Title: Chlorthalidone or Hydrochlorothiazide for Treatment of Hypertension
Abstract: •Thiazide diuretics are a first-line therapy for the treatment of hypertension in blacks and older adults.•Chlorthalidone (CLTD) is more potent than hydrochlorothiazide (HCTZ).•CLTD is associated with more metabolic side effects than HCTZ.•Differences between CLTD and HCTZ in reducing cardiovascular risk are not universally present. Thiazide diuretics chlorthalidone (CLTD) and hydrochlorothiazide (HCTZ) have been a mainstay of the therapy of primary hypertension (HTN).1Whelton P.K. Carey R.M. Aronow W.S. et al.2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: executive summary: a report of the American College of Cardiology/American Heart Association Task force on clinical practice guidelines.Hypertension. 2018; 71: 1269-1324Crossref PubMed Scopus (1246) Google Scholar As a class of medications, thiazide diuretics inhibit sodium-chloride cotransporters at the distal tubule of the nephron, which reabsorbs approximately 10% of the filtered sodium load.2Burnier M. Bakris G. Williams B. Redefining diuretics use in hypertension: why select a thiazide-like diuretic?.J Hypertens. 2019; 37: 1574-1586Crossref PubMed Scopus (29) Google Scholar The initial hypotensive effect of thiazides is attributable to a decrease in sodium and water reabsorption and a reduction in intravascular volume. However, the early fall in blood pressure (BP) becomes partially reversed by hypovolemia-triggered activation of the renin-angiotensin-aldosterone response and partial restoration of the plasma volume to near-normal levels.2Burnier M. Bakris G. Williams B. Redefining diuretics use in hypertension: why select a thiazide-like diuretic?.J Hypertens. 2019; 37: 1574-1586Crossref PubMed Scopus (29) Google Scholar The long-term hypotensive effect of thiazide diuretics is mediated by an overall reduction in systemic vascular resistance. Although the exact mechanism of thiazide-induced vasodilation has yet to be confirmed, it is likely that diuretics diminish the excretion of endogenous vasodilatory peptides.2Burnier M. Bakris G. Williams B. Redefining diuretics use in hypertension: why select a thiazide-like diuretic?.J Hypertens. 2019; 37: 1574-1586Crossref PubMed Scopus (29) Google Scholar Thiazide diuretics are considered a first-line therapy for HTN. On average, compared with placebo, thiazides reduce systolic BP by 10 to 15 mm Hg and diastolic BP by 5 to 10 mm Hg.2Burnier M. Bakris G. Williams B. Redefining diuretics use in hypertension: why select a thiazide-like diuretic?.J Hypertens. 2019; 37: 1574-1586Crossref PubMed Scopus (29) Google Scholar Half of the patients will respond initially to low doses of diuretics (eg, HCTZ 12.5-25 mg/d). Increasing the dose by 12.5 mg/d may result in a response in an additional 20% of patients.2Burnier M. Bakris G. Williams B. Redefining diuretics use in hypertension: why select a thiazide-like diuretic?.J Hypertens. 2019; 37: 1574-1586Crossref PubMed Scopus (29) Google Scholar Thiazides are especially effective in the treatment of salt-sensitive HTN, which is common in blacks and older adults.1Whelton P.K. Carey R.M. Aronow W.S. et al.2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: executive summary: a report of the American College of Cardiology/American Heart Association Task force on clinical practice guidelines.Hypertension. 2018; 71: 1269-1324Crossref PubMed Scopus (1246) Google Scholar,2Burnier M. Bakris G. Williams B. Redefining diuretics use in hypertension: why select a thiazide-like diuretic?.J Hypertens. 2019; 37: 1574-1586Crossref PubMed Scopus (29) Google Scholar When used in combination with other antihypertensive drugs, thiazide diuretics produce an additive decrease in BP while minimizing adverse reactions. Thiazides are generally considered ineffective in patients with severe kidney disease (estimated glomerular filtration rate < 30 mL/min per 1.73 m2). The use of thiazide diuretics with advanced renal disease is usually limited by reduced glomerular filtration that diminishes filtered sodium load reaching the distal nephron. It underlines the rational of replacing thiazide diuretics by loop diuretics that act more proximally, in the loop of Henle, in patients with advanced kidney disease. The side effects of thiazide diuretics are dose dependent. Most complications of thiazides are observed at increasing doses and include renal abnormalities (acute kidney injury and worsening of chronic kidney disease) and metabolic dysregulations (hypokalemia, hyponatremia, hyperuricemia, hyperglycemia, hypomagnesemia, and hypercalcemia).1Whelton P.K. Carey R.M. Aronow W.S. et al.2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: executive summary: a report of the American College of Cardiology/American Heart Association Task force on clinical practice guidelines.Hypertension. 2018; 71: 1269-1324Crossref PubMed Scopus (1246) Google Scholar,2Burnier M. Bakris G. Williams B. Redefining diuretics use in hypertension: why select a thiazide-like diuretic?.J Hypertens. 