Review Article

The effect of chlorthalidone on cardiovascular and renal disease: A systematic review

Introduction

The WHO global report regarding the increase in hypertension in adults in the European region/Americas and the South-East Asia/Western Pacific region for 30 years from 1990 to 2020 was 302 million to 427 million and 262 million to 640 million, respectively. Furthermore, there has been a 41% increase in the number of hypertensive patients in the European region/Americas. The most significant increase occurred in the Southeast Asia/Western Pacific region of 144%. This emphasizes the need to control hypertension, especially in the South-East Asia/Western Pacific region¹.

Hypertension is a common risk factor for cardiovascular disease (CVD).² In 2019, the CVD death rate caused by hypertension in adults increased by 43%, with the leading causes of death being ischemic heart disease and respectively.³ Apart from being a risk factor for CVD, hypertension is also a risk factor for renal disease that causes an increase in serum creatinine as a marker of renal dysfunction. Many large-scale observational studies in hypertensive patients have shown that blood pressure is an independent risk factor for renal disease.⁴ The higher the blood pressure, the greater the risk of chronic kidney disease (CKD) and end-stage renal disease (ESRD). The relationship between blood pressure and CKD is more complex because renal disease itself can increase blood pressure, so it is often difficult to conclude whether CKD is caused solely by hypertension or due to primary renal disease, which causes hypertension, or a combination of both. CKD affects 9% of the world’s population, with a prevalence ranging from 8% to 16% in low-income countries as of 2017. The death rate caused by CKD over the last three decades has increased rapidly by around 41%.⁵

One way to control hypertension is by administering antihypertensive drugs. Thiazide and thiazide-like diuretics like chlorthalidone (CTDN) have become one of the recommended first pharmacological therapies as antihypertensive drugs.^4,6 In recent years, new observations and approaches have emerged to treat hypertension in patients with CKD and to reduce the incidence of CVD. The publication was conducted on a randomized controlled study between placebo and CTDN. CTDN can effectively reduce blood pressure in stage 4 CKD patients.⁵ There is still very little literature regarding the use of CTDN as antihypertensive therapy and the guidelines from WHO as the first choice of antihypertensive therapy still use the ACEI/ARB group. In contrast, many benefits can be obtained if CTDN is the first choice drug as an antihypertensive and can prevent CVD. However, several studies reported the adverse events of CTDN in specific patients, especially in the case of patients with renal diseases. Therefore, this study aims to systematically evaluate the effects of CTDN on cardiovascular and renal diseases.

Methods

This systematic review was developed following the PRISMA-P 2015 guidelines (Preferred Reporting Items for Systematic Review and Meta-analysis Protocols).⁷ The primary research query for this systematic review was to assess the impact of CTDN on cardiovascular and renal diseases. We aimed to investigate studies involving any use of CTDN in adult patients, including reported cardiovascular and renal outcomes, especially chronic renal disease, diuretic side effects, and complications of therapy. The keywords consist of ‘’Cardiovascular’’ or ‘’Chronic Renal Disease’’ with ‘and’ Boolean logic to combine with ‘’Chlorthalidone”. There were no restrictions on the country of origin and year of publication. The inclusion criteria were research papers published in English and full-text availability based on the database literature search. The exclusion criteria were review articles, guidelines, commentary, and letter publication types. The literature search was performed on June 30, 2023. Detailed keywords are shown in Supplementary file 1. Additional literature was explored using hand searching that identified the relevant literature in the citation of included studies.

Study selection and quality assessment

The study entries from those queries have been combined into Rayyan.ai, and duplicates have been removed.⁸ The entries were then methodically screened to remove those without an abstract, those with a publication type of letter or correspondence, and those irrelevant to the primary search query. Two independent reviewers (WI and AIT) evaluated the full-text articles to exclude review articles, case reports, qualitative surveys, fundamental science, and diagnostic testing publications. Two reviewers also independently assessed the methodological quality of included studies using the Newcastle-Ottawa Scale (NOS) for quality assessment of non-randomized studies in systematic reviews and meta-analyses.⁷ The NOS is composed of three primary domains: comparability (comparing study groups), outcome (evaluating the study’s findings), and selectivity (choosing the study population). Each study receives an overall score of up to nine points on the NOS scale, which indicates the methodological quality of the study. Data extraction was created with the following headings: author, year of publication, study patient population size, study type, duration of follow-up, and study conclusion.

