COZAAR (Page 6 of 8)

14.3 Nephropathy in Type 2 Diabetic Patients

The RENAAL study was a randomized, placebo-controlled, double-blind, multicenter study conducted worldwide in 1513 patients with type 2 diabetes with nephropathy (defined as serum creatinine 1.3 to 3.0 mg/dL in females or males ≤60 kg and 1.5 to 3.0 mg/dL in males >60 kg and proteinuria [urinary albumin to creatinine ratio ≥300 mg/g]).

Patients were randomized to receive COZAAR 50 mg once daily or placebo on a background of conventional antihypertensive therapy excluding ACE inhibitors and angiotensin II antagonists. After one month, investigators were instructed to titrate study drug to 100 mg once daily if the trough blood pressure goal (140/90 mmHg) was not achieved. Overall, 72% of patients received the 100-mg daily dose more than 50% of the time they were on study drug. Because the study was designed to achieve equal blood pressure control in both groups, other antihypertensive agents (diuretics, calcium-channel blockers, alpha- or beta-blockers, and centrally acting agents) could be added as needed in both groups. Patients were followed for a mean duration of 3.4 years.

The study population was diverse with regard to race (Asian 16.7%, Black 15.2%, Hispanic 18.3%, White 48.6%). Overall, 63.2% of the patients were men, and 66.4% were under the age of 65 years. Almost all of the patients (96.6%) had a history of hypertension, and the patients entered the trial with a mean serum creatinine of 1.9 mg/dL and mean proteinuria (urinary albumin/creatinine) of 1808 mg/g at baseline.

The primary endpoint of the study was the time to first occurrence of any one of the following events: doubling of serum creatinine, end-stage renal disease (ESRD) (need for dialysis or transplantation), or death. Treatment with COZAAR resulted in a 16% risk reduction in this endpoint (see Figure 4 and Table 4). Treatment with COZAAR also reduced the occurrence of sustained doubling of serum creatinine by 25% and ESRD by 29% as separate endpoints, but had no effect on overall mortality (see Table 4).

The mean baseline blood pressures were 152/82 mmHg for COZAAR plus conventional antihypertensive therapy and 153/82 mmHg for placebo plus conventional antihypertensive therapy. At the end of the study, the mean blood pressures were 143/76 mmHg for the group treated with COZAAR and 146/77 mmHg for the group treated with placebo.

Figure 4
(click image for full-size original)

Figure 4: Kaplan-Meier curve for the primary composite endpoint of doubling of serum creatinine, end stage renal disease (need for dialysis or transplantation) or death.

Table 4: Incidence of Primary Endpoint Events
IncidenceRisk Reduction95% C.I.p-Value
Primary Composite Endpoint43.5%47.1%16.1%2.3% to 27.9%0.022
Doubling of Serum Creatinine, ESRD and Death Occurring as a First Event
Doubling of Serum Creatinine21.6%26.0%
Overall Incidence of Doubling of Serum Creatinine, ESRD and Death
Doubling of Serum Creatinine21.6%26.0%25.3%7.8% to 39.4%0.006
ESRD19.6%25.5%28.6%11.5% to 42.4%0.002
Death21.0%20.3%-1.7%-26.9% to 18.6%0.884

The secondary endpoints of the study were change in proteinuria, change in the rate of progression of renal disease, and the composite of morbidity and mortality from cardiovascular causes (hospitalization for heart failure, myocardial infarction, revascularization, stroke, hospitalization for unstable angina, or cardiovascular death). Compared with placebo, COZAAR significantly reduced proteinuria by an average of 34%, an effect that was evident within 3 months of starting therapy, and significantly reduced the rate of decline in glomerular filtration rate during the study by 13%, as measured by the reciprocal of the serum creatinine concentration. There was no significant difference in the incidence of the composite endpoint of cardiovascular morbidity and mortality.

The favorable effects of COZAAR were seen in patients also taking other anti-hypertensive medications (angiotensin II receptor antagonists and angiotensin converting enzyme inhibitors were not allowed), oral hypoglycemic agents and lipid-lowering agents.

For the primary endpoint and ESRD, the effects of COZAAR in patient subgroups defined by age, gender and race are shown in Table 5 below. Subgroup analyses can be difficult to interpret and it is not known whether these represent true differences or chance effects.

Table 5: Efficacy Outcomes within Demographic Subgroups
Primary Composite EndpointESRD
No. of PatientsCOZAAREvent Rate%PlaceboEvent Rate%Hazard Ratio(95% CI)COZAAREvent Rate%PlaceboEvent Rate%Hazard Ratio(95% CI)
Overall Results151343.547.10.84 (0.72, 0.98)19.625.50.71 (0.58, 0.89)
<65 years100544.149.00.78 (0.65, 0.94) (0.52, 0.86)
≥65 years50842.343.50.98 (0.75, 1.28)16.519.60.85 (0.56, 1.28)
Female55747.854.10.76 (0.60, 0.96)22.832.80.60 (0.44, 0.83)
Male95640.943.30.89 (0.73, 1.09)17.521.50.81 (0.60, 1.08)
Asian25241.954.80.66 (0.45, 0.95)18.827.40.63 (0.37, 1.07)
Black23040.039.00.98 (0.65, 1.50)17.621.00.83 (0.46, 1.52)
Hispanic27755.054.01.00 (0.73, 1.38) (0.66, 1.59)
White73540.543.20.81 (0.65, 1.01) (0.43, 0.83)

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