HCTZ is a thiazide class anti-hypertensive medication. It works in the kidney at the distal convoluted tubule by reducing sodium (Na+) reabsorption. Since it decreases the reabsorption of Na+ you eliminate more of it in the urine. Water follows sodium in the body so HCTZ decreases intravascular volume by increasing urine production.
HCTZ for Hypertension
The Joint National Committee on Hypertension, 7th Edition (JNC 7) recommended a thiazide diuretic as first-line management for hypertension requiring medications.2 This report was published in 2003 and has since been updated. JNC 8 still recommends HCTZ as an option for first-line therapy.
HCTZ has been available for more than half a century. It is the most common blood pressure medication prescription in the entire world. In 2007, over 130 million prescriptions were written for HCTZ in the U.S. alone.29
The JNC 7 recommendation to use a thiazide diuretic as first-line medication therapy was based on studies like the ALLHAT trial.4 However, HCTZ wasn’t the thiazide diuretic medication used in these studies. It was chlorthalidone.
HCTZ is much more commonly used than chlorthalidone and it is available in a large number of combination drugs. But the recommendation to use HCTZ was not based on these clinical trials. The decision was made to substitute HCTZ due to the fact that most physicians were already aware of HCTZ and it was available in these combination medications.
Chlorthalidone and HCTZ are NOT the same. In fact, they aren’t even in the same class of medication. HCTZ is a thiazide diuretic. Chlorthalidone is a phthalimidine diuretic or “thiazide-like” diuretic. Chlorthalidone is more effective than HCTZ and doesn’t cause as much sudden cardiac death as HCTZ.13-14,27
We definitely want good control of blood pressure throughout the day (full 24 hour period). Yet, HCTZ does not provide sufficient effect across a full 24 hours.10 In the past, physicians often prescribed HCTZ to be taken twice daily. I’ve never seen it prescribed twice daily in my career.
Benefits of HCTZ
HCTZ does help decrease blood pressure. One study showed decreased Systolic Blood Pressure (SBP) 6.5 mmHg and Diastolic Blood Pressure (DBP) 4.5 mmHg.1
The problem is that this reduction is just not very good when compared to the other classes of medications.1
- Angiotensin Converting Enzyme Inhibitors (ACEi) reduced SBP 12.9 mmHg and DBP 7.7 mmHg (p < 0.003)
- Angiotensin Receptor Blockers (ARBs) reduced SBP 13.3 mmHg and DBP 7.8 mmHg (p < 0.001)
- Beta Blockers reduced SBP 11.2 mmHg and DBP 8.5 mmHg (p < 0.00001)
- Calcium Channel Blockers (CCBs) reduced SBP 11.0 mmHg and DBP 8.1 mmHg(p < 0.05)
Conclusions: The antihypertensive efficacy of HCTZ in its daily dose of 12.5 to 25 mg as measured in head-to-head studies by ambulatory BP measurement is consistently inferior to that of all other drug classes. Because outcome data at this dose are lacking, HCTZ is an inappropriate first-line drug for the treatment of hypertension.1
Don’t forget, placebo pills also have an effect and can significantly reduce blood pressure.11 In other words, HCTZ may decrease blood pressure but it isn’t really any better for that than placebo.
On the basis of these data, we have to conclude that, for the most prescribed antihypertensive drug in the U.S., outcome evidence is lacking. In its commonly used dose of 12.5 to 25 mg once a day, there has been no evidence that HCTZ reduces myocardial infarction, stroke, or death. This lack of outcome data together with the poor antihypertensive efficacy should strongly motivate physicians to refrain from prescribing HCTZ as initial therapy in hypertension.1
In a 1986 study comparing Nebivolol (a beta blocker) with Nebivolol plus HCTZ they stated “12.5 mg of hydrochlorothiazide per day has no significant antihypertensive effect.” They went on to say “a dose of 50 mg of hydrochlorothiazide was required to lower both systolic and diastolic blood pressure significantly below the level obtained with nadolol alone.”15 However, when you increase the dose to this level side effects increase substantially.12
HCTZ Removes the “Good Effects” of Some Medications
Calcium Channel Blockers are known to be beneficial for vascular structures (the blood vessel wall). A study in 2014 used Lercanidipine alone for baseline therapy for the first 4 weeks of the study. The wall-to-lumen ratio (retinal artery measurement), capillary density, and pulse wave velocity & central blood pressure (measured by SphygmoCor) were all “significantly improved” with 4 weeks of lercanidipine therapy.
