Chlortalidone

Hypertension is an important risk factor for ischaemic heart disease, heart failure, stroke, dementia, chronic kidney disease and peripheral vascular disease. It is estimated that 30–45% of European adults have hypertension; the prevalence increasing with age. Hypertension is common in those with diabetes and blood pressure management is important as part of a comprehensive treatment strategy to manage cardiovascular risk in this group. NICE includes thiazide-like diuretics in its hypertension guideline with inadequate control on a calcium-channel blocker and/or an ACE inhibitor. The thiazide-like diuretics indapamide and chlortalidone (also known as chlorthalidone) have a longer half-life, proven efficacy, and cardiovascular benefits with many guidelines favouring these over thiazide diuretics such as hydrochlorothiazide and bendroflumethiazide. Chlortalidone is also licensed for use in patients with oedema due to nephrotic syndrome, stable ascites in liver cirrhosis and nephrogenic diabetes insipidus. Chlortalidone inhibits the Na+/Cl- symporter in the renal distal convoluted tubule (see Figure 1). This increases natriuresis, prevents water re-absorption from the kidneys, and reduces circulating volume, thereby decreasing afterload on the heart. It also reduces oedema by reducing intravascular hydrostatic pressure. It has other effects such as decreased platelet aggregation and vascular permeability and promoting angiogenesis in vitro, partly through reductions in carbonic anhydrase dependent pathways. Chlortalidone is taken orally and has a bioavailability of approximately 65%. It has a half-life of 40–50 hours. Following hepatic metabolism around 50% of the drug is renally excreted in its inactive form and its elimination is characterised by a rapid phase followed by a slow secretory phase. Its efficacy decreases in renal impairment, being contraindicated in severe renal impairment. Common adverse effects include GI upset, postural hypotension and metabolic disturbances such as hyponatraemia, hypokalaemia and hypomagnesaemia. The SHEP study (Systolic Hypertension in the Elderly Program) was a placebo- controlled randomised, double-blinded trial in 4736 patients over 60 years with isolated systolic hypertension (systolic blood pressure [SBP] ≥160mmHg and diastolic blood pressure < 90mmHg) designed to determine whether antihypertensive treatment reduced the incidence of stroke.1 Participants in the active treatment arm were treated in a step wise fashion with chlortalidone, followed by atenolol or reserpine if blood pressure targets were not met. At the end of the study, the average SBP was 155/72mmHg for the placebo group and 143/68mmHg for the active treatment group. Chlortalidone reduced the rate of total stroke by 36% (relative risk 0.64, 95% CI 0.50–0.82, p = 0.0003), major cardiovascular (CV) events by 32% and all-cause mortality by 13%, although due to the sample size the latter was not statistically significant. The ALLHAT (Antihypertensive and Lipid Lowering Treatment to prevent Heart Attack Trial) study compared chlortalidone to amlodipine, lisinopril or doxazosin in 33,347 participants with hypertension.2 The primary outcome was fatal coronary heart disease or non-fatal myocardial infarction. The doxazosin arm was terminated early after showing that it was associated with a higher incidence of heart failure. Chlortalidone, amlodipine and lisinopril were equally efficacious in the prevention of coronary events. Compared to chlortalidone, the relative risks (RR) were 0.98 (95% CI 0.90–1.07) for amlodipine and 0.99 (95% CI 0.91–1.08) for lisinopril. Chlortalidone was shown to be superior to amlodipine and lisinopril in the prevention of heart failure (RR 1.38, 95% CI 1.24–1.51, p < 0.001, and RR 1.15, 95% CI 1.07–1.31, p < 0.001 respectively). As expected, hypokalaemia was more common in patients treated with chlortalidone with 8% of participants requiring potassium supplementation compared to amlodipine and lisinopril (4% and 2% respectively, p < 0.001). Clinical studies directly comparing chlortalidone to thiazide diuretics give inconsistent results. For example, a meta-analysis showed chlortalidone to be more potent in reducing night-time SBP and 24-hour mean SBP compared to hydrochlorothiazide with prolonged treatment (> four years) associated with a 21% reduction in CV events (HR 0.79, 95% CI 0.72–0.88, p < 0.0001).3 However, in a more recent comparative cohort study of 730,255 patients, chlortalidone was not associated with improved CV outcomes when compared to hydrochlorothiazide and had an increased risk of electrolyte disturbance and acute renal impairment.4 In the SHEP trial, the rate of CV disease in patients with and without diabetes was 34% lower in those treated with chlortalidone compared to placebo. A subgroup analysis of patients with type 2 diabetes (36%) in ALLHAT found no difference in outcomes in those treated with chlortalidone. In a priori subgroup analysis of patients with diabetes in the double-blind PREVER trial (Prevention of Hypertension in Patients with PreHypertension), SBP was significantly lower in the patients treated with chlortalidone/amiloride compared to losartan.5 Diabetic kidney disease is an important complication in patients with diabetes and albuminuria is used to detect it early as well as an indicator of disease progression. Several studies have demonstrated a reduction in proteinuria with chlortalidone. The CLICK (Chlortalidone in Chronic Kidney Disease) study was a double-blind trial which randomised 160 patients with stage 4 CKD and uncontrolled hypertension to chlortalidone or placebo;6 76% of participants had diabetes. In patients treated with chlortalidone for 12 weeks, there was a significant reduction in 24-hour SBP compared to placebo with a difference of -10.5mmHg (95% CI -14.6 to -6.4, p < 0.001) and a 50% reduction in albuminuria at 12 weeks compared to placebo (95% CI 37–60). There has always been a concern that thiazide diuretics are associated with a dose-dependent risk of developing diabetes. In the ALLHAT trial mean fasting glucose levels increased during follow-up in all treatment groups. At year two, those randomised to the chlortalidone group had the greatest increase (+8.5mg/dL [0.47mmol/L] vs +5.5mg/dL [0.31mmol/L] for amlodipine and + 3.5mg/dL [0.19mmol/L] for lisinopril).7 While the exact mechanisms underlying this relationship are unclear, hypokalaemia seems to be an important factor and can impair beta-cell insulin secretion. Importantly, both SHEP and ALLHAT demonstrated that diuretic-associated diabetes was not associated with an increased CV risk, with the benefits associated with CV risk reduction using chlortalidone considered to outweigh the small risk of developing diabetes. Several hypertension guidelines recommend the use of thiazide-like diuretics such as chlortalidone over thiazide diuretics based on their differing efficacy and safety profiles. Chlortalidone is an efficacious antihypertensive and may be associated with additional CV benefits and reductions in proteinuria including in those with diabetes. Although metabolic disturbances such as new onset diabetes have been noted, the benefits of therapy are thought to outweigh any additional CV risk of hyperglycaemia. There are no conflicts of interest declared.