The role of diuretics in the treatment of hypertension: a focus on chlorthalidone (lecture)


  • Yu.M. Sirenko State Institution “National Scientific Center “M.D. Strazhesko Institute of Cardiology” of the National Academy of Medical Sciences of Ukraine”, Kyiv, Ukraine



diuretics, arterial hypertension, treatment, chlorthalidone


The lecture discusses the role of thiazide and thiazide-like diuretics, in particular chlorthalidone, in the modern treatment of arterial hypertension. The modern concepts about the mechanism of action of thiazide diuretics and chlorthalidone are presented. Differences in the degree of antihypertensive effect of hydrochlorothiazide and chlorthalidone are discussed. The results of large randomized trials SHEP, MRFIT, ALLHAT were analyzed, in which chlorthalidone therapy significantly reduced the risk of developing cardiovascular and cerebrovascular complications of hypertension. The effect of thiazide diuretics on glucose metabolism and the impact of carbohydrate metabolism disorders during treatment with chlorthalidone on the risk of cardiovascular complications was considered. The lecture also discusses the effect of chlorthalidone therapy on kidney function, the possibility of its use in chronic kidney disease. The data are presented on the prevention of resistant hypertension and chro-nic heart failure during long-term therapy of hypertension with chlorthalidone. The frequency and terms of the development of side effects of hypertension therapy with thiazide-like diuretics were also analyzed.


Titze J., Machnik A. Sodium sensing in the interstitium and relationship to hypertension. Curr. Opin. Nephrol. Hypertens. 2010. 19(4). 385-392.

Kirabo A. A new paradigm of sodium regulation in inflammation and hypertension. Am. J. Physiol. Integr. Comp. Physiol. 2017. 313(6). R706-R710.

Verdecchia P., Staessen J.A., Angeli F. et al. for Cardio-Sis investigators. Usual versus tight control of systolic blood pressure in non-diabetic patients with hypertension (Cardio-Sis): an open-label randomised trial. Lancet. 2009. 374(9689). 525-33.

Chang T.I., Evans G., Cheung A. et al. for the SPRINT Study Research Group. Correlates of Baseline Thiazide-Type Diuretic Prescription in the Systolic Blood Pressure Intervention Trial. Hypertension. 2016. 67. 550-555.

Suchard M.A., Schuemie M.J., Krumholz H.M. et al. Comprehensive comparative effectiveness and safety of first-line antihypertensive drug classes: a systematic, multinational, large-scale analysis. Lancet. 2019 Nov 16. 394(10211). 1816-1826.

Ellison D.H., Velázquez H., Wright F.S. Thiazide-sensitive sodium chloride cotransport in early distal tubule. Am. J. Physiol. 1987. 253. F546-F554.

Winer B.M. The antihypertensive actions of benzothiadiazines. Circulation. 1961. 23. 211-218.

Ram C.V., Garrett B.N., Kaplan N.M. Moderate sodium restriction and various diuretics in the treatment of hypertension. Arch. Intern. Med. 1981. 141. 1015-1019.

Numabe A., Uehara Y., Hirawa N. et al. Effects of thiazide diuretic on vascular eicosanoid system of spontaneously hypertensive rats. J. Hypertens. 1989. 6. 493-499.

Zhu Z., Zhu S., Liu D., Cao T., Wang L., Tepel M. Thiazide-like diuretics attenuate agonist-induced vasoconstriction by calcium desensitization linked to Rho kinase. Hypertension. 2005. 45. 233-239.

Woodman R., Brown C., Lockette W. Chlorthalidone decreases platelet aggregation and vascular permeability and promotes angiogenesis. Hypertension. 2010. 56(3). 463-70.

Sica D.A. Chlorthalidone: has it always been the best thiazide-type diuretic? Hypertension. 2006. Vol. 47. P. 321-322.

Carter B.L., Ernst M.E., Cohen J.D. Hydrochlorothiazide versus chlorthalidone: evidence supporting their interchangeability. Hypertension (Dallas, Tex: 1979). 2004. 43. 4-9.

Materson B.J., Oster J.R., Michael U.F. et al. Dose response to chlorthalidone in patients with mild hypertension. Efficacy of a lower dose. Clin. Pharmacol. Ther. 1978. 24(2). 192-198.

Psaty B.M., Smith N.L., Siscovick D.S. et al. Health outcomes associated with antihypertensive therapies used as first-line agents. A systematic review and meta-analysis. JAMA. 2004. 277. 739 -745.

Ernst M.E., Carter B.L., Goerdt C.J. et al. Comparative antihypertensive effects of hydrochlorothiazide and chlorthalidone on ambulatory and office blood pressure. Hypertension. 2006. 47. P. 352-358.

Pareek A.K., Messerli F.H., Chandurkar N.B. et al. Efficacy of Low-Dose Chlorthalidone and Hydrochlorothiazide as Assessed by 24-h Ambulatory Blood Pressure Monitoring. J. Am. Coll. Cardiol. 2016. 67(4). 379-389.

