Though diuretics have been the gold-standard for hypertension management due to them offering a consistent reduction not only in BP but also in CVS outcomes, their usage has still declined over the years due to concerns regarding their safety and tolerability.

 

Background

Since the time primary hypertension (uncomplicated hypertension) was identified as a contributor of morbidity and mortality and required to be treated, diuretics have emerged as the first line antihypertensive therapy. Time after time several trials have demonstrated not only morbidity but mortality benefit with diuretic therapy in uncomplicated hypertension.

Interestingly, in real world practice, despite this robust clinical data, the use of diuretics has continued to decline. The reason of-course is not just because of the availability of newer, both effective and safer drugs, but also the number of misconceptions prevailing about the use of diuretics in ‘garden variety’ of hypertension such as:

• Diuretics are not as effective as other anti-hypertensive agents
• Diuretics are less safe
• Diuretics are less convenient to administer/poorly tolerated
• The use of diuretics is associated with significant adverse metabolic effects (increased lipid levels, adverse effects on glucose metabolism, effects on arrhythmias, etc.)
• Newer diuretics could be costly

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Efficacy

In hypertension all the five major classes of drugs (low-dose diuretics, calcium channel blockers (CCBs), angiotensin-converting enzyme inhibitors (ACE - Is) or angiotensin receptor blockers (ARBs) and beta-blockers (BB) are effective in reducing blood pressure (BP) and cardiovascular (CVS) events.

Furthermore, it is the tight control of BP which leads to the reduction of CVS morbidity and mortality rather than class of drug used. However, the early landmark trials in treatment of hypertension did reveal a significant reduction of stroke, CVS morbidity and mortality when diuretics particularly thiazide diuretics were used.

Even the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), which undertook head-to-head comparison between different anti-hypertensive agents, revealed that chlorthalidone was superior to other agents in preventing one or more major forms of CV disease. Several subsequent trials and meta-analysis revealed the same.

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Safety and Tolerability

Concerns about safety of diuretics have been a major reason for limiting their use. However, the available data reveals that diuretics either do not interfere with or may improve the quality of life in hypertensive patients.

In particular, low-dose diuretic treatment is well-tolerated and could be an excellent initial choice for hypertensive patients, even the elderly. A deeper insight may be obtained if the studies in which patients have had to stop their treatment because of adverse effects are analysed.

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Metabolic Effects

There is a small extra risk of type 2 diabetes with the long-term use of thiazide diuretics, but that risk may be more linked to the use of hydrochlorothiazide. The data with use of low-dose chlorthalidone or low-dose newer diuretics like indapamide may be more promising (daily doses of chlorthalidone and indapamide not exceeding 12.5 mg and 1.5 mg respectively).

Low dose diuretics are also safer in patients with renal dysfunction and electrolyte imbalance, however it would still be prudent to record serum potassium, urea/creatinine, uric acid, and fasting glucose before initiating the therapy and avoiding it in case of manifest dysfunction.

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Convenience of Administration

Diuretics can generally be used once as a daily dose but should be preferably administered in the morning (to avoid increased nocturnal micturition).

Cost Analysis

Cost of therapy is always a major factor in choice of the therapy when there are no major differences in efficacy, safety and convenience. Several analyses have revealed that a diuretic based therapy is the cheapest among all the anti-hypertensive agents.

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Conclusions

Historically, diuretics have remained first-line therapy in management of uncomplicated hypertension. They are perhaps the only anti-hypertensive agents that have demonstrated a robust and a consistent reduction not only in BP but also in CVS outcomes and even mortality. However, despite impressive clinical data their use has been declining in recent years perhaps related to concerns about safety, tolerability and adverse effects on metabolic profile contributing to diabetes mellitus or electrolyte / renal dysfunctions.

Indeed, high dose hydrochlorothiazide has a poor safety profile. However, lower dose thiazides have a much better safety profile although hydrochlorothiazide is not efficacious in this dose. On the other hand, low dose chlorthalidone is not only safe but also effective. Newer diuretic indapamide is another anti-hypertensive which is very safe in low dose while preserving its effectiveness. Thus, it seems that hydrochlorothiazide should no longer be used as an anti-hypertensive, instead low dose chlorthalidone or indapamide can be considered.

Disclaimer- The views and opinions expressed in this article are those of the author's and do not necessarily reflect the official policy or position of M3 India.

The writer, Dr. Sundeep Mishra is a noted Professor of Cardiology.