Received: 25 May 2021 Revised: 1 November 2021 Accepted: 13 November 2021

DOI: 10.1111/bcp.15156

META-ANALYSIS

Effect of diuretics on plasma aldosterone and potassium in

primary hypertension: A systematic review and meta-analysis

Ryan J. McNally | Bushra Farukh | Philip J. Chowienczyk | Luca Faconti

Department of Clinical Pharmacology, King's

College London British Heart Foundation
Centre, London, UK
Correspondence
Luca Faconti, Clinical Pharmacology,
St Thomas' Hospital, London, UK, SE1 7EH.
Email: luca.faconti@kcl.ac.uk
Funding information
British Heart Foundation; Department of
Health via the National Institute for Health
Research
Aim: By contrast with drugs inhibiting the renin-angiotensin-aldosterone system
(RAAS), diuretics stimulate renin release by the kidneys. Although plasma aldosterone
(PA) is thought to be mainly regulated by RAAS activity, serum potassium has been
shown to be an important factor in animal models and humans. Here we perform a
systematic review and meta-analysis of randomised controlled trials (RCT) in hyper-
tension investigating the effects of diuretic therapy on PA and the correlation of
change in PA with that of potassium and blood pressure (BP).
Methods: Three databases were searched: MEDLINE, EMBASE and the Cochrane
Central Register of Controlled Trials (CENTRAL). Titles were first screened by title
and abstract for relevance before full-text articles were assessed for eligibility
according to a predefined inclusion/exclusion criteria.
Results: A total of 1139 articles were retrieved, of which 42 met the prespecified
inclusion/exclusion criteria. The average standardised difference in mean PA was
similar for all classes of diuretic: thiazide/thiazide-like 0.299 (95% confidence interval
[CI] 0.150, 0.447), loop 0.927 (0.37, 1.49), MRA/potassium-sparing 0.265 (0.173,
0.357) and combination 0.466 (0.137, 0.796), Q = 6.33, P = .097. In subjects
untreated with another antihypertensive, there was a significant relationship
between change in PA and change in systolic BP but no relationship with the change
in potassium.
Conclusion: In RCTs of diuretic therapy in hypertension, there is an increase in PA
with all classes of diuretic and no significant between-class heterogeneity. Change in
PA is not related with potassium but correlates with the change in BP in subjects
untreated with another antihypertensive medication.

KEYWORDS
aldosterone, blood pressure, hypertension, potassium, renin

1 | I N T RO DU CT I O N RAAS are a cornerstone in the treatment of hypertension, working at

least in part by reducing the formation or blocking the effects of
The renin-angiotensin-aldosterone system (RAAS) is a complex neuro- angiotensin II and plasma aldosterone (PA), an independent cardiovas-
endocrine system that regulates salt and water homeostasis and blood cular risk factor promoting cardiovascular and renal inflammation,
pressure (BP) amongst several other actions.1 Drugs that inhibit the fibrosis and cardiovascular remodelling.2

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium,
provided the original work is properly cited.
© 2021 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

1964 wileyonlinelibrary.com/journal/bcp Br J Clin Pharmacol. 2022;88:1964–1977.


