Thiazide Diuretics: Independent Evidence on Safety & Funding

Table of contents

• Evidence summary
• What thiazide diuretics are
• How they work
• What they are prescribed for
• What works and what does not
• Benefits by claim
• Risks and all side effects
• All interactions
• Who should avoid thiazide diuretics
• Dosage and how to take them
• Follow the money: who makes them and who funded the evidence
• Related research
• Frequently asked questions
• Sources and funding notes

Evidence summary

Independent evidence and credibility scorecard

Independence tiers: 1 = regulator, government body or government-funded trial; 2 = academic or Cochrane team with no declared commercial funding for the work; 3 = independent authors analysing mostly manufacturer trials, or text written by a manufacturer and approved by a regulator; 4 = manufacturer-funded or manufacturer-supported. Credibility runs from A (highest) to D. Most sources come from North America and the UK, so the verdict reflects those health systems.

What thiazide diuretics are

Thiazide diuretics are "water tablets" that make the kidneys pass more salt and water. Two groups are used for blood pressure. Classic thiazides include hydrochlorothiazide and bendroflumethiazide. Thiazide-like drugs have a different chemical structure but the same main action, and include indapamide and chlortalidone (spelt chlorthalidone in the US). In the UK, bendroflumethiazide is the long-standing favourite; in the US, hydrochlorothiazide and chlortalidone dominate.

The drugs are old, off-patent and sold as cheap generics. In the UK, hydrochlorothiazide on its own is not sold for blood pressure. It is only available inside combination tablets, taken by an estimated 28,000 patients when the MHRA reviewed it in 2018 (MHRA). Indapamide is sold in plain and prolonged-release forms; the prolonged-release 1.5 mg tablet is licensed for essential hypertension in adults (UK SmPC).

Which one is preferred depends on where you live. The 2011 NICE hypertension guideline recommended thiazide-like drugs such as indapamide over thiazides such as bendroflumethiazide, yet bendroflumethiazide was still prescribed to 78% of patients taking either drug in a Scottish pilot, and the authors describe the supporting evidence as sparse (Flynn et al., Pilot Feasibility Stud 2022). The current guideline is NICE NG136, which secondary summaries say keeps that preference once a diuretic is needed. We could not open it, so please check it directly.

How they work

Thiazides block a salt-and-chloride transporter in part of the kidney tube, so more sodium and water leave in the urine. Blood volume falls first. Over weeks, blood vessels relax and blood pressure stays lower even after the extra urine settles. That second effect, and why thiazide-like drugs may last longer, is proposed rather than proven in every detail, and we have not cited a source for the mechanism because the sources we opened concentrate on outcomes. What is proven in people is the result: lower blood pressure and fewer events in trials.

The same kidney action explains most side effects. Less sodium and potassium in the blood, more uric acid retained, and more water lost when someone is already dehydrated.

What they are prescribed for

• High blood pressure. Usually by itself in older people or as part of a combination. The US label lists hypertension "alone or to enhance other antihypertensives" (US label).
• Fluid build-up (oedema) from heart failure, liver cirrhosis, kidney disease, or from corticosteroid or oestrogen treatment (US label). The NHS lists bendroflumethiazide for high blood pressure and oedema (NHS).

Indapamide's UK licence is for essential hypertension only (UK SmPC).

What works and what does not

Benefits by claim

Do thiazides prevent heart attacks and strokes?

Yes, and ALLHAT is the key independent test. The whole trial enrolled more than 42,000 people aged 55 or over with high blood pressure and another risk factor; the JAMA 2002 paper compares chlortalidone with amlodipine or lisinopril in 33,357 of them (doxazosin was a separate arm). For the main outcome (fatal heart disease or non-fatal heart attack) neither amlodipine nor lisinopril beat chlortalidone. Amlodipine caused more heart failure (10.2% vs 7.7%), and lisinopril was linked to more combined cardiovascular disease (33.3% vs 30.9%), stroke (6.3% vs 5.6%) and heart failure (8.7% vs 7.7%) (ALLHAT). The doxazosin arm was stopped a year early because of more heart failure (NHLBI). In plain terms, no newer drug did better, and the old diuretic did slightly better on heart failure.

