Dual Blockade of the Renin-Angiotensin System in Diabetic Nephropathy

Abstract

OBJECTIVE—Many patients with diabetic nephropathy (DN) have levels of albuminuria >1 g/day and blood pressure >135/85 mmHg, despite antihypertensive combination therapy, including recommended doses of ACE inhibitors, e.g., lisinopril/enalapril at 20 mg daily. We tested the concept that such patients might benefit from dual blockade of the renin-angiotensin system (RAS). RESEARCH DESIGN AND METHODS—We performed a randomized double-blind crossover study of 2 months treatment with candesartan cilexetil 8 mg once daily and placebo in addition to previous antihypertensive treatment. We included 18 type 2 diabetic patients with DN fulfilling the above-mentioned criteria. All received recommended doses of ACE inhibitor and, in addition, 15 patients received diuretics, 11 received a calcium channel antagonist, and 3 received a β-blocker. At the end of each treatment period, we measured the glomerular filtration rate (GFR), 24-h blood pressure, albuminuria, and IgGuria . RESULTS—The addition of candesartan to usual antihypertensive therapy induced a mean (95% CI) reduction in albuminuria of 25% (2–58), P = 0.036 (geometric mean [95% CI] from 1,764 mg/24 h [1,225–2,540] to 1,334 mg/24 h [890–1,998]). It also produced a mean reduction of 35% (9–53) in the fractional clearance of albumin (P = 0.016), a reduction of 32% (1–54) in fractional clearance of IgG (P = 0.046), a reduction in 24-h systolic blood pressure of 10 mmHg (2–18) (P = 0.019) (mean ± ± SE) from 148 ± 3 to 138 ± 5 mmHg, and a mean reduction in GFR of 5 ml · min−1 · 1.73 m−2 (0.1–9) (P = 0.045). CONCLUSIONS—Dual blockade of the RAS reduces albuminuria and blood pressure in type 2 diabetic patients with DN responding insufficiently to previous antihypertensive therapy, including ACE inhibitors in recommended doses.