Discussion The findings of this study demonstrate that both antihypertensive combinations—olmesartan plus am- lodipine and olmesartan plus hydrochlorothiazide— are well tolerated and effective in non-diabetic hypertensive subjects with MetS, and allow achieve- ment of adequate BP control in the majority of pati- ents using a simple treatment strategy. Combination treatment has been shown to increase the efficacy of treatment and reduce adverse effects.19 A recent large meta-analysis has shown that the extra BP reduction that can be obtained with a combination of drugs from different classes is approximately five times greater than the BP reduction produced by doubling the dose of one drug.20 The olmesartan/ amlodipine combination was factorially evaluated in the COACH trial, a large, multicentre, randomized, double-blind, placebo-controlled study.21 The olme- sartan/hydrochlorothiazide combination has also been extensively studied.22 Each of these olmesar- tan-based combinations has been found to be well tolerated and effective. However, to the best of our knowledge, neither of the combinations has been studied specifically in patients with MetS, and data on their effects in obese hypertensive patients are very scarce. Most of our patients were obese, as expected in a group with MetS; moreover, the prevalence of obesity in our community is among the highest in Europe.23 The validity of the MetS concept has been recently challenged for CV risk prediction,24 but it remains a useful predictor of T2DM development. In the present study, significant reductions in urinary albumin/creatinine quotient were also observed in both treatment arms. Microalbuminuria is highly prevalent in non-diabetic hypertensive subjects with MetS,25 and is a well-known marker of both renal and CV risk.26 The LIFE trial, in hypertensive patients with left ventricular hyper- trophy, showed that reductions in albumin excretion during treatment translate into a reduction in the risk of CV events.27 The OLAS study also shows that there are clear differences between the two olmesartan-based com- binations with regard to metabolic and inflamma- tory markers. It has long been established that thiazide diuretics impair insulin sensitivity and increase the incidence of T2DM.4 This adverse effect can only partially be explained by hypokalaemia; a systematic review of the available evidence found that thiazides are diabetogenic even in the absence of changes in the plasma potassium level.28 Thiazide diuretics have been shown to reduce hard CV endpoints in many large controlled trials, and are recommended as first-line treatment for hypertension in the current guidelines.6,29 However, most of these trials have been based on chlorthali- done or indapamide, whereas the currently recom- mended low doses (up to 25 mg per day) of hydrochlorothiazide have never been shown to reduce CV morbidity and mortality.30 Nevertheless, OLAS: Olmesartan/Amlodipine vs Olmesartan/Thiazide FJ Martinez-Martin et al hydrochlorothiazide is, by far, the most prescribed thiazide diuretic worldwide, and the one used in almost all of the available single-pill combinations containing a diuretic. The MEchanisms for the DIabetes preventing effect of CAndesartan (MEDICA) study found that, compared with candesartan, hydrochlorothiazide increased insulin resistance in a manner that was not related to hypokalaemia, but was associated with fat redistribution, an increase in visceral adiposity, steatohepatitis and low-grade inflamma- tion.31 The Pharmacogenomic Evaluation of Anti- hypertensive Responses study found that the ad- verse metabolic effects (including new-onset T2DM) of hydrochlorothiazide, alone or associated with atenolol, were more frequent and severe in patients with abdominal obesity.32 The Study of Trandolapril/ Verapamil SR And Insulin Resistance (STAR), showed that in non-diabetic hypertensive patients with MetS, an angiotensin-converting enzyme in- hibitor/CCB combination was associated with a much lower risk of developing diabetes than an ARB/hydrochlorothiazide combination, despite si- milar reduction in BP;7 a correlation with potassium levels was also excluded. Our results regarding the development of T2DM are comparable, and also ruled out thiazide-induced hypokalaemia as the cause. Moreover, we were able to establish the predictive role of low adiponectin levels in this model, even independently of the changes in the insulin sensitivity index. In fact, low adiponectin is a powerful independent predictor of T2DM.9 The clinical relevance of the changes in these metabolic parameters is unknown, although a higher incidence of T2DM may not be trivial. The importance of new-onset T2DM in hypertension trials has been challenged, as it does not seem to be associated with a higher risk of mortality or clinical events in the short term,33 and for some authors its possible occurrence should not influence the selection of antihypertensive drug.34 Moreover, the STAR Long-Term Extension Trial showed that it is partially reversible.35 The risk associated with new-onset T2DM may become apparent only in very long-term studies, except in very high-risk situations. In the VALIANT trial, after an acute myocardial infarction, patients with pre- viously known or newly diagnosed diabetes melli- tus had similarly increased risks of mortality and CV events, much higher than non-diabetic patients.36 Recently, the Avoiding Cardiovascular events through COMbination therapy in Patients LIving with Systolic Hypertension (ACCOMPLISH) trial showed a 20% reduction in the risk of CV events and mortality with the use of a fixed-dose combination of benazepril/amlodipine, compared with a fixed- dose combination of benazepril/hydrochlorothia- zide, despite similar reduction in BP.37 These results point to an, as yet, unknown BP-independent mechanism, although a reduction in central BP may also be implied.38 Although an ARB was prescribed instead of an angiotensin-converting 351 Journal of Human Hypertension