specifically in hypertensive patients with MetS.7,8 In addition to decreased insulin sensitivity, a low circulating level of adiponectin is a central feature of MetS and is strongly associated with the incidence of T2DM.9 High circulating levels of inflammatory markers such as tumour necrosis factor-a (TNF-a), C-reactive protein (CRP) and interleukins-1b (IL-1b), IL-6 and IL-8 are also a feature of MetS and increase the risk of developing T2DM.10 The adhesion mole- cules, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) are also strongly associated with certain features of MetS,11 particularly postprandial triglyceride and insulin levels, and may therefore be implicated in the development of atherosclerosis and T2DM.11 Olmesartan is the latest ARB to become available in clinical practice. A systematic review of the efficacy of ARBs in studies that used 24-h ambula- tory blood pressure (BP) monitoring revealed that olmesartan may achieve greater ambulatory BP reductions than other ARBs, even though reductions in office BP were similar.12 Fixed-dose combinations of olmesartan with amlodipine and with hydro- chlorothiazide have recently become available. In addition to other ancillary actions, amlodipine has been shown to have a modest insulin-sensitising effect that is additive to the effect of an ARB.13,14 The primary objective of this stand-alone study, OLAS (OLmesartan/Amlodipine vs olmesartan/ hydrochlorothiazide in metabolic Syndrome), was to investigate the effects of olmesartan/amlodipine and olmesartan/hydrochlorothiazide combination therapy on inflammatory (including TNF-a, CRP, IL-1b, -6 and -8, ICAM-1 and VCAM-1) and meta- bolic parameters (including insulin sensitivity and adiponectin), with new-onset T2DM as a secondary outcome measure, in non-diabetic hypertensive patients with MetS. Methods The patients recruited for this study were all Europid, aged 25–75 years and had stage I and II hypertension (systolic BP (SBP) 140–179 mm Hg) and MetS, as defined by the International Diabetes Federation for Europid populations15 (waist circum- ference 494 cm in men and 480 cm in women, and at least two of the following criteria: triglycerides 41.7 mmol l 1; high-density lipoprotein-cholesterol o1.03 mmol l 1 in men and o1.29 mmol l 1 in women; fasting blood glucose 45.6 mmol l 1; BP 4135/80 mm Hg). Previous antihypertensive ther- apy, if any, was withdrawn during a washout period of 3–5 weeks before inclusion. Patients with diabetes mellitus were excluded from the study and, in order to unmask hidden diabetes, a standard oral glucose tolerance test was performed in patients with fasting blood glucose 45.6 mmol l 1. Patients were also excluded if they showed evidence of unstable angina, acute coronary OLAS: Olmesartan/Amlodipine vs Olmesartan/Thiazide FJ Martinez-Martin et al syndrome, myocardial infarction, decompensated congestive heart failure, stroke or transient ischemic attack within the previous 6 months, left ventricular outflow obstruction, liver dysfunction (serum bilir- ubin 41.5 or plasma aminotransferases 2 the upper normal limit), renal insufficiency (plasma creatinine 4133 mmol l 1 in men and 4124 mmol l 1 in women) or overt proteinuria (4300 mg per day). Patients with known hypersensitivity or a history of severe adverse effects with any ARB, CCB, thiazide diuretic or a-adrenergic blocker were excluded, as well as those with any contraindication for olmesartan, amlodipine, hydrochlorothiazide or doxazosin (based on the prescribing information for each drug). Pregnant women, nursing mothers, women of childbearing potential not using adequate contraceptive methods and patients with a history of mental illness or psychiatric disorders were also excluded. The study was conducted according to standard good clinical practice guidelines and approved by the local ethics committee of participating centres. All participants provided written informed consent before inclusion. A parallel-group, prospective, randomized, open- label, blinded end point design (PROBE) was used, and all measurements and procedures were per- formed by personnel blinded to the treatment allocation.16 The study design is shown in Figure 1. After baseline measurements were taken, patients were randomized to receive olmesartan (20 mg) þ amlodipine (5 mg) daily (OA group), or olmesartan (20 mg) þ hydrochlorothiazide (12.5 mg) daily (OH group). After 13±2, 26±2, 39±2 and 78±2 weeks (approximately 3, 6, 9 and 18 months) all measure- ments were repeated. Those patients not reaching the SBP target (o140 mm Hg) were successively uptitrated to a double dose of the initial treatment after 13 weeks, an additional 4 mg of doxazosin (long-acting formulation) after 26 weeks, and 8 mg of doxazosin after week 39. Additional visits were performed after 52±2 and 65±2 weeks (12 and 15 months) but only BP, fasting blood glucose, compliance and tolerance data were obtained. 347 Figure 1 Design of the OLAS study showing the antihyperten- sive treatment schedule. The treatment was uptitrated if the target systolic blood pressure (o140 mm Hg) had not been reached. A, amlodipine; D, doxazosin; H: hydrochlorothiazide; O, olmesartan. Journal of Human Hypertension