2019; 37: 1574-1586Crossref PubMed Scopus (29) Google Scholar Other side effects (insomnia and sexual disturbances) are dose independent and may not be minimized by a dose reduction. The mechanism of these idiosyncratic reactions has not been elucidated. Thiazide diuretics are not a homogenous class of medications. CLTD and HCTZ are different in many important ways, and each of these drugs has several pros and cons. The 2017 American College of Cardiology/American Heart Association guideline expressed a preference for CLTD over HCTZ as a first-line thiazide diuretic based on the superior performance of CLTD in indirect comparison with HCTZ in several large randomized trials.1Whelton P.K. Carey R.M. Aronow W.S. et al.2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: executive summary: a report of the American College of Cardiology/American Heart Association Task force on clinical practice guidelines.Hypertension. 2018; 71: 1269-1324Crossref PubMed Scopus (1246) Google Scholar CLTD is 1.5 to 2 times as potent as HCTZ at lowering BP at the same dose.2Burnier M. Bakris G. Williams B. Redefining diuretics use in hypertension: why select a thiazide-like diuretic?.J Hypertens. 2019; 37: 1574-1586Crossref PubMed Scopus (29) Google Scholar The greater potency of CLTD is attributable to its longer half-life (24 hours for CLTD vs 6-12 hours for HCTZ) and, thus, the ability to maintain a low BP throughout the night and to blunt a gradual rise of BP that occurs between daily doses.2Burnier M. Bakris G. Williams B. Redefining diuretics use in hypertension: why select a thiazide-like diuretic?.J Hypertens. 2019; 37: 1574-1586Crossref PubMed Scopus (29) Google Scholar In addition, CLTD appears to be more effective than HCTZ in the reduction of cardiovascular events, specifically premature cardiovascular death and nonfatal myocardial infarctions.1Whelton P.K. Carey R.M. Aronow W.S. et al.2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: executive summary: a report of the American College of Cardiology/American Heart Association Task force on clinical practice guidelines.Hypertension. 2018; 71: 1269-1324Crossref PubMed Scopus (1246) Google Scholar,3Hripcsak G. Suchard M.A. Shea S. et al.Comparison of cardiovascular and safety outcomes of chlorthalidone vs hydrochlorothiazide to treat hypertension.JAMA Intern Med. 2020; 180: 542-551Crossref PubMed Scopus (25) Google Scholar Nevertheless, despite its efficacy, patients treated with CLTD have a significantly higher risk of electrolyte disturbances.2Burnier M. Bakris G. Williams B. Redefining diuretics use in hypertension: why select a thiazide-like diuretic?.J Hypertens. 2019; 37: 1574-1586Crossref PubMed Scopus (29) Google Scholar In a recent observational study, the incidence of hypokalemia was almost 3 times higher in patients treated with CLTD compared with those who received HCTZ.3Hripcsak G. Suchard M.A. Shea S. et al.Comparison of cardiovascular and safety outcomes of chlorthalidone vs hydrochlorothiazide to treat hypertension.JAMA Intern Med. 2020; 180: 542-551Crossref PubMed Scopus (25) Google Scholar HCTZ is a more commonly prescribed thiazide that is also available in several single-pill combinations with nondiuretics. HCTZ has a shorter duration and less potency per milligram than CLTD for BP lowering (HCTZ 50 mg is equipotent with CLTD 12.5-25 mg). However, in contrast to CLTD, HCTZ has a more favorable side effect profile, with fewer metabolic and renal abnormalities. With respect to long-term cardiovascular protection of HCTZ, the evidence is mixed. Some randomized controlled trials did not demonstrate that HCTZ alone reduces the rate of cardiovascular events, whereas other trials showed cardiovascular benefits when HCTZ was used at a higher dose (50 mg/d).2Burnier M. Bakris G. Williams B. Redefining diuretics use in hypertension: why select a thiazide-like diuretic?.J Hypertens. 2019; 37: 1574-1586Crossref PubMed Scopus (29) Google Scholar A contemporary large cohort study that compared 693,000 patients who received HCTZ with 37,000 patients who were prescribed CLTD showed no difference between groups for a wide range of cardiovascular outcomes, such as acute myocardial infarction, hospitalizations for heart failure, ischemic or hemorrhagic stroke, and sudden cardiac death.3Hripcsak G. Suchard M.A. Shea S. et al.Comparison of cardiovascular and safety outcomes of chlorthalidone vs hydrochlorothiazide to treat hypertension.JAMA Intern Med. 2020; 180: 542-551Crossref PubMed Scopus (25) Google Scholar So far, there are no randomized comparisons that match these 2 medications against each other, although 1 is in progress.4Lederle F.A. Cushman W.C. Ferguson R.E. Brophy M.T. Fiore Md LD. Chlorthalidone versus hydrochlorothiazide: a new kind of Veterans Affairs cooperative study.Ann Intern Med. 2016; 165: 663-666Crossref PubMed Scopus (16) Google Scholar Given the pros and cons of each thiazide diuretic HCTZ and CLTD, clinicians should use their clinical judgment and patients’ preferences in selecting a specific medication. For patients who do not achieve BP goals on HCTZ, a switch to more potent CLTD may be warranted. Slow-dose titration and frequent monitoring for electrolyte, metabolic, and renal abnormalities are required for a subset of individuals treated with CLTD. On the other hand, hypertensive patients who attain a desired level of BP on HCTZ should continue it without changing to CLTD. With careful attention to appropriate medication selection, dosing, and monitoring, thiazide diuretics greatly improve BP control and reduce cardiovascular complications in patients with HTN.