Since the 1970s, diuretics—especially hydrochlorothiazide (HCTZ)—have been frequently utilized as antihypertensive agents. Unfortunately, there have been many “chinks” in the HCTZ armor when it is evaluated as a pharmaceutical used to lower blood pressure. The antihypertensive action of HCTZ is only 8 hours in duration, but it is administered once a day.1 In a large prospective trial (ACCOMPLISH), HCTZ did not reduce the occurrence of heart failure when it was compared to amlodipine.2 Recent data suggest that 12.5 mg HCTZ may not have any impact on elevated blood pressures.3 Many combination anti-hypertensives contain only 12.5 mg. HCTZ. In another commentary, attention was focused on chlorthalidone as a potential substitute for HCTZ.4 Here, I would like to propose another diuretic choice, indapamide.
Indapamide, a non-thiazide diuretic, lowers systolic blood pressure 54% more than HCTZ.5 In addition to being more potent that HCTZ, indapamide has a number of other benefits.
A large segment of the population with hypertension is comprised of persons > 65 years of age who have diabetes. In this geriatric cohort, indapamide sustained release (SR) combined with amlodipine was compared to enalapril/amlodipine in a post-hoc analysis.6 At 52 weeks, mean systolic blood pressure reductions were significantly greater with the indapamide/amlodipine combination. Considering the well-earned antihypertensive reputation of enalapril, this favorable comparison with indapamide is impressive.
In another study pairing an ACEI (perindopril) with indapamide as the diuretic in hypertensive diabetic persons,7 the relative risks of diabetic micro- and macrovascular disease were reduced in the ACEI-indapamide combination by 9%, cardiovascular mortality by 18%, and all cause mortality by 14%.7
The RENAAL (Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan) study8 demonstrated that microalbuminuria in diabetic patients is associated with greater cardiovascular risks and death. In a cohort of patients with diabetes, hypertension, and microalbuminuria, systolic blood pressure below target was reached in 84% of persons taking perindopril/indapamide at the lower dose range and 90% at the higher dose range of both agents. In addition, microalbuminria decreased in 75% of those treated with the indapamide-ACEI combination.
Indapamide does not have more adverse metabolic effects than HCTZ. But, it clearly provides more “bang for the buck” when treating hypertension. Not only does it have a longer half-life, but it confers more antihypertensive potency and important pleiotropic effects that may include micro- and macrovascular benefits in patients with diabetes while it also reduced microalbuminuria.
Would any of your current patients benefit?
Pool PE, Applegate WB, Woehler T, et al. A randomized, controlled trial comparing diltiazem, hydrochlorthiazide, and their combination in the therapy of essential hypertension. Pharmacotherapy. 1993;13:487-493.
Roush GC, Ernst ME, Kostis JB, et al. Not just chlorthalidone: evidence-based, single tablet diuretic alternatives to hydrochlorothiazide for hypertension. Curr. Hypertens. Rep. 2015; 17:31.
Pareek AK, Messerli FH, Chandurkar NB, et al. Efficacy of low-dose chlorthalidone and hydrochlorothiazide as assessed by ambulatory blood pressure monitoring. J Am Coll Cardiol. 2016; 67:379-389.
Rutecki GW. Chlorthalidone: underappreciated, underutilized, and undervalued. Practical Cardiology. Accessed Feb 7, 2018.
Roush GC, Ernst ME, Kostis JB, et al. Head-to-head comparisons of hydrochlorthiazide with indapamide and chlorthalidone: antihypertensive and metabolic effects. Hypertension 2015; 65:1041-1046.
Hanon O, Caillard L, Chaussade E, et al. Blood pressure-lowering efficacy of indapamideSR/amlodipine combination in older patients with hypertension: A post hoc analysis of the NESTOR trial (Natrilix SR vs. Enalapril in Hypertensive Type 2 diabtecs with microalbuminuria. J Clin Hypertens. 2017; 10:965-972.
Levy BL, Taddei S. Vascular legacy beyond blood pressure control: benefits of perindopril/idapamide combination in hypertensive patients with diabetes. Curr. Med. Res. Opin. 2018; doi: 10.1080/03007995.2018.
Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001; 345:861-869.