The participants were then randomized to one of two treatments: Lercanidipine + Enalapril (an ACEi) or Lercanidipine + HCTZ– for 6 weeks. The patients assigned to Lercanidipine + Enalapril improved even more. However, those taking Lercanidipine + HCTZ regressed to where they were before starting the Lercanidipine. In other words, the HCTZ removed the benefit of the Lercanidipine.19
Arterial Wall Remodeling In Hypertension
The arterial wall undergoes changes in the setting of hypertension. However, some medications actually reverse these changes.
Negative Effects of HCTZ
Low potassium (Hypokalemia)
There are several negative side effects of HCTZ including lipid alterations, hypokalemia, glucose metabolism impairment, and Type-2 Diabetes. The ALLHAT trial demonstrated that these effects may be noticeable even at 4 years of follow up.
Low potassium (hypokalemia) occurs in a dose-dependent fashion of HCTZ. Hypokalemia can increase risk for sudden death and cardiovascular events. Hypokalemia can also inhibit optimal glucose metabolism by affecting insulin sensitivity and secretion. Serum potassium levels should be maintained in the high-normal range (above 4.0). Remember, “normal” isn’t necessarily optimal!
Increased Risk of Diabetes
Risk of diabetes is higher in patients taking HCTZ and even higher if on both HCTZ and a β-blocker. Thiazide diuretics increase the risk of new-onset Type-2 diabetes.5 In fact, the risk of new onset diabetes increases 32% if taking HCTZ.12 Several other studies reveal similar findings.6-9
The ACCOMPLISH trial compared patients taking benazepril + amlodipine against those taking benazepril + HCTZ. The trial was stopped early due to the fact that the benazepril + amlodipine group had a 20% reduction in cardiovascular disease mortality as well as a 25% reduced risk of new-onset Type-2 Diabetes. The only difference here is the amlodipine and the HCTZ. When you consider that there are numerous studies on amlodipine showing benefit it becomes obvious that HCTZ is a terrible drug and shouldn’t be used.22
Imagine the impact of an increased risk of diabetes. I argue that diabetes is one of the single most damaging disease processes to our body. You may have heard that diabetes is considered a cardiovascular disease equivalent. This means that the risk of having a heart attack is the same as if you’ve already had a heart attack. The impacts of this are huge! Why on earth would we do something to patients that INCREASES their risk? It is completely counter to what we are trying to accomplish.
The risk of diabetes as well as insulin resistance, visceral fat accumulation, hyperuricemia, hyponatremia, and hypokalemia are dose dependent. The higher the dose the more significant these problems become. These problems become more clinically significant when daily doses exceed 25mg.12
The Journal of Human Hypertension published a study in 2011 comparing Olmesartan/Amlodipine against Olmesartan/HCTZ in patients with Metabolic Syndrome. 120 patients with Metabolic Syndrome and either Stage 1 or Stage 2 hypertension were randomized to receive either Olmesartan/Amlodipine or Olmesartan/HCTZ. Blood pressure reduction was similar in both groups with 80% of patients achieving the target BP. Only the Olmesartan/Amlodipine group had reduced insulin resistance index (24% reduction, p <0.01), increased adiponectin (increased 16%, p <0.05), and reduced all inflammatory markers compared to the Olmesartan/HCTZ group.31
A study published in the New England Journal of Medicine compared the effects of hydrochlorothiazide (HCTZ) & captopril on lipids and blood glucose. 50 patients were randomized to receive either hydrochlorothiazide (HCTZ) or Captopril over a 4 month period. This was a crossover trial so after 4 months each group stopped taking their respective medications and started the other drug for another 4 months. Captopril improved insulin sensitivity and HCTZ decreased it. HCTZ increased total cholesterol (5%) and LDL (6%). VLDL increased 25%. We conclude that hydrochlorothiazide for the treatment of essential hypertension has adverse effects on glucose and lipid metabolism. It is possible, but not proved in this study, that these changes may contribute to the risk for diabetes mellitus and coronary heart disease. In contrast, captopril appears to have beneficial or no effects on glucose and lipid metabolism.16
Obviously, multiple studies demonstrate that HCTZ increases risk of Type-2 Diabetes. An increased risk of diabetes is certainly one of the many reasons that no one should ever take HCTZ for any reason!
