Chlorthalidone

What it is

Chlorthalidone is a synthetic sulfonamide diuretic tablet, first approved in the United States in 1988 in its current branded form and in use far longer. It is called "thiazide-like" rather than a thiazide: it is not chemically a thiazide but acts at the same place in the kidney, the distal convoluted tubule. Its distinguishing property is a long duration of action, which is why 12.5 to 25 mg once daily is a usual dose where hydrochlorothiazide needs 25 to 50 mg. It is prescription-only and does not occur in food.

What the research says

Chlorthalidone makes the kidney excrete sodium and water, which lowers blood pressure, and that lowering is one of the best-evidenced benefits in medicine. In SHEP, 4736 older people with isolated systolic hypertension had five-year stroke rates of 5.2 per 100 on chlorthalidone-led treatment against 8.2 per 100 on placebo - an absolute benefit the investigators put at 30 stroke events per 1000 people over five years, and 55 major cardiovascular events per 1000. In ALLHAT, 33,357 people showed it was at least as good as amlodipine or lisinopril, with less heart failure. What it does not have is an advantage over its cheaper cousin hydrochlorothiazide: the 13,523-person Diuretic Comparison Project found no difference in cardiovascular events, and more low potassium on chlorthalidone. It reliably disturbs electrolytes and metabolism: low potassium, low sodium, raised uric acid and gout, raised glucose, raised calcium.

Evidence grade: Well established.

How it works

Drug class: Thiazide-like (sulfonamide) diuretic, long-acting; an antihypertensive

Chlorthalidone acts on the distal convoluted tubule of the kidney, blocking the reabsorption of sodium there so that sodium and water leave in the urine. The resulting loss of sodium and water is what lowers blood pressure; the label is explicit that the full mechanism is not completely understood. The same handle on sodium transport is what drags potassium and magnesium out with it, which is why electrolytes have to be watched. (Source 1)

What it is used for

• This is the best-evidenced use of the drug. In SHEP, chlorthalidone-led treatment cut five-year stroke from 8.2 to 5.2 per 100 people, an absolute benefit of 30 events per 1000 over five years - about 33 people treated for five years to prevent one stroke. ALLHAT found it at least as good as amlodipine or lisinopril in 33,357 people, with less heart failure than either. Cochrane rates the mortality and morbidity evidence for low-dose thiazide-type diuretics as high quality. Evidence: established. (Source 2)
• This is an approved adjunctive indication on the label, at much higher doses than for blood pressure - 50 to 200 mg daily. No outcome trial of chlorthalidone for oedema was reached in this search, so the evidence behind the indication is not characterised here; it rests on the regulatory position. Evidence: unknown. (Source 3)
• Thiazides were long assumed not to work when kidney function is very low. The CLICK trial randomised 160 people with stage 4 CKD and found chlorthalidone lowered 24-hour systolic blood pressure by 10.5 mm Hg more than placebo over 12 weeks and cut albuminuria by half. It is one small, short trial measuring blood pressure and albuminuria rather than heart attacks, strokes or dialysis, and harms were clearly more frequent. Evidence: limited. (Source 4)
• A 2025 meta-analysis of 10 randomised trials in 1322 people with hypercalciuria found thiazide diuretics cut stone recurrence (RR 0.63). But the largest and most recent placebo-controlled trial, NOSTONE, tested hydrochlorothiazide at three doses in 416 people and found no benefit at any dose. The two cannot both be right, and NOSTONE tested hydrochlorothiazide rather than chlorthalidone. Evidence: disputed. (Source 5)

Interactions

• Lithium (label): Chlorthalidone makes the kidney hold on to lithium, so lithium levels rise and can reach toxic concentrations. Lithium levels need checking when the two are used together. (Source 6)
• Other blood-pressure drugs (label): Chlorthalidone adds to the effect of other antihypertensives. That is usually the intention, but it is also how blood pressure drops too far, especially in someone who is volume-depleted or salt-restricted. (Source 6)
• Potassium (and potassium-containing supplements or salt substitutes) (label): Chlorthalidone lowers blood potassium, and the label says that if low potassium is causing symptoms the drug should be stopped, and that low potassium and low magnesium should be corrected before a thiazide is started. Low magnesium makes low potassium hard to fix with potassium alone. (Source 7)
• Calcium and vitamin D supplements (label): Chlorthalidone makes the kidney excrete less calcium, so blood calcium can rise. Adding calcium or vitamin D pushes in the same direction; the label says to monitor calcium in anyone already hypercalcaemic. (Source 8)
• Magnesium (label): Thiazide-like diuretics increase magnesium loss in the urine and can cause low blood magnesium, which in turn makes low potassium stubborn. (Source 9)
• Licorice (Glycyrrhiza glabra, including licorice root tea and confectionery) (case reports): Licorice's metabolite glycyrrhetinic acid blocks the enzyme 11-beta-hydroxysteroid dehydrogenase-2 in the kidney, which drives potassium out and pushes blood pressure up - the opposite of what chlorthalidone is prescribed for and the same direction as its worst electrolyte effect. In the reported case a man drinking three to four cups of licorice root tea daily for three months developed uncontrolled hypertension, muscle weakness and low potassium. The combination with chlorthalidone has not been studied; this is a mechanism and case reports, not a trial. Limit: This is a single published case report - one patient - together with a known mechanism. That is enough to take the interaction seriously and not enough to say how often it happens or how large it is. (Source 10)
• Alcohol (label): The label's patient information says alcohol increases the chance of dizziness on chlorthalidone - the drug already lowers blood pressure and can cause orthostatic hypotension, and alcohol adds to that. (Source 11)
• Corticosteroids and ACTH (label): Steroids given alongside chlorthalidone make low blood potassium more likely, on top of the drug's own potassium loss. (Source 9)
• Digoxin and other digitalis drugs (label): Chlorthalidone's potassium loss makes digitalis more dangerous for the heart; the label says digitalis can exaggerate the effects of low potassium on heart muscle. (Source 9)
• Diabetes medicines including glimepiride and insulin (label): Chlorthalidone can raise blood glucose, so a diabetes drug may need a larger dose, and diabetes that was previously hidden can show itself. The glimepiride label makes the same point from the other side, listing thiazides and other diuretics among the drugs that blunt its glucose-lowering effect. (Source 12)
• Salt and water intake, and hot weather (label): How much salt and water a person takes in changes what chlorthalidone does. The label notes that poor electrolyte intake adds to potassium loss, and that dilutional low sodium can occur in people with oedema in hot weather - for which the answer is restricting water, not adding salt. (Source 9)

