The Journal of International Medical Research 24; 32: 26 213 Clinical Usefulness of Doxazosin in Patients with Type 2 Diabetes Complicated by Hypertension: Effects on Glucose and Lipid Metabolism T INUKAI, Y INUKAI, R MATSUTOMO, K OKUMURA, K TAKANASHI, K TAKEBAYASHI, K TAYAMA, Y ASO AND Y TAKEMURA Department of Internal Medicine, Koshigaya Hospital, Dokkyo University School of Medicine, Koshigaya-shi, Japan This uncontrolled study investigated the effects of using the α 1 -blocker doxazosin (2 mg or 4 mg daily for 3 months) to treat 21 hypertensive patients with type 2 diabetes, including eight obese individuals (body mass index [BMI] 25. kg/m 2 ). A significant reduction in systolic and diastolic blood pressure, beginning after 1 month of treatment, was seen. There was no significant change in BMI. Although there was no obvious improvement in glucose metabolism, doxazosin treatment noticeably reduced insulin resistance and significantly lowered triglyceride and free fatty acid levels. No significant changes were found in total cholesterol, highor low-density lipoprotein-cholesterol, atherosclerotic index, or small or large subfractions of low-density lipoproteincholesterol. None of the patients showed any adverse effects. The beneficial effects of doxazosin on blood pressure and lipid and glucose metabolism shown in this study suggest that this drug is clinically useful as an anti-hypertensive agent for patients with diabetes. KEY WORDS: DOXAZOSIN; TYPE 2 DIABETES; INSULIN RESISTANCE; LIPID METABOLISM; LOW-DENSITY LIPOPROTEIN SUBFRACTION Introduction The two lifestyle diseases of hypertension and diabetes are independent risk factors for cardiovascular disease, and when both conditions are present the prevalence of cardiovascular disease greatly increases. 1,2 In addition, patients with abnormal glucose tolerance are known to show a relatively high incidence of abnormal lipid metabolism. 3 Thus, when selecting anti-hypertensive medications for patients with diabetes, it is wise to use a drug that improves glucose and lipid metabolism as well as lowering blood pressure. Doxazosin is an α 1 -blocker widely known for its clinical usefulness as an antihypertensive agent. Previous findings indicate that this drug can improve abnormal glucose metabolism, reduce insulin resistance and improve lipid metabolism. 4 6 26
We used doxazosin to treat hypertensive patients with type 2 diabetes and investigated the effects of this treatment on glucose and lipid metabolism. We also monitored the time-course of changes in the low-density lipoprotein (LDL) subfraction and insulin resistance, as indicated by the homeostasis model assessment (HOMA-R) score. The HOMA-R, first proposed by Matthews and colleagues 7 and calculated from fasting plasma glucose (FPG) and plasma immunoreactive insulin (IRI) levels, is widely used as a simple indicator of insulin resistance. It can be used as an insulin resistance indicator in patients with type 2 diabetes when patients show an appropriate blood glucose level (126 2 mg/dl). 8 LDLs are strongly associated with arteriosclerosis, and small LDLs, identified by electrophoresis 9 from the LDL subfraction, have been closely implicated in the formation of atherosclerotic plaques. 1 Patients and methods PATIENTS This uncontrolled trial comprised patients with type 2 (non-insulin-dependent) diabetes complicated by hypertension (systolic blood pressure [SBP] 14 mmhg or diastolic blood pressure [DBP] 9 mmhg). Patients receiving insulin therapy were excluded from the study, although non-insulin treatments, including other anti-hypertensive agents were permitted. The Dokkyo University School of Medicine Ethics Committee (Koshigaya-shi, Japan) approved the study, which complied with the 1965 Declaration of Helsinki and the 1975 Declaration of Tokyo (revised in 1983). All participants gave written informed consent. DRUG REGIMEN Patients were initially treated with 2 mg/day of doxazosin orally, but if patients still had high blood pressures after one month of doxazosin treatment, the dose was increased to 4 mg/day. The duration of doxazosin therapy was 3 months. No changes were made to the dosage of any concomitant drugs