MCNALLY ET AL.
Compared to RAAS inhibitors, diuretics have a more complex
mechanism of action3 which includes an initial reduction in plasma
volume and a sustained decline in peripheral resistance, thereby
improving an underlying haemodynamic defect of hypertension.4–7
Under acute and chronic conditions, diuretics induce an increase in
plasma renin activity (PRA)8 but whether diuretics also increases PA
9
has been debated. Apart from the level of activation of the RAAS,
potassium,10–12 which is also affected by diuretic treatment, plays an
important role in the regulation of PA production and some diuretics
(such as mineralocorticoid receptor antagonists) are known to have
direct inhibitory action on aldosterone formation.
The objective of the present study was to perform a systematic
review and meta-analysis of randomised clinical trials (RCTs) where
diuretics were used to treat hypertension and measurements of PA
were available before and after diuretic treatment to determine if
they lead to a sustained increased in PA and whether this differs
according to class of diuretic. Secondary objectives were to
establish if there is correlation between difference in PA and that of
serum potassium and if the decrease in BP relates to the difference
in PA.
2 | METHODS
2.1 | Search strategy
This systematic review and meta-analysis was carried out in accor-
dance with PRISMA (Preferred Reporting Items for Systematic
Reviews and Meta-Analyses) guidelines,13 similarly to our previously
published review.14 A systematic literature search was performed on
three databases: Ovid MEDLINE (1946 to 16 September 2020),
EMBASE (1974 to 16th September 2020) and the Cochrane Central
Register of Controlled Trials (CENTRAL) databases (up to
16 September 2020). Studies which were included were trials of
diuretics used either as mono- or multitherapy in hypertension, and
which examined how they affected plasma aldosterone +/ renin,
serum potassium and blood pressure. The keywords used included
“thiazide”, “thiazide-like”, “potassium-sparing”, and “diuretic”. Medi-
cal subject headings (MeSH) and non-MeSH terms were used to sea-
rch the databases for relevant publications. The full search strategy
for MEDLINE is provided in the Supporting Information. The review
protocol was not registered but the PROSPERO database was
searched before starting the review to ensure that a similar review
was not ongoing.
2.2 | Study selection and eligibility criteria
Papers were initially screened by title and abstract. Studies were
eligible for inclusion if they were an RCT performed in hypertensive
human subjects ≥18 years old, examining antihypertensive effects of
a thiazide, thiazide-like, loop, mineralocorticoid receptor antagonist
(MRA) or potassium-sparing diuretic with a duration of at least
1 week. Studies investigating novel diuretics or “diuretic-like” drugs
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1965
not currently licensed for clinical use were excluded as were studies
in which subjects had pulmonary arterial hypertension or heart
failure. We included in the analysis all the diuretic compounds
currently licenced in the UK for the treatment of arterial
hypertension. We also included drugs which were licenced for hyper-
tension at the time that the original study was conducted. All studies
were required to have examined PA with results available before and
during diuretic treatment or, in the case of placebo-controlled trials,
during treatment with placebo. Studies were eligible if diuretic
therapy was added to either no previous therapy or to stable
background treatment. The search was limited to the English
language only and review articles were disregarded. Titles and
abstracts were screened by one author (R.J.M.), and the same author
reviewed the full-text articles.
2.3 | Data collection process
Data were extracted independently by one author (R.J.M.) using a
standard form. This included author, year of publication, class of
diuretic(s) and dose used, protocol (including presence of background
therapy and whether placebo controlled), sample size, average age,
sex distribution, ethnicity (if available) and prevalence of diabetes
(if available). For the outcome measurements, mean (± standard
deviation/standard error) of values for BP and aldosterone before and
during diuretic (and before and during placebo treatment in placebo-
controlled studies) and the difference between values on and before
treatment were extracted from the relevent articles. Where available,
the differences in renin, serum potassium and systolic blood pressure
(SBP) were extracted. If standard deviations were not reported these
were calculated from standard errors, P values or confidence intervals.
The duration of diuretic treatment at the time of measurement was
also recorded. Where only graphical reports of measurements were
available, an estimation from the graph was taken if it was judged to
be accurate to within 10%. Units of aldosterone were converted to
pmol/L for analysis if other units were used.
2.4 | Quantitative data synthesis and statistical
analysis
Meta-analysis was conducted using Comprehensive Meta-Analysis
Software Version 3 (Biostat, Englewood, New Jersey, USA).15 Net
changes in PA, renin, potassium and SBP were obtained as the
difference from baseline after treatment with either diuretic or
placebo. If there was no standard error of the mean change stated, it
was estimated from the P value, number of observations and size of
the change. A random-effects model was used to compensate for
between-study heterogeneity in terms of demographic inconsis-
tencies and different diuretic doses16 with calculation of the
standardised mean difference in PA and its 95% confidence interval
(CI). The standardized mean difference expresses the size of the inter-
vention effect in each study relative to the standard deviation of the
measurement (in this case PA). Raw mean differences were calculated

1966
for plasma potassium, and SBP and standardised differences for PRA.
Statistical heterogeneity was assessed using Cochran's Q test.17
P < .05 was considered statistically significant and all tests were
two-tailed.
2.5 | Meta-regression
Random-effects meta-regression was performed using the method of
moments to evaluate the association between standardised difference
in PA and change in SBP in the overall data and in subjects previously
untreated with another antihypertensive. The same method was used
to examine the association between change in PA and change in
serum potassium.
2.6 | Publication bias
Potential publication bias was assessed by inspection of Begg's funnel
18
plot asymmetry and Egger's asymmetry tests. We did not perform
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MCNALLY ET AL.
any risk of bias within individual studies because we were not
examining the primary outcome of the studies.
3 | RE SU LT S
3.1 | Description of studies
The study selection process is detailed in a flow chart as per PRISMA
guidelines (Figure 1). The initial MEDLINE search returned 191 results,
Embase 384 and Central 564 (1139 in total). After removal of dupli-
cates there were 967 articles of which 769 were excluded based on
title and abstract. The remaining 198 full-text articles were assessed
for eligibility and 156 were excluded for various reasons (Figure 1).
The remaining 42 articles were included in the qualitative synthesis.
MRA and potassium-sparing diuretics were grouped together for the
analysis as only one study had measurements for a potassium-sparing
diuretic (amiloride) with the remainder MRA. The most commonly
used diuretic class was the MRA/potassium-sparing class. Classes of
F I G U R E 1 PRISMA diagram.
Flow-chart of included and
excluded studies against a
predefined search criteria
 T A B L E 1 Summary of randomized controlled antihypertensive trials in which plasma aldosterone (PA) was measured before and after treatment with a placebo/diuretic in one or more arms or
treatment phases

Time
MCNALLY ET AL.