Stopping it

• A 2026 meta-analysis of four randomised trials in 2173 older adults found that deliberately stopping or reducing blood-pressure drugs did not raise death, cardiovascular death, hospitalisation, major cardiovascular events, serious adverse events or falls. The authors still call the evidence base limited and uncertain. (Source 13)
• A separate 2026 meta-analysis of the same literature found a signal in the other direction for heart failure, with roughly three times the odds after deprescribing across three randomised trials, on very few events and a wide confidence interval. This is the reason stopping is not a neutral act. (Source 14)
• The label gives one explicit reason to stop: low potassium with clinical signs such as muscle weakness, paresis or ECG changes. It also says to consider withholding or discontinuing if kidney function drops meaningfully. (Source 7)
• The older generic label adds that if kidney impairment is progressing, as shown by a rising blood urea nitrogen, therapy needs careful reappraisal with withholding or stopping the diuretic considered. (Source 9)

What goes wrong

Chlorthalidone caused more low blood potassium than hydrochlorothiazide in a 13,523-person randomised trial. (Source 15)

• Randomized trial, High certainty.
• Size: 13,523 patients.
• Who: Veterans aged 65 and over with hypertension.
• How long: Median 2.4 years.
• Result: Hypokalaemia in 6.0% on chlorthalidone vs 4.4% on hydrochlorothiazide, P<0.001. Absolute increase 1.6 percentage points, about one extra case of low potassium for every 63 people switched over 2.4 years.
• Funding: independent (VA Cooperative Studies Program)

The incidence of hypokalemia was higher in the chlorthalidone group than in the hydrochlorothiazide group (6.0% vs. 4.4%, P<0.001)

In advanced kidney disease, chlorthalidone caused more low potassium, creatinine rises, high glucose, dizziness and high uric acid than placebo. (Source 4)

• Randomized trial, Moderate certainty.
• Size: 160 participants.
• Who: Adults with stage 4 chronic kidney disease and poorly controlled hypertension.
• How long: 12 weeks.
• Result: The trial reports these as more frequent on chlorthalidone than placebo but the abstract gives no rates for them. The creatinine rises are described as reversible.
• Funding: independent (NHLBI and Indiana Institute of Medical Research)

Hypokalemia, reversible increases in serum creatinine level, hyperglycemia, dizziness, and hyperuricemia occurred more frequently in the chlorthalidone group than in the placebo group.

Starting a thiazide carries an average excess risk of moderate-to-severe low blood sodium of about 1.8% within 120 days, concentrated in a high-risk minority. (Source 16)

• Cohort study, Moderate certainty.
• Size: Development cohort 185,699 (2014-18); validation cohort 75,030 (2019-20)
• Who: Danish adults aged 40 and over starting a thiazide or a non-thiazide antihypertensive, 2014 to 2020.
• How long: 120 days after starting treatment.
• Result: Average 120-day excess risk of plasma sodium under 130 mmol/L 1.8% (95% CI 1.3 to 2.2%), about one extra case per 56 people started; individual-level excess risk ranged from -1.6% to 15.9%, and for the highest-risk 10% averaged 7.4% (95% CI 4.4 to 10.5%). Observational, so an association, and the exposure is the thiazide class rather than chlorthalidone specifically.
• Funding: not stated.

Limit of this finding: One pair of figures in this paper does not divide out on screen: an absolute reduction of 0.7% against an average excess risk of 1.8% is 39%, not the 42% relative reduction the paper states. It reconciles if the unrounded values are used, so this is rounding rather than an error, but the two numbers will not agree if a reader does the arithmetic. The study is also observational and covers the thiazide class rather than chlorthalidone alone, so it shows an association, not proof of cause.

The average 120 day excess risk of hyponatraemia among thiazide-treated patients was 1.8% (95% CI, 1.3-2.2%), with individual-level heterogeneity ranging from -1.6% to 15.9%. For the 10% of thiazide-treated with the highest excess risk of hyponatraemia, the average excess risk was 7.4% (95% CI, 4.4-10.5%).