or to the advice concerning diet and exercise therapy during the course of the study. MEASUREMENT OF BLOOD PRESSURE AND BODY WEIGHT Systolic and diastolic blood pressures were measured every 4 weeks during treatment, using the auscultation method on the right brachial artery in the seated position after resting for 5 1 min. The baseline values were calculated from the average measurements taken 4 weeks, 2 weeks and immediately before the start of doxazosin therapy. Body weight was measured every 4 weeks and height was measured for the body mass index (BMI) calculation (weight [kg]/height [m 2 ]). ASSESSMENT OF GLUCOSE METABOLISM Glucose metabolism was assessed every 4 weeks during treatment. FPG and glycated haemoglobin (HbA 1c ) were measured by standard methods, and IRI was measured using a commercial kit based on an enzymelinked immunoassay (Tosoh, Tokyo, Japan). The FPG and IRI levels were used to calculate the HOMA-R using the formula 7 FPG (mg/dl) IRI (µu/ml)/45. ASSESSMENT OF LIPID METABOLISM Lipid metabolism was assessed every 4 weeks during treatment by measuring free fatty acids (FFAs), total cholesterol (TC), triglyceride (TG), high-density lipoproteincholesterol (HDL-C) and LDL-cholesterol (LDL-C) using standard methods. The ratio of LDL-C to HDL-C was used to calculate the atherosclerotic index (AI). In addition, LDL subfractions were measured using polyacrylamide electrophoresis, 9 and small and large LDL particles were identified. 27
STATISTICAL ANALYSIS To determine whether there is an association between the correction of insulin resistance and significant improvements in triglyceride and FFA levels after doxazosin treatment, we investigated the correlation between the magnitude of the lipid changes and the magnitude of the change in HOMA-R. The size of each change was calculated by subtracting values measured after 12 weeks of treatment from baseline values. The Student s paired t-test was used to compare measured values for each drug treatment period, and linear regression analysis was used to assess correlations between the test items. A P-value <.5 was considered statistically significant. Results This study comprised 21 patients (12 men and nine women) with a mean age of 54.3 ± 7.3 years. The mean duration of illness was 5.7 ±.8 years and mean BMI was 24.6 ± 3.7 kg/m 2. The participants included eight patients (38%) with ischaemic heart disease and four (18%) with a history of medical treatment for hypertension. Eight subjects (38%) were obese (BMI 25. kg/m 2 ). Five patients were treating their diabetes with dietary therapy, and 16 used oral hypoglycaemics (sulphonylureas, 12 patients and α-glucosidase inhibitors, four patients). Six patients had confirmed simple retinopathy, and three had proliferative retinopathy. Eighteen patients received 2 mg/day doxazosin and three patients received 4 mg/day doxazosin. There were no adverse events, and no patients dropped out during the course of the study. CHANGES IN BLOOD PRESSURE AND BODY WEIGHT The effect of doxazosin on SBP and DBP are shown in Fig. 1. No significant change in BMI was noted in either the obese or the nonobese patients during doxazosin treatment. Furthermore, no patients exhibited marked changes in their individual body weights. 2 SBP DBP SBP/DBP (mmhg) 15 1 5 4 8 12 Week FIGURE 1: Changes in systolic blood pressure (SBP) and diastolic blood pressure (DBP) in 21 patients with type 2 diabetes and hypertension during 3 months of treatment with doxazosin. Values shown are the mean ± SD.P <.5 compared with baseline 28
CHANGES IN GLUCOSE METABOLISM During the first 2 months of treatment with doxazosin, almost no change was observed in the FPG or HbA 1c levels. A clear tendency towards reduction was noted in both FPG and HbA 1c levels after 3 months of doxazosin treatment, although these changes were not statistically significant. The effects of doxazosin treatment on IRI are shown in Fig. 2. These results are reflected in the HOMA-R values (Fig. 2). CHANGES IN LIPID METABOLISM Total cholesterol, HDL-C, LDL-C and AI levels showed no significant changes during treatment with doxazosin. There were also no significant changes in either the small or the