eMJA     The Medical Journal of Australia

Home | Issues | eMJA shop | My account | Classifieds | Contact | More... | Topics | Search   

Letters

Renal protection by angiotensin II receptor antagonists in patients with type 2 diabetes

Roger E Peverill
MJA 2002; 176 (6): 296-297

To the Editor: A recent editorial in the Journal attempted to define a role for angiotensin II receptor (AIIR) antagonists in patients with type 2 diabetes.1 This was in the light of recent trial evidence that these agents reduce progression to renal failure in patients with type 2 diabetes and diabetic renal disease. Unfortunately, the guidelines provided were somewhat confusing and fragmented. I believe that a simpler treatment guide can be constructed, particularly when it is emphasised that the aim in diabetes is to use agents that prevent not only renal failure but also cardiovascular events.

Substantial evidence already supports a role for the angiotensin-converting enzyme (ACE) inhibitor ramipril in treatment of diabetes. The HOPE study included 3577 people with diabetes and another risk factor for cardiovascular disease who were randomised to either placebo or ramipril (10 mg) for 4.5 years.2 This group had a mean baseline blood pressure of 142/80 mmHg and no clinical proteinuria. Ramipril lowered the risk of the combined primary outcome of myocardial infarction, stroke and cardiovascular death by 25% (P 0.001), and this effect was independent of blood-pressure lowering. Furthermore, ramipril reduced progression to overt nephropathy by 22%, with a reduction evident in patients with or without proteinuria.2

This protective effect of ramipril on renal function is consistent with previous evidence that ACE inhibitors slow progression of chronic renal failure in diabetes,3,4 and that ramipril slows progression of chronic renal failure in non-diabetic nephropathy.5

Whether other ACE inhibitors have the same effect as ramipril on cardiovascular events, and what doses obtain such an effect, remains speculative. Similarly, while there is now evidence that AIIR antagonists also have renal-protective effects, there is no definitive evidence that they protect against cardiovascular events.

In view of this, and in the absence of comparative trials, ramipril (and not other ACE inhibitors or AIIR antagonists) is currently the first choice for treatment for diabetic patients with hypertension, with normotension and microalbuminuria, or with hypertension and micro- or macroalbuminuria. As most patients with diabetes and hypertension require multiple agents to achieve a target blood pressure less than 130/80 mmHg, additional therapy with a β-blocker, diuretic or calcium-channel blocker is often necessary.

The significance of the newly available trial data is that AIIR antagonists provide an alternative to ramipril for reducing progression to chronic renal failure in patients with diabetic nephropathy who cannot tolerate ACE inhibitors because of the side effect of cough.

  1. Jerums G, Cooper ME, Gilbert RE, Atkins RC. Renal protection by angiotensin II receptor antagonists in patients with type 2 diabetes [editorial]. Med J Aust 2001; 175: 397-399. <PubMed>
  2. Heart Outcomes Prevention Evaluation (HOPE) Investigators. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy [published correction appears in Lancet 2000; 356: 860]. Lancet 2000; 355: 253-259. <PubMed>
  3. Ravid M, Savin H, Jutrin I, et al. Long-term stabilizing effect of angiotensin-converting enzyme inhibition on plasma creatinine and on proteinuria in normotensive type II diabetic patients. Ann Intern Med 1993; 118: 577-581. <PubMed>
  4. 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: 286-289. <PubMed>
  5. Ruggenenti P, Perna A, Gherardi G, et al. Renoprotective properties of ACE-inhibition in non-diabetic nephropathies with non-nephrotic proteinuria. Lancet 1999; 354: 359-364. <PubMed>

(Received 24 Oct 2001, accepted 26 Nov 2001)

Centre for Heart and Chest Research, Monash University Department of Medicine, Monash Medical Centre, Clayton, VIC.

Roger E Peverill, PhD, FRACP, Cardiologist and Senior Lecturer.

Correspondence: Dr Roger E Peverill, Centre for Heart and Chest Research, Monash University Department of Medicine, Monash Medical Centre, Clayton, VIC 3168. roger.peverillATmed.monash.edu.au

AntiSpam note: To avoid spam, authors' email addresses are written with AT in place of the usual symbol, and we have removed "mail to" links. Replace AT with the correct symbol to get a valid address.