Elevated Uric Acid Levels
Elevated uric acid levels are an independent risk factor for cardiovascular disease. The goal level for Uric Acid is <6. HCTZ increases uric acid levels.12 This is yet another mechanism by which HCTZ could actually contribute to cardiovascular disease.
HCTZ Decreases Magnesium
HCTZ increases the excretion of magnesium from the kidneys. Low magnesium is a serious problem for a number of conditions and are associated with cardiac arrhythmias, neuromuscular changes, and dyslipidemia. All of these problems have been reported in patients using HCTZ. Patients taking diuretics consistently have lower levels of magnesium.30
Increased Risk of Chronic Kidney Disease
Electrolytes are messed up when taking HCTZ, type-2 diabetes increases, magnesium decreases, and uric acid increases when taking HCTZ. If that weren’t enough, HCTZ also increases the risk of chronic kidney disease (CKD).
A study of 312 patients (not on dialysis) were followed. “The use of diuretics was significantly associated with decline in eGFR. A total of 36 (11.5%) patients initiated renal replacement therapy (RRT) and need of RRT was more profound among diuretic users.”17 They went on to say “it is cautiously suggested to carefully prescribe diuretics by keeping in view benefits versus harm for each patient.”
A review of 3 cohort studies with a total of 1,226,229 patients, diuretic therapy increased risk of renal cell cancer 100%. This seems to affect women worse than men: women had a higher odds ratio (2.01, confidence interval 1.56 to 2.67) than men (1.69 confidence interval 1.34 to 2.13). Therefore, long-term use of diuretics may increase your risk of renal cell cancer.20
There Are BETTER Options
Obviously, the goal is to optimize blood pressure, reduce risk of cardiovascular disease, minimize side effects, and save money. Many physicians and patients think that HCTZ fits the bill but, as you’ve already read, that simply isn’t the case. So, if hydrochlorothiazide (HCTZ) is so bad then what SHOULD we be using?
Angiotensin Converting Enzyme Inhibitors (ACEi), Angiotensin Receptor Blockers (ARB), and Calcium Channel Blockers (CCBs) are great options. There are some diuretics that are beneficial as well as some beta blockers (BBs). Here are some of the studies validating these recommendations.
HCTZ vs Spironolactone
566 patients with uncontrolled hypertension were randomized to receive 4 weeks of either spironolactone or HCTZ. Carotid-Femoral pulse wave velocity (cf-PWV) was measured at baseline and again at 4 weeks to compare the effect of spironolactone vs HCTZ on the blood vessel. At baseline, there were no significant differences between the 2 groups. However, cf-PWV was markedly improved in the spironolactone group at 4 weeks (p < 0.05). Patients with uncontrolled hypertension treated with spironolactone seem to have better control of their blood pressure and their arteries are less stiff.18
Evidence-Based Diuretic Therapy for Improving Cardiovascular Prognosis in Systemic Hypertension
Prescriptions for anti-hypertensive medications by American physicians are not consistent with current medical literature. Diuretics are among the most common prescriptions for hypertension. The benefits of these medications varies from class to class and even within the same class. Despite the fact that hydrochlorothiazide (HCTZ) is one of the most common diuretics prescribed for hypertension, the medical literature suggests that chlorthalidone, indapamide, and even the aldosterone receptor blockers (spironolactone & eplerenone) are superior to HCTZ.23
The Anglo-Scandinavian Cardiac Outcomes Trial Blood Pressure Lowering Arm (ASCOT-BPLA) study was published in 2005. In the background, they noted that the disadvantages of diuretics and beta-blockers may account for the shortfalls noted in the prevention of coronary heart disease. When blood pressure levels are reduced a given amount, some agents noted improved outcomes over others.