The 2023 Cochrane review, covering 20 active-comparator trials, reached a similar view. Against ACE inhibitors, total cardiovascular events were similar (RR 0.97, 0.92 to 1.02) and stroke was slightly lower with diuretics (RR 0.89, 0.80 to 0.99). Against calcium channel blockers, heart failure was lower (RR 0.74, 0.66 to 0.82). Against alpha-blockers, total events were much lower (RR 0.74, 0.69 to 0.80). The authors found no other class with a clinically important advantage (Cochrane).

Does it work in people aged 80 and over?

HYVET randomised 3,845 people aged 80 or older with systolic pressure of 160 mmHg or more to sustained-release indapamide 1.5 mg or placebo, with perindopril added if needed. After a median 1.8 years, blood pressure was 15.0/6.1 mmHg lower. All-cause death fell 21% (95% CI 4% to 35%), heart failure fell 64%, and serious adverse events were fewer (358 vs 448). The headline stroke reduction of 30% had a confidence interval that crossed zero (−1% to 51%) (HYVET). This was co-funded by the maker of both drugs (report), and the result is for indapamide specifically.

Is chlortalidone better than hydrochlorothiazide?

The case for chlortalidone came from lower blood pressure in some trials and its role in ALLHAT. The Diuretic Comparison Project tested it directly. Veterans already on hydrochlorothiazide were randomised to switch to chlortalidone or carry on. Major cardiovascular events were 10.4% vs 10.0% (HR 1.04, 95% CI 0.94 to 1.16), and hypokalaemia was more common with chlortalidone (6.0% vs 4.4%). In people with a prior heart attack or stroke the HR was 0.73 (0.57 to 0.94), which the authors called hypothesis-generating (ACC). A 2024 systematic review of six observational studies (368,066 patients) found no significant difference in heart events and about double the odds of low potassium with chlortalidone (OR 2.10, 1.15 to 3.84) (Song et al. 2024).

Do thiazide-like drugs lower blood pressure more?

A 2017 meta-analysis of 12 trials found a further 5.6 mmHg systolic reduction with indapamide or chlortalidone than with hydrochlorothiazide, and no clear difference in low potassium or sodium (Liang et al.). Lower pressure does not guarantee fewer events, which is why the outcome trials above matter more. A UK trial comparing indapamide with bendroflumethiazide in routine care is under way (EVIDENCE).

Risks and all side effects

Gout

Thiazides reduce the kidney's removal of uric acid. In UK primary care data, current diuretic use carried a relative risk of 2.36 (95% CI 2.21 to 2.52) for new gout, the highest of the classes studied, while calcium channel blockers (0.87) and losartan (0.81) were lower. That is a class-wide figure, and the design cannot prove cause (Choi et al.). The NHS asks people with gout to tell their doctor before starting bendroflumethiazide (NHS).

Diabetes and blood sugar

US labels say hyperglycaemia may unmask latent diabetes and antidiabetic doses may need adjusting (US label). A 2017 network meta-analysis of 23 trials (224,832 patients) found diuretics did not help prevent new-onset diabetes. We could not retrieve its numerical estimates, so we do not quote them (Yang and Xu). The UK SmPC advises blood glucose monitoring, especially with low potassium (SmPC).

Skin cancer and sun sensitivity

This applies mainly to hydrochlorothiazide. In 2018 the EU safety committee (PRAC) recommended updating product information for all hydrochlorothiazide medicines after Danish studies. For 50,000 mg or more cumulative use, basal cell carcinoma risk may be about 1.3 times higher and squamous cell carcinoma about 4 times higher; 50,000 mg is roughly 12.5 mg daily for 11 years (AEMPS, Spain). The MHRA reported that the Danish studies found no similar association with bendroflumethiazide, furosemide, calcium channel blockers, ACE inhibitors or ARBs, and gave a squamous cell odds ratio of 7.38 at the highest cumulative use (MHRA; Pedersen et al., JAAD 2018). The FDA added non-melanoma skin cancer to hydrochlorothiazide labels on 20 August 2020 after a Sentinel comparison with ACE inhibitors, with the excess mainly squamous cell cancer in White patients taking large cumulative doses (FDA via Sentinel).