In reply: Renal protection by angiotensin II receptor antagonists in patients with type 2 diabetes

George Jerums, Mark E Cooper, Richard E Gilbert and Robert C Atkins
MJA 18 March 2002 176 (6: 297

In reply: Peverill raises the question of how to integrate the new data on renal protection by angiotensin II receptor (AIIR) antagonists with existing data on cardiovascular protection by angiotensin-converting enzyme (ACE) inhibitors in patients with type 2 diabetes. An AIIR antagonist would be favoured for renal protection for a diabetic patient with hypertension and evidence of early or overt nephropathy. With regard to patients with microalbuminuria, the HOPE and MICRO-HOPE studies showed that therapy with the ACE inhibitor ramipril (10 mg/day) was associated with a 24% relative risk reduction for the development of overt nephropathy over 4.5 years.1 In contrast, treatment of similar patients with the AIIR antagonist irbesartan (300 mg/day) for 2.6 years resulted in a 70% risk reduction for the development of overt nephropathy.2 Use of an AIIR antagonist in patients with overt nephropathy has also been shown to slow progression to end-stage renal failure.3,4 As the HOPE and MICRO-HOPE studies specifically excluded such patients, evidence supporting use of an ACE inhibitor in this context is lacking.

An ACE inhibitor could be used if a diabetic patient has microalbuminuria and a history of coronary heart disease or additional risk factors for cardiovascular disease, especially if normotensive. However, almost all patients with microalbuminuria require antihypertensive therapy as well as therapy to protect target organs. The relative importance of blood-pressure-lowering versus non-lowering effects of antihypertensive therapy on reducing risk of cardiovascular disease remains uncertain.5 Furthermore, a recent meta-analysis of cardiovascular protection in 62 605 patients with hypertension (including the HOPE and United Kingdom Prospective Diabetes studies) did not find that ACE inhibitors affected cardiovascular prognosis beyond their antihypertensive effects.6

Finally, it is important to note that neither ACE inhibitors nor AIIR antagonists provide total protection from cardiovascular and renal events, and that further improvements are needed for both microvascular and macrovascular protection in patients with type 2 diabetes.

  1. Heart Outcomes Prevention Evaluation (HOPE) Investigators. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Lancet 2000; 355: 253-259. <PubMed>
  2. Parving H-H, Lenhert H, Brochner-Mortensen J, et al for the Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria Study Group. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med 2001; 345: 870-878. <PubMed>
  3. Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001; 345: 851-860. <PubMed>
  4. Brenner BM, Cooper ME, De Zeeuw D, et al for the RENAAL Study Investigators. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001; 345: 861-869. <PubMed>
  5. He J, Whelton PK. Selection of initial antihypertensive drug therapy. Lancet 2000; 356: 1942-1943. <PubMed>
  6. Staessen JA, J-G Wang, Lutgarde T. Cardiovascular protection and blood pressure reduction: a meta-analysis. Lancet 2001; 358: 1305-1314. <PubMed>

(Received 14 Nov 2001, accepted 26 Nov 2001)

Austin and Repatriation Medical Centre, Heidelberg, VIC.

George Jerums, Professorial Fellow and Director of Endocrinology.

Department of Medicine, Austin and Repatriation Medical Centre, Melbourne, VIC.

Mark E Cooper, Professor.

Department of Medicine, St Vincent's Hospital, Melbourne, VIC.

Richard E Gilbert, Associate Professor.

Department of Nephrology, Monash Medical Centre, Melbourne, VIC.

Robert C Atkins, Professor of Medicine.

Correspondence: Professor George Jerums, Austin and Repatriation Medical Centre, Heidelberg, VIC 3084. endoATaustin.unimelb.edu.au

Home | Issues | eMJA shop | My account | Classifieds | More... | Contact | Topics | Search

The Medical Journal of Australia    eMJA  

©The Medical Journal of Australia 2002 www.mja.com.au PRINT ISSN: 0025-729X ONLINE ISSN: 1326-5377