Thiazide Diuretics in the Treatment of Hypertension:

An Update
Antonio Salvetti and Lorenzo Ghiadoni
Department of Internal Medicine, University of Pisa, Pisa, Italy
Thiazide diuretics were the first tolerated efficient antihypertensive drugs that significantly reduced cardiovascular morbidity
and mortality in placebo-controlled clinical studies. Although these drugs today still are considered a fundamental therapeutic
tool for the treatment of hypertensive patients, the following considerations should be taken into account. Although there are
some indications that chlorthalidone can offer additional advantages as compared with other compounds, a recent metaanalysis of placebo-controlled trials suggested that the beneficial effects of thiazide diuretics could be a class effect. Thiazide
diuretics must be used at appropriate and/or optimal doses to achieve the optimal antihypertensive effect with the smallest
occurrence of side effects, including alterations in glucose and lipid profiles and hypokalemia. Moreover, because thiazide
diuretics can increase the incidence of new-onset diabetes, especially when combined with blockers, caution is advised in
using these drugs above all in patients who are at high risk for developing diabetes, in whom thiazide diuretics should be used
at the lowest active dose and possibly in combination with drugs that block the renin-angiotensin system. Finally, the current
debate on whether thiazide diuretics are the first-choice drug for most patients with uncomplicated hypertension, as stated in
the Seventh Joint National Committee Report, or are included in the major classes of antihypertensive agents that are suitable
for initiation and maintenance of therapy, as reported in the European Society of HypertensionEuropean Society of
Cardiology Guidelines, derives from different interpretations of controlled clinical trial data on drug class comparison and of
cost-benefit analyses. However, considering that the benefit of antihypertensive drugs seems to be due principally to BP
lowering per se without definitive evidence of the superiority of a particular drug class and that there is no cost-benefit
analysis showing the superiority of thiazide diuretics, it is believed that these drugs should not be considered as the only
first-choice drug but included among first-choice drugs.
J Am Soc Nephrol 17: S25S29, 2006. doi: 10.1681/ASN.2005121329

ince the discovery of thiazide diuretics in 1957, which

for the first time offered the possibility of efficiently
reducing BP, these drugs have represented a fundamental tool for the treatment of hypertension. Moreover, placebocontrolled clinical studies have documented clearly the benefit
of thiazide diuretics, either given alone or combined with
blockers, in reducing cardiovascular (CV) morbidity and mortality (1), a benefit similar to that achieved with other antihypertensive drug classes, such as angiotensin-converting enzyme (ACE) inhibitors and calcium antagonists (2). In this
article, we review topics concerning the role of thiazide diuretics in the treatment of hypertension.

Do All Thiazide Diuretics Give the Same

Benefit?
This debate first was raised by data from the Multiple Risk
Factor Intervention Trial (3), which aimed to examine special
intervention and usual care groups. The data indicated that
coronary heart disease (CHD) and total mortality trends were
less favorable at clinics where special intervention clinicians
favored hydrochlorothiazide over chlorthalidone. This led to a
protocol change with the recommendation that all patients

Address correspondence to: Prof. Antonio Salvetti, Department of Internal Medicine, University of Pisa, Via Roma 67, 56127 Pisa, Italy. Phone/Fax: 39-050553407; E-mail: a.salvetti@med.unipi.it
Copyright 2006 by the American Society of Nephrology

switch from hydrochlorothiazide to chlorthalidone at a maximum dose from 100 to 50 mg/d, which subsequently led to a
more favorable trend in CHD and total mortality (3). Although
these results suggested a beneficial effect of chlorthalidone as
compared with hydrochlorothiazide, such conclusions are not
robust, especially considering that they are based on a post hoc
subgroup analysis. Furthermore, the data are based on a group
identifier (clinic) rather than individual patient treatments, and
the beneficial effect of the change in treatment could be due to
reduction in the chlorthalidone dose (4).
The debate has been reinforced further by the data from two
large, controlled, clinical studies on drug class comparison.
Whereas in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) (5) chlorthalidone as compared with lisinopril-based treatment showed no
inferiority for primary outcomes (CHD mortality and nonfatal
myocardial infarction) and a superiority for stroke and heart
failure (HF) prevention, the Second Australian National Blood
Pressure trial (ANBP2) (6) indicated a marginal superiority of
enalapril versus hydrochlorothiazide-based treatment on primary end points (all CV [first and recurrent] plus all-cause
mortality) with no substantial difference for stroke and HF.
Although these conflicting results could be dependent on the
specific thiazide diuretic used, there are other likely explanations, such as samples studied, trial design, and type of statistical analysis (4). Finally, a recent meta-analysis of placeboISSN: 1046-6673/1704-0025

