Chapter 9
Which Diuretics for Which Patients
with Hypertension?
RAGHAV BANSAL • SIVASUBRAMANIAN RAMAKRISHNAN
INTRODUCTION
Diuretics constitute a heterogeneous group of drugs
with distinct structures and mode of action. They
are commonly prescribed to control hypertension.
Diuretics act directly at different tubular sites where
solute reabsorption occurs in the nephron and
thereby increase the renal excretion of sodium and
water (natriuresis)1. Prolonged alteration of sodium
balance by diuretics induces haemodynamic
changes which result in reduction of peripheral
vascular resistance and sustained decrement of
blood pressure (BP)1. Diuretic-based treatment strat-
egy has been proven to prevent stroke and cardio-
vascular (CV) disease in the randomized clinical
trials as early as in 1960s till recent times2. Large
number of hypertensives respond well to a simple,
once a day, two-drug fixed-dose combination (FDC)
containing a thiazide-like diuretic with either an
angiotensin-converting enzyme (ACE) inhibitor or
a calcium channel blocker2.
Prominent diuretics used to treat hypertension
include thiazide and thiazide like. Loop diuretics
and potassium-sparing diuretics are also used in
some patients. Till recent times, thiazide and thia-
zide-like drugs have been the gold standard of anti-
hypertensive therapy for primary hypertension and
were prescribed as first line of drugs. However, their
use has been waning currently despite the availabil-
ity of ample clinical evidence supporting their CV
mortality and morbidity benefits. Some of the
common misconceptions prevailing on diuretics
are1 they have mild BP-lowering efficacy which
therefore makes them suitable only in combination
with other antihypertensive drugs,2 they are poorly
tolerated due to adverse events and3 they do not
confer morbidity or mortality benefits, etc.3. How-
ever, it has to be reiterated that thiazide-like drugs
such as chlorthalidone and indapamide have been
repeatedly shown to provide CV benefits and have
better safety profile when compared to thiazide di-
uretics. Therefore, there is a quintessential need for
cascading this information to the health care profes-
sionals and explain the importance of these drugs in
the hypertension management scenario in India.
This chapter discusses different types of diuretics
that are useful to treat primary hypertension, and
their place in various hypertension guidelines. Spe-
cial focus is given to the most commonly used cat-
egories: thiazide and thiazide-like diuretics.
DIURETICS USED FOR TREATING
HYPERTENSION
THIAZIDE AND THIAZIDE-LIKE
DIURETICS
Thiazide diuretics have been part of the antihyper-
tensive armamentarium since 1950. These agents
are the gold standard of hypertension management
with an acceptable side effect profile4. Apart from
reducing BP, they also increase the efficacy of other
antihypertensive agents and decrease the morbidity
and mortality associated with hypertension. Pa-
tients with low renin (e.g. black, elderly and dia-
betic individuals) and those with metabolic syn-
drome respond well to these drugs1. Additionally,
these drugs are also widely used in volume overload
conditions such as heart failure (HF) and chronic
kidney disease (CKD). Despite their common modes
of action, these classes of drugs present significantly
different pharmacokinetic characteristics and side
effect profiles. Due to flat dose–response curve, inci-
dence of dose-dependent electrolyte imbalances
and metabolic disturbances is common with high
doses of thiazide diuretics1.
67
68 SECTION II — Preventive Cardiology
Efficacy and Benefits
Thiazide-like diuretics including chlorthalidone
and indapamide have been established as more po-
tent antihypertensive drugs than hydrochlorothia-
zide. Indapamide and chlorthalidone can reduce
systolic BP (SBP) better than hydrochlorothiazide
and also have longer duration of action (24 h)5,6.
Duration of action is particularly beneficial while
targeting night-time BP which might reduce CV
events better than while targeting daytime BP7. In a
meta-analysis of 14 randomized trials, at commonly
used doses, indapamide and chlorthalidone low-
ered SBP more than hydrochlorothiazide6. Further-
more, in a systematic review of 14 randomized tri-
als, the BP-lowering efficacy of hydrochlorothiazide
was found to be inferior to other antihypertensive
drugs (ACE inhibitors, angiotensin receptor block-