People started on a low-dose thiazide were more than twice as likely to stop the drug because of side effects as people on placebo. (Source 17)

• Systematic review, Low certainty.
• Size: Trials within the 24-trial, 58,040-patient Cochrane review.
• Who: Adults with moderate to severe primary hypertension.
• How long: Three to five years.
• Result: Withdrawals due to adverse effects 5.0% on control vs 11.3% on low-dose thiazides (RR 2.38, 95% CI 2.06 to 2.75). Absolute increase 6.3 percentage points, about one extra withdrawal for every 16 people treated. High-dose thiazides were worse again, 2.2% vs 9.8% (RR 4.48). Cochrane rates this low-quality evidence.
• Funding: independent (Cochrane Hypertension review)

There was low-quality evidence that withdrawals due to adverse effects were increased with first-line low-dose thiazides (5.0% with control versus 11.3% with treatment; RR 2.38, 95% CI 2.06 to 2.75), high-dose thiazides (2.2% with control versus 9.8% with treatment; RR 4.48, 95% CI 3.83 to 5.24)

Chlorthalidone predictably disturbs metabolism: glucose tolerance, cholesterol and triglycerides, uric acid and gout, and blood calcium. (Source 8)

• Official position, Certainty not rated.
• Size: Not applicable.
• Who: Regulatory position, label dated 2026-06-25.
• How long: Not applicable.
• Result: No rates are given in the label for any of these. The CLICK trial independently found hyperglycaemia and hyperuricaemia more frequent on chlorthalidone than placebo.
• Funding: not stated.

Chlorthalidone may raise the serum uric acid level due to reduced clearance of uric acid and may cause or exacerbate hyperuricemia and precipitate gout in susceptible patients.

For most of the adverse reactions listed on the chlorthalidone label there is no rate at all, because the data were never collected systematically. (Source 18)

• Official position, Certainty not rated.
• Size: Not applicable.
• Who: Regulatory position, label dated 2026-06-25.
• How long: Not applicable.
• Result: No frequencies. The listed reactions include pancreatitis, cholestatic jaundice, agranulocytosis, aplastic anaemia, photosensitivity, cutaneous vasculitis and toxic epidermal necrolysis.
• Funding: not stated.

The following adverse reactions have been observed, but there is not enough systematic collection of data to support an estimate of their frequency.

What the evidence supports

Chlorthalidone-led treatment of isolated systolic hypertension in older people cut the five-year rate of stroke by about a third. (Source 19)

• Randomized trial, High certainty.
• Size: 4736 participants (2365 active treatment, 2371 placebo), drawn from 447,921 people screened.
• Who: People aged 60 and over with systolic blood pressure 160 to 219 mm Hg and diastolic under 90 mm Hg; mean age 72, 57% women, 14% Black.
• How long: Average follow-up 4.5 years.
• Result: Five-year total stroke 5.2 per 100 on active treatment vs 8.2 per 100 on placebo; relative risk 0.64 (P=.0003). Absolute difference 3.0 per 100 over five years, about 33 people treated for five years per stroke prevented. Non-fatal myocardial infarction plus coronary death RR 0.73; major cardiovascular events RR 0.68; all-cause death RR 0.87. Five-year mean systolic pressure 143 vs 155 mm Hg.
• Funding: independent (National Heart, Lung, and Blood Institute programme)

The 5-year incidence of total stroke was 5.2 per 100 participants for active treatment and 8.2 per 100 for placebo. The relative risk by proportional hazards regression analysis was 0.64 (P = .0003).

SHEP reported its benefit in absolute terms: 30 strokes and 55 major cardiovascular events prevented per 1000 people treated over five years. (Source 20)

• Randomized trial, High certainty.
• Size: 4736 participants.
• Who: People aged 60 and over with isolated systolic hypertension.
• How long: Five years.
• Result: Five-year absolute benefit 30 stroke events per 1000 participants (NNT about 33) and 55 major cardiovascular events per 1000 (NNT about 18), from a 36% relative reduction in stroke.
• Funding: independent (NHLBI programme)

antihypertensive stepped-care drug treatment with low-dose chlorthalidone as step 1 medication reduced the incidence of total stroke by 36%, with 5-year absolute benefit of 30 events per 1000 participants. Major cardiovascular events were reduced, with 5-year absolute benefit of 55 events per 1000.

In 33,357 high-risk hypertensive people, chlorthalidone matched amlodipine and lisinopril on coronary events and death, and beat both on heart failure. (Source 2)

• Randomized trial, High certainty.
• Size: 33,357 participants (chlorthalidone 15,255; amlodipine 9048; lisinopril 9054)
• Who: People aged 55 or older with hypertension and at least one other coronary risk factor, 623 North American centres.
• How long: Mean follow-up 4.9 years.
• Result: Primary outcome (fatal coronary heart disease or non-fatal myocardial infarction) six-year rate 11.5% on chlorthalidone, 11.3% amlodipine (RR 0.98, 95% CI 0.90 to 1.07), 11.4% lisinopril (RR 0.99, 0.91 to 1.08); all-cause mortality no different. Heart failure at six years 7.7% on chlorthalidone vs 10.2% amlodipine (RR 1.38, 1.25 to 1.52) and 8.7% lisinopril (RR 1.19, 1.07 to 1.31); stroke 5.6% vs 6.3% on lisinopril (RR 1.15, 1.02 to 1.30). Against amlodipine the absolute heart-failure difference is 2.5 percentage points over six years, about 40 treated with chlorthalidone instead per case avoided.
• Funding: independent (NHLBI-sponsored trial; study drugs supplied by manufacturers)