They used Amlodipine/Perindopril vs Atenolol/Thiazide to evaluate this notion. It was stopped prematurely at 5.5 years with a total of 106,153 patient years of observation.
Compared to the Atenolol/Thiazide group, the Amlodipine/Perindopril group showed:
- 10% reduction in fatal & non-fatal MI
- 25% reduction in CV mortality
- 15% reduction in coronary events
- 11% reduction in all cause mortality
- 15% reduction in all coronary events
- 23% reduction in stroke
- 30% reduction in new-onset diabetes.21
Thiazides, Oxidative stress, & Endothelial Function24
Indapamide vs Hydrochlorothiazide (HCTZ) in patients with hypertension and diabetes27
Hydrochlorothiazide is a commonly, and inappropriately, prescribed diuretic medication typically for hypertension. It is inexpensive but doesn’t have good reduction in blood pressure and certainly doesn’t reduce the risk of cardiovascular disease.
Hydrochlorothiazide (HCTZ) removes the beneficial effects of some medications and it comes with a whole host of negative effects. It decreases magnesium and potassium. It increases uric acid. It increases the risk of Type-2 Diabetes. It decreases kidney function and increases the risk of renal cell carcinoma.
There aren’t significant benefits with Hydrochlorothiazide (HCTZ) and there are numerous negative effects.
In short, when it comes to HCTZ the risks outweigh the benefits and this medication should not be used. Ever. If you are taking HCTZ then you should talk to your doctor about stopping it.
In my experience, they probably don’t know the literature about this medication and why it shouldn’t be used. They may also not know how to use the many better alternatives such as indapamide.
- , , , , C, Am Coll Cardiol 2011;57:590
- The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) Hypertension. 2003;42:1206
- Thiazide Diuretics in the Treatment of Hypertension: An Update.
- ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial: 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). JAMA 288:2981–2997, 2002.
- Verdecchia P, Reboldi G, Angeli F, Borgioni C, Gattobigio R, Filippucci L, Norgiolini S, Bracco C, Porcellati C: Adverse prognostic significance of new diabetes in treated hypertensive subjects. Hypertension 43:963 –969,2004
- Pepine CJ, Handberg EM, Cooper-DeHoff RM, Marks RG, Kowey P, Messerli FH, Mancia G, Cangiano JL, Garcia-Barreto D, Keltai M, Erdine S, Bristol HA, Kolb HR, Bakris GL, Cohen JD, Parmley WW: A calcium antagonist vs a non-calcium antagonist hypertension treatment strategy for patients with coronary artery disease. The International Verapamil-Trandolapril Study (INVEST): A randomized controlled trial. JAMA 290 :2805 –2816, 2003
- Julius S, Kjeldsen SE, Weber M, Brunner HR, Ekman S, Hansson L, Hua T, Laragh J, McInnes GT, Mitchell L, Plat F, Schork A, Smith B, Zanchetti A: Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: The VALUE randomised trial. Lancet 363 : 2022 –2031,2004
- Lindholm LH, Persson M, Alaupovic P, Carlberg B, Svensson A, Samuelsson O: Metabolic outcome during 1 year in newly detected hypertensives: Results of the Antihypertensive Treatment and Lipid Profile in a North of Sweden Efficacy Evaluation (ALPINE study). J Hypertens 21 : 1563 –1574, 2003
- Alderman MH, Cohen H, Madhavan S: Diabetes and cardiovascular events in hypertensive patients.Hypertension 33 : 1130 –1134, 1999
- Comparative antihypertensive effects of hydrochlorothiazide and chlorthalidone on ambulatory and office blood pressure.Hypertension. 2006;47(3):352–358. , , , et al.