ers [ARBs] and calcium channel blockers) when
12.5–25 mg doses were used8. Even though 50 mg
dose of hydrochlorothiazide produced better effi-
cacy, it was associated with significant metabolic
and electrolyte abnormalities. Indapamide 1.5 mg
SR (sustained release) has better or equivalent BP-
lowering efficacy (22.7–31.8 mm Hg SBP reduction)
in elderly patients with various comorbidities when
compared to standard doses of hydrochlorothiazide
or amlodipine (calcium channel blocker) or enala-
pril (ACE inhibitor)9. In the Systolic Hypertension
in the Elderly Program (SHEP), chlorthalidone (25–
50 mg) reduced SBP by 17 mm Hg and diastolic BP
(DBP) by 6 mm Hg10. Furthermore, in hypertensive
veterans already on hydrochlorothiazide, signifi-
cant reductions were observed in mean SBP (15.8
mm Hg; P  .0001) and DBP (4.2 mm Hg; P 
.0035) when shifted to chlorthalidone11.
Several trials in the past have demonstrated that
reduction of BP, primarily with thiazide diuretics,
significantly lowers stroke, CV morbidity and mor-
tality12–15. Furthermore, in a network meta-analysis
of 42 trials, low-dose diuretics were found to pro-
vide significantly better benefits when several CV
outcomes and total mortality were studied16. More-
over, addition of an aldosterone receptor antagonist
such as spironolactone to any antihypertensive
agents including thiazide and thiazide-like diuretics
provides better CV risk benefits17. Studies such as
European Working Party on Hypertension in the
Elderly (EWPHE)18, Medical Research Council MRC
(elderly)14 and Veterans Administration (VA)19 have
shown some CV event reduction with hydrochloro-
thiazide. According to the International Nifedipine
GITS (Gastrointestinal Therapeutic System) Study:
Intervention as a Goal in Hypertension Treatment
(INSIGHT), CV outcomes of hydrochlorothiazide
and amiloride arm were found to be equal to cal-
cium antagonists20. However, the dose of hydro-
chlorothiazide used in these studies was in between
25 and 100 mg, which has the propensity to cause
severe adverse effects. Moreover, low doses (12.5–25
mg) of hydrochlorothiazide were shown to not
have any evidence of reduction in CV outcomes8.
On the other hand, thiazide-like diuretics such as
chlorthalidone and indapamide were shown to pro-
duce remarkable CV benefits. In the Multiple Risk
Factor Intervention Trial (MRFIT), chlorthalidone
was superior to hydrochlorothiazide in lowering CV
events and in inducing reduction of left ventricular
hypertrophy21,22. In the Antihypertensive and Lipid-
Lowering Treatment to Prevent Heart Attack Trial
(ALLHAT), chlorthalidone was found equivalent to
amlodipine and lisinopril in protecting from CV
events23.
In several landmark trials such as Hypertension
in the Very Elderly Trial (HYVET), Perindopril Pro-
tection Against Recurrent Stroke Study (PROG-
RESS), Action in Diabetes and Vascular Disease:
Preterax and Diamicron MR Controlled Evaluation
(ADVANCE) and Post-stroke Antihypertensive
Treatment Study (PATS), indapamide was consis-
tently superior in lowering BP and reducing stroke,
CV disease, and all-cause mortality24–27. In fact, the
HYVET study was terminated midterm due to phe-
nomenal 21% reduction in all-cause mortality in
the indapamide arm. Moreover, continuation of
indapamide for 1 more year in the HYVET trial has
shown even better reduction of 52% in all-cause
mortality28.
Furthermore, indapamide in combination with
perindopril has shown significant reduction in
stroke by 43% in PROGRESS trial and all-cause
mortality by 14%, CV mortality by 18% and renal
events by 21% in ADVANCE trial25,26. Notably, 2.5
mg immediate release or the superior 1.5 mg SR
dose of indapamide was used in these studies. Ad-
ditionally, in the X-CELLENT (The NatriliX SR
versus CandEsartan and amLodipine in the reduc-
tion of systoLic blood prEssure in hyperteNsive
patienTs study) trial, blood pressure variability
(BPV) was significantly reduced with indap-
amide29. Of late BPV has been proved to be one of
the prime causes of CV morbidity and mortality
in hypertensive patients. Furthermore, indap-
amide was demonstrated to be more effective in
reducing left ventricular mass index, preserving
renal function to a great extent than hydrochlo-
rothiazide, improving microalbuminuria (in dia-
betes patients), inhibiting platelet aggregation
 Chapter 9 — Which Diuretics for Which Patients with Hypertension? 69