For amlodipine vs chlorthalidone, secondary outcomes were similar except for a higher 6-year rate of HF with amlodipine (10.2% vs 7.7%; RR, 1.38; 95% CI, 1.25-1.52). For lisinopril vs chlorthalidone, lisinopril had higher 6-year rates of combined CVD (33.3% vs 30.9%; RR, 1.10; 95% CI, 1.05-1.16); stroke (6.3% vs 5.6%; RR, 1.15; 95% CI, 1.02-1.30); and HF (8.7% vs 7.7%; RR, 1.19; 95% CI, 1.07-1.31)

Cochrane rates as high-quality evidence that first-line low-dose thiazide-type diuretics reduce death, stroke, coronary heart disease and total cardiovascular events against placebo. (Source 21)

• Systematic review, High certainty.
• Size: 24 trials, 28 active treatment arms, 58,040 patients across all drug classes.
• Who: Adults with moderate to severe primary hypertension; mean age 56.
• How long: Mean follow-up three to five years.
• Result: Mortality 11.0% control vs 9.8% treated (RR 0.89, 95% CI 0.82 to 0.97; ARR 1.2%, NNT about 83); total cardiovascular events 12.9% vs 9.0% (RR 0.70, 0.64 to 0.76; ARR 3.9%, NNT about 26); stroke 6.2% vs 4.2% (RR 0.68, 0.60 to 0.77; ARR 2.0%, NNT about 50); coronary heart disease 3.9% vs 2.8% (RR 0.72, 0.61 to 0.84; ARR 1.1%, NNT about 91). This is the thiazide-type class, in which chlorthalidone trials such as SHEP are a major contributor, not chlorthalidone alone.
• Funding: independent (Cochrane Hypertension review)

High-quality evidence showed that first-line low-dose thiazides reduced mortality (11.0% with control versus 9.8% with treatment; RR 0.89, 95% CI 0.82 to 0.97); total CVS (12.9% with control versus 9.0% with treatment; RR 0.70, 95% CI 0.64 to 0.76), stroke (6.2% with control versus 4.2% with treatment; RR 0.68, 95% CI 0.60 to 0.77), and coronary heart disease (3.9% with control versus 2.8% with treatment; RR 0.72, 95% CI 0.61 to 0.84)

Against calcium channel blockers, diuretics as first-line treatment probably reduce total cardiovascular events and heart failure, with no difference in death. (Source 22)

• Systematic review, Moderate certainty.
• Size: 20 trials, 26 comparator arms, over 90,000 participants randomised.
• Who: Older male and female hypertensive patients aged 50 to 75 with multiple comorbidities including type 2 diabetes.
• How long: Trials of at least one year.
• Result: Diuretic versus calcium channel blocker, with the calcium-channel-blocker figure first in each pair as the review writes it: total mortality RR 1.02 (95% CI 0.96 to 1.08, moderate certainty); total cardiovascular events 14.3% on a calcium channel blocker versus 13.3% on a diuretic (RR 0.93, 0.89 to 0.98; ARR 1.0%, moderate certainty); heart failure 4.4% versus 3.2% (RR 0.74, 0.66 to 0.82; ARR 1.2%, moderate certainty); withdrawals for adverse effects 7.6% versus 6.2% (RR 0.81, 0.75 to 0.88; ARR 1.4%, low certainty). Fewer events on the diuretic in each case. The review concludes no drug class showed any clinically important advantage over first-line thiazides. Class-level, not chlorthalidone-specific.
• Funding: independent (Cochrane Hypertension review)

Limit of this finding: In the review's own wording the first percentage of each pair is the calcium-channel-blocker group and the second is the diuretic group - the opposite of the order the sentence reads in. So heart failure '4.4% versus 3.2%' means 4.4% on a calcium channel blocker and 3.2% on a diuretic: fewer on the diuretic, not more. This passage is also only the comparison against calcium channel blockers; the same review's comparisons against beta-blockers, ACE inhibitors and alpha-blockers give different numbers and should not be read off this one.

probably reduce heart failure (4.4% versus 3.2%; RR 0.74, 95% CI 0.66 to 0.82; 6 trials, 35,217 participants; ARR 1.2%; moderate-certainty)

In advanced chronic kidney disease, chlorthalidone lowered 24-hour blood pressure and albuminuria substantially more than placebo over 12 weeks. (Source 4)

• Randomized trial, Moderate certainty.
• Size: 160 participants.
• Who: Adults with stage 4 chronic kidney disease and poorly controlled hypertension confirmed by 24-hour ambulatory monitoring; mean eGFR 23.2 mL/min/1.73 m2, 76% with diabetes, 60% on loop diuretics, mean 3.4 antihypertensives already.
• How long: 12 weeks.
• Result: Adjusted change in 24-hour systolic blood pressure -11.0 mm Hg (95% CI -13.9 to -8.1) on chlorthalidone vs -0.5 mm Hg (-3.5 to 2.5) on placebo; between-group difference -10.5 mm Hg (95% CI -14.6 to -6.4), P<0.001. Urinary albumin-to-creatinine ratio fell 50 percentage points more (95% CI 37 to 60). These are surrogate outcomes, not events.
• Funding: independent (National Heart, Lung, and Blood Institute and Indiana Institute of Medical Research)

The between-group difference was -10.5 mm Hg (95% CI, -14.6 to -6.4) (P<0.001). The percent change in the urinary albumin-to-creatinine ratio from baseline to 12 weeks was lower in the chlorthalidone group than in the placebo group by 50 percentage points (95% CI, 37 to 60).

