Addition of manidipine improves the antiproteinuric effect of candesartan in hypertensive patients with type II diabetes and microalbuminuria

Background: We sought to compare the effect of manidipine versus hydrochlorothiazide (HCT Z) in addition to candesartan on the urinary albumin excretion rate (UAER) in hypertensive patients with type 11 diabetes and microalbuminuria. Methods: After a 2-week washout and run-in period, and 8-week monotherapy with candesartan 16 mg every day, 174 microalbuminuric diabetic hypertensive patients with uncontrolled blood pressure (BP) (> 130/80 mm Hg) were randomized to addition of manidipine 10 mg every day (n = 87) or HCTZ 12.5 mg every day (n = 87) for 24 weeks, with a titration after 4 weeks (manidipine or HCTZ dose-doubling) in nonresponder patients. Blood pressure, UAER, creatinine clearance, serum electrolytes, fasting plasma glycemia, and glycosylated hemoglobin were evaluated at baseline (end of run-in period), after candesartan monotherapy, and at the end of the combination treatment period. Results: Both combinations produced greater systolic BP/diastolic BP reduction than candesartan monotherapy (- 28/21 mm Hg versus - 16/11 mm Hg and - 28/20 rum Hg versus -15/11 rum Hg, respectively; all P <.05 versus monotherapy), with no significant difference between the two combinations. The addition of manidipine produced a greater reduction in UAER than candesartan monotherapy (-55.4 mg/24 h v -36.1 mg/24 h, P < .05), whereas the addition of HCTZ did not significantly modify UAER; the difference between the two combinations was statistically significant (P < .05). Similarly, the percentage of patients moving to a normoalbuminuric state (UAER <30 mg/24 h) was increased by the addition of manidipine to candesartan (from 35% to 64%, P <.05), but not by the addition of HCTZ (from 34% to 39%, NS), with a statistical difference between the two combinations (P < .05). Conclusions: These findings show that, despite equivalent reduction in BP, the addition of manidipine to candesartan further reduced the UAER, whereas the addition of HCTZ did not modify the UAER. This suggests that the antiproteinuric effect of manidipine is partially independent of BP reduction, and is attributable to mechanisms different from those mediated by angiotensin receptor blockade.