TABLE 9-1 LIFE-SAVING BENEFITS WITH THIAZIDE-LIKE DIURETICS (BASED ON NNT)32

NNT to Prevent 1 Event NNT to Prevent 1 Event with NNT to Prevent 1 Event
Outcomes with Chlorthalidone Indapamide SR with Thiazide
Stroke 40 29 46
CV death 96 55 59
All-cause mortality 82 37 95

Note: NNT, Numbers needed to treat; CV, cardiovascular; SR, sustained release.

and reducing oxidative stress7,30. Apart from
this, common side effects on lipid and glucide
metabolism induced by diuretics are not shown
by indapamide31. Through a meta-analysis of 12
randomized controlled trials (RCTs), Thomopou-
los, et al.32 calculated numbers needed to treat
(NNT) stroke or CV death or all-cause mortality us-
ing chlorthalidone or indapamide SR or thiazide
diuretics (Table 9-1). The results clearly denote that
in all cases, NNT for indapamide are fairly lower
when compared to chlorthalidone or thiazides.
Adverse Events
Electrolyte abnormalities such as hyponatraemia
and hypokalaemia are a major concern with thia-
zide and thiazide-like diuretics. At equivalent dose,
chlorthalidone has higher hyponatraemia risk when
compared to hydrochlorothiazide11. Even though
hyponatraemia may occur with indapamide, it
seems to be a rare phenomenon30. Hypokalaemia is
another adverse effect seen in patients using these
three drugs. Nonetheless, indapamide 1.5 mg (SR) is
much safer in this respect, when compared to 2.5
mg immediate release33.
High doses of hydrochlorothiazide could increase
the risk of cardiac arrest34. Even in the Avoiding
Cardiovascular events through COMbination ther-
apy in Patients Living with Systolic Hypertension
(ACCOMPLISH) study, hydrochlorothiazide in com-
bination with ACE inhibitor increased the risk of
CV mortality, stroke and progression of CKD by
25%, 18% and 90%, respectively, when compared
to the same ACE inhibitor in combination with
amlodipine35. In addition, hydrochlorothiazide has
the propensity to cause new-onset diabetes as ob-
served in the International Verapamil-Trandolapril
Study (INVEST)36.
Similarly, chlorthalidone has also been reported
to increase the incidence of new-onset diabetes. In
the SHEP, chlorthalidone was associated with 50%
increase in risk when compared to placebo and in
ALLHAT, it was associated with 39% and 48% en-
hanced risk when compared to amlodipine and
lisinopril, respectively15,23. Furthermore, chlorthali-
done is also known to cause erectile dysfunction
in men. In the Trial of Antihypertensive Interven-
tions and Management (TAIM), 28% of men using
chlorthalidone had erection-related problems when
compared to 3% with placebo37. This can be a cause
of concern for male hypertensive patients. List of
contraindications for different diuretics is provided
in Table 9-2.
Scientific awareness about the benefits of thiazide-
like diuretics is not being properly translated into
clinical practice in India. This might be mainly due
to the availability of hydrochlorothiazide as FDC
with many other drugs, whereas such combinations
with indapamide are not commonly available in the
Indian market. Furthermore, physicians are usually
reluctant to shift from their routine practice into
providing new combinations and this can be over-
come through streamlined awareness programmes.
LOOP DIURETICS
Loop diuretics act on the thick ascending limb of
the loop of Henle at sites distinct to thiazide-like