A 2024 meta-analysis of 42 articles found thiazides linked to squamous cell carcinoma (RR 1.36, 95% CI 1.15 to 1.61) but rated the evidence low or very low quality (Cohen et al., JID Innov 2024). A 2022 meta-analysis found hydrochlorothiazide with OR 1.16 (1.08 to 1.24) for non-melanoma skin cancer and no meaningful increase for bendroflumethiazide or indapamide (Shao et al.). After the warning, Danish hydrochlorothiazide use fell by 44% with no sign of increased harm (Pottégard et al. 2021).

Photosensitivity is a separate, rarer reaction. The indapamide SmPC lists it as "not known" frequency and says to stop treatment if it happens and protect exposed skin if the drug is restarted (SmPC). Our skin-cancer pages cover sunscreen and squamous cell carcinoma.

Other side effects

• Common (NHS, bendroflumethiazide): passing urine more often, thirst and dry mouth, nausea, vomiting, diarrhoea, loss of appetite, constipation, and dizziness from low blood pressure (NHS).
• Indapamide (SmPC): common low potassium and rash; uncommon low sodium, vomiting, purpura and erectile dysfunction; "not known" torsade de pointes, QT prolongation, hepatitis and hepatic encephalopathy (SmPC).
• Hydrochlorothiazide (US label): orthostatic hypotension, pancreatitis, jaundice, aplastic anaemia, thrombocytopenia, interstitial nephritis, hair loss, tingling and vertigo (US label).
• Doping: indapamide can give a positive doping test (SmPC).

Sick-day rules

Diuretics can cause or worsen dehydration in an unwell patient, and NHS Scotland's sick-day guidance names diuretics, including furosemide and bendroflumethiazide, as medicines that can cause or worsen dehydration in an ill patient (NHS Scotland). Typical triggers are vomiting, diarrhoea, fever or sweats. The ones to check with a pharmacist or doctor are diuretics, ACE inhibitors, ARBs, NSAIDs and metformin. We have not found an authoritative page we could open that gives a single national restart rule, so ask your own prescriber.

All interactions

• Lithium: "not recommended" with indapamide, and generally to be avoided with hydrochlorothiazide, because lithium can reach toxic levels (SmPC; US label). See our lithium page.
• NSAIDs and high-dose salicylates: can blunt the blood pressure effect and raise the risk of acute kidney injury in dehydrated people (SmPC).
• QT-prolonging drugs (some antiarrhythmics, some antipsychotics) and digitalis medicines: low potassium raises the risk of dangerous rhythms (SmPC).
• ACE inhibitors: sudden low blood pressure or kidney failure can occur if sodium is depleted (SmPC). See ramipril and losartan.
• Metformin: lactic acidosis risk rises if the diuretic impairs the kidneys (SmPC).
• Other listed: potassium-sparing diuretics, allopurinol, iodinated contrast media, ciclosporin or tacrolimus, corticosteroids and calcium salts (SmPC).
• US label also lists: antidiabetic medicines (dose changes may be needed), alcohol, barbiturates and narcotics (worse standing-up dizziness), cholestyramine and colestipol (less absorption), and corticosteroids (more potassium loss) (US label).

Supplement and herbal interactions were not covered in the sources we could open; see our page on supplements and heart-medicine interactions.

Who should avoid thiazide diuretics

• Anuria or allergy to sulfonamide-derived drugs (hydrochlorothiazide) (US label).
• Indapamide: contraindicated with severe kidney failure (creatinine clearance below 30 ml/min), hepatic encephalopathy or severe liver impairment, existing low potassium, or sulfonamide hypersensitivity (SmPC).
• Take care and tell your doctor first if you have Addison's disease, kidney or liver problems, diabetes, gout, lupus, abnormal sodium, potassium, magnesium, calcium or uric acid levels, or are being sick or have diarrhoea (NHS). The US label also warns of possible activation of systemic lupus.
• Pregnancy: the US label says routine diuretic use in a normal pregnancy is inappropriate and use should be only if clearly needed; thiazides cross the placenta, with risks including newborn jaundice and low platelets (US label). The UK indapamide SmPC advises avoiding it in pregnancy as a precaution (SmPC).
• Breastfeeding: indapamide should not be used (SmPC); hydrochlorothiazide passes into milk (US label).
• Older adults, women of low weight, people on several drugs: higher risk of low sodium and potassium; the SmPC asks for closer monitoring (SmPC).
• Prior skin cancer: regulators advise reconsidering hydrochlorothiazide (MHRA). That is a decision for the prescriber.

Dosage and how to take them

The figures below are label or trial doses, not personal advice.