- Asmar R, Safar M, Queneau P. Evaluation of the placebo effect and reproducibility of blood pressure measurement in hypertension. Am J Hypertens. 2001 Jun;14(6 Pt 1):546-52.
- Messerli F.H., Bangalore S., Julius S. (2008) Risk/benefit assessment of beta-blockers and diuretics precludes their use for first-line therapy in hypertension. Circulation 117:2706–2715, discussion 2715.
- Siscovick D.S., Raghunathan T.E., Psaty B.M., et al. (1994) Diuretic therapy for hypertension and the risk of primary cardiac arrest. N Engl J Med 330:1852–1857.
- Ernst M.E., Carter B.L., Zheng S., Grimm R.H. Jr. (2010) Meta-analysis of dose-response characteristics of hydrochlorothiazide and chlorthalidone: effects on systolic blood pressure and potassium. Am J Hypertens 23:440–446.
- Magee PF, Freis E. Is Low-Dose Hydrochlorothiazide Effective? Hypertension 8 [Suppl II]: II-135-II-139, 1986
- Pollare T, Lithell H, Berne C. A Comparison of the Effects of Hydrochlorothiazide and Captopril on Glucose and Lipid Metabolism in Patients with Hypertension. N Engl J Med 1989; 321: 868–73.
- Khan Y, Sarriff A, Adnan A, Khan A, Mallhi T. Chronic Kidney Disease, Fluid Overload and Diuretics: A Complicated Triangle. PLoS One. 2016; 11(7): e0159335.
- Liu Y, Dai S, Liu L, Liao H, Xiao C. Spironolactone is superior to hydrochlorothiazide for blood pressure control and arterial stiffness improvement. Medicine (Baltimore). 2018 Apr; 97(16): e0500.
- De Ciuceis C, Salvetti M, Rossini C, Muiesan M, Paini A, Duse S, La Boria E, Semeraro F, Cancarini A, Rosei C, Sarkar, A, Ruggeri G, Caimi L, Ricotta D, Rizzoni D, Rosei E. Effect of antihypertensive treatment on microvascular structure, central blood pressure and oxidative stress in patients with mild essential hypertension. J Hypertension: March 2014 – Volume 32 – Issue 3 – p 565–574
- Grossman E, Messerli FH, Goldbourt U. Does diuretic therapy increase the risk of renal cell carcinoma? Am J Cardiol. 1999;83:1090–1093.
- Dahlöf B, Sever PS, Poulter NR, Wedel H, Beevers DG, Caulfield M, Collins R, Kjeldsen SE, Kristinsson A, McInnes GT, Mehlsen J, Nieminen M, O’Brien E, Ostergren J; ASCOT Investigators. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial. Lancet. 2005 Sep 10-16;366(9489):895-906.
- Jamerson K, Weber M, Bakris G, Dahlöf B, Pitt B, Shi V, Hester A, Gupte J, Gatlin M, Velazquez E. Benazepril plus Amlodipine or Hydrochlorothiazide for Hypertension in High-Risk Patients. NEJM 2008,359;2417-28
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- Ong KL, Barter PJ, Waters DD. Cardiovascular drugs that increase the risk of new-onset diabetes. Am Heart J. 2014 Apr;167(4):421-8.
- Vinereanu D, Dulgheru R, Magda S, Dragoi Galrinho R, Florescu M, Cinteza M, Granger C, Ciobanu AO. The effect of indapamide versus hydrochlorothiazide on ventricular and arterial function in patients with hypertension and diabetes: results of a randomized trial. Am Heart J. 2014 Oct;168(4):446-56.
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- Messerli FH, Bangalore S. Antihypertensive efficacy of aliskerin. Is hydrochlorothiazide an appropriate benchmark? Circulation. 2009;119:371–373.
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- Martinez-Martin F, Rodriguez-Rosas H, Peiro-Martinez I, Soriano-Perera P, Pedrianes-Martin P, Comi-Diaz C. Olmesartan/amlodipine vs olmesartan/hydrochlorothiazide in hypertensive patients with metabolic syndrome: the OLAS study. J Hum Hypertens. 2011 Jun; 25(6): 346–353.