ORIGINAL ARTICLE Effects of Doxazosin and Irbesartan on Blood Pressure and Metabolic Control in Patients with Type 2 Diabetes and Hypertension Giuseppe Derosa, MD, PhD,* Arrigo F. G. Cicero, MD,† Antonio Gaddi, MD,† Amedeo Mugellini, MD, PhD,* Leonardina Ciccarelli, MD,* and Roberto Fogari, MD* Abstract: The objective of this trial was to compare the metabolic effects of long-term treatment with doxazosin to those of irbesartan in patients with type 2 diabetes and hypertension. We evaluated 96 hypertensive diabetic patients who were randomized to 12 months of double-blind treatment with doxazosin 4 mg/d or irbesartan 300 mg/d. At the end of the study, systolic and diastolic blood pressure (SBP and DBP) were significantly reduced from 152 to 140 mm Hg and from 97 to 87 mm Hg, respectively, with doxazosin (P , 0.01). SBP and DBP were reduced from 150 to 134 mm Hg and from 94 to 83 mm Hg, respectively, with irbesartan (P , 0.01). Irbesartan had significantly better antihypertensive efficacy than doxazosin (P , 0.05). Doxazosin had the greatest effect on glucose metabolism and lipid parameters, with significant (P # 0.05) reductions observed at study end com- pared with baseline in glycosylated hemoglobin, fasting plasma glucose, fasting plasma insulin, total cholesterol, low-density lipo- protein cholesterol, high-density lipoprotein cholesterol, triglycer- ides, and Homeostasis Model Assessment Index. In conclusion, both doxazosin and irbesartan reduced BP during long-term treatment, but not to recommended levels, and doxazosin had the more beneficial effect on glucose metabolism and lipid profile. Key Words: hypertension, diabetes mellitus, lipids, insulin sensitivity (J Cardiovasc Pharmacol TM 2005;45:599–604) C oronary artery disease (CAD) causes much of the serious morbidity and mortality in patients with diabetes, in whom the risk of CAD is increased two- to four-fold. 1 Hypertension, hypercholesterolemia, and low high-density lipoprotein–cholesterol (HDL-C) levels exponentially increase the cardiovascular (CV) risk profile of patients with type 2 diabetes, and intensive treatment of modifiable risk factors can significantly improve the prognosis of these patients. 2 In particular, good blood pressure (BP) control has been shown to prevent/slow down diabetes-related renal damage. 3 It is not sufficient, however, to simply treat isolated risk factors. Treatment should be intensive enough to reach recommended target levels and should have a beneficial effect not only on BP but also on glucose and lipid metabolism, particularly levels of blood cholesterol. The third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults defined diabetes as a coronary heart disease risk equivalent. 4 Angiotensin II type 1 (AT1) receptor blockers (ARBs) represent a class of effective and well-tolerated orally active antihypertensive drugs. Activation of angiotensin 1 receptors leads to vasoconstriction, stimulates the release of catechol- amines and antidiuretic hormone, and promotes growth of vascular and cardiac muscle. Angiotensin II receptor blockers therefore relax vascular smooth muscle, increase salt ex- cretion, decrease cellular hypertrophy, and induce antihyper- tensive effects without modifying heart rate or cardiac output. 5 Most of the ARBs in use today control BP without producing tolerance and are relatively well tolerated during long-term use. Monotherapy in patients with mild to moderate hyper- tension controls BP in 40%–50% of patients, and addition of a low-dose diuretic controls BP in 60%–70% of patients. The antihypertensive efficacy of ARBs is similar to those of angiotensin-converting enzyme (ACE) inhibitors, diuretics, calcium antagonists, and b-blocking agents. 6 ARBs are par- ticularly indicated in hypertensive patients in whom ACE inhibitors are poorly tolerated. 7 Recent studies suggest a role for ARBs as nephroprotective drugs in diabetic patients. In particular, irbesartan has been shown to significantly prevent or slow down the deterioration in renal function, both at early stage and advanced stage renal insufficiency. 8 There is, how- ever, a general lack of data on the metabolic effects of long- term treatment with irbesartan relative to other antihyperten- sive agents in diabetic hypertensive patients. a 1 -Receptor blockers have a positive effect on metabolic control in type 2 diabetic patients. 9 Doxazosin appears to be the most effective a 1 -receptor blocker at significantly reducing plasma triglycerides (TG) and increasing HDL-C. 10 Moreover, doxazosin slightly reduces low-density lipoprotein cholesterol (LDL-C) in hypercholesterolemic diabetic subjects 11 and improves diabetes control in hypertensive patients. 12 Despite discontinuation of the doxazosin arm of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) because of evidence of a significant increase in Received for publication July 27, 2004; accepted February 18, 2005. From the *Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy; and †‘‘G. Descovich’’ Atherosclerosis Study Center, ‘‘D. Campanacci’’ Department of Clinical Medicine and Applied Biotechnology, University of Bologna, Bologna, Italy. Reprints: Giuseppe Derosa, MD, PhD, Department of Internal Medicine and Therapeutics, University of Pavia, P le C Golgi, 2, 27100 Pavia, Italy (e-mail: giuderosa@tin.it). Copyright Ó 2005 by Lippincott Williams & Wilkins J Cardiovasc Pharmacol ä  Volume 45, Number 6, June 2005 599