Issue 173 Item 14 High Doses of Angiotensin-Converting Enzyme Inhibitors and Ang

Results from recent studies have led the ADA to recommend ARBs as the treatment of choice for patients with type 2 diabetes and diabetic nephropathy, and ARBs or ACEIs for patients with microalbuminuria.

Recent studies have demonstrated that angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) can have significant renoprotective effects, in addition to known antihypertensive benefits.

Blood pressure reduction has been used to determine the doses of ARBs and ACEIs required to effectively block the renin angiotensin system (RAS). However, recent evidence has suggested that reduction of proteinuria may provide a better standard for determining maximal renoprotective and cardiovascular effects.

To examine the optimal dosages of ACE inhibitors and ARBs, Marc S. Weinberg, MD, Rush Presbyterian/St Luke’s Medical Center, Chicago, Illinois, United States, and colleagues reviewed several comparative studies in diabetic subjects that evaluated the effect of usual or high doses of RAS blockers as monotherapy or combination therapy.

According to Dr. Weinberg, the studies demonstrate that higher doses of ACE inhibitors and/or ARBs beyond peak blood pressure lowering are required to achieve maximal proteinuria reduction and renoprotective effects. The higher dose benefit was observed in studies with both type 1 and type 2 diabetes.

The magnitude of the high dosage benefit differed in each study, possibly reflecting a large individual variability in response to RAS blockade therapy. The variability may be influenced by patient factors such as degree of renal dysfunction, race, sodium intake, length of therapy, and use of concomitant medications. For example, one study using ACE inhibitor/ARB combination therapy revealed a greater reduction in proteinuria for subjects on a low-sodium diet compared to those on a high sodium diet.

Several studies using ACE inhibitors and ARBs in combination suggested additional effects compared to monotherapy.

However, the reviewers note a tendency in the studies to combine very low or moderate doses of ACE inhibitors and ARBs together without first titrating the initial agent to its maximum. It therefore remains unclear whether supramaximal doses of monotherapy may be equally beneficial.

"The question of how high the doses of ACEI or ARBs must be for optimal benefit in diabetic nephropathy has not been widely answered," the reviewers conclude. Based on the available data, they recommend, "The optimal dose and strategy for renoprotection using ACEI and ARBs should be guided by titrating to the maximum antiproteinuric effect."

For patients who maintain elevated proteinuria despite high dose monotherapy, they recommend combined use of ACE inhibitors and ARBs. Curr Hypertens Rep 2003 Oct;5:5:418-25

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