Study design, Male measured Aldosterone Aldosterone Serum K

Study ID, year Diuretic, dose sample size Age (years) (%) (weeks) unit before Aldosterone after + before Serum K + after
Hood, 200719 SPIRO 50-100 mg Crossover, 51 59.5 ± 11.9 54 10 Pmol/L 375 (276-438) 1116 (893-1339) 4 (3.9-4.1) 4.5 (4.4-4.6)
Hood, 2007* AMIL 20-40 mg Crossover, 51 59.5 ± 11.9 54 10 Pmol/L 375 (276-438) 963 (797-1129) 4 (3.9-4.1) 4.8 (4.6-4.9)
Hood, 2007* BENDRO 2.5-5 mg Crossover, 51 59.5 ± 11.9 54 10 Pmol/L 375 (276-438) 374 (330-419) 4 (3.9-4.1) 3.6 (3.4-3.8)
20
Ubaid-Girioli, 2009 SPIRO 25 mg Parallel, 39 … … 24 Ng/mL 15.4 ± 8.2 19.2 ± 9 4.2 ± 0.4 4.4 ± 0.5
Ubaid-Girioli, 2009* SPIRO 25 mg Parallel, 32 … … 24 Ng/mL 16.8 ± 5.4 22.3 ± 12.6 4.1 ± 0.3 4.3 ± 0.4
Weinberger, 200221 E 50 mg Parallel, 49 … 70 8 Ng/dL Mean-adjusted Mean-adjusted 4.26 …
changes changes
Weinberger, 2002* E 100 mg Parallel, 43 … 61 8 Ng/dL “ “ 4.17 …
Weinberger, 2002* E 400 mg Parallel, 52 … 64 8 Ng/dL “ “ 4.2 …
Weinberger, 2002* E 25 mg BD Parallel, 51 … 73 8 Ng/dL “ “ 4.18 …
Weinberger, 2002* E 50 mg BD Parallel, 49 … 70 8 Ng/dL “ “ 4.22 …
Weinberger, 2002* E 200 mg BD Parallel, 43 … 69 8 Ng/dL “ “ 4.20 …
Weinberger, 2002* SPIRO 50 mgBD Parallel, 42 … 75 8 Ng/dL “ “ 4.24 …
Weinberger, 2002* Placebo Parallel, 49 … 58 8 Ng/dL “ “ 4.2 …
Karns, 201222 E 50 mg BD Parallel, 33 56.2 ± 7.7 57.6 8 … % change % change reported … …
reported
Karns, 2012* Placebo Parallel, 33 59.8 ± 9.33 66.7 8 … “ “ … …
Vasavada, 200323 TORS 40 mg or Crossover, 14 67 ± 11 93 3 Ng/mL 7.46 ± 2.14 10.38 ± 2.14 (w1), … …
FURO 80 mg 11.47 ± 1.84 (w3)
Matsui, 201024 HCTZ 12.5 mg Parallel, 104 68 ± 9.1 40 24 Pg/mL 37 (32.2-42.5) 46.14 (est. from % … …
change)
Lijnen, 198125 HCTZ 100 mg Parallel, 5 37.2 ± 2.7 57.1 12 Ng% 4.28 ± 1.48 [SE] 8.11 ± 1.31 4.12 ± 0.15 3.44 ± 0.22
Lijnen, 1981* TIE 250 mg Parallel, 5 37.2 ± 2.7 57.1 12 Ng% 4.78 ± 1.25 5.15 ± 1.2 4.07 ± 0.12 3.68 ± 0.14
Lijnen, 1981* TIE 1000 mg Parallel, 4 37.2 ± 2.7 57.1 12 Ng% 2.72 ± 1.5 14.92 ± 1.18 4.08 ± 0.12 3.23 ± 0.16
Koenig, 199126 HCTZ 25 mg Crossover, 51 68 ± 8 20 12 & 24 Pg/mL 70.4 ± 30.6 91.5 ± 42 (3 m), 4.2 ± 0.4 4.5 ± 0.4 (3 m),
78.9 ± 31 (6 m) 4.3 ± 0.4 (6 m)
Saruta, 200427 Placebo Parallel, 48 54.3 ± 10.55 68 8 … % change % change reported … …
reported
Saruta, 2004* E50mg Parallel, 48 54.2 ± 11.3 63.3 8 … % change % change reported … …
reported
Saruta, 2004* E100mg Parallel, 45 52.8 ± 10.02 69.6 8 … % change % change reported … …
reported
1967

(Continues)

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 1968

TABLE 1 (Continued)