TABLE 9-2 CONTRAINDICATIONS FOR DIURETICS

Diuretic Class Contraindication
Loop Hypovolaemia, hypokalaemia, hypomagnesaemia, hyperuricaemia, hyperglycaemia, hypercholes-
terolaemia, pregnancy
Thiazide and thiazide- Gout, postural hypotension, dizziness, hypokalaemia, hypovolaemia, hyponatraemia, hyperuricae-
like diuretics mia, new-onset diabetes, erectile dysfunction, hypercholesterolaemia, pregnancy
Potassium-sparing Hyperkalaemia
70 SECTION II — Preventive Cardiology
drugs and inhibit the largest amount of Na reab-
sorption2,38. Furosemide, torsemide, bumetanide
and ethacrynic acid are the common loop diuretics
available. Due to lack of proper outcome trials with
loop diuretics, they are not recommended as first-
line of therapy for hypertension treatment39. How-
ever, they can be prescribed in clinically significant
conditions such as advanced renal failure (eGFR 
30 mL/min, creatinine  1.5 mg/dL) and in treating
resistant hypertension caused due to excess salt and
water retention40,41.
POTASSIUM-SPARING DIURETICS
Potassium-sparing diuretics induce relatively low
natriuresis and are rarely used alone due to their
weak antihypertensive effect. As they prevent K loss,
potassium-sparing diuretics are used in combina-
tion with thiazide-like or loop diuretics which
have the propensity to cause hypokalaemia42. Fur-
thermore, their ability to reduce magnesium loss
provides a crucial advantage during the correction
of diuretic-induced hypokalaemia4. Combination
of potassium-sparing drugs with thiazide or loop
diuretics may further reduce BP and maintain nor-
mal potassium levels. Relatively weak diuretic
properties of potassium-sparing diuretics are espe-
cially beneficial in cirrhotic patients with ascites
where in other effective diuretics are hazardous43.
IMPORTANCE OF DIFFERENTIATING
INDIVIDUAL DRUGS WITHIN THE
SAME CLASS AND SUBCLASS
A conspicuous message visible from the above infor-
mation is that the diuretics constitute a heteroge-
neous subgroup of agents with varied mechanisms of
action which ultimately cause diuresis and BP reduc-
tion. It has to be borne in the mind that each of
these subclasses has different efficacy, safety, benefits
and adverse events profile. Not only that, even with
in the subclass, individual agents (chlorthalidone
TABLE 9-3 THIAZIDE AND THIAZIDE-LIKE DIURETICS USAGE IN DIFFERENT PATIENT GROUP (BASED
ON AVAILABLE EVIDENCES)3,6,15,24
Hydrochlorothiazide
(12.5 mg)
Young hypertensives (50 years)  
Elderly hypertensives (50 years)  
Systolic HT  
Hypertensive with diabetes NA
and indapamide or spironolactone and eplerenone)
have dissimilar characteristics. Therefore, physicians
have to carefully choose appropriate drugs from this
diverse pack and tailor the treatment to individual
patient’s symptoms and features. Table 9-3 provides
information about which thiazide or thiazide-like
diuretic can be given in which type of patient group.
PLACE OF DIURETICS IN DIFFERENT
GUIDELINES
Diuretics were formerly considered as one of the
most effective antihypertensive agents and were
frequently recommended as the preferential first-
line therapy41. High doses of diuretics were used
initially due to the assumption that higher the
dose, higher the BP reduction. As evidence emerged
on the adverse effects of high doses of diuretics,
guidelines started recommending the use of low-
dose diuretics. After the introduction of new agents
such as ACE inhibitors and ARBs, diuretics are
downgraded to one of the possible first-line therapy
among a large pool of antihypertensive mole-
cules41,44–47. Nonetheless, the WHO guidelines
recommend low-dose diuretic as the preferential
first-line therapy due to comparative trial data,
availability and cost, unless there is a strong indica-
tion for other class of drugs48. Within the thiazide
and thiazide-like diuretics, the longer acting thia-
zide-like diuretics (chlorthalidone and indapamide)
are preferred more in comparison to the thiazide
drugs46. Furthermore, thiazide and thiazide-like di-
uretics are considered as preferential treatment
choice in a variety of circumstances such as salt-
sensitive patients and elderly patients with systolic
hypertension41, whereas in other clinical scenarios,
they are recommended as one among the five first-
line antihypertensive agents. Diuretics are highly
effective in reducing the BP when used in combina-
tion with ACE inhibitors and ARBs.
However, hypotension could occur with the use
of these combinations which can be circumvented
Indapamide
(1.5 mg SR) Chlorthalidone (12.5–25 mg)
 (use with caution in males due to risk of
erectile dysfunction)


 
 Chapter 9 — Which Diuretics for Which Patients with Hypertension? 71

by skipping a dose of diuretic before starting with
either ACE inhibitor or ARBs49. Other types of di-
uretics including loop diuretics and potassium-
sparing diuretics are not mentioned in the guide-
lines frequently and are underutilized. Role of
diuretics in the management of hypertension as
recommended in different guidelines is provided
in Table 9-4. Even though various recommenda-
tions encourage individualized treatment based
on patient characteristics, majority of guidelines
are based on evidence for drug classes rather than
individual drugs50. Nonetheless, Australian and
National Institute for Health and Clinical Excel-
lence (NICE) guidelines specifically recommend to

