New onset of type 2 diabetes mellitus during antihypertensive therapy: What evidence?

Hypertension is a widely diffused clinical condition in the general population and it is often associated with people who are overweight (i.e. have abdominal adiposity) or obese and with metabolic syndrome. Evidence shows that hypertensive patients are at increased risk of developing type 2 diabetes mellitus (T2DM) since angiotensin II is involved in the pathogenesis of hypertension and insulin resistance, which are both the key components of metabolic syndrome. The preventive effect of renin-angiotensin system (RAS) inhibition on the development of T2DM could reflect the closely linked mechanisms of blood pressure and blood glucose homeostasis. Since hyperglycaemia is a consequence of insulin resistance and β-cell dysfunction, preventing T2DM by RAS inhibition may result from an improvement of β-cell function and/or an enhancement of insulin sensitivity, which are secondary to modifications in microcirculation and changes in ionic status. On the basis of this hypothesis, several trials in treating hypertensive patients have shown a positive effect of drugs inhibiting RAS in reducing the number of hypertensive patients that develop T2DM. We analysed the results of the following clinical studies that found a reduction in the incidence of new-onset T2DM in hypertensive patients using angiotensin II type 1 receptor blockers (ARBs): LIFE (Losartan Intervention For Endpoint reduction in hypertension) [losartan]; SCOPE (Study on COgnition and Prognosis in the Elderly) [candesartan]; ALPINE (Antihypertensive treatment and Lipid Profile In a North of Sweden Efficacy evaluation) [candesartan]; CHARM (Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity) [candesartan]; and VALUE (Valsartan Antihypertensive Long-term Use Evaluation) [valsartan]. Evidence shows that blood pressure reduction, when associated with lifestyle modifications (especially in high-risk patients), is more important than the mechanism of action of the antihypertensive drugs, which is to normalise blood pressure and thus reduce the incidence of cardiovascular events. In this regard, the identification of the potential influence of RAS inhibition in preventing new-onset T2DM in hypertensive subjects is a promising topic for the healthcare system. In the future, data from the ongoing trials, where prevention of diabetes is the primary endpoint, may prove to what extent this class of drugs is actually effective. However, in the previously mentioned clinical trials, the superior effectiveness of ARBs in preventing T2DM is associated with a lower efficacy in preventing cardiovascular events, because of their lesser capacity in lowering blood pressure. Evidence so far suggests the use of ARBs preferably in association with other classes of antihypertensive drugs and under a constant control of blood pressure. In this latter regard, in the recently published ASCOT-BPLA (Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm) study, a combination therapy based on a drug inhibiting RAS (perindopril) and a calcium-channel blocker (amlodipine) significantly reduced the incidence of major cardiovascular events and new onset of diabetes in high-risk hypertensive patients, compared with a combination therapy based on thiazide diuretic and a β-blocker.