large subfractions of LDL-C. The effects of doxazosin treatment on TG and FFA levels are shown in Fig. 3. CORRELATION BETWEEN IMPROVEMENTS IN LIPID METABOLISM AND CHANGES IN HOMA-R The correlation between the changes in TG level and HOMA-R value can be seen in Fig. 4A. Patients who showed a pronounced reduction in HOMA-R also had the best results for TG reduction. Results for the change in FFA level were similar to those obtained for the change in triglyceride level, and also showed a significant positive correlation to the change in the HOMA-R (Fig. 4B). Discussion The α 1 -blockers have blood pressurelowering effects (as do anti-hypertensives such as angiotensin-converting enzyme inhibitors and calcium antagonists), and also produce clear improvements in insulin 1 IRI HOMA-R IRI (µu/ml)/homa-r 8 6 4 2 4 8 12 Week FIGURE 2: Changes in plasma immunoreactive insulin (IRI) and homeostasis model assessment (HOMA-R) in 21 patients with type 2 diabetes and hypertension during a 3-month treatment period with doxazosin. Values shown are the mean ± SD. P <.5 and P <.1 compared with baseline 29
12 TG FFA TG (mg/dl)/ffa (µeq/l) 1 8 6 4 2 4 8 12 Week FIGURE 3: Changes in triglyceride (TG) and free fatty acid (FFA) levels in 21 patients with type 2 diabetes and hypertension during 3 months of treatment with doxazosin. Values shown are the mean ± SD. P <.5 and P <.1 compared with baseline sensitivity and lipid metabolism. 11 We examined the pharmacological effects of the α 1 -blocker doxazosin. The results showed that although doxazosin was not associated with greatly improved glucose metabolism, indicators such as the IRI and HOMA-R levels showed a clear reduction in insulin resistance. Doxazosin treatment was also associated with significant reductions in TG and FFA levels, although no significant changes were observed in the other lipid metabolism markers. Insulin resistance has been noted in patients with essential hypertension. 12 Furthermore, clustering of risk factors, including diabetes mellitus, is a significant predictor of development of hypertension. 13 There are indications that doxazosin may reduce insulin resistance in patients with essential hypertension as well as in patients with diabetes, 12,14 and some reports have indicated that this pharmacological action of doxazosin may also contribute to the reduction of ischaemic heart disease. 15 These findings suggest that doxazosin may be a highly suitable treatment for patients with both hypertension and diabetes. 16 We found that doxazosin lowered insulin resistance and reduced blood pressure. Earlier studies reported that doxazosin provided the greatest glucose metabolismimproving effects in patients who initially showed the most profound glucose tolerance abnormalities. 17,18 We noted, however, only slight improvements in glucose metabolism, and there was no correlation between the severity of glucose tolerance abnormalities at baseline and the extent of subsequent improvements. We hope to investigate these relationships further in a larger patient population. Our study confirmed a reduction in TG levels as previously reported, 19 and also demonstrated a significant reduction in FFA levels. Two pharmacological mechanisms may be involved in producing TG reduction. First, it is possible that a doxazosin-induced reduction in insulin resistance is accompanied 21
A 1 TG (mg/dl) 1 n = 19 R =.465 P <.5 2 3 2 1 1 HOMA-R B 5 FFA (µeq/l) 5 n = 19 R =.53 P <.5 1 3 2 1 1 HOMA-R FIGURE 4: Correlations between the reduction in homeostasis model assessment ( HOMA-R) and (A) the reduction in triglyeride ( TG) and (B) the reduction in free fatty acids ( FFA), in 21 patients with type 2 diabetes and hypertension after 3 months of treatment with doxazosin by accelerated lipoprotein lipase (LPL) activity, 2 promoting serum TG degradation. Secondly, the reduction in serum FFA levels may be associated with a reduction in hepatic production of very low-density lipoproteins (VLDLs). This would result in lower TG levels, since the liver would release less TG. Since LPL activity or hepatic VLDL content were not directly measured in our study, such interpretations must remain theoretical. It is possible that recovery of insulin sensitivity results in the blocking of fatty tissue lipolysis, which consequently lowers serum FFA levels. Our findings differ somewhat from those of earlier reports in that we found no significant changes in TC, LDL-C or HDL-C. 21 This discrepancy may be due to differences in the number of patients 211