TABLE 9-4 ROLE OF DIURETICS IN THE MANAGEMENT OF HYPERTENSION AS PER VARIOUS

GUIDELINES
Guidelines Condition Recommendation on Diuretics
51
JNC 8 Hypertensive nonblack and black patients, with Thiazide-like diuretic as initial therapy
or without diabetes
Canadian Diastolic hypertension with or without systolic • Thiazide-like diuretics as initial monotherapy or in
guidelines hypertension combination with other drugs
201746 Isolated systolic hypertension without other • Thiazide-like diuretics as initial monotherapy
indications
Nondiabetic CKD with proteinuria • Diuretics as additive therapy
Diabetes mellitus
• With microalbuminuria, renal disease, CV • Second-line therapy with thiazide/thiazide-like diuretic
disease or additional CV risk factors but combination of a dihydropyridine CCB is preferred
• Loop diuretic is considered in hypertensive CKD patients
with extracellular fluid volume overload
• Without above factors • Thiazide/thiazide-like diuretics as initial therapy
CV disease
• LVH, past stroke or TIA • Thiazide/thiazide-like diuretics as initial therapy
• Heart failure • Thiazide/thiazide-like or loop diuretics as additive therapy
NICE 201145 Heart failure, oedema, people aged 55 years • Thiazide as first-line therapy
• If diuretic treatment is to be initiated or changed, thia-
zide-like diuretic should be offered as first-line therapy
Resistant hypertension in step 4 treatment • Low-dose spironolactone if K levels  4.5 mmol/L
• Higher dose thiazide-like diuretic if K levels  4.5 mmol/L
NHFA 201647 Uncomplicated hypertension • Thiazide diuretics as first-line antihypertensives
• Thiazide diuretics in combination with ACE inhibitor
or ARB as second-line drug in presence of heart failure
or poststroke
• Potassium-sparing diuretics in combination with ACE
inhibitor or ARB as combination to use for care
• Amiloride in patients with hyperaldosteronism who do
not tolerate spironolactone
• Loop diuretics in case of volume overload
ASH/ISH All hypertensive black patients with/without • Thiazide diuretic as initial drug treatment
201449 diabetes, all hypertensive white patients aged
 60 years
Hypertensive white patients  60 years • Thiazide diuretic as second-line treatment
Hypertensive patients with diabetes or CKD or • Thiazide diuretics as second-line therapy; indapamide is
clinical coronary artery disease or stroke specifically recommended in patients with stroke history
ESH/ESC Hypertension • Diuretics (thiazides, chlorthalidone, indapamide) as ini-
201344 tial drug treatment, either as monotherapy or in combi-
nation with beta blockers, CCB, ACE inhibitors and ARBs
Isolated systolic hypertension in elderly, black • Diuretic is preferred
individuals
Metabolic syndrome • Diuretics only as additional drugs, preferably in association
with a potassium-sparing agent

Note: ASH, American Society for Hypertension; CCB, calcium channel blocker; ESC, European Society of Cardiology; ESH, European
Society for Hypertension; ISH, International Society for Hypertension; JNC, Joint National Committee; LVH, left ventricular hyper-
trophy; NHFA, National Heart Foundation of Australia; TIA, transient ischaemic attack.
72 SECTION II — Preventive Cardiology
prescribe thiazide-like diuretics such as chlorthali-
done or indapamide while initiating or changing
treatment45,47.
CONCLUSION
Prime objective of treating hypertension, as ascer-
tained by many hypertension guidelines, is to reduce
CV morbidity and mortality. Despite the proven CV
benefits, diuretics are losing their fame due to fear of
side effects such as electrolyte imbalance, diabetes
and sexual dysfunction. One reason behind this is
looking at all diuretics as a single class. Physicians
must realize that each and every diuretic is different
so much so that within a subclass, individual drugs
have different safety, side effect and benefit profiles,
which is exemplified by chlorthalidone and indap-
amide, both belonging to thiazide-like diuretics
but still may produce different side effects. Further-
more, low-dose use of thiazide-like diuretics is not
associated with significant adverse events and even
the prevailing mild effects can be circumvented
with careful monitoring and by providing adjunct
medications.
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