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Do ACE inhibitors prevent nephropathy in type 2 diabetes without proteinuria?

* EVIDENCE-BASED ANSWER

Angiotensin-converting enzyme (ACE) inhibitors make a significant difference for patients with diabetes as a whole. If patients both with and without microalbuminuria are included together, ACE inhibitors significantly reduce the progression of the albumin excretion rate (strength of recommendation [SOR]: A, based on multiple randomized controlled trials) and the development of overt nephropathy (SOR: A, based on 1 randomized controlled trial).

However, studying diabetes without microalbuminuria separately, the effect of ACE inhibitors on progression to nephropathy does not reach statistical significance. This applies to both type 1 and 2 diabetes (SOR: A, based on randomized controlled trials with heterogenous results). Results are contradictory regarding whether ACE inhibition delays new onset of diabetic microalbuminuria.

* EVIDENCE SUMMARY

There are 3 prospective randomized controlled trials studying the effect of ACE inhibitors on albumin excretion for patients with diabetes who do not have microalbuminuria. A 2-year randomized controlled trial compared lisinopril (Prinivil; Zestril) 10 mg/d with placebo in 530 normotensive adults (aged 20-59 years) with insulin-dependent diabetes, defined as those diagnosed with diabetes before age 36 and using continuous insulin therapy within 1 year of diagnosis. At the beginning of the study, 90 patients had microalbuminuria--defined as an albumin excretion rate (AER) >29 mg/24 hr--and 440 patients did not. When the results for all patients who had and did not have microalbuminuria were combined, there was a significantly smaller rise in the AER for the lisinopril group vs the placebo group (3.2 mg/24 hr lower; P=.03). However, for the patients without initial microalbuminuria, the reduction in the rise of AER with lisinopril was not significant (1.4 mg/24 hr lower; P=.10). The decreased rate of developing new microalbuminuria was also not significant (relative risk reduction [RRR]=12.7%; P=.10). (1)

A subsequent trial compared enalapril (Vasotec) 10 mg/d with placebo in 194 normotensive patients (aged 40-60) with type 2 diabetes and without microalbuminuria, defined as AER >30 mg/24 hr. Over the 6-year course of the study, the AER in the placebo group rose from 10.8 mg/24 hr to 26.5 mg/24 hr. The AER of the treatment group dropped from 11.6 rag/24 hr initially to 9.7 mg/24 hr at 2 years, then rose to 15.8 mg/24 hr at 6 years. Enalapril significantly slowed the rise in AER (RRR=0.4; P=.001). Nineteen percent of the placebo group developed microalbuminuria, compared with 6.5% of those taking enalapril (absolute risk reduction[ARR]=12.5%; number needed to treat=8; P=.042). While this study described a modest and statistically significant renal protective effect of enalapril, it did not use an intention-to-treat analysis. (2)

MICRO-HOPE, a subset of the HOPE trial, studied ramipril (Altace) 10 mg/d vs placebo in 2437 patients with diabetes who did not have clinical proteinuria. Patients were aged 55 years or older and had either a previous cardiovascular event or at least 1 other cardiovascular risk factor. There were 1140 patients with microalbuminuria, defined as an albumin/creatinine ratio [greater than or equal to] 2 mg/mmol, and 2437 patients without. After 4.5 years, 10% of patients had developed overt nephropathy, defined as albumin/creatinine >36 mg/mmol.

When all patients in the study were examined together, ramipril provided significant renal protection over placebo (RRR=24%; ARR=1%; P=.027). It also lowered the risk of MI by 22%, stroke by 33%, and cardiovascular death by 37%. But in a separate analysis of the patients without microalbuminuria, ramipril did not significantly reduce overt nephropathy (P=.50). Ramipril also did not significantly reduce the risk of developing new microalbuminuria in this group (RRR=9%; P=.17). Further, for patients without microalbuminuria, ramipril did not reduce the combined outcomes of myocardial infarction, stroke, or cardiovascular death (odds ratio=0.85; 95% CI, 0.70-1.02). (3)

* RECOMMENDATIONS FROM OTHERS

We could find no guidelines recommending for or against the use of ACE inhibitors for patients with diabetes without microalbuminuria.

* CLINICAL COMMENTARY

ACE inhibitors should still be used in most patients with type 2 diabetes

ACE inhibitors do not prevent the development of type 2 diabetic nephropathy. In contrast to type i diabetes, cardiovascular disease is the primary cause of death in type 2. The HOPE study demonstrated that ACE inhibitor therapy significantly reduces cardiovascular events in type 2 diabetes independent of hypertension status. (4) These benefits are so compelling that the American Diabetes Association strongly recommends ACE inhibitor therapy for type 2 diabetics aged [greater than or equal to] 55 years with 1 additional risk factor. (5) Despite not preventing the development of nephropathy, ACE inhibitors should be used for most patients with type 2 diabetes for cardiovascular risk reduction.

Joseph Saseen, PharmD, FCCP, BCPS, University of Colorado Health Sciences Center, Denver

REFERENCES

(1.) Randomised placebo-controlled trial of lisinopril in normotensive patients with insulin-dependent diabetes and normoalbuminuria or microalbuminuria. The EUCLID Study Group. Lancet 1997; 349:1787-1792.

(2.) Ravid M, Brosh D, Levi Z, Bar-Dayan Y, Ravid D, Rachmani R. Use of enalapril to attenuate decline in renal function in normotensive, normoalbuminuric patients with type 2 diabetes mellitus. A randomized, controlled trial. Ann Intern Med 1998; 128:982-988.

(3.) Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICR0-HOPE substudy. Heart Outcomes Prevention Evaluation Study Investigators. Lancet 2000; 355:253-259.

(4.) Yusuf S, Sleight R Pogue J, Bosch J, Davies R, Dagenais G. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000; 342:145-153.

(5.) Arauz-Pacheco C, Parrott MA, Raskin P; American Diabetes Association. Treatment of hypertension in adults with diabetes. Diabetes Care 2003; 26 Suppl 1:S80-S82.

Lisa Sferra, MD, Gary Kelsberg, MD, Valley Family Care Medicine Residency, Renton, Wash; Sherry Dodson, MLS, University of Washington Health Sciences Libraries, Seattle
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Article Details
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Title Annotation:Clinical Inquiries; Angiotensin-converting enzyme
Author:Sferra, Lisa; Kelsberg, Gary; Dodson, Sherry
Publication:Journal of Family Practice
Geographic Code:1USA
Date:Jan 1, 2004
Words:986
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