Time
Study design, Male measured Aldosterone Aldosterone Serum K
Study ID, year Diuretic, dose sample size Age (years) (%) (weeks) unit before Aldosterone after + before Serum K + after
Saruta, 2004* E200mg Parallel, 47 52.6 ± 10.76 72.9 8 … % change % change reported … …
reported
Chalmers, 198228 INDA 2.5 mg Crossover, 16 53 ± 10 44 8 Ng/100 mL 8 (placebo) 13.8 (INDA) 4.4 (placebo) 3.6 (INDA)
29
Calhoun, 2011 E 50 mg BD Parallel, 68 55.3 ± 9.1 59.7 8 Pmol/L 189.7 379.8 … …
Calhoun, 2011* Placebo Parallel, 60 53.9 ± 8.7 66.7 8 Pmol/L 181.7 172.3 … …
30
Svendsen, 1983 HCTZ+AMIL Parallel, 15 48.5 43 12 Pmol/L 208 478.4 3.3 3.80 (Est from %)
Ubaid-Girioli, 200731 HCTZ 25 mg Parallel, 18 49.3 ± 7.2 46 12 Ng/dL 9.1 ± 2.2 14.1 ± 1.4 … …
32
Ramsay 1981 SPIRO 25 mg Crossover, 14 50 43 4 Pmol/L 12.02 ± 1.70 15.85 ± 2.45 3 ± 0.43 3.37 ± 0.44
Ramsay 1981* SPIRO 50 mg Crossover, 14 50 43 4 Pmol/L 12.02 ± 1.70 31.62 ± 1.41 3 ± 0.43 3.52 ± 0.48
Ramsay 1981* SPIRO 100 mg Crossover, 14 50 43 4 Pmol/L 12.02 ± 1.70 34.67 ± 1.32 3 ± 0.43 3.83 ± 0.43
Ramsay 1981* SPIRO 200 mg Crossover, 14 50 43 4 Pmol/L 12.02 ± 1.70 42.66 ± 1.78 3 ± 0.43 3.91 ± 0.35
33
O'Connor, 1980 HCTZ Crossover, 19 50.1 ± 2.6 100 4 Pg/mL 48.3 ± 8 [SE] 98.4 ± 19 4.1 ± 0.1 3.8 ± 0.1
Ferguson, 198234 HCTZ 50 mg Crossover, 4 51 66 2 Ng/dL 13.5 (group 1), 21.8 (group 1), 20.8 … …
11.6 (group 2) (group 2)
Matthesen, 201235 AMIL 5 mg BD Crossover, 23 60 (45-70) 60.9 4 Pmol/L 84 (placebo) 303 … …
Matthesen, 2012* SPIRO 25 mg BD Crossover, 23 60 (45-70) 60.9 4 Pmol/L 84 (placebo) 299 … …
Ni, 201436 SPIRO 25 mg Parallel, 40 55.7 ± 12.3 60 12 Pg/mL 23.8 ± 10.9 24.5 ± 11 4.1 ± 1.5 4.4 ± 0.7
Ni, 2014* Placebo Parallel, 36 54.9 ± 14.2 58.3 12 Pg/mL 23.4 ± 10.2 23.5 ± 9.8 3.9 ± 0.9 4.1 ± 1.4
Koopmans, 198737 HCTZ 50 mg OD Crossover, 9 50.5 ± 9.1 55.6 4 Ng/100 mL 8.5 ± 4.8 11.8 ± 5.2 3.8 ± 0.17 3.2 ± 0.26
Swaminathan, SPIRO 25-50 mg Crossover, 33 62.6 … 4 Pmol/L 150.84 ± 83.1 264.33 ± 107.81 4.4 ± 0.3 4.8 ± 0.37
200838 (placebo)
Kreeft, 198339 CLTD 100 mg Crossover, 19 42-66 52.6 8 Ng/L 7.8 ± 4.8 11.56 ± 10.9 4.31 ± 0.4 3.35 ± 0.3
Kreeft, 1983* SPIRO 400 mg Crossover, 19 42-66 52.6 8 Ng/L 7.8 ± 4.8 14.4 ± 13.3 4.31 ± 0.4 5 ± 0.6
Jarvis, 201540 HCTZ 12.5-25 mg Parallel, 10 68 ± 6 50 24 Ng/dL 5.4 ± 4.7 11.8 ± 10.5* … …
41
Yang, 2016 SPIRO 20-40 mg Parallel, 15 44.7 ± 10.8 … 12 Ng/dL 18 ± 5.4 8.2 ± 3.3 4.3 ± 0.3 4.3 ± 0.2
Karashima, 201642 HCTZ 6.25 mg Parallel, 22 65 ± 1 68 48 Pg/mL 87 ± 6 (SEM) 83 ± 5 4.1 ± 0.1 4.1 ± 0.1
Karashima, 2016* E 50 mg Parallel, 23 66 ± 2 68 48 Pg/mL 85 ± 7 103 ± 1* 4.2 ± 0.1 4.3 ± 0.1
Karashima, 2016 SPIRO Parallel, 27 56.1 ± 9.9 40.7 48 Pg/mL 128 ± 55 244 ± 84 3.9 ± 0.3 4.3 ± 0.3
12.5-100 mg
Karashima, 2016* EPLER 25-100 mg Parallel, 27 54.9 ± 10.7 48.1 48 Pg/mL 140 ± 60 184 ± 88 3.9 ± 0.3 4.2 ± 0.3
43
Ferrara, 1988 CLTD 25 mg Parallel,16 49 ± 8 50 6 Pg/mL 222 ± 105 320 ± 227 … …
Ferrara, 1988* Placebo Parallel, 16 49 ± 8 50 6 Pg/mL 327 ± 185 356 ± 166 … …
MCNALLY ET AL.

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 TABLE 1 (Continued)

Time
Study design, Male measured Aldosterone Aldosterone Serum K
MCNALLY ET AL.

