Are all thiazides created equal?

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At the Brigham Renal Board Review course (review of board prep options) a few weeks ago, Dr Burton Rose argued that for all of us who use thiazide diuretics (review of thiazides) to treat mild hypertension, chlorthalidone should be used instead of hydrochlorothiazide. I tend to like HCTZ as a blood pressure agent because of its cost and availability in combination pills, so I decided to look into the evidence for one thiazide over the other in order to make an informed choice. Here are the arguments for each:
Chlorthalidone, tested and true: chlorthalidone has been the thiazide used in many clinical trials, most notably ALLHAT, showing morbidity and mortality benefit from blood pressure control. HCTZ has a much shorter track record. Chlorthalidone also has a much longer half-life (45-50 hours, compared to 8-15 hours for HCTZ), so putatively it should provide a more sustained effect.

HCTZ, does the job and my drugstore stocks it: HCTZ has been shown in clinical trials to be effective in reducing blood pressure, and remains the most readily available thiazide in pharmacies. It exists in many combination pills, which are also extremely affordable. There is a small amount of data suggesting that HCTZ causes less hypokalemia than chlorthalidone, but results are mixed.

How did they match up head to head? Naturally, the definitive study is still waiting for an enterprising renal fellow to come along and take charge. There have been two studies that indicate chlorthalidone might be the more efficacious agent.

  1. As part of the MRFIT (Multiple Risk Factor Intervention Trial) trial, first published in the 1980s, physicians were initially given the option of HCTZ or chlorthalidone as the step 1 diuretic in the treatment group. After five years of the study, however, the protocol was changed to recommend only chlorthalidone, given a significant mortality benefit compared to participants on HCTZ.
  2. The only trial comparing the two drugs head to head, with the primary purpose of assessing blood pressure reduction, was published in 2006 by Ernst et al. The trial was a single-blinded crossover study assessing the antihypertensive effects of HCTZ 25 mg daily (force-titrated to 50 mg/d) versus chlorthalidone 12.5 mg/d (force-titrated to 25 mg/d). After eight weeks, the chlorthalidone group showed a significantly greater reduction in 24h ambulatory blood pressure compared to HCTZ, with most of the difference occurring in nighttime BP measurements. Interestingly, a significant order-drug-time interaction was found, so the second half of the crossover study was not analyzed. Hypokalemia rates were similar in the two groups.

In my mind, it seems reasonable to choose chlorthalidone over HCTZ in patients for whom adding a thiazide to their antihypertensive regimen is appropriate. For those who are stable on HCTZ, the hassle of rechecking potassium levels after switching agents may not be worth the potential benefits. For those patients who require more than one BP agent (most of our patients), and especially ACE inhibition, the HCTZ-lisinopril combo is an attractive and inexpensive option that is hard to beat.

Nate discussed thiazide side effects, including hyperglycemia on a prior post. Conall discusses hyponatremia as a side effect.


  1. Any studies that look at changes in hemodynamic parameters with thiazides versus chlorthalidone? thanks

  2. You are right– ALLHAT was designed to evaluate the effects of several antihypertensive medications. A more correct sentence would have been "chlorthalidone has been the thiazide used in many trials, most notably ALLHAT, where blood pressure control with thiazides showed similar morbidity and mortality benefits as with other antihypertensives". The main point was to emphasize that chlorthalidone was the thiazide used in that trial.

  3. I think you are misrepresenting the aim and results of the ALLHAT trial. You write:

    ALLHAT, showing morbidity and mortality benefit from blood pressure control

    The primary endpoint showed no difference in the effectiveness of chlorthalidone, lisinopril and amlodipine. From the abstract:

    Mean follow-up was 4.9 years. The primary outcome occurred in 2956 participants, with no difference between treatments… Likewise, all-cause mortality did not differ between groups

  4. Check this out!

    Meta-analysis of dose-response characteristics of hydrochlorothiazide and chlorthalidone: effects on systolic blood pressure and potassium.

    They agree with you Lisa :-). Keep up the good work.

  5. Oops, I screwed up! Second chlorthalidone should be HCTZ. Will edit the post.

  6. "After eight weeks, the chlorthalidone group showed a significantly greater reduction in 24h ambulatory blood pressure compared to chlorthalidone…"

    Is the second "chlorthalidone" in that sentence supposed to be "hctz"? (or is the first one supposed to be hctz?) I'm easily confused!!

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