Pooled randomised trials in people with hypercalciuria found thiazide diuretics reduced kidney stone recurrence by about a third. (Source 23)

• Meta-analysis, Low certainty.
• Size: 10 trials, 650 in the intervention group and 672 on placebo.
• Who: People with recurrent nephrolithiasis and hypercalciuria.
• How long: Varied by trial.
• Result: Recurrence RR 0.63 (95% CI 0.49 to 0.83, P=0.0007, I-squared 65%); 24-hour calciuria mean difference -40.59 (95% CI -76.39 to -4.79, I-squared 84%); no difference in 24-hour citraturia. Heterogeneity is substantial and the analysis is of the thiazide class, not chlorthalidone alone.
• Funding: not stated.

Overall, our findings favor thiazide diuretics, through recurrence rate in patients that received thiazides (RR 0.63; 95% CI 0.49, 0.83; P=0.0007; I2=65%)

Oedema in heart failure, cirrhosis and renal disease is an approved adjunctive indication, at doses up to eight times the hypertension dose. (Source 3)

• Official position, Certainty not rated.
• Size: Not applicable.
• Who: Regulatory position, label dated 2026-06-25.
• How long: Not applicable.
• Result: Label dose for oedema 50 to 100 mg daily or 100 mg on alternate days, up to a maximum of 200 mg daily, against 15 to 25 mg daily for hypertension. No outcome trial for this indication was reached in this search.
• Funding: not stated.

as adjunctive therapy in edema associated with heart failure, cirrhosis of the liver, and renal disease, including nephrotic syndrome

What the evidence does not support

Switching older patients from hydrochlorothiazide to chlorthalidone did not reduce major cardiovascular events. (Source 15)

• Randomized trial, High certainty.
• Size: 13,523 patients randomised.
• Who: Veterans aged 65 and over on hydrochlorothiazide 25 or 50 mg/d; mean age 72, mean baseline systolic 139 mm Hg; 94.5% had been on 25 mg/d.
• How long: Median 2.4 years.
• Result: Primary composite outcome 702/6756 (10.4%) on chlorthalidone vs 675 (10.0%) on hydrochlorothiazide; hazard ratio 1.04 (95% CI 0.94 to 1.16), P=0.45, with no difference in any component. Absolute difference 0.4 percentage points in the direction of harm, not statistically distinguishable from zero.
• Funding: independent (Veterans Affairs Cooperative Studies Program)

there was little difference in the occurrence of primary-outcome events between the chlorthalidone group (702 patients [10.4%]) and the hydrochlorothiazide group (675 patients [10.0%]) (hazard ratio, 1.04; 95% confidence interval, 0.94 to 1.16; P = 0.45)

A 2026 randomised trial found no detectable difference in blood pressure or laboratory results between chlorthalidone 25 mg and hydrochlorothiazide 50 mg over 12 weeks. (Source 24)

• Randomized trial, Moderate certainty.
• Size: Factorial superiority randomised trial; participant number not stated in the abstract.
• Who: Patients with hypertension.
• How long: 12 weeks.
• Result: Between-group differences (hydrochlorothiazide minus chlorthalidone) for 24-hour systolic blood pressure -1.1 mm Hg (95% CI -8.0 to 5.9, P=0.8) and night-time systolic -2.3 (95% CI -10.3 to 5.7, P=0.6). Laboratory parameters did not differ. The confidence intervals are wide, so this rules out only large differences.
• Funding: not stated.

Limit of this finding: The two doses compared were not equal - 25 mg of chlorthalidone against 50 mg of hydrochlorothiazide, a one-to-two ratio - so this says nothing about dose-for-dose equivalence. The confidence intervals are wide: the 24-hour systolic difference could be anywhere from 8.0 mm Hg lower to 5.9 mm Hg higher. That makes this an absence of any demonstrated difference rather than a demonstration that the two drugs are the same, and the trial makes no equivalence or non-inferiority claim.

Hydrochlorothiazide and chlorthalidone had similar effects on systolic and diastolic BP measured at the office and by ambulatory BP monitoring. The between-group δs (hydrochlorothiazide minus chlorthalidone) for systolic 24-hour and nighttime BP were -1.1 (95% CI, -8.0 to 5.9; P=0.8), and -2.3 (95% CI, -10.3 to 5.7; P=0.6), respectively. The effects of amiloride 5 mg and 10 mg on BP were similar. Laboratory parameters did not differ between hydrochlorothiazide and chlorthalidone.

