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Trials showing that angiotensin II receptor blockers slow renal disease in Type 2 diabetes are promising, but one physician questions the exclusion of angiotensin-converting enzyme (ACE) inhibitors from the studies.
In the past, clinicians have assumed that renin-angiotensin-aldosterone system blockage was of special value in slowing nephropathy related to Type 2 diabetes and have used ACE inhibitors in the hope of attenuating it, says Thomas H. Hostetter, MD, of the National Institute of Diabetes and Digestive and Kidney Diseases in Bethesda, MD. His editorial appeared in the Sept. 20 issue of the New England Journal of Medicine (NEJM), along with the trial results. "Why, then, were ACE inhibitors not tested in the present studies?" [For more information about the studies, see "Drugs may reduce kidney risk in diabetics," in this issue.]
He suggests that the expense and difficulty of such a trial were primary roadblocks. In a published interview, Edmund J. Lewis, MD, director of nephrology at Rush-Presbyterian-St. Luke’s Medical Center, Chicago, and the lead investigator of the Irbesartan Diabetic Nephropathy Trial (IDNT), says funding was a problem. In a study published in the Nov. 11, 1993, issue of NEJM, his research group reported that the ACE inhibitor captopril (Capoten) prevented kidney disease in patients with Type 1 diabetes. They weren’t able to get funding for a similar trial in a Type 2 diabetic population.
"Remarkably, both the NIH and the American Diabetes Association decided that Type 2 diabetic nephropathy, the most common cause for people going on dialysis, wasn’t a high enough priority for them to fund, so we had to go back to the industry," he says. The studies were funded by the manufacturers of two of the drugs.
In the NEJM article, Lewis and his investigators say that they cannot directly address the issue of whether the effects of ACE inhibitors and angiotensin II receptor blockers would be equivalent in the treatment of patients with nephropathy due to Type 2 diabetes. "It may seem reasonable to assume that agents that primarily reduce the generation or effect of angiotensin II would have similar clinical results," they say. "However, it is important to caution that ACE inhibitors and angiotensin-receptor blockers are distinctly different classes of drugs and that one cannot assume equivalence between them."
Testing multiple agents increases the difficulty of identifying clear differences among them, Hostetter adds. "If ACE inhibitors and angiotensin-receptor blockers are indistinguishable with respect to efficacy, as many previous data predict, decisions about which type of drug to prescribe should be based on side effects and cost." ACE inhibitors have a disadvantage in that they cause a cough in 5-20% of patients.
They are less expensive than the angiotensin II receptor blockers, however. This will not change soon because ACE inhibitors will lose their patent protection sooner. Hostetter suggests that one reason ACE inhibitors were not tested in these trials was because a result of equal effectiveness would reduce the sale of the angiotensin II receptor blockers. He finds the idea troubling.
"We must focus more attention on the regrettable tendency of study sponsors to drop good drugs from important trials when their patents expire and the drugs therefore become less profitable," he says. "The legitimate need to develop and profit from new compounds must be explicitly balanced against the obligation to test established and effective, but cheaper, agents."
Fran Kaufman, MD, president-elect of the American Diabetes Association in Alexandria, VA, won’t enter the debate about the study’s exclusion of ACE inhibitors. "This study is just comparing a different way to get at angiotensin-converting enzyme inhibition through the receptor vs. the calcium channel blocker — to see whether there is efficacy to either one of those."
These are important studies and may change practice over time, she says. "This may slowly become as widely used a modality as ACE inhibition." She agrees, though, that more research is needed. "Now they maybe need to go head-to-head with an ACE inhibitor and see how [the angiotensin II receptor blockers] compare in efficacy, safety, and cost."