Manidipine versus enalapril monotherapy in patients with hypertension and type 2 diabetes mellitus: A multicenter, randomized, double-blind, 24-week study

Abstract

Background: Blood pressure reduction is associated with a reduced risk for cardiovascular events and death, particularly in patients with both hypertension and type 2 diabetes mellitus. Objective: The aim of this study was to compare theantihypertensive efficacy, tolerability, and effect on metabolic risk factors of manidipine, a new dihydropyridine calcium channel antagonist, and enalapril, a widely used angiotensin-converting enzyme inhibitor, in patients with mild to moderate essential hypertension and type 2 diabetes. Methods: This multicenter, double-blind trial compared manidipine and enalapril in patients with type 2 diabetes and hypertension (diastolic blood pressure [DBP] 90–104 mm Hg, systolic blood pressure [SBP] ≤190 mm Hg). Following a 3-week, single-blind placebo run-in period, eligible patients were randomized to receive either manidipine 10 mg or enalapril 10 mg once daily for 24 weeks. The dose was doubled after 3 weeks in patients who had not responded to treatment (DBP ≥90 mm Hg). The primary efficacy end point was change in DBP from baseline to the end of the study. Secondary outcomes were the responder rate (DBP <90 mm Hg and/or a DBP reduction of ≥10 mm Hg) at the end of the study. Other secondary measures were changes from baseline to the end of the study in heart rate and in the following measures obtained by ambulatory blood pressure monitoring (ABPM): 24-hour, daytime, and nighttime mean DBP and SBP, and the trough:peak ratio. Blood glucose, glycosylated hemoglobin (HbA 1c), total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, uric acid, and creatinine were measured at the end of the placebo run-in period and the end of treatment. The study had 80% power to detect a between-treatment difference in mean sitting DBP of >3 mm Hg. Results: One hundred twenty-four patients were enrolled in the study. After the placebo run-in period, 13 patients were excluded from the study: 4 for DBP values outside the specified limits, 7 at their request, and 2 for adverse events. Thus, 111 patients met the eligibility criteria and were randomized to treatment (53 manidipine, 58 enalapril). The population consisted of 61 men and 50 women with a mean (SD) age of 62 (11) years and a body mass index of 28.2 (2.4) kg/m 2. Among patients who completed the study, drug doses were doubled in 67.6% (25/37) of patients in the manidipine group and 60.0% (24/40) of patients in the enalapril group ( P = NS). Similar reductions in blood pressure were observed in both groups, from a mean (SD) of 164 (12)/97.5 (5) mm Hg at baseline to 141 (12)/84.5 (6) mm Hg at the end of the study in the manidipine group ( P < 0.01), and from 159 (12)/98 (4) mm Hg to 139 (12)/86 (8) mm Hg in the enalapril group ( P < 0.01). The proportion of responders was 66.7% (32/48) in the manidipine group and 60.0% (30/50) in the enalapril group; the difference between groups was not significant. Twenty-four-hour ABPM revealed significant ( P < 0.01) and similar reductions in blood pressure in both groups, with a trough:peak ratio of ∼-50%. Neither drug affected heart rate. Among the statistically significant changes in metabolic parameters, significant reductions in HbA 1c (from 6.7% [1.4%] to 6.2% [1.1%]) and blood glucose concentrations (from 152 [44] to 143 [44] mg/dL) were observed only in the manidipine group ( P < 0.05). The incidence of adverse events was similar between groups. Conclusions: In the present study, manidipine wasas metabolically neutral and as effective as enalapril in reducing blood pressure in hypertensive patients with type 2 diabetes, providing a sustained 24-hour antihypertensive effect.