96th Meeting of the Cardiovascular and Renal Drugs Advisory Committee Meeting
Losartan potassium (Cozaar), manufactured by Merck and Company, Inc, was proposed for the prevention of progression of nephropathy in patients with type II diabetes. Losartan is an angiotensin II receptor blocker (ARB) previously approved for the treatment of hypertension. It was examined in the Reduction of Endpoints in NIDDM with Angiotensin II Antagonist Losartan (RENAAL) study of 1513 normotensive/hypertensive patients with type II diabetes and nephropathy. At baseline, these patients had mean systolic and diastolic blood pressures of 152 mm Hg and 82 mm Hg, respectively, a mean creatinine of 1.9 mg/dL, and a mean proteinuria (UA/Cr) of 1808 mg/g Cr. Although patients could have received an ACE inhibitor or ARB in the past, no such treatment was allowed for the enrolled patients during the course of the trial.
The primary hypothesis was that long-term treatment with losartan, beginning with a daily dose of 50 mg and increasing to 100 mg, would reduce the primary composite triple end point of a doubling of serum creatinine. It would also reduce the development of end-stage renal disease (ESRD, defined as the need for chronic dialysis or renal transplantation) and all-cause mortality. Because proteinuria has been demonstrated to be an independent risk factor for the progression of renal disease in diabetic and nondiabetic patients, subjects were stratified by baseline proteinuria according to UA/Cr <2000 mg/Cr or ≥2000 mg/Cr.
Although the original study was to conclude after 3.5 years of follow-up, the Steering Committee recommended early termination of the trial because of increasing evidence that inhibition of the renin-angiotensin system reduced cardiovascular events in patients with cardiovascular risk factors and/or diabetes with renal impairment, and because of concern that half of all RENAAL patients were receiving placebo.
Patients in the RENAAL study were randomized to receive either placebo or losartan (titrated for blood pressure control as tolerated from 50 mg to 100 mg) and monitored for a mean of 3.4 years. The principal end point was a time-to-first event comparison, and a 16% risk reduction (P=0.022) in the primary composite triple end point was evident after 6 months of therapy; in a secondary analysis, losartan also reduced the occurrence of ESRD and death by 19.9% (P=0.009). Post-hoc adjustment of these findings for baseline proteinuria (known to be prognostically relevant and for which there was an imbalance) strengthened the magnitude and significance of the losartan effect. No difference in cardiovascular morbidity or mortality was observed. The principal adverse effect was hyperkalemia, which was seen approximately twice as frequently, or in 1 of 4 losartan-treated patients. The incidence of hyperkalemia progressively increased over the 3.4 years of the study.
The committee discussed at some length whether the RENAAL study alone provided sufficient evidence to support the treatment of diabetes with nephropathy by losartan and agreed that this single study did not meet the usual definitive standard (P=0.00125) for the primary end point. Some researchers expressed concern that if approval were granted, it might lead to some patients being switched from ACE inhibitors to losartan, which could result in the potential loss of cardiac protection. It was suggested that appropriate caution and context be provided in any approved labeling change.
The Committee was also asked whether the available data from a trial in type II diabetes with nephropathy using another ARB (irbesartan) could support the use of losartan. The Irbesartan in Diabetic Nephropathy Trial (IDNT) reported similar effects of irbesartan at reducing the risk of progression of renal disease and mortality. Although concerned about the precedent of relying on data from another drug in the same pharmacological class, and warning against any issues of class labeling, the Committee recommended that such data could be used to support the efficacy of losartan. After reflecting on the weight of additional evidence from the IDNT trial, the Committee voted 8 to 3 to recommend approval of losartan for the treatment of type II diabetes with nephropathy.