Metabolic and antihypertensive effects of moxonidine and moxonidine plus irbesartan in patients with type 2 diabetes mellitus and mild hypertension: a sequential, randomized, double-blind clinical trial.

BACKGROUND: The autonomic nervous system plays an important part in the homeostasis of blood pressure (BP), and sympathetic overactivity may contribute to metabolic conditions such as glycemic intolerance or insulin resistance. OBJECTIVE: This study evaluated the anti-hypertensive and metabolic effects of moxonidine, a selective imidazoline II-receptor agonist that lowers BP by central inhibition of the sympathetic nervous system, and moxonidine plus the angiotensin II-receptor blocker irbesartan in patients with type 2 diabetes mellitus and mild hypertension. METHODS: This was a study in patients with type 2 diabetes previously untreated with medication and untreated mild hypertension (diastolic blood pressure [DBP] >90 and <105 mm Hg). For the first 3 months of the study, all patients were treated for hypertension with moxonidine 0.2 mg once daily (M0.2) to establish a moxonidine baseline. After this single-arm period, patients were randomized to receive double-blind treatment with moxonidine 0.2 mg BID (M0.4) or moxonidine 0.2 mg plus irbesartan 150 mg (M0.2+1) once daily for 3 months. Changes in DBP, systolic blood pressure (SBP), body mass index (BMI), fasting and postprandial plasma glucose (FPG and PPG), fasting and postprandial plasma insulin (FPI and PPI), glycosylated hemoglobin (HbA(1c)), Homeostasis Model Assessment of insulin sensitivity (HOMA-S), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) were evaluated at baseline, 3 months (end of single arm period), and 6 months (end of randomized treatment period). RESULTS: The study enrolled 99 patients (50 men, 49 women; mean [SD] age, 55 [7] years; mean BMI, 26.8 [0.9]). No significant changes in BMI, PPG, PPI, TC, or LDL-C were observed over the entire study period. At 3 months, treatment with M0.2 was associated with significant improvements from baseline in SBP and DBP (P < 0.05), whereas there were no significant changes in HbA(1c), FPG, FPI, HOMA-S, HDL-C, or TG. At 6 months, significant decreases from baseline in HbA(1c), FPG, FPI, HOMA-S, and TG were observed in the M0.4 group (all, P < 0.05), but not in the M0.2+1 group. The M0.4 group also had a significant increase from baseline in HDL-C (P < 0.05) that was not seen in the M0.2+1 group. The changes in FPI and HOMA-S were significantly greater in the M0.4 group compared with the M0.2+1 group (P < 0.05). Significant decreases from baseline in SBP and DBP were observed in both the M0.4 and M0.2+1 groups (P < 0.02 and P < 0.01, respectively). No patient withdrew from the study because of a drug-related adverse event, and there were no clinically significant drug-related changes in laboratory values during the study. CONCLUSION: In these patients with type 2 diabetes and mild hypertension, the M0.4 group had greater improvements in measures of glucose metabolism and the plasma lipid profile compared with those treated with M0.2+1.

Synergistic effect of doxazosin and acarbose in improving metabolic control in patients with impaired glucose tolerance.

OBJECTIVE: The aim of this study was to evaluate if the expected improvement in glucose and lipid metabolism obtainable with doxazosin is or is not synergistic with standard antihyperglycaemic treatment using the alpha-glucosidase inhibitor acarbose. METHODS: Patients in this randomised, controlled, double-blind clinical trial were enrolled, evaluated and followed up at three Italian centres. We evaluated 107 patients (53 males and 54 females) with impaired glucose tolerance (IGT) as determined by oral glucose tolerance tests (OGTTs). All patients took a fixed dose of acarbose 150 mg/day for 3 months, after which they were titrated up to 300 mg/day for the next 3 months. In addition, patients were randomised to either placebo (53 patients: 27 males and 26 females, aged 50 +/- 4 [mean +/- SD] years) or doxazosin 4 mg/day (54 patients: 26 males and 28 females, aged 51 +/- 5 years) for the entire 6-month treatment period. Parameters evaluated during the 6-month treatment period included body mass index (BMI), glycaemic control (glycosylated haemoglobin [HbA(1c)], fasting plasma [FPG] and post-prandial plasma [PPG] glucose, fasting plasma [FPI] and post-prandial plasma [PPI] insulin levels, homeostasis model assessment [HOMA]-index [insulin resistance]), lipid profile (total cholesterol [TC], low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C], and triglycerides [TG]), and systolic (SBP) and diastolic (DBP) blood pressure. RESULTS: Significant reductions in BMI, HbA(1c), FPG and PPG compared with baseline were observed after 6 months in both groups (p < 0.05). A significant decrease in FPI was obtained after 6 months (p < 0.05) in the doxazosin group compared with baseline, and this difference was also significant (p < 0.05) compared with the placebo group. Similarly, a significant decrease in HOMA-index was observed at 6 months (p < 0.05) compared with baseline in the doxazosin group, and this difference was also significant (p < 0.05) compared with the placebo group. Significant decreases in TC, LDL-C, HDL-C and TG (p < 0.05) were observed in the doxazosin group after 6 months compared with baseline values. Significant decreases in SBP and DBP were also observed at 3 months in the doxazosin group compared with baseline (p < 0.05), and these differences were significant (p < 0.05) compared with placebo. Furthermore, significant decreases in SBP and DBP were observed at 6 months (p < 0.01) in the doxazosin group compared with baseline, and these differences were also significant (p < 0.01) compared with placebo. All patients who completed an OGTT at 6 months (96 patients) were restored to normal glucose tolerance status. CONCLUSION: In patients with IGT, doxazosin given in combination with acarbose seemed to improve glycaemic and lipid control compared with placebo, with the benefits observed appearing to extend beyond those expected from improvements in blood pressure. Patients in this study also benefited from acarbose therapy, which restored all patients from IGT to normal glucose tolerance status.