Study ID, year Diuretic, dose sample size Age (years) (%) (weeks) unit before Aldosterone after + before Serum K + after
Derosa, 201844 CAN 50-100 mg Parallel, 81 53.4 ± 7.2 53.4 24 & 48 Pg/dL 143.1 ± 22.5 121.8 ± 16.5 (6 m), 3.9 ± 0.4 4.1 ± 0.6 (6 m),
104.6 ± 13.2 4.3 ± 0.7
(12 m) (12 m)
Derosa, 2018* HCTZ 12.5-25 mg Parallel, 82 52.6 ± 6.9 48.8 24 & 48 Pg/dL 153.8 ± 25.6 164.1 ± 27.9 (6 m), 4.1 ± 0.5 3.8 ± 0.4 (6 m),
169.4 ± 30.6 3.5 ± 0.3*
(12 m) (12 m)
Henning, 198045 AMIL+HCTZ Crossover, 43 … 56.4 8 Pmol/L 416 1257 4.26 3.82
Krum, 200246 Placebo (added to Parallel, 60 54.7 51 8 Ng/dL 6.9 6.7 4.36 +0.06 ± 0.04
ACE)
Krum, 2002* Placebo (added to Parallel, 58 55.1 40 8 Ng/dL 7.4 6.9 4.28 +0.05 ± 0.03
ARB)
Krum, 2002* EPLER 50-100 mg Parallel, 63 55.7 47 8 Ng/dL 7.1 11.8 4.32 +0.14 ± 0.04
(+ ACE)
Krum, 2002* EPLER 50-100 mg Parallel,64 54.2 49 8 Ng/dL 7.8 12.4 4.31 +0.20 ± 0.04
(+ ARB)
Derosa, 201647 CAN 50 mg Parallel, 87 57.15 ± 8.91 65.5 12 Pg/dL 58.64 ± 54.67 77.76 ± 72.14 4.25 ± 0.43 4.50 ± 0.45
Derosa, 2016* CAN 100 mg Parallel, 88 57.75 ± 9.18 63.6 12 Pg/dL 68.77 ± 63.19 68.50 ± 66.01 4.32 ± 0.72 4.65 ± 0.40
Belleau, 198248 HCTZ 50 mg Crossover, 18 44 (23-58) 54.6 4 Ng/100 mL 10.99 ± 5.6 10.90 ± 4.84 … …
Fouassier, 202049 SPIRO+FUR Parallel, 73 53.7 ± 10.3 79 12 Pmol/L 104 (69-152) 270 (177-344) 3.8 ± 0.4 4.3 ± 0.5
+AMIL median + IQR
Dorresteijn, 201350 HCTZ 25 mg Crossover, 29 60 (55-63) 74 8 Ng/L Placebo: 53 87 4.1 (4-4.5) 3.82
(33-74)
median IQR
Parthasarathy, SPIRO 75-225 mg Parallel, 61 53.2 ± 10.92 73.2 4 & 16 Ng/dL 20.1 37.7 (4w), 44.1 (16w) … 3.93 (w4), 3.95
201151 (w16)
Parthasarathy, E 100-300 mg Parallel, 67 53.9 ± 10.89 62.9 4 & 16 Ng/dL 18.6 26.4 (4w), 33.3 (16w) … 3.84 (w4), 3.95
2011* (w6)
Solini, 201952 HCTZ 12.5 mg Parallel, 20 62 ± 8 70 4 Pg/mL 1.44 ± 0.95 1.01 ± 0.43 4.57 ± 0.35 4.47 ± 0.31
53
Ohta, 2015 EPLER 50 mg Crossover, 20 71 ± 13 55 12 Ng/dL 15.4 ± 8.0 21.0 ± 11.8 4.3 ± 0.5 4.8 ± 0.4
Ohta, 2015* INDA 1 mg Crossover, 20 71 ± 13 55 12 Ng/dL 15.4 ± 8.0 20.2 ± 9.3 4.3 ± 0.5 4.2 ± 0.4
54
Vaclavik, 2014 Placebo Parallel, 76 59.7 ± 9.9 63.2 8 Ng/L 117 111 4.1 ± 0.5 +0
Vaclavik, 2014 SPIRO 25 mg Parallel, 74 60.4 ± 9.5 67.6 8 Ng/L 87 143 4.1 ± 0.5 +0.4
55
Kithas, 2010 HCTZ Parallel, 21 69 ± 6 52.4 24 Ng/dL 106 ± 49 157 ± 9 3.8 ± 0.4 3.8 ± 0.4
Kithas, 2010* SPIRO Parallel, 24 70 ± 5 58.3 24 Ng/dL 107 ± 51 300 ± 37 4.1 ± 0.2 4.2 ± 0.3

(Continues)
1969

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1970 MCNALLY ET AL.