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Journal of the American Society of Nephrology

controlled trials that used chlorthalidone or other thiazide-like

diuretics indicated that major health outcomes did not differ
between two treatments, a finding that suggests that the beneficial effects of thiazide diuretics could be a class effect (7).

Choice of Optimal Dose

The relevance of dosage choice of thiazide diuretics can be
evaluated considering both the effect of different diuretic therapy doses on CV mortality and morbidity and the dose-response curve in terms of antihypertensive efficacy and metabolic effects. With regard to the first issue, a meta-analysis of
clinical studies indicated that low-dose (12.5 to 25 mg/d
chlorthalidone or hydrochlorothiazide) and high-dose (50
mg/d or more of both drugs) diuretic therapy lowered BP to a
similar degree and exerted a similar benefit in reducing stroke,
congestive HF, CV, and total mortality, but only low-dose
diuretic therapy significantly reduced CHD incidence (8). The
concept of a high dose of diuretic therapy should be replaced
by that of optimal dose, which derives from studies that evaluated the dose-response curve of thiazide diuretics, as recently
reviewed (9).
Data obtained with chlorthalidone so far indicate that the
plateau of the dose-response antihypertensive curve is reached
with a daily dose of 25 mg and that increasing the dosage does
not increase the BP-lowering effect but further increases the
occurrence of negative metabolic effects, principally hypokalemia (10,11). Data obtained with hydrochlorothiazide, the most
widely used thiazide diuretic in clinical practice, are less certain
and suggest that the plateau of the dose-response BP-lowering
curve is reached with the dose of 50 mg/d, whereas negative
metabolic effects, principally hypokalemia, occur in a dosedependent manner with a dose up to 100 mg/d (9,12). Therefore it seems rational to recommend that diuretic treatment
with chlorthalidone should start with 6.25 mg in the elderly and
12.5 mg in younger patients, with a maximum dose of 25 mg/d,
whereas the starting doses of hydrochlorothiazide should be
12.5 mg in the elderly and 25 mg in younger patients, with a
maximum dose of 50 mg/d (9). Moreover the decision to increase the dosage of these drugs to achieve BP control should
be weighed against the occurrence of negative metabolic effects.

Negative Metabolic Effects of Thiazide

Diuretics
Metabolic effects that can have a negative impact on CV risk
profile include alterations in lipids, hypokalemia, impairment
of glucose metabolism, and, therefore, the occurrence of type 2
diabetes (13). Although changes in lipid profile, characterized
by an increase in total and LDL cholesterol and decrease in
HDL cholesterol, have been reported to be modest and transient (13), data from ALLHAT (5) indicate that the increase in
total cholesterol is detectable up to 4 yr of follow-up.
Hypokalemia, which as already stated is a dose-dependent
phenomenon, can worsen the patients prognosis because it can
increase the risk for sudden death (14) and CV events among
diuretic-treated hypertensive patients (15) and could abolish
the benefit of treatment in elderly patients with isolated systolic