The largest placebo-controlled trial of a thiazide for kidney stones found no benefit at any of three doses. (Source 5)

• Randomized trial, High certainty.
• Size: 416 patients randomised.
• Who: Adults with recurrent calcium-containing kidney stones.
• How long: Median 2.9 years.
• Result: Primary end-point event (symptomatic or radiologic recurrence) in 59% on placebo, 59% on hydrochlorothiazide 12.5 mg (rate ratio 1.33, 95% CI 0.92 to 1.93), 56% on 25 mg (1.24, 0.86 to 1.79) and 49% on 50 mg (0.92, 0.63 to 1.36); no dose-response (P=0.66). The drug tested was hydrochlorothiazide, not chlorthalidone.
• Funding: independent (Swiss National Science Foundation and Inselspital)

Limit of this finding: The percentages and the rate ratios in this trial measure different things, which is why they look mismatched. The percentages are the share of patients who had at least one stone event; the rate ratios count all events per unit of time, so one patient can contribute several. That is how the 12.5 mg group can have the same percentage as placebo (59% against 59%) and still show a rate ratio of 1.33. None of the three doses differed significantly from placebo, the 50 mg dose included (rate ratio 0.92, 95% CI 0.63 to 1.36) - that is not a benefit. The drug tested was hydrochlorothiazide, not chlorthalidone.

There was no relation between the hydrochlorothiazide dose and the occurrence of a primary end-point event (P = 0.66)

The FDA label for Thalitone states there are no controlled trials demonstrating risk reduction with that product itself. (Source 25)

• Official position, Certainty not rated.
• Size: Not applicable.
• Who: Regulatory position held by the FDA, label dated 2026-06-25.
• How long: Not applicable.
• Result: No effect size. The outcome trials - SHEP, ALLHAT, the Diuretic Comparison Project - used generic chlorthalidone, and the label elsewhere states Thalitone cannot be substituted for other chlorthalidone formulations.
• Funding: not stated.

These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including the class to which this drug principally belongs. There are no controlled trials demonstrating risk reduction with THALITONE.

Where the evidence is mixed

A 2026 meta-analysis found chlorthalidone lowered blood pressure more than hydrochlorothiazide but also caused more low potassium. (Source 26)

• Meta-analysis, Low certainty.
• Size: 11 studies including randomised trials, cohort studies and clinical studies, 2005 to 2025.
• Who: Adults with primary hypertension.
• How long: Varied by study.
• Result: Systolic blood pressure mean difference 5.18 mm Hg (95% CI 4.28 to 6.08) and diastolic 2.91 mm Hg (1.96 to 3.87) in favour of chlorthalidone; no difference in stroke or all-cause mortality; hypokalaemia relative risk 0.52 (95% CI 0.38 to 0.72) favouring hydrochlorothiazide. The analysis mixes randomised and observational designs, and its blood-pressure conclusion conflicts with the 2026 head-to-head randomised trial and the 13,523-person Diuretic Comparison Project.
• Funding: not stated.

Limit of this finding: This paper's results section contains a sentence that contradicts itself. It describes 'a potential significant (P = 0.052) reduction in the risk of MI (relative risk: 1.30, 95%CI: 1.00-1.70)'. A relative risk of 1.30 is a 30% higher risk, not a reduction; the interval reaches down to 1.00, meaning no difference; and P = 0.052 does not clear the usual 0.05 threshold the paper itself is applying. Nothing about heart attack risk should be taken from this paper in either direction. Its blood-pressure and potassium figures are internally consistent and its own conclusion describes the two drugs' cardiovascular safety as comparable, which is what those numbers support. Note also that it pools randomised trials with cohort and other observational studies.

A safety analysis revealed a significantly lower risk of hypokalemia associated with hydrochlorothiazide (relative risk: 0.52, 95%CI: 0.38-0.72)

Where the research disagrees

Whether chlorthalidone is better than hydrochlorothiazide

• Diuretic Comparison Project investigators, New England Journal of Medicine, 2022, pragmatic randomised trial, 13,523 patients, median 2.4 years: patients who received chlorthalidone did not have a lower occurrence of major cardiovascular outcome events or non-cancer-related deaths than patients who received hydrochlorothiazide. (Source 27)
• 2026 meta-analysis in World Journal of Cardiology, meta-analysis of 11 studies mixing randomised trials with cohort and other clinical studies: Chlorthalidone was associated with greater reductions in systolic blood pressure [mean difference: 5.18 mmHg, 95% confidence interval (CI): 4.28-6.08] and diastolic blood pressure (2.91 mmHg, 95%CI: 1.96-3.87) compared to hydrochlorothiazide. (Source 26)
• 2026 factorial randomised trial in Journal of the American Heart Association, randomised, blinded factorial trial over 12 weeks, comparing chlorthalidone 25 mg with hydrochlorothiazide 50 mg: Hydrochlorothiazide and chlorthalidone had similar effects on systolic and diastolic BP measured at the office and by ambulatory BP monitoring. (Source 24)

Whether thiazide-type diuretics prevent recurrent kidney stones

• 2025 systematic review, meta-analysis and trial sequential analysis, Minerva Urology and Nephrology, meta-analysis of 10 randomised trials in 1322 patients with hypercalciuria, I-squared 65%: Overall, our findings favor thiazide diuretics, through recurrence rate in patients that received thiazides (RR 0.63; 95% CI 0.49, 0.83; P=0.0007; I2=65%) (Source 23)
• NOSTONE investigators, New England Journal of Medicine, 2023, double-blind placebo-controlled dose-response randomised trial, 416 patients, median 2.9 years, using hydrochlorothiazide: A primary end-point event occurred in 60 of 102 patients (59%) in the placebo group, in 62 of 105 patients (59%) in the 12.5-mg hydrochlorothiazide group (rate ratio vs. placebo, 1.33; 95% confidence interval [CI], 0.92 to 1.93), in 61 of 108 patients (56%) in the 25-mg group (rate ratio, 1.24; 95% CI, 0.86 to 1.79), and in 49 of 101 patients (49%) in the 50-mg group (rate ratio, 0.92; 95% CI, 0.63 to 1.36) (Source 5)