Results

Systematic review findings

The initial screen generates 26 articles on PubMed and 14 articles from hand searching (Figure 1). After exclusion from irrelevant studies and applying inclusion criteria, 22 references were obtained where CTDN, a diuretic and anti-hypertensive drug, was associated with cardiovascular events and its effect on the renal (Figure 1). The summary of the NOS quality assessment is presented in Table 1. There are 3 references discussing the benefits of CTDN, 3 references discussing the side effects of using CTDN on CVD, 11 references discussing comparisons of CTDN with other antihypertensive drugs, and 5 references discussing the effects of CTDN on the kidney (Table 2).

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Figure 1.

PRISMA flow chart of chlorthalidone and cardiovascular–renal diseases

Figure 1.

PRISMA flow chart of chlorthalidone and cardiovascular–renal diseases

The effect of chlorthalidone on cardiovascular conditions

As illustrated in Table 2, the included studies show promising effects on the use of CTDN for CVD. Many studies compare the effectiveness of CTDN and other antihypertensive drugs such as HCTZ, calcium channel blockers, and beta-blockers. Half of the studies (8 out of 16, 50%) reported that CTDN was more effective in reducing systolic blood pressure and diastolic blood pressure than other antihypertensive drugs. So, the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure recommends CTDN as the first-line treatment of uncomplicated hypertension and no comorbidities.²³ Moreover, 3 of 16 studies (18.75%) reported a greater effect of CTDN in reducing LV mass and remodeling in the LA and LV compared to other antihypertensive drugs. On the other hand, 3 of 16 studies (18.75%) reported the effect of CTDN as a therapy to prevent and reduce CVD (CHD, stroke, angina, HF, and PAD). On the other hand, 2 of 16 studies (12.5%) reported that CTDN had lower side effects on the incidence of hypokalemia compared to HCTZ. The results showed promising effects on the use of CTDN for CVDs.

The effect of chlorthalidone on renal disease

Based on table 2 which states the effect of CTDN on kidney disease. The majority of studies (3 out of 5, 60%) have evaluated CTDN’s impact on the incidence of electrolyte imbalance: hypokalemia, hyponatremia; hyperglycemia; and hyperuricemia. On the other hand, 2 out of 5 studies (40%) reported that the use of CTDN can increase eGFR. Therefore, the use of CTDN must pay attention to kidney disease in patients.

Discussion

This study provides updated evidence regarding the usage of CTDN in hypertension therapy. CTDN is a diuretic derived from the sulfonamide group such as thiazides because it has the same functional group as hydrochlorothiazide (HCTZ), so it is often called diuretic-like thiazide.³¹ Although often referred to as diuretic-like thiazide, the pharmacokinetic and pharmacodynamic modes of action of CTDN and HCTZ are very different. The first reason CTDN is distinguished from HCTZ is because CTDN has a long half-life of around 40 hours, while HCTZ is only 6-9 hours. The cause of the long CTDN half-life is after CTDN enters the body and is immediately concentrated in the erythrocytes. A study states that CTDN is concentrated 7-10 times more in erythrocytes than plasma.³² The mechanism of action of CTDN involves inhibiting Na ⁺ /Cl - co-transporter (NCC) in the luminal membrane of the distal convoluted tubule of the renal. The NCC is responsible for about 5-7% of total sodium reabsorption or 130 mmol/day in the nephron.²⁰

The results showed that CTDN has beneficial effects on the cardiovascular system, such as decreasing systolic and diastolic blood pressure, cardiac remodeling, and preventing CVD. The effect of CTDN on reducing blood pressure is explained by Davis in 2012 explained HCTZ and CTDN are more effective in lowering blood pressure than other diuretics but have less ability to affect patients with volume overload. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure recommends CTDN as the first-line treatment of uncomplicated hypertension and no comorbidities.¹⁶ Reduced sodium reabsorption increases the amount of urine output, thereby reducing circulating blood volume and lowering blood pressure.