diuretic were thiazide/thiazide-like (21/42, 50%), MRA/potassium-

Abbreviations: AMIL, amiloride; BENDRO, bendroflumethiazide; CAN, canrenone; CLTD, chlortalidone; E, eplerenone; FURO, furosemide; HCTZ, hydrochlorothiazide; INDA, indapamide; SPIRO, spironolactone;
Serum K + after
sparing (28/42, 67%), loop (4/42, 9.5%) and combination (3/42, 7%).
Individual diuretics were hydrochlorothiazide, amiloride, indapamide,

4.3 ± 0.2

3.4 ± 0.1

3.1 ± 0.2
bendroflumethiazide, chlorthalidone, canrenone, furosemide,
spironolactone, eplerenone, tielinic acid and torsemide. Details of indi-
vidual trials are summarised in Table 1. In those studies where
patients where previously treated with another antihypertensive med-
+ before
4.2 ± 0.1

4.0 ± 0.1

3.8 ± 0.1
Serum K

ication before the diuretic was added, an Angiotensin-converting

enzyme (ACE) inhibitor/Angiotensin II Receptor Blocker (ARB) was
…

included in over 50%. For renin subanalysis, plasma renin activity

(PRA) was used as this was the most common measure.
Aldosterone after

9.1 ± 3.4 & 22.8

12.5 ± 3.1 & 39
234.6 ± 37.3*

3.2 | Primary outcome meta-analysis: Effect of

85.4 ± 18.4

± 15.2

placebo and diuretic on plasma aldosterone

± 5.9

Placebo had a negligible effect on PA in the present analysis

(Figure 2D). The standardized difference in mean PA after placebo
6.1 ± 1.3 (supine)

4.1 ± 0.9 (supine)

was 0.11 (95% CI 0.36, 0.14). With diuretic therapy, all diuretic
± 9 (supine)
Placebo: 66.1
212.7 ± 31.3
Aldosterone

classes led to a significant increase in PA but there was no between-

before

class heterogeneity (Figure 2A). The average standardised difference

in mean PA change was: thiazide/thiazide-like 0.299 (0.150, 0.447),
loop 0.927 (0.37, 1.49), MRA/potassium-sparing 0.265 (0.173, 0.357)
Aldosterone

and combination 0.466 (0.137, 0.796), Q = 6.33, P = .097. In studies

Ng/100 mL

Ng/100 mL
Pmol/L

where there was no background antihypertensive use, the average

Pg/mL
unit

increase in PA was 0.398 (0.229, 0.566; Figure 2B). There was a

similar increase in PA for those in whom diuretic was added to
previous antihypertensives: 0.301 (0.040, 0.563; Figure 2C). After
measured

separating MRA from potassium-sparing diuretics, the same homoge-

(weeks)
Time

neity between classes was found.

24
4

6
Male

3.3 | Secondary outcomes meta-analysis: Effect of

100
(%)

80

80
…

placebo and diuretic on serum potassium, plasma renin

activity and blood pressure
Age (years)

51.6 ± 2.7

45 ± 5

54 ± 3

Changes in serum potassium were thiazide/thiazide-like 0.239

( 0.40, 0.08) mEq/L, loop 0.617 ( 0.98, 0.254) mEq/L, K
…

+ sparing/MRA 0.248 (0.152, 0.344) mEq/L and combination 0.048

Crossover, 12
Study design,

( 0.324, 0.420) mEq/L, with significant between-class heterogeneity

sample size
Parallel, 17

Parallel, 11

Parallel, 9

(Q = 41.5, P < .001; Figure 3). The analysis of PRA and SBP can be
found in the Supporting Information. Of the 42 included studies,
26 had differences in SBP, 26 had differences in serum potassium and
23 had differences in PRA both before and after diuretic. All diuretics
CLTD 100 mg/day

CLTD 100 mg/day

(nonresponders)

decreased blood pressure significantly, apart from the loop diuretics,

(responders)
Diuretic, dose

*More than one result in the same study.

FURO 40 mg
CAN 50 mg

with combination diuretics lowering SBP by the largest amount

( 23.4 [ 35.56, 11.28] mmHg). In studies where there was no
background antihypertensive use, the average decrease in SBP was
(Continued)

13.46 ( 18.53, 8.39) mmHg and was similar to those in which

diuretic was added to previous antihypertensives: 14.94 ( 19.04,
10.83) mmHg.
Olshan, 198157
56
Study ID, year

Meier, 198258

TIE, tienilic acid.

Meier, 1982*
Grandi, 2002

The overall average increase standardised mean PRA difference

TABLE 1

was 0.556 (0.272, 0.846) with a similar trend in both previously

untreated subjects and those receiving another antihypertensive
medication.