• Indapamide prolonged-release (UK SmPC): one 1.5 mg tablet every 24 hours, preferably in the morning, swallowed whole. Electrolyte changes become more marked above that dose (SmPC). HYVET used the same 1.5 mg sustained-release form.
• Bendroflumethiazide (NHS): 2.5 mg once a day for blood pressure; 5 mg to 10 mg a day for oedema; lower doses may apply over 65 or with kidney problems; usually in the morning (NHS).
• Hydrochlorothiazide (US label): hypertension, 25 mg once daily, which may go up to 50 mg; the label says doses above 50 mg are often linked to marked drops in potassium. Oedema, 25 to 100 mg daily (US label). In the UK the MHRA said 25 mg products should be used for hypertension only if lower-dose products do not control pressure (MHRA).
• Chlortalidone (trial conversion): in the Diuretic Comparison Project, hydrochlorothiazide 25 mg was switched to chlortalidone 12.5 mg, and 50 mg to 25 mg (ACC). We did not open a chlortalidone label, so we give no label dose.

Missed dose (NHS): take it when you remember, unless it is late afternoon and you normally take it in the morning, and never double up (NHS). Product quality issues were not identified in the sources we opened.

Follow the money: who makes them and who funded the evidence

Who makes and sells them

Almost everything in this class is a generic. Hydrochlorothiazide, bendroflumethiazide and chlortalidone are old compounds sold by many makers. The indapamide label we opened belongs to Krka, a Slovenian generic company (UK SmPC). Natrilix SR (branded indapamide) and perindopril (Coversyl) are Servier products, as listed in search results from Irish and UK medicine databases and in Servier's portfolio on Wikipedia; we did not open those listings. Servier is a French company described as governed by a non-profit foundation and headquartered in Suresnes (Wikipedia, low-reliability source; we could not open Servier's own site to confirm).

Price shapes behaviour. A UK trial protocol excluded chlortalidone from its design because it cost about £88 a month and was rarely used in the UK (EVIDENCE protocol).

Who funded the trials

The most useful studies had no commercial sponsor: ALLHAT (NHLBI), the Diuretic Comparison Project (US Veterans Affairs), the Cochrane review (University of British Columbia and the BC Ministry of Health), Ontario's Dhalla study (provincial health ministry and CIHR), and the Scottish pilot (Chief Scientist Office, Scotland) (Flynn et al.). The exception is HYVET, co-funded by the British Heart Foundation and Servier's research institute (report). Because HYVET is the only large placebo-controlled trial of treating the very old with a diuretic-based regimen, its maker support cannot be avoided, only labelled.

Documented integrity events

• Perindopril generics (2014). The European Commission fined Servier €331 million, and five generic makers €96.7 million in total, for patent settlements and a technology purchase that delayed generic perindopril entry by about four more years (GaBI). This concerns a different drug from the diuretics here, and we did not check the appeal outcome.
• Mediator (benfluorex) (2021). A Paris court found Servier guilty of manslaughter, involuntary wounding and aggravated deception, acquitted it of fraud, and fined it €2.7 million, with damages to more than 6,500 plaintiffs. The French medicines agency was also convicted (Associated Press). Mediator is not a diuretic, and we did not verify any appeal (Wikipedia summary; we have not verified the appeal outcome).
• Regulator action on hydrochlorothiazide (2018 to 2020). Not an integrity event for the makers, but a safety finding by the PRAC, MHRA, AEMPS and FDA that led to label changes (MHRA).

Whether any individual in these trials holds personal ties to makers was not something we could check from the abstracts we opened, so we state none.

Related research

• Hypertension: accurate measurement, treatment, safety and evidence funding
• Blood pressure medicines: types, monitoring, side effects and safety
• Resistant hypertension
• Furosemide: uses, monitoring and safety
• Amlodipine
• Ramipril
• Losartan
• Chronic kidney disease and the heart
• Heart disease in older adults
• Lithium
• Sunscreen and skin cancer
• Supplements and heart medicines: interactions

Frequently asked questions

Sources and funding notes

What we could not verify. NICE NG136 would not open for our research tools, so the current wording of its diuretic recommendation is unchecked. We read the Diuretic Comparison Project through the American College of Cardiology's summary, not the NEJM paper. Secondary reports say drug companies supplied study medication in ALLHAT, but the NHLBI page does not mention it and we did not open the JAMA acknowledgements. We could not retrieve numerical diabetes estimates, a funding statement for Pedersen et al. 2018 or Shao et al. 2022, the FDA's own excess-risk figures, an authoritative restart rule for sick-day guidance, a chlortalidone label, or Servier's own ownership statement. Prescribing volumes for England were not retrieved. The Servier appeals were not checked. We could not open the full Cochrane review, so its funding statement (University of British Columbia, BC Ministry of Health, and one Thermo Fisher employee author) is reported from our research notes and not independently confirmed here. Most pages are abstracts and summaries, not full papers.