This systematic review demonstrated the effect of CTDN on cardiovascular events by lowering blood pressure in hypertensive patients. The result of this decrease in blood pressure impacts reducing the LV mass. Strengthening the explanation of the effect of CTDN on reducing LVM, Liebson et al compared five types of antihypertensives including diuretic (CTDN), β-blocker (acebutolol), α-antagonist (doxazosin mesylate), calcium antagonist (amlodipine maleate), and angiotensin-converting enzyme inhibitor (enalapril maleate). All antihypertensives demonstrated a 10% to 15% reduction in LVM. However, the CTDN group experienced the greatest effect on reducing LVM with an average of around 35 grams after giving CTDN for 12 months.¹⁰ Besides impacting the mass in the LV, CTDN was found to be more effective than HCTZ in reducing the risk of patients with cardiovascular events.

A secondary analysis of a randomized clinical trial of mortality and morbidity in individuals receiving antihypertensive medications diuretic-like-thiazide (CTDN), ACE inhibitors, and calcium channel blockers explained that CTDN as an antihypertensive is more effective in reducing CVD than ACE Inhibitors. Compared with CTDN, the ACE Inhibitors group had a 19% higher risk of death from stroke.³³

Besides CVD, CTDN is also helpful in reducing morbidity rates from cerebrovascular disease. The SHEP cooperative research group also explained the effect of CTDN on the incidence of stroke. There were several adverse events following treatment with CTDN. The use of CTDN was associated with an increase in electrolyte and renal disorders, including hypokalemia, hyponatremia, acute renal failure, and chronic renal disease. Based on electrolyte findings, CTDN’s association with an increase in the incidence of type II diabetes may be related to potassium depletion or dehydration.³⁴ Current literature shows that CTDN has different results in lowering blood pressure in patients with renal diseases. Many studies support that CTDN effectively reduces blood pressure in patients with CKD.^15,19,25 Thiazide-like diuretics have also been reported to have renoprotective properties. CTDN administration could decrease urine albumin excretion, according to results from the CLICK study and its pilot phase, designed to treat patients with severe CKD.³⁰

Besides electrolyte imbalance, CTDN also affects the estimated glomerulus filtration rate (eGFR). This was explained by Barzilay et al that CTDN had a much higher rate of decrease in eGFR compared to the use of amlodipine and lisinopril.²⁷ CTDN may be used in case of hypertension, but the adverse event should be monitored in each comorbidity. This systematic review has limitations that cannot determine which dose has a blood pressure-lowering effect with fewer adverse events. Therefore, future research can be conducted to explore the effect in different populations, comorbidities, dose ranges, and longer follow-ups to monitor the long-term effects of using CTDN in individuals with hypertension without renal disease. This study has some limitations. Our study only analyzed literature published in English; the findings of this study may not combine other studies published in other languages. The systematic review in this study was only conducted in the PubMed database; further studies that evaluate the evidence in other databases are needed in the future.

Conclusion

CTDN has a beneficial effect on lowering blood pressure, preventing CVDs, and cardiac remodeling. However, the use of CTDN in renal disease should be monitored because of its side effects. CTDN should not be given if there is a severe decline in renal function. Therefore, we recommend that CTDN can be used in case of hypertension without renal comorbidities.

Competing Interests

The authors declare there is no conflict of interest related to the publication of this work.

Data Availability Statement

All data in this study were available in the manuscript. Further information may be asked to the corresponding author.

Ethical Approval

Ethical approval and informed consent were not required for this study, as these studies were based on previously published articles.

Ethical Approval

This study does not need ethical approval because the authors did not include any human or animal subjects in this review

Supplementary Files

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