Welcome to the Circle of Knowledge Program
Two Canadian experts, Dr. Jordan Weinstein and Dr. Louis Girard, nephrologists, will share how to translate clinical evidence into daily practice for optimal hypertension patient care.
Thiazide and thiazide-like diuretics remain a mainstay of hypertension management. They are recommended among the first-line agents for the management of hypertension and perform very well when added on to other anti-hypertensives, namely ACE-inhibitors (ACEi) and angiotensin receptor blockers (ARB). All ACEi and ARB are offered in a fixed-dose combination format and with only a few exceptions, hydrochlorothiazide is the diuretic offered in these fixed-dose combinations. However, thiazide and thiazide-like diuretics have different pharmacokinetic and pharmacodynamic properties which affect how these drugs perform in the management of hypertension. For this brief review, we will focus on three main choices within this diuretic class.
Hydrochlorothiazide (HCTZ) is the most widely prescribed diuretic and is generally dosed at 12.5 to 25 mg. It is a modestly effective agent but is inferior to chlorthalidone and indapamide in terms of blood pressure reduction. Raising the dose beyond 25mg is not associated with significantly greater efficacy but side effects (hypokalemia, glucose intolerance, and hyperuricemia) do increase with dose. HCTZ is generality short-acting with a half-life range of 6 to 15 hours. Because it nearly always dosed once per day, patients will remain sub-optimally treated for a significant portion of the day. As a result of these shortcomings, HCTZ use should generally be reserved for fixed-dose combinations or when looking for an only modest reduction in blood pressure.
Chlorthalidone (CLTD) is much less widely prescribed than HCTZ and yet has considerable advantages. It is modestly more effective than HCTZ from the perspective of blood pressure lowering (-3.6 mmHg) without a clear increase in additional side effects, apart from a possible increase in the rate of hypokalemia which is apparent mainly upon initiating therapy or when increasing dose1,2. The main benefit of CLTD, however, is not the slight improvement in blood pressure but in its much longer half-life of 40-60 hours. This ensures sustained blood pressure lowering throughout the day. CLTD is only available in 50 mg tablets and so patients need to start on a quarter or half tablet in most cases. CLTD was the agent used in the landmark SPRINT study3 in hypertension as well as in the equally important ALLHAT5 study where this diuretic produced superior outcomes compared to using lisinopril or amlodipine. For this reason and because they are longer acting, the Hypertension Canada guidelines suggest that longer-acting diuretics are preferred over HCTZ. Unfortunately, there is only one fixed-dose combination - azilsartan/chlorthalidone - that uses this diuretic with an ARB.
Indapamide is also a thiazide-like diuretic with a longer half-life (14 hours) than HCTZ and with superior blood pressure lowering to HCTZ (-5.1 mmHg) without additional adverse events1. Unfortunately, there are no robust head-to-head clinical trials comparing thiazide with thiazide-like diuretics with respect to cardiovascular outcomes and we are left to draw conclusions from meta-analyses where, compared with thiazide diuretics, thiazide-like diuretics significantly lowered the relative risk of cardiovascular events by 12 percent and heart failure by 21 percent4.
Monthly Clinical Pearl
- Thiazide-like diuretics provide superior blood pressure control to HCTZ mainly due to their longer half-life
- Side effects of thiazide-like diuretics are similar to HCTZ but there is more hypokalemia with thiazide-like diuretics compared to HCTZ especially when starting or increasing the dose
- 2018 hypertension guidelines suggest considering longer-acting agents for the optimal management of hypertension