Synergistic Effect of Doxazosin and Acarbose in Improving Metabolic Control
Synergistic Effect of Doxazosin and Acarbose in Improving Metabolic Control
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 α-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 [HbA1c], 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, HbA1c, 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.
In patients with impaired glucose metabolism, the main aims of therapy are usually to prevent the emergence of insulin resistance, maintain a favourable lipid profile and adequately control hypertension in order to minimise cardiovascular complications and improve patient prognosis. In fact, patients with diabetes mellitus appear to have a 2- to 4-fold increase in the risk of coronary artery disease compared with age-matched subjects, especially when diabetes is associated with well known cardiovascular disease risk factors such as hypertension, hypercholesterolaemia and low high-density lipoprotein cholesterol (HDL-C). However, intensive treatment of all modifiable risk factors significantly improves prognosis in these patients.
Control of high blood pressure is the most important intervention for limiting cardiovascular events, and is far more effective than tight glycaemic control. Importantly, not all antihypertensive treatments appear to have the same impact on metabolic control in diabetic patients. For instance, some classes of antihypertensive drugs can detrimentally influence lipid metabolism. It is well known that thiazide diuretics and β-adrenoceptor antagonists without intrinsic sympathomimetic activity can significantly increase low-density lipoprotein cholesterol (LDL-C) and plasma triglyceride (TG) concentrations. A reduction in HDL-C levels induced by some antihypertensive agents may also be harmful. On the other hand, metabolic abnormalities such as insulin resistance and dyslipidaemias, which are frequently associated with diabetes, can be improved by treatment with ACE inhibitors. Angiotensin II type 1 (AT1) receptor antagonists do not appear to influence glucose homeostasis, but some (although not all) of these agents have been associated with a significant decrease in plasma cholesterolaemia. Another class of antihypertensive drugs with well documented positive effects on both glucose and lipid metabolism are the α1-adrenoceptor antagonists, of which the most important example is doxazosin.
With respect to antihyperglycaemic agents, there is consistent evidence to suggest that the α-glucosidase inhibitor acarbose, like metformin, prevents both diabetes and cardiovascular events in patients with impaired glucose tolerance (IGT).
The aim of our study was to evaluate if the expected improvement in glucose and lipid metabolism associated with doxazosin is or is not synergistic with standard antihyperglycaemic treatment with acarbose.
Abstract and Introduction
Abstract
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 α-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 [HbA1c], 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, HbA1c, 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.
Introduction
In patients with impaired glucose metabolism, the main aims of therapy are usually to prevent the emergence of insulin resistance, maintain a favourable lipid profile and adequately control hypertension in order to minimise cardiovascular complications and improve patient prognosis. In fact, patients with diabetes mellitus appear to have a 2- to 4-fold increase in the risk of coronary artery disease compared with age-matched subjects, especially when diabetes is associated with well known cardiovascular disease risk factors such as hypertension, hypercholesterolaemia and low high-density lipoprotein cholesterol (HDL-C). However, intensive treatment of all modifiable risk factors significantly improves prognosis in these patients.
Control of high blood pressure is the most important intervention for limiting cardiovascular events, and is far more effective than tight glycaemic control. Importantly, not all antihypertensive treatments appear to have the same impact on metabolic control in diabetic patients. For instance, some classes of antihypertensive drugs can detrimentally influence lipid metabolism. It is well known that thiazide diuretics and β-adrenoceptor antagonists without intrinsic sympathomimetic activity can significantly increase low-density lipoprotein cholesterol (LDL-C) and plasma triglyceride (TG) concentrations. A reduction in HDL-C levels induced by some antihypertensive agents may also be harmful. On the other hand, metabolic abnormalities such as insulin resistance and dyslipidaemias, which are frequently associated with diabetes, can be improved by treatment with ACE inhibitors. Angiotensin II type 1 (AT1) receptor antagonists do not appear to influence glucose homeostasis, but some (although not all) of these agents have been associated with a significant decrease in plasma cholesterolaemia. Another class of antihypertensive drugs with well documented positive effects on both glucose and lipid metabolism are the α1-adrenoceptor antagonists, of which the most important example is doxazosin.
With respect to antihyperglycaemic agents, there is consistent evidence to suggest that the α-glucosidase inhibitor acarbose, like metformin, prevents both diabetes and cardiovascular events in patients with impaired glucose tolerance (IGT).
The aim of our study was to evaluate if the expected improvement in glucose and lipid metabolism associated with doxazosin is or is not synergistic with standard antihyperglycaemic treatment with acarbose.