Roush G.C., Ernst M.E., Kostis J.B., Tandon S., Sica D.A. Head-to-head comparisons of hydrochlorothiazide with indapamide and chlorthalidone: antihypertensive and metabolic effects. Hypertension. 2015. 65(5). 1041-1046.

Fernandes L.A., Cestario E.D., Cosenso-Martin L.N. et al. Chlorthalidone Plus Amiloride Reduces the Central Systolic Blood Pressure in Stage 1 Hypertension Patients. Cardiol. Res. 2016. 6. 196-201.

Multiple Risk Factor Intervention Trial Research Group. Mortality after 10 1/2 years for hypertensive participants in the Multiple Risk Factor Intervention Trial. Circulation. 1990. 82(5). 1616-28.

Dorsch M.P., Gillespie B.W., Erickson S.R. et al. Chlorthalidone reduces cardiovascular events compared with hydrochlorothiazide: a retrospective cohort analysis. Hypertension. 2011. 57. P. 689-694.

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. 2002. 288. 2981-2997.

Black H.R., Davis B., Barzilay J. et al for Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Metabolic and clinical outcomes in nondiabetic individuals with the metabolic syndrome assigned to chlorthalidone, amlodipine, or lisinopril as initial treatment for hypertension: a report from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Diabetes Care. 2008. 31(2). 353-360.

Barzilay J.I., Davis B.R., Cutler J.A. et al. for ALLHAT Collaborative Research Group. Fasting glucose levels and incident diabetes mellitus in older nondiabetic adults randomized to receive 3 different classes of antihypertensive treatment: a report from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Arch. Intern. Med. 2006. 166(20). 2191-2201.

Kostis J.B., Wilson A.C., Freudenberger R.S. et al. Long-term effect of diuretic-based therapy on fatal outcomes in subjects with isolated systolic hypertension with and without diabetes. Am. J. Cardiol. 2005. Vol. 95. P. 29-35.

Wright J.T. Jr, Probstfield J.L., Cushman W.C. et al. ALLHAT findings revisited in the context of subsequent analyses, other trials, and meta-analyses. Archives of Internal Medicine. 2009. 169(9). 832-842.

Barzilay J.I., Davis B.R., Pressel S.L. et al. ALLHAT Collaborative Research Group. Long-term effects of incident diabetes mellitus on cardiovascular outcomes in people treated for hypertension: the ALLHAT Diabetes Extension Study. Circ. Cardiovasc. Qual. Outcome. 2012. 5. 153-162.

Rahman M., Pressel S., Davis B.R. et al. for the ­ALLHAT Collaborative Research Group. Cardiovascular Outcomes in High-Risk Hypertensive Patients Stratified by Baseline Glomerular Filtration Rate. Ann. Intern. Med. 2006. 144. 172-180.

Agarwal R., Sinha A.D., Pappas M.K., Ammous F. Chlorthalidone for poorly controlled hypertension in chronic kidney disease: an interventional pilot study. Am. J. Nephrol. 2014. 39(2). 171-182.

Alderman M.H., Davis B.R., Piller L.B. et al. for ALLHAT Collaborative Research Group. Should Antihypertensive Treatment Recommendations Differ in Patients With and Without Coronary Heart Disease? (from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial [ALLHAT]). Am. J. Cardiol. 2016. 117(1). 105-115.

Williams B., Mancia G., Spiering W. et al. 2018 ESC/ESH Guidelines for the management of arterial hypertension. J. Hypertens. 2018. 36. 1953-2041.

Bangalore S., Davis B.R., Cushman W.C. et al. for ALLHAT Collaborative Research Group. Treatment-Resistant Hypertension and Outcomes Based on Randomized Treatment Group in ALLHAT. Am. J. Med. 2017. 130(4). 439-448.e9.

Carey R.M., Calhoun D.A., Bakris G.L. et al. American Heart Association Professional/Public Education and Publications Committee of the Council on Hypertension; Council on Cardiovascular and Stroke Nursing; Council on Clinical Cardiology; Council on Genomic and Precision Medicine; Council on Peripheral Vascular Disease; Council on Quality of Care and Outcomes Research; and Stroke Council. Resistant Hypertension: Detection, Evaluation, and Management: A Scientific Statement From the American Heart Association. Hypertension. 2018. 72(5). e53-e90.

Davis B.R., Kostis J.B. et al. for ALLHAT Collaborative Research Group. Heart failure with preserved and reduced left ventricular ejection fraction in the antihypertensive and lipid-lowering treatment to prevent heart attack trial. Circulation. 2008. 25. 118(22). 2259-2267.

Puttnam R., Davis B.R., Pressel S.L. et al. for ALLHAT Collaborative Research Group. Association of 3 Different Antihypertensive Medications With Hip and Pelvic Fracture Risk in Older Adults: Secondary Analysis of a Randomized Clinical Trial. JAMA Intern. Med. 2017. 177(1). 67-76.

Alderman M.H., Piller L.B., Ford C.E. et al. for Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial Collaborative Research Group. Clinical significance of incident hypokalemia and hyperkalemia in treated hypertensive patients in the antihypertensive and lipid-lowering treatment to prevent heart attack trial. Hypertension. 2012. 59(5). 926-933.