1. ALLHAT Officers and Coordinators, JAMA 2002 (PMID 12479763) — primary trial; US NHLBI grant N01-HC-35130.
2. NHLBI ALLHAT summary — US government institute; funder of the trial.
3. Reinhart et al., Cochrane 2023 (PMID 37439548) — systematic review; University of British Columbia, BC Ministry of Health; one author employed by Thermo Fisher Scientific.
4. Beckett et al., HYVET, NEJM 2008 (PMID 18378519) — trial; British Heart Foundation and Servier institute.
5. Healthcare in Europe news report, 31 Aug 2007 — source for the HYVET funding statement; trade news site.
6. American College of Cardiology, Diuretic Comparison Project — summary of Ishani et al., NEJM 2022; trial sponsor VA Cooperative Studies Program; the ACC is a US professional society.
7. Dhalla et al., Ann Intern Med 2013 (PMID 23552325); Song et al. 2024 (PMID 39484134) — observational cohort and systematic review; Ontario ministry/CIHR; Song et al. funding not in record.
8. Liang et al., J Cell Mol Med 2017 (PMID 28631393) — meta-analysis; National Natural Science Foundation of China.
9. Barber et al., Br J Clin Pharmacol 2015 (PMID 25139696) — systematic review; Medical Research Council, Academy of Medical Sciences.
10. Choi et al., BMJ 2012 (PMID 22240117) — case-control; NIAMS (US).
11. Yang and Xu, J Cell Mol Med 2017 (PMID 28230330) — network meta-analysis; funding not in record.
12. Shao et al., BMC Med 2022 (PMID 35794547); Cohen et al., JID Innov 2024 (PMID 38736521); Pottégard et al. 2021 (PMID 34435407) — skin-cancer meta-analyses and use study; Cohen et al.: NIH, NCI, Wellcome Trust and others; Shao and Pottégard: no funding in record.
13. Pedersen et al., J Am Acad Dermatol 2018 (PMID 29217346) — Danish case-control; funding not retrieved.
14. MHRA Drug Safety Update, 14 November 2018 — UK regulator; government funded.
15. AEMPS (Spain) safety note 13/2018 — national regulator summarising the EU PRAC review; government funded.
16. FDA Sentinel labelling-change record, 20 August 2020 — US regulator; government funded with user fees for drug review.
17. Hydrochlorothiazide tablet label (A-S Medication Solutions repackage, DailyMed) — regulator-approved label; generic maker text.
18. Indapamide Krka 1.5 mg prolonged-release tablets SmPC (updated 31 January 2023) — regulator-approved; written by the generic licence holder Krka (Slovenia).
19. NHS: bendroflumethiazide (with side effects, who can take it and how to take it) — patient information; funded by UK government via NHS England.
20. NHS Scotland, Sick Day Rules — Effective Prescribing and Therapeutics; NHS Scotland, government funded.
21. Flynn et al., Pilot Feasibility Stud 2022 (EVIDENCE feasibility) — Catalyst Grant from the Chief Scientist Office, Scotland; and HRA summary of EVIDENCE, sponsored by the University of Dundee; funder not named.
22. NICE NG136 — UK guideline body; government funded; page could not be opened by our tools.
23. GaBI Online, EC perindopril decision — trade publication summarising the European Commission decision of 9 July 2014; publisher is a generics-industry news site.
24. Associated Press via News4Jax, 29 March 2021 — newswire report of the Mediator verdict.
25. Wikipedia: Servier — crowd-edited; used only for ownership, headquarters and appeal context; low reliability.

Educational research reviewed 6 October 2026. This article is not medical advice; talk to a qualified clinician or pharmacist before starting, stopping or combining treatments.