Abstract Background and aim The aim of this trial was to evaluate the effect of doxazosin as add-on therapy in patients with hypertension not adequately controlled on current antihypertensive therapy, and impaired glucose metabolism. The effect of doxazosin administered as add-on therapy was to be considered significant both from clinical and statistical viewpoints if the proportion of patients with adequate control of blood pressure (BP<130/85 mmHg) would be at least 30% after 16 weeks of combined therapy. Method and results It was an open, multicenter phase IV study, lasting 19 weeks: 3-week qualifying/placebo run-in period+16-week dose titration/add on therapy period, involving 264 out-patients (158 m and 106 f; mean age±SD: 60.9±8.6 years; mean BMI±SD: basal 29.5±5.1, final 30.2±4.6) with blood pressure still >130/85 mmHg in spite of the antihypertensive treatment (ACE inhibitors 44%, AT II antagonists 21%, Ca antagonists 12%, other drugs 8%, polytherapy 15%) and affected by type 2 diabetes ( n=219), impaired fasting glucose (IFG; n=16) or impaired glucose tolerance (IGT; n=29). Following a run-in, 3-week qualifying phase during which placebo was added to ongoing antihypertensive treatment, 16-week treatment with doxazosin was added at dosages from 1 up to 8 mg/day. Main outcome measures were: the percentage of patients with blood pressure <130/85 mmHg at the end of treatment; the effects of the combination therapy on glyco-lipidic metabolism: fasting plasma glucose, fasting insulin, glycated hemoglobin, insulin resistance (HOMA-R), plasma lipids; and the effect on the 10-year CHD risk (Framingham equation). Results 35% of patients were responsive (BP<130/85 mmHg) to add-on treatment with doxazosin (CI 90%: 30.3%−40.4%; P<0.05, stat. an. intention to treat). During the run-in phase with placebo, mean SBP/DBP (±SD) decreased from 155.6±13.2/91.8±6.8 mmHg (Week −3) to 151.9±12.9/90.1±7.2 mmHg (Week −1) and to 151.2±11.5/90.1±6.9 mmHg (Week 0). During add-on treatment with doxazosin, mean SBP/DBP (±SD) further decreased to 144.9±15.2/86.3±8.3 mmHg (Week 4), 139.7±15.3/83.4±7.9 mmHg (Week 8), 135.5±14.3/81.7±7.6 mmHg (Week 12) and 136.4±14.5/81.0±7.0 mmHg (Week 16). Overall, mean BP changes reached a plateau of about −15 mmHg (SBP) and −9 mmHg (DBP) after 16 weeks of treatment; at each visit the mean decreases from baseline were statistically significant. The following mean values of metabolic parameters were reduced during the study: fasting plasma glucose (−4.1 mg/dl; −2.8%), fasting insulin (−2 μU/ml; −12.3%; P<0.05), glycated hemoglobin (−0.12%; −1.7%), HOMA-R (−1.03; −18.2%; P<0.05), total cholesterol (−1.85 mg/dl; −1.1%), LDL cholesterol (−1.35 mg/dl; −0.8%) and triglycerides (−5.64 mg/dl; −2.4%); mean HDL cholesterol increased (+1.79 mg/dl; +3.9%; P<0.01). At the end of study treatment, the percentage of patients with lab values returned within normal ranges, in comparison with basal values, was statistically significant ( P<0.05) for the following parameters: fasting plasma glucose (6.3%), fasting insulin (7.5%), LDL cholesterol (6.0%). Ten-year CHD risk (±SD) decreased from 16.4±7.8% to 13.6±7.4% (final vs. basal: −2.87±3.9; −17%; P<0.01). Six patients (2.3%) reported 8 adverse drug reactions: dizziness (3), edema (2), headache (2), asthenia (1). In one out of these 6 patients, in whom doxazosin was associated to the ACE inhibitor quinapril, adverse reaction (peripheral edema) led to treatment withdrawal. Conclusion In patients not responsive to antihypertensive treatment and concomitantly affected by impaired glucose metabolism, achievement of target BP was obtained in more than one third of cases after 16-week add-on treatment with doxazosin. Changes in glyco-lipidic parameters and reduction of 10-year CHD risk observed during the study, although of moderate extent, confirm the overall favourable effect of antihypertensive combinations including doxazosin.