MCNALLY ET AL.
F I G U R E 2 Forest plots displaying
standardized difference in mean PA and 95%
confidence intervals: (A) overall,
(B) previously untreated with another
antihypertensive, (C) previously treated with
another antihypertensive and (D) placebo.
Std diff, standardised difference; CI,
confidence interval; MRA, mineralocorticoid
receptor antagonists. A positive difference
indicates an increase after diuretic
3.4 | Meta-regression: Relation of change in
plasma aldosterone to that of serum potassium after
diuretic
Random-effects meta-regression was also used to examine whether
the change in PA was associated with that of serum potassium and
we found there was no relationship (coefficient 0.09, 95% CI
0.15, P = .466; Figure 4A) with similar findings in studies where the
participants were on no background therapy (coefficient 0.14, 95%
CI 0.36, 0.07, P = .186; Figure 4B).
3.5 | Meta-regression: Relation of change in SBP
to change in plasma aldosterone
Random-effects meta-regression was performed to examine whether
change in SBP was associated with change in PA. In the overall
13652125, 2022, 5, Downloaded from https://bpspubs.onlinelibrary.wiley.com/doi/10.1111/bcp.15156 by Cochrane Philippines, Wiley Online Library on [27/04/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
1971
population, changes in SBP were independent of changes in PA
(coefficient 0.005, 95% CI –0.019, 0.008, P = .44; Figure 5A). How-
ever, in studies where the participants were not on background treat-
ment with another antihypertensive, there was a significant
relationship between the change in SBP and change in PA (coefficient
0.02, 95% CI –0.034, 0.01, P < .001; Figure 5B).
0.32,
3.6 | Publication bias
The funnel plot of standard error vs effect size was asymmetric and
suggestive of potential publication bias. Presence of publication bias
was also suggested by Egger's linear regression (P = < 0.001). After
adjustment of effect size for potential publication bias using the “trim
and fill” correction, 14 potentially missing studies on the left side of
the funnel plot were imputed, leading to a corrected overall effect size
that was slightly but not significantly less than the initial estimate
(0.21 (95% CI 0.17-0.26; Figure 6).

1972
4 | DISCUSSION
As far as we are aware, this is the first study to systematically
review the effect of diuretic therapy on PA and the relationship of
change in PA with that of serum potassium and BP in hypertensive
individuals. The abstract of this manuscript was submitted and pres-
ented at the British and Irish Hypertension Society Annual Scientific
Meeting.59 Diuretics have been used in treatment of hypertension
for more than 50 years,60 both as monotherapy and in combination
with other anti-hypertensive agents. They are safe, effective, well
tolerated61,62 and considered as first line pharmacological agents in
specific populations.63 However, the short- and long-term mecha-
nisms of action of the various classes of diuretics has been debated.
Chronic diuretic treatment leads to an increase in PRA suggesting
activation of the RAAS.14 Whether the raised PRA is accompanied
by an increase in PA and if this relates to specific classes of
13652125, 2022, 5, Downloaded from https://bpspubs.onlinelibrary.wiley.com/doi/10.1111/bcp.15156 by Cochrane Philippines, Wiley Online Library on [27/04/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
MCNALLY ET AL.
F I G U R E 3 Forest plots displaying raw
difference in mean plasma potassium and
95% confidence intervals: (A) overall,
(B) previously untreated with another
antihypertensive, (C) previously treated
with another antihypertensive and
(D) placebo. CI, confidence interval; MRA,
mineralocorticoid receptor antagonists. A
positive difference indicates an increase
after diuretic
diuretics and/or concomitant change of serum potassium is
unknown.
The main finding of the present meta-analysis is that diuretics
lead to an increase in PA that does not differ significantly between
classes of diuretic, but which is significantly associated with change in
SBP in previously untreated subjects. In the studies where PRA was
also measured before and after treatment, a raise in PRA occurred
(a finding in line with a previously published systematic review14),
demonstrating activation of the RAAS, which is likely to be the driver
of the increased PA.
Whether activation of the RAAS could be harmful has been
debated. The RAAS is a complex system in which angiotensin II acts
through two main receptor subtypes, the AT1 and AT2 receptors. All
classic physiological effects of angiotensin II, such as vasoconstriction,
aldosterone production and water retention, are largely mediated by
the AT1 receptor which promotes hypertension, endothelial

MCNALLY ET AL.
F I G U R E 4 Meta-regression plot of the
association between mean changes in PA
with diuretic therapy and the change in
serum potassium (mEq/L) in (A) overall and
(B) previously untreated with another
antihypertensive. Std diff, standardised
difference
dysfunction, vascular remodelling and end organ damage. On the
other hand, the AT2 receptor elicits antithrombotic, anti-inflammatory
64
and natriuretic effects. Thus, the activation of the RAAS could have
complex actions according to the balance of the activation between
the AT1 and AT2 receptors which counteract each other in their
biological actions on the cardiovascular system.65,66 However, the
increase in PA is thought to have a number of adverse actions,
including renal inflammation, fibrosis and cardiovascular remodelling.2
Whilst there is evidence that PRA is helpful in selecting patients
who will benefit from diuretic therapy,67 the potential use of change
in PRA in guiding dose-titration and selecting class of diuretic remains
speculative and was not confirmed by a recently published systematic
review.68 PA is another potential biomarker that could be used to
13652125, 2022, 5, Downloaded from https://bpspubs.onlinelibrary.wiley.com/doi/10.1111/bcp.15156 by Cochrane Philippines, Wiley Online Library on [27/04/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
1973
guide treatment. In our analysis the change in SBP related to that of
PA. Failure of PA to rise after initiation of a diuretic could therefore
be used to assess adherence to diuretic therapy and to guide dose
adjustment, although this is speculative and would require testing in
prospective studies. It could be also speculated that the use of a
concomitant medication might play a role in limiting the rise in PA,
which in turn could have a beneficial effect per se since that
aldosterone may cause cardiac remodelling without affecting arterial
pressure.69–71
Apart from the RAAS, the other major factor regulating aldoste-
rone secretion is potassium. In humans and in experimental animals,
alterations in potassium balance as well as acute increments in serum
potassium can stimulate aldosterone production. For example, in
 13652125, 2022, 5, Downloaded from https://bpspubs.onlinelibrary.wiley.com/doi/10.1111/bcp.15156 by Cochrane Philippines, Wiley Online Library on [27/04/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
1974 MCNALLY ET AL.

