LOSARTAN POTASSIUM 25 Mg (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 losartan potassium 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 losartan potassium resulted in a 16% risk reduction in this endpoint (see Figure 4 and Table 4). Treatment with losartan potassium 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 losartan potassium 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 losartan potassium and 146/77 mmHg for the group treated with placebo.

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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
Incidence Risk Reduction 95% CI p-Value
Losartan Placebo
Primary Composite Endpoint 43.5% 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 Creatinine 21.6% 26.0%
ESRD 8.5% 8.5%
Death 13.4% 12.6%
Overall Incidence of Doubling of Serum Creatinine, ESRD and Death
Doubling of Serum Creatinine 21.6% 26.0% 25.3% 7.8% to 39.4% 0.006
ESRD 19.6% 25.5% 28.6% 11.5% to 42.4% 0.002
Death 21.0% 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, losartan potassium 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 losartan potassium 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 losartan potassium 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 Endpoint ESRD
No. of Patients Losartan potassium Event Rate % Placebo Event Rate % Hazard Ratio (95% CI) Losartan potassium Event Rate % Placebo Event Rate % Hazard Ratio (95% CI)
Overall Results 1513 43.5 47.1 0.84 (0.72, 0.98) 19.6 25.5 0.71 (0.58, 0.89)
<65 years 1005 44.1 49.0 0.78 (0.65, 0.94) 21.1 28.5 0.67 (0.52, 0.86)
≥65 years 508 42.3 43.5 0.98 (0.75, 1.28) 16.5 19.6 0.85 (0.56, 1.28)
Female 557 47.8 54.1 0.76 (0.60, 0.96) 22.8 32.8 0.60 (0.44, 0.83)
Male 956 40.9 43.3 0.89 (0.73, 1.09) 17.5 21.5 0.81 (0.60, 1.08)
Asian 252 41.9 54.8 0.66 (0.45, 0.95) 18.8 27.4 0.63 (0.37, 1.07)
Black 230 40.0 39.0 0.98 (0.65, 1.50) 17.6 21.0 0.83 (0.46, 1.52)
Hispanic 277 55.0 54.0 1.00 (0.73, 1.38) 30.0 28.5 1.02 (0.66, 1.59)
White 735 40.5 43.2 0.81 (0.65, 1.01) 16.2 23.9 0.60 (0.43, 0.83)

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