J Am Soc Nephrol 17: S25S29, 2006

hypertension (16). Furthermore, hypokalemia can impair glucose metabolism by reducing insulin secretion and insulin sensitivity (13).
Data from controlled clinical trials, recently reviewed (17),
indicate that the incidence of new-onset diabetes (NOD) is
lower in patients who are treated with drugs that block the
renin-angiotensin system (RAS), such as ACE inhibitors and
angiotensin receptor blockers, as compared with those who are
treated with conventional therapy, i.e., thiazide diuretics alone
and above all combined with blockers.
These findings prompted the debate on whether this difference in the incidence of NOD is due to the beneficial effects of
RAS-blocking drugs or, conversely, to the negative action of
conventional therapy on glucose metabolism. This second hypothesis seems to be a rational explanation for the following
considerations. Incidence of NOD also is reduced in patients
who receive calcium antagonists, drugs that are believed to be
neutral on glucose metabolism, when compared with conventional therapy (17). A longitudinal observational study showed
that given similar fasting blood glucose values, low-dose thiazide diuretic treatment further increased the incidence of NOD
(18). In the International Verapamil SR-Trandolapril Study
(INVEST) (19), the addition of hydrochlorothiazide dose-dependently increased the risk for NOD not only in patients who
received atenolol but also in those who were treated with
verapamil. Similarly, in the Valsartan Antihypertensive Longterm Use Evaluation (VALUE) Trial (20), the greater incidence
of NOD in the amlodipine arm can be explained tentatively by
the greater occurrence of hypokalemia induced by the association of hydrochlorothiazide. Finally, the Antihypertensive
Treatment and Lipid Profile in a North of Sweden Efficacy
Evaluation (ALPINE) Study (21) showed that in 1 yr of follow-up of previously untreated hypertensive patients, treatment with hydrochlorothiazide frequently associated with
atenolol impaired glucose metabolism, whereas treatment with
candesartan frequently associated with felodipine was neutral.
Considering that NOD has a bad prognostic significance because it increases the incidence of CV events in hypertensive
diuretic users even when BP is well controlled (22) and gives
the same CV risk as pre-existing diabetes in treated hypertensive patients (18), caution is advised in using thiazide diuretics,
especially when combined with blockers, above all in patients
who are at high risk for developing diabetes, such as those with
genetic (familial or ethnic) predisposition, obesity, fasting glucose intolerance, and/or the metabolic syndrome. Particularly
in these patients, thiazide diuretics should be used at the lowest
active dose with close monitoring of metabolic parameters and
possibly in combination with RAS-blocking drugs.

Are Thiazide Diuretics the First-Choice Drug

or One of the First-Choice Drugs?
The debate on whether thiazide diuretics are the first-choice
drug, as recommended by the Seventh Joint National Committee (JNC-7) Report (23), or are among first-choice drugs, as
recommended by European Society of HypertensionEuropean
Society of Cardiology (ESH-ESC) Guidelines (24), is principally

J Am Soc Nephrol 17: S25S29, 2006

based on different interpretations of controlled clinical trials

and secondly on drug cost considerations.
The JNC-7 Report (23) recommendation arose from the twofold recognition that thiazide-type diuretics have been the basis
of antihypertensive therapy in most outcome trials and that in
these trials, including the recently published ALLHAT (5,25),
diuretics have been virtually unsurpassed in preventing the CV
complications of hypertension. Moreover, diuretics can be useful in achieving BP control as well as enhancing the antihypertensive efficacy of multidrug regimens, and they are more
affordable than other antihypertensive agents. These recommendations need to be evaluated according to these lines of
reasoning.
The strengths and limitations of ALLHAT already have been
commented on (26) and can be summarized as follows. The
main strength of this study is that with regard to primary
outcomes (coronary mortality and nonfatal myocardial infarction), chlorthalidone-based treatment was equally as effective
as treatment that was based on amlodipine or lisinopril or
doxazosin, and with regard to some secondary end points such
as prevention of stroke, it was superior when compared with
doxazosin and lisinopril. It was also more effective in prevention of morbidity but not mortalityfrom congestive HF
when compared with the other three treatments (5,25). However, the difference with regard to stroke could be due to a
difference in systolic BP (26). In contrast, the difference with
regard to congestive HF might be explained by poor accuracy
and/or difficulty in diagnosis; alternatively, withdrawal of previous diuretic therapy may have unmasked congestive HF
symptoms in patients with left ventricular dysfunction (26).
Therefore, ALLHAT confirmed and strengthened the clinical
relevance of thiazide diuretics in the treatment of hypertension
but did not prove the superiority of these drugs. This conclusion is in agreement with an expanded analysis of the ALLHAT
data presented at the American Society of Hypertension Meeting 2004 (27), which suggests the following interpretations:
The superiority of chlorthalidone versus lisinopril was detectable in black but not in white patients. Therefore, it would be
reasonable to state that whereas diuretics remain the preferred first-line drugs for black patients, ACE inhibitors and
diuretics could be regarded as coequal recommendations for
initiating therapy in white patients.
The primary coronary end point was not different for amlodipine compared with the other two drugs, and the other
major end points of stroke and all-cause mortality tended
slightly in its favor. Therefore, for many patients, the excellent antihypertensive efficacy and tolerability of calcium antagonists continue to make them a popular and appropriate
choice.
The nonsuperiority of a particular drug class, beyond BP
reduction, is also supported by the following considerations:
Placebo-controlled clinical studies have shown that the benefit of antihypertensive therapy in preventing CV events
with diuretics alone or combined with a blocker (1) is
similar to that achieved with ACE inhibitors and calcium

