Which Diuretic is Best for Hypertension? HCTZ or Chlorthalidone?

When a patient is diagnosed with high blood pressure that is not controlled by diet, exercise or other lifestyle interventions, doctors start writing prescriptions. One of their first-line drugs is almost always hydrochlorothiazide (HCT or HCTZ). About 9 million people take it daily for hypertension. But wait, there’s more! HCTZ is often combined with other blood pressure pills such as lisinopril, losartan, triamterene and valsartan. That adds up to over 15 million people taking hydrochlorothiazide. Doctors prescribe a different diuretic, chlorthalidone (CTD), to only about 1.5 million people. When it comes to HCTZ or chlorthalidone, are prescribers making a mistake?

The Chlorthalidone Challenge

Before we try to answer the question, which is best: HCTZ or chlorthalidone, we have some sad news. The FDA recently initiated a recall for over 11,400 bottles of the 25 mg pills. That may not sound like a lot, but many of these bottles contained 100 or 1,000 pills.

Pharmacies purchase big bottles of a generic medication and then transfer them to small bottles containing a month’s worth (30 pills) or three months’ worth (90 pills). The chlorthalidone pills in question apparently fail to dissolve as they are supposed to.

How would you know if your pills were recalled? That, dear reader, is a great question. We have addressed the problem of pharmacy recalls at this link.

The manufacturer is Mumbai-based Inventia Healthcare Limited. The distributor was a New Jersey-based company called Rising Pharma Holdings.

How Can You Tell If Your Drug is Recalled?

That was the title of an article I wrote on October 29, 2019. What I discovered was shocking. It all started when a reader complained that he could not find “lot numbers on prescription drug labels.”

When a bottle from a brand name drug manufacturer is distributed, the pharmaceutical company must print the lot numbers on all brand name and generic medications that they ship to drug stores. But when a pharmacist buys a big bottle of generic pills, say 1000 pills of chlorthalidone, then puts 30 pills into a small amber bottle for a customer, the lot number could be lost during the repackaging process.

Another reader recently looked on his bottle of chlorthalidone pills. They have a bar code, but NO lot number. You can read about this dilemma at this link.

The chlorthalidone batch and NDC numbers are:

100 tablet bottle: RISA24001          NDC (National Drug Code): 64980-599-01

1000 tablet bottle: RISB24002       NDC: 64980-599-10

Good luck finding any of those numbers on your bottle of pills, though. Do not assume a pharmacy or generic manufacturer will contact you if there has been a recall. Scandalous? I think so! That is what I wrote about in this article six years ago. You could call your pharmacy and ask if your pills have been recalled. Please let us know what the pharmacy tells you.

The Diuretic Comparison Project (DCP): HCTZ or Chlorthalidone (CTD)?

Some very smart researchers set up the Diuretic Comparison Project (DCP) and started recruiting patients in 2016. Over 70 VA healthcare centers were involved in this study to compare the diuretics chlorthalidone (CTD) vs. hydrochlorothiazide (HCTZ).

The question that was asked in the study (JAMA Network Open, May, 2024):

“Is there a difference in major adverse cardiovascular events (MACEs) and noncancer deaths associated with chlorthalidone (CTD) vs hydrochlorothiazide (HCTZ) among older patients with hypertension with and without prior myocardial infarction (MI) or stroke?”

Rarely are such questions asked and rarely are such large studies undertaken. There were 13,523 participants. We only wish this sort of head-to-head comparison was done more often.

Which drug performed better? HCTZ or chlorthalidone (CTD)?

For the volunteers who had a prior heart attack or stroke, the comparison of HCTZ or chlorthalidone resulted in a winner:

“The findings suggest that CTD may be associated with reduced MACEs and noncancer deaths in patients with prior MI [heart attack] or stroke compared with HCTZ. Accounting for this subgroup knowledge when treating patients, CTD may benefit those with prior MI or stroke.”

Those who did not have a prior heart attack or stroke did not experience any difference.

One downside of chlorthalidone: it produced a lower potassium level compared to HCTZ.

Why Would CTD Be Better than HCTZ in High-Risk Patients?

The authors offer this explanation:

“Thiazide diuretics are commonly used to treat hypertension, as they both lower blood pressure (BP) and prevent cardiovascular (CV) events. Currently, they are recommended as first-line agents. There are mechanistic reasons that suggest chlorthalidone (CTD) may be superior to hydrochlorothiazide (HCTZ) for preventing CV [cardiovascular] outcomes. Chlorthalidone has a longer half-life and has been shown to be more effective in reducing 24-hour BP compared with HCTZ. Chlorthalidone also has other pleotropic effects, such as decreased platelet aggregation and vascular permeability mediated through inhibition of carbonic anhydrase.”

That was complicated. The bottom line appears to be that chlorthalidone lasts longer in the body, produces a more robust BP-lowering effect, helps reduce blood platelet stickiness that could lead to a blood clot that could trigger a heart attack.

Not the First Time Investigators asked: HCTZ or Chlorthalidone (CTD)?

In 2011, research into the effectiveness of CTD vs HCTZ was published in the journal Hypertension. It was part of the MRFIT (Multiple Risk Factor Intervention Trial) study.

The authors concluded:

“Our study demonstrates that both HCTZ and CTD reduce CVEs [cardiovascular events] compared with neither drug. When comparing both drugs, CTD reduces CVEs more than HCTZ, suggesting that CTD may be the preferred thiazide-type diuretic for hypertension in patients at high risk of cardiovascular events.”

The biggest downside with CTD appears to be low potassium levels. Anyone on a diuretic such as HCTZ or chlorthalidone should have blood potassium levels checked on a regular basis.