Whether stopping blood-pressure drugs in older adults is safe

• 2026 systematic review and meta-analysis, International Journal of Cardiology Cardiovascular Risk and Prevention, meta-analysis of 4 randomised trials, 2173 participants: Deprescribing showed no significant difference versus usual care in all-cause mortality (RR 1.02, 95 % CI 0.93-1.12), cardiovascular mortality (RR 1.11, 95 % CI 0.80-1.55), or all-cause hospitalizations (RR 0.95, 95 % CI 0.85-1.05). (Source 13)
• 2026 systematic review and meta-analysis, BMC Geriatrics, meta-analysis of 17 studies, with 3 to 6 randomised trials per outcome and very few events: pooled ORs were 1.32 (95% CI 0.30-5.92) for myocardial infarction (3 RCTs), 3.16 (95% CI 1.53-6.55) for heart failure (3 RCTs) (Source 14)

How much

• Reference intake: There is no reference intake for a prescription medicine; the dose is set by the prescriber. As a position, the Thalitone label in force on 2026-06-25 gives an initial 15 mg once daily with food for hypertension, increased after 2 weeks to a single daily dose of 25 mg if additional blood pressure reduction is needed. (Source 28)
• Upper limit: As a position, the label states doses above 25 mg daily are not expected to result in increased blood pressure reduction; the label's separate edema dosing section allows up to 200 mg daily (label dated 2026-06-25). No independent upper limit is set by any scientific body. (Source 28)
• Studied: SHEP gave chlorthalidone as step 1, starting at 12.5 mg/d and increasing to 25 mg/d, with atenolol 25 to 50 mg/d as step 2, in 2365 people aged 60 and over against 2371 on matching placebo. (Source 29)
• Studied: ALLHAT randomised 15,255 people to chlorthalidone 12.5 to 25 mg/d against amlodipine 2.5 to 10 mg/d (n=9048) and lisinopril 10 to 40 mg/d (n=9054) for a planned 4 to 8 years. (Source 30)
• Studied: The Diuretic Comparison Project switched people from hydrochlorothiazide 25 or 50 mg/d to chlorthalidone 12.5 or 25 mg/d, or kept them on hydrochlorothiazide, in 13,523 veterans aged 65 and over. (Source 31)
• Studied: CLICK started chlorthalidone at 12.5 mg/d in stage 4 chronic kidney disease, increasing every 4 weeks if needed to a maximum of 50 mg/d, against placebo over 12 weeks. (Source 32)

A common belief, and what the research shows

The belief: Chlorthalidone is the proven superior thiazide, so anyone on hydrochlorothiazide should switch.

What the research shows: That was tested directly. The Diuretic Comparison Project randomised 13,523 veterans aged 65 and over, and the result was that "patients who received chlorthalidone did not have a lower occurrence of major cardiovascular outcome events or non-cancer-related deaths than patients who received hydrochlorothiazide." What did differ was harm: "The incidence of hypokalemia was higher in the chlorthalidone group than in the hydrochlorothiazide group (6.0% vs. 4.4%, P<0.001)." A 2026 randomised trial also found the two produced the same blood pressure and the same laboratory changes when dosed at a 1:2 ratio. The case for chlorthalidone rests on it having the big outcome trials, SHEP and ALLHAT, not on it beating hydrochlorothiazide head-to-head.

Questions and answers

What is it?

Chlorthalidone is a prescription water tablet - a diuretic - used mainly for high blood pressure and sometimes for fluid retention. It is called thiazide-like rather than a thiazide, because it is a different chemical that acts at the same place in the kidney, and it lasts much longer than hydrochlorothiazide. It is not a nutrient and is not found in food. (Source 3)

What does it do in the body?

It works on the distal convoluted tubule of the kidney, where it blocks sodium reabsorption so that sodium and water pass out in the urine. Losing that sodium and water is what brings blood pressure down - the label says so explicitly while noting the full mechanism is not completely clear. The same effect on the tubule drags potassium and magnesium out too, which is where most of its side effects come from. (Source 1)

Is it good or bad for you?

For high blood pressure in people at risk, it is one of the better-evidenced drugs there is. SHEP found five-year stroke rates of 5.2 per 100 on chlorthalidone-led treatment against 8.2 per 100 on placebo, a 30-per-1000 absolute benefit over five years. The bad side is consistent and measurable: more low potassium than hydrochlorothiazide (6.0% vs 4.4% in a 13,523-person trial), about a 1.8% excess risk of significantly low sodium in the first four months, raised uric acid and gout, raised blood glucose, and more than twice the rate of stopping the drug for side effects compared with placebo. (Source 15)

How do you get more of it?

You cannot get more of it outside a prescription; it is in no food or supplement. The dose is a prescriber's decision. As a position, the Thalitone label in force on 2026-06-25 starts at 15 mg once daily with food for blood pressure, rising to 25 mg after two weeks if needed, and says doses above 25 mg are not expected to lower blood pressure any further. The outcome trials used generic chlorthalidone at 12.5 to 25 mg daily. (Source 28)

If it is harmful, what reduces it?