Thiazide Diuretics in Hypertension

S27

antagonists (2). Such a finding suggests that this benefit is

due to BP lowering per se (1,2).
Meta-analyses of controlled clinical studies, including those
on drug class comparison, indicate that reduction in CV
morbidity and mortality rates depends BP reduction and that
larger reductions in BP produce larger reductions in risk for
major CV events (2,28,29).
These conclusions are supported further by data from the
VALUE Trial (30), which indicate that early (within 6 mo)
control of systolic BP (140 mmHg) can significantly reduce
the incidence of CV events in high-risk hypertensive patients.
The overall data given above do not point to a greater benefit
of a particular drug class, beyond reduction in BP values, which
is actually the more likely explanation of the benefit of antihypertensive therapy. In this setting, thiazide-like diuretics can be
viewed as efficient but not as superior to other antihypertensive
drugs. Therefore, their preferential choice should be based
principally on drug cost and, in particular, whether they are
really less expensive.
Certainly thiazide-like diuretics are less expensive than
newer types of antihypertensive agents and therefore are favored in terms of cost minimization (4), but cost is not the sole
consideration, and further cost benefit analyses, announced by
the ALLHAT authors although not performed so far (4), are
awaited. We believe that their analysis also should take into
account the adverse metabolic effects of thiazide diuretics, consisting of an increase in cholesterol levels, blood glucose, NOD,
and hypokalemia (4,5). Although these metabolic effects did
not translate into a greater frequency of CV events in the
relatively short-term follow-up of ALLHAT (5), they could
have a major impact on cost benefit analyses because in the
long term, they can reduce the benefit of treatment and increase
the cost owing to the need for further pharmacologic therapy
that is designed to treat the metabolic abnormalities (26).
The last point to be taken into account is that choice of
antihypertensive drugs should be based on additional considerations, as follows. First, efficacy in reducing BP and tolerability, the latter also including metabolic effects, must be evaluated in individual patients. Second, as shown in Table 1, the
presence of associated clinical conditions with compelling indications (23), subclinical target organ damage (24), and other
associated (but not causally related to hypertension) clinical
conditions can indicate the choice of a particular antihypertensive drug class not necessarily including thiazide diuretics.
Finally, a combination of two or more drugs, not always including diuretics, is needed in the majority of hypertensive
patients to achieve goal BP (24). Above all, these last considerations could indicate that the debate on the first-choice drug
class probably has been overemphasized (24).

Conclusion
The answer to the question of whether thiazide diuretics are
the first-choice drug for treatment of hypertension is two-fold:
No, if the diuretic is the only first-choice drug; yes, if the
diuretic is one of the first-choice drugs.

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Journal of the American Society of Nephrology

Table 1. Indications for antihypertensive drug classes

choice
Compelling indications
heart failure, after myocardial infarctionsa, high
coronary risk, diabetes, chronic kidney diseasea,
recurrent stroke prevention
Subclinical target organ damage
left ventricular hypertrophya, carotid atherosclerosisa,
microalbuminuriaa
Associated, not causally related, clinical conditions
headachea, Raynauds phenomenona, irritable bowela,
gouta, prostatic hypertrophya, palpitationsa,
depression and panica, tremora, renal stones,
osteoporosis
a

Drug classes other than thiazide diuretics.

J Am Soc Nephrol 17: S25S29, 2006

10.

11.

12.

13.
14.

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