studied (our study was smaller than some of the previous studies), the doxazosin dose used and/or treatment duration. It has been suggested that doxazosin may increase LDL particle size. Changes in serum levels of small and large LDL were monitored during treatment, but no significant changes were seen. Most of the patients in our study (18 out of 21) were treated with 2 mg/day doxazosin, and it is possible that this dosage is not associated with a change in LDL size. Further studies of LDL changes in patients receiving 4 mg/day doxazosin would be valuable. Kano et al. 22 previously reported the effects of doxazosin on microangiopathic nephropathy. Their results indicated a significant reduction in microalbuminuria after 3 months of treatment with doxazosin. We did not investigate possible doxazosininduced improvements in diabetic complications. We plan to follow up these questions by performing longer-term studies with doxazosin. In conclusion, we observed no adverse effects of doxazosin treatment in any of our patients with hypertension and type 2 diabetes. We were able to confirm the induction of improvements in glucose and lipid metabolism, in addition to antihypertensive effects. Our results indicate that doxazosin provides a high level of clinical usefulness as an anti-hypertensive agent for treating patients with diabetes. Received for publication 9 September 23 Accepted subject to revision 17 September 23 Revised accepted 5 November 23 Copyright 24 Cambridge Medical Publications References 1 Hypertension in Diabetes Study Group: Hypertension in Diabetes Study (HDS): II. Increased risk of cardiovascular complications in hypertensive type 2 diabetic patients. J Hypertens 1993; 11: 319 325. 2 Katayama S: Management of hypertension in diabetic patients an approach to therapeutic guidelines (in Japanese). Ther Res 1998; 19: 2953 2961. 3 Reaven GM: Banting lecture 1988. Role of insulin resistance in human disease. Diabetes 1988; 37: 1595 167. 4 Giorda C, Appendino M: Effects of doxazosin, a selective alpha 1-inhibitor, on plasma insulin and blood glucose response to a glucose tolerance test in essential hypertension. Metabolism 1993; 42: 144 1442. 5 Sato Y, Fukuzawa M, Toyota T: Metabolic abnormalities and α-blockers (in Japanese). J Blood Press 1998; 5: 1123 1128. 6 Miyashita H, Shirai K: Abnormal lipid metabolism and α-blockers (in Japanese). J Blood Press 1998; 5: 1129 1133. 7 Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC: Homeostasis model assessment: insulin resistance and β-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985; 28: 412 419. 8 Maruyama S, Yanagisawa K, Kanamuro R, Teno S, Iwamoto Y: Serum leptin level as an indicator to predict the clinical efficacy of troglitazone in patients with type 2 diabetes mellitus. Diabetes Res Clin Pract 21; 53: 161 164. 9 McNamara JR, Campos H, Ordovas JM, Peterson J, Wilson PWF, Schaefer EJ: Effect of gender, age, and lipid status on low density lipoprotein subfraction distribution: results from the Framingham Offspring Study. Arteriosclerosis 1987; 7: 483 49. 1 Musliner TA, Krauss RM: Lipoprotein subspecies and risk of coronary disease. Clin Chem 1988; 34: B78 B83. 11 Giordano M, Matsuda M, Sanders L, Canessa ML, DeFronzo RA: Effects of angiotensinconverting enzyme inhibitors, Ca 2+ channel antagonists, and alpha-adrenergic blockers on glucose and lipid metabolism in NIDDM patients with hypertension. Diabetes 1995; 44: 665 671. 12 Kageyama S, Yamamoto J, Mimura A, Sakurai T, Ishibashi K, Aihara K, et al: Doxazosin improves insulin sensitivity in hypertensive patients. Clin Ther 1993; 15: 829 837. 13 Tozawa M, Iseki K, Iseki C, Oshiro S, Higashiuesato Y, Ikemiya Y, et al: Impact of multiple risk factor clustering on the elevation of blood pressure. Hypertens Res 22; 25: 811 816. 212
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