Which thiazide to choose as add-on therapy for hypertension?

Combined therapy is required in the majority of patients with hypertension to achieve blood pressure (BP) targets. Although different antihypertensive drugs can be combined, not all combinations are equally effective and safe. In this context, the combination of a Renin angiotensin system inhibitor with a diuretic, usually a thiazide, particularly hydrochlorothiazide (HCTZ) or thiazide-like diuretics, such as chlorthalidone or indapamide, is recommended. However, not all diuretics are equal. Although HCTZ, chlorthalidone, and indapamide as add-on therapy effectively reduce BP levels, the majority of studies have obtained greater BP reductions with chlorthalidone or indapamide than with HCTZ. Moreover, there are data showing benefits with chlorthalidone or indapamide beyond BP. Thus, chlorthalidone seems to have pleiotropic effects beyond BP reduction. Moreover, compared with placebo, chlorthalidone has small effects on fasting glucose and total Cholesterol, and compared with HCTZ, chlorthalidone achieves significantly lower total Cholesterol and low-density lipoprotein Cholesterol levels. Similarly, indapamide has demonstrated no negative impact on glucose or lipid metabolism. More importantly, although head-to-head clinical trials comparing the effects of indapamide or chlorthalidone with HCTZ are not available, indirect comparisons and post hoc analyses suggest that the use of chlorthalidone or indapamide is associated with a reduction in cardiovascular events. Despite this, the most frequent diuretic used in clinical practice as add-on therapy for hypertension is HCTZ. The purpose of this review is to update the published data on the efficacy and safety of HCTZ, chlorthalidone, and indapamide as add-on therapy in patients with hypertension.