The drug clears on its own, though slowly - its long action is the point of it. When it is causing harm, the label's answer is to stop it: low potassium with muscle weakness, paresis or ECG changes is an explicit reason to discontinue, and so is a meaningful fall in kidney function. On deliberately stopping it in older people, a meta-analysis of four randomised trials in 2173 people found no increase in death, hospitalisation or falls, though a second meta-analysis found a heart-failure signal, so it is not a decision to make alone. (Source 13)

Why might someone be low in it or missing it?

Nobody is naturally low in chlorthalidone. The nearest equivalent is being on a smaller dose or none, and the label's reasons are the people most likely to come to harm: those with impaired sympathetic responses, volume depletion or salt restriction are at higher risk of symptomatic low blood pressure, and those with chronic kidney disease, heart failure or volume depletion are at particular risk of acute kidney injury. Low potassium and low magnesium are meant to be corrected before a thiazide is started at all. (Source 7)

Which whole foods contain it or feed it?

No whole food contains chlorthalidone. Food still matters in three documented ways. The tablet is taken with food. Salt and water intake change what the drug does - poor electrolyte intake adds to potassium loss, and dilutional low sodium can happen in hot weather, where the answer is restricting water rather than adding salt. And licorice, as root tea or confectionery, works against it: its metabolite blocks a kidney enzyme and pushes potassium down and blood pressure up. (Source 9)

What happens if you do not have it?

If high blood pressure goes untreated, the events the drug prevents happen more often. In SHEP's placebo group 8.2 per 100 older people with isolated systolic hypertension had a stroke within five years, against 5.2 per 100 on chlorthalidone-led treatment. Cochrane's pooled figures for low-dose thiazide-type diuretics against placebo are mortality 11.0% untreated versus 9.8% treated and stroke 6.2% versus 4.2%. What you also avoid without it is its harms - the low potassium, low sodium and gout. (Source 21)

How can you test for it?

There is no routine test for the drug itself; what gets tested is what it disturbs and what it is meant to fix. Blood pressure is the target - CLICK used 24-hour ambulatory monitoring rather than clinic readings, which is the more reliable method. Serum electrolytes are the safety test and the label says to check them periodically, along with kidney function. These blood tests are well standardised and reliable; what is less reliable is a single clinic blood-pressure reading, which is why ambulatory monitoring was used in the trials. (Source 7)

References

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2. JAMA. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).. 2002. PMID 12479763, DOI 10.1001/jama.288.23.2981. Read the source
3. DailyMed / Casper Pharma LLC (FDA label). THALITONE (chlorthalidone) tablets, for oral use - Highlights of Prescribing Information, INDICATIONS AND USAGE. 2026. Read the source
4. The New England journal of medicine. Chlorthalidone for Hypertension in Advanced Chronic Kidney Disease.. 2021. PMID 34739197, DOI 10.1056/nejmoa2110730. Read the source
5. The New England journal of medicine. Hydrochlorothiazide and Prevention of Kidney-Stone Recurrence.. 2023. PMID 36856614, DOI 10.1056/nejmoa2209275. Read the source
6. DailyMed / Casper Pharma LLC (FDA label). THALITONE (chlorthalidone) tablets, for oral use - Full Prescribing Information, section 7 DRUG INTERACTIONS. 2026. Read the source
7. DailyMed / Casper Pharma LLC (FDA label). THALITONE (chlorthalidone) tablets, for oral use - full prescribing information. 2026. Read the source
8. DailyMed / Casper Pharma LLC (FDA label). THALITONE (chlorthalidone) tablets, for oral use - full prescribing information. 2026. Read the source
9. DailyMed / Mylan Pharmaceuticals Inc (FDA label). CHLORTHALIDONE tablet - full prescribing information. 2026. Read the source
10. BMJ case reports. Liquorice-induced pseudohyperaldosteronism: a rare cause for severe hypertension.. 2025. PMID 39753286, DOI 10.1136/bcr-2024-263140. Read the source
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22. The Cochrane database of systematic reviews. First-line diuretics versus other classes of antihypertensive drugs for hypertension.. 2023. PMID 37439548, DOI 10.1002/14651858.cd008161.pub3. Read the source
23. Minerva urology and nephrology. Thiazide diuretics for preventing calcium oxalate recurrent kidney stones: an updated systematic review, meta-analysis and trial sequential analysis of randomized controlled trials.. 2025. PMID 40528770, DOI 10.23736/s2724-6051.25.05903-8. Read the source
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28. DailyMed / Casper Pharma LLC (FDA label). THALITONE (chlorthalidone) tablets, for oral use - Full Prescribing Information, section 2.2 Hypertension (dosage and administration). 2026. Read the source
29. JAMA. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP). SHEP Cooperative Research Group.. 1991. PMID 2046107, DOI 10.1001/jama.265.24.3255. Read the source
30. JAMA. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). [structured-abstract section 'Interventions']. 2002. PMID 12479763, DOI 10.1001/jama.288.23.2981. Read the source
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32. The New England journal of medicine. Chlorthalidone for Hypertension in Advanced Chronic Kidney Disease.. 2021. PMID 34739197, DOI 10.1056/nejmoa2110730. Read the source