto, MD, Katherine Tuttle, MD, Janice Douglas, MD, Willa Hsueh, MD, and James Sowers, MD for the National Kidney Foundation Hypertension and Diabetes Executive Committees Working Group. American Journal of Kidney Diseases,Vol 36, No 3 (September), 2000: pp 646-661
     
  20. Randomised controlled trial of dual blockade of renin-angiotensin system in patients with hypertension, microalbuminuria, and non-insulin dependent diabetes: the candesartan and lisinopril microalbuminuria (CALM) study. Carl Erik Mogensen, Steen Neldam, Ilkka Tikkanen, Shmuel Oren, Reuven Viskoper, Richard W Watts, Mark E Cooper for the CALM study groupBMJ VOLUME 321 9 DECEMBER 2000
     
  21. Drug-resistant hypertension: A specialist approach. Alla VD, Murtaza SJ, Grim CE Am J Hypertens (May) 13:149A 2000
     
  22. ARCH INTERN MED/VOL 160, MAY 8, 2000 p 1277. Cost-effectiveness of the Lower Treatment Goal for Diabetes.

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