F I G U R E 5 Meta-regression plot of the

association between mean changes in PA with
diuretic therapy and the change in SBP in
(A) overall and (B) previously untreated with
another antihypertensive. SBP, systolic blood
pressure; Std diff, standardised difference

F I G U R E 6 Funnel plot displaying

publication bias in the studies reporting
the impact of diuretic therapy on PA
change. Open diamond represents
observed effect size; closed diamond
represents imputed effect size. Std diff,
standardised difference

MCNALLY ET AL.
normal subjects, infusion of 10 mEq of potassium produces a 25%
increase in plasma aldosterone.10 Changes in dietary potassium intake
for as little as 24 hours can also substantially modify the secretion of
aldosterone from the adrenal glands induced by acute potassium
administration: high dietary potassium intake enhances aldosterone
secretion, while low potassium intake reduces it.11 Our results suggest
that variation of serum concentration of potassium per se has a lim-
ited effect in regulating PA. However, there are suggestions that this
mechanism could be relevant in specific populations.72
Finally, the subanalysis investigating MRA showed similar effects
of these agents on PA compared to other diuretic classes. It has been
reported that similarly to other RAAS inhibitors,73,74 after an initial
suppression/blockade of aldosterone, the PA level often returns to
normal or even rises above pre-treatment levels.75,76
This review is subject to several limitations. We were unable to
stratify results by ethnicity (and difference in RAAS activity between
ethnic groups have been described) because the majority of studies
were performed in Caucasians and in many studies ethnicity was not
reported. Studies in specific ethnic groups will be required to
determine if effects of diuretics on PA differ according to ethnicity.
The use of background therapy in some studies and a variable dose in
others prevent a useful estimate of the effect size relating to a
standard dose of diuretic. The duration of studies was relatively short
and very few studies were performed with loop diuretics (which are
not commonly used in hypertension). The MRA/potassium sparing
group was mostly composed of spironolactone, which in many trials
was used at high dose unrepresentative of its current use in primary
hypertension. Finally, the present study is limited by the lack of
availability of some full-text articles.
In conclusion, this systematic review and meta-analysis demon-
strates that diuretic therapy in hypertension leads to an increase in
PA which does not differ between classes of diuretics. The use of
drugs that might antagonise the effects of this rise in PA or the combi-
nation of other diuretics with RAAS inhibitors is a rational means to
prevent the adverse effects of this rise in PA, but whether such a
treatment strategy leads to BP-independent effects remains to be
tested.
4.1 | Nomenclature of targets and ligands
Key protein targets and ligands in this article are hyperlinked to
corresponding entries in http://www.guidetopharmacology.org, the
common portal for data from the IUPHAR/BPS Guide to PHARMA-
COLOGY, and are permanently archived in the Concise Guide to
PHARMACOLOGY 2019/20.77,78
ACKNOWLEDGMENTS
Ryan McNally was supported by an interdisciplinary studentship from
the British Heart Foundation, King's BHF Centre of Research Excel-
lence. The authors acknowledge financial support from the Depart-
ment of Health via the National Institute for Health Research (NIHR)
comprehensive Biomedical Research Centre and Clinical Research
Facilities awards to Guy's and St Thomas' NHS Foundation Trust in
13652125, 2022, 5, Downloaded from https://bpspubs.onlinelibrary.wiley.com/doi/10.1111/bcp.15156 by Cochrane Philippines, Wiley Online Library on [27/04/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
1975
partnership with King's College London and King's College Hospital
NHS Foundation Trust.
COMPETING INTER ESTS
The authors have no conflict of interest to declare.
CONT RIB UTOR S
All authors developed the study concept and designed the research.
R.J.M. conducted the electronic searches, study selection and
extraction. R.J.M. and L.F. performed data analysis, and B.F. helped to
interpret the results. R.J.M., L.F. and P.J.C. wrote the majority of the
manuscript. All authors read and approved the final version of the
manuscript.
DISCLOS URES
None.
OR CID
Ryan J. McNally https://orcid.org/0000-0003-2395-183X
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How to cite this article: McNally RJ, Farukh B,
Chowienczyk PJ, Faconti L. Effect of diuretics on plasma
aldosterone and potassium in primary hypertension: A
systematic review and meta-analysis. Br J Clin Pharmacol.
2022;88(5):1964-1977. doi:10.1111/bcp.15156