Metabolic effects of isradipine in non-insulin-dependent diabetes mellitus (NIDDM) hypertensive patients
Dear Sir: Some antihypertensive drugs have been shown to induce untoward side effects on glucose and lipid metabolism that may accelerate the early development of arteriosclerotic lesions. Several calcium entry blockers have been shown to have a neutral effect on both glucose and lipid metabolism [1]. Isradipine, one of the most recently developed molecules of the dihydropiridine derivatives, has already been proven to cause a significant reduction in blood pressure [2]. The present study was intended to evaluate whether the antihypertensive effect of slow-release isradipine given at the dosage of 5 mg o.d. for 6 months is accompanied by untoward side effects on insulin secretion, glucose control, and lipid profile in hypertensive patients with concomitant type II diabetes mellitus. This open trial included 12 patients (both sexes) with a mild to moderate hypertension [diastolic blood pressure (DBP) 95110 mmHg] and non-insulin-dependent diabetes mellitus (NIDDM) in stable phase treated for diabetes with either nonpharmacological means alone (well-balanced, low-fat diet enriched in undigestible fibers) or diet plus oral hypoglycemic drugs. The protocol excluded patients with malignant or secondary hypertension, target organ damage, moderate hypercholesterolemia (serum cholesterol >250 mg/dl), frank obesity [body mass index (BMI = weight/height 2) >30 for males and >28 for females], use of other drugs interfering with blood pressure and/ or carbohydrate metabolism, pregnancy, lactation, or use of oral contraceptives. Compliance with t reatment was evaluated by questioning the patients at each visit and by counting the remaining pills in each box. After a 4 week washout placebo period, patients were prescribed isradipine at the dose of 5 mg once daily for 6 months. Duplicate measurements of blood pressure (BP) and heart rate (HR) were taken between 9 and 11 a.m. on two occasions before beginning treatment: at 2-week intervals during the first month of therapy and at monthly intervals until the end of the study using an automatic sphygmomanometer (Sentron, Bard Biomedical). The last tablet before BP measurements was taken at 9 am on the previous day. Fasting blood glucose (FBG), giycosylated hemoglobin (Hb Ale), total cholesterol (Chol), triglycerides (Tg) and HDL cholesterol (HDL-chol) were measured before treatment, at the end of the first month of treatment, and at the end of the study. At the same time, glucose and insulin responses to an intravenous glucose tolerance test (IvGTT) were also evaluated. The probability of a patient developing CHD within 10 years was calculated by using the Framingham equations for coronary heart disease (CHD) [3]. Data are given as means -+ SD. Statistical analysis was performed by analysis of variance. Since four patients were unable to complete the 6 month follow-up, the statistical analysis was performed only on the remaining 8 cases. The mean age of the patients was 53 -+ 5 years; body mass index (weightfaeight 2) was 28.1 _ 4.3. Diabetes mellitus at ent ry was well compensated, as shown by the values of HbAlc, FBG, and postprandial blood glucose. No change in these parameters was observed throughout the study (Table 1). Systolic and diastolic BP were reduced after 1 month of isradipine therapy, and the fall in BP remained unchanged during the 6 month observation period. HR was only slightly reduced during isradipine therapy (Table 1). Glucose and insulin responses during IvGTT were similar during the study period, as shown in Figure 1. Total cholesterol and Tg were unchanged, whilst HDL cholesterol increased significantly during treatment (Table 1). The calculated risk of developing CHD within 10 years was significantly reduced from 9.15% to 6.43% (p < 0.01), during treatment. Calcium entry blockers might impair insulin secretion, which is a calcium-mediated process, as shown with acute administration of nifedipine [4]. In the present study we have found that the BP reduction was not accompanied by any impairment in carbohydrate or lipid metabolism, thus extending to isradipine the metabolic neutrality of other dihydropiridine derivatives.