Drugs may reduce kidney risk in diabetics

We really have something,’ investigator says

Three recent clinical trials are showing that angiotensin II receptor blockers, used to treat high blood pressure, can slow the progression of renal disease among patients with Type 2 diabetes.

"These studies constitute a major sea change for Type 2 diabetes. We really have something," Barry M. Brenner, MD, told the Washington Post. Brenner is a kidney specialist at the Brigham and Women’s Hospital in Boston, and principal author of one of the studies that featured the angiotensin II receptor blocker losartan. The studies, which were published in the Sept. 20 issue of the New England Journal of Medicine, did not test the drugs against angiotensin-converting enzyme (ACE) inhibitors, an omission that some find troubling. (For more information on this omission, see "Is politics a part of ACEs' exclusion from studies?," in this issue.)

Drugs that can reduce the risk of kidney deterioration in diabetics are welcomed. Forty percent of patients with Type 2 diabetes will develop diabetic kidney disease, the leading cause of kidney failure in the United States, Japan, and Europe. Patients with Type 2 diabetes, hypertension, and kidney disease also are at significant risk of experiencing major cardiovascular events. According to data from the National Institute of Diabetes and Digestive and Kidney Diseases, both the prevalence and the incidence of end-stage renal disease (ESRD) are approximately twice what they were 10 years ago.

Here is a look at the three trials, which were funded by the drug manufacturers.

• The Irbesartan Diabetic Nephropathy Trial (IDNT) compared the effects of the angiotensin II receptor blocker irbesartan (Avapro, Bristol-Myers Squibb, and Sanofi-Synthelabo), the calcium channel blocker amlodipine, and a placebo on a background of antihypertensive therapy. The 1,715 men and women who participated in the trial were between the ages of 30 and 70 and had documented hypertension and proteinuria, with urinary protein excretion of at least 900 mg/24 hours. The mean duration of follow-up was 2.6 years.

The primary composite endpoint was defined as the doubling of baseline serum creatinine and the development of ESRD, indicated by renal transplantation or death from any cause. Treatment of irbesartan was associated with a risk of developing a composite endpoint event that was 20% lower than that in the placebo group, and 23% lower than that in the amlodipine group. The risk of doubling the serum creatinine concentration was 33% lower in the irbesartan group than in the placebo group and 37% lower in the irbesartan group than in the amlodipine group.

Treatment with irbesartan was associated with a relative risk of ESRD that was 23% lower than that found in both other groups. These differences were not explained by differences in the achieved blood pressures. The serum creatinine concentration increased 24% more slowly in the irbesartan group than in the placebo group and 21% more slowly than in the amlodipine group. There were no significant differences in the rates of death from any cause or in the cardiovascular composite endpoint.

The study researchers concluded that irbesartan is effective in protecting against the progression of nephropathy due to Type 2 diabetes. "Irbesartan is not only an excellent blood pressure drug for patients with diabetes and hypertension, but more importantly, it protects their kidneys from damage independent of its effect on blood pressure," says Edmund J. Lewis, MD, director of nephrology at Rush-Presbyterian- St. Luke’s Medical Center in Chicago.

• The Irbesartan MicroAlbuminuria Type 2 Diabetes Mellitus in Hypertensive Patients (IRMA 2) trial was a double-blind, placebo-controlled study conducted in 590 patients with hypertension, Type 2 diabetes, and microalbuminuria.

The patients received 150 or 300 mg of irbesartan daily, and were followed for two years. The primary outcome was the time to the onset of diabetic nephropathy, defined by persistent albuminuria in overnight specimens, with a urinary albumin excretion rate that was greater than 200 mcg/min and at least 30% higher than the baseline level. All were treated with antihypertensive therapy.

Ten of the 194 patients in the 300 mg group (5.2%) and 19 of the 195 patients in the 150 mg group (9.7%) reached the primary endpoint, as compared with 30 of the 201 patients in the placebo group (14.9%). The average blood pressure during the course of the study was 144/83 mm Hg in the placebo group, 143/83 mm Hg in the 150 mg group, and 141/83 mm Hg in the 300 mg group. Serious adverse events were less frequent among the patients treated with irbesartan.

The investigators concluded that Irbesartan is renoprotective independently of its blood pressure-lowering effect in patients with Type 2 diabetes and microalbuminuria.

• A total of 1,513 patients were enrolled in Reduction of Endpoints in Non-Insulin Dependent Diabetes Mellitus with the Angiotensin II Antagonist Losartan (RENAAL) trial. The randomized, double-blind study compared the angiotensin II receptor blocker losartan (Cozaar, Merck &, Co.), 50 to 100 mg once daily, with placebo. Both were taken in addition to conventional antihypertensive treatment for a mean of 3.4 years.

The primary outcome was the composite of a doubling of the baseline serum creatinine concentration, ESRD, or death. Secondary endpoints included a composite of morbidity and mortality from cardiovascular causes, proteinuria, and the rate of progression of renal disease.

A total of 327 patients in the losartan group reached the primary endpoint, as compared with 359 in the placebo group (risk reduction 16%). Losartan reduced the incidence of a doubling of the serum creatinine concentration (risk reduction 25%) and ESRD (risk reduction 28%), but had no effect on the rate of death.

The benefit exceeded that attributable to changes in blood pressure. The composite of morbidity and mortality from cardiovascular causes was similar in the two groups, although the rate of first hospitalization for heart failure was significantly lower with losartan (risk reduction, 32%). The level of proteinuria declined by 35% with losartan.

As in the other studies, the investigators concluded that losartan conferred significant renal benefits in patients with Type 2 diabetes and nephropathy, and it was generally well- tolerated.