Thiazide (hydrochlorothiazide) vs Thiazide–like (Chlorthalidone, Indapamide)

Thiazide and Thiazide diuretics have been an important tool in treating primary hypertension for many years. At low doses (eg, 12.5 to 25 mg/day of chlorthalidone or hydrochlorothiazide, or 1.25 mg/day of indapamide) there is the antihypertensive response and minimized metabolic effects. Higher doses may have less antihypertensive effect because of greater activation of the renin-angiotensin system. 

Low-dose thiazide diuretics decrease mortality & cardiovascular morbidity outcomes. The best evidence for reducing cardiovascular morbidity & mortality has been illustrated with chlorthalidone - SHEP, ALLHAT trials - and indapamide – HYVET and ADVANCE (in combo with perindopril).

Chlorthalidone is more potent (1.5 to 2x) due to its longer duration action than hydrochlorothiazide. Indapamide is also more potent and longer acting than hydrochlorothiazide. When initiating diuretics, some experts suggest chlorthalidone 12.5-25 mg per day or indapamide 1.25-2.5 mg per day as the drug of choice.

Issues of concern include the fact there is no 12.5mg tablet of chlorthalidone and splitting tablets can lead to variability in dosing. In addition, there are more choices for combo products with hydrochlorothiazide. Hypokalemia (↓ K+ 0.3), hyperglycemia (↑ 0.28) and increased cholesterol (↑0.044) may be of concern. Hypercalcemia is also a concern with the thiazide-like diuretics however; decreased hip/pelvic fractures resulted in the ALLHAT trial.