DISCUSSION
As far as we are aware, this is the first study to systematically review
the effect of diuretic therapy on PA its correlation with potassium and
BP change in hypertensive individuals. Diuretics have been used in
treatment of hypertension for more than 50 years [18], both as
monotherapy and in combination with other anti-hypertensive agents.
Several investigations have confirmed that diuretic agents are safe,
effective, well tolerated [19,20] and can be considered as first
line pharmacological agent in specific populations [21]. However,
the short- and long-term mechanisms of action of the various classes of
diuretics has been debated and it is known that chronic diuretic
treatment leads to an increase in PRA suggesting activation of the RAAS.
Wherever the raised PRA would also be accompanied by an increase in PA
is still subject of debate and it is unclear if this relates to specific
classes of diuretics and/or concomitant change of serum potassium which
is an important regulator of aldosterone.
The main finding of the present analysis is that
diuretics lead to an increase in
PA, which doesn’t differ 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 review[22]) suggesting that increase in PRA
could be driven by activation of the RAAS.
Whether the increased PA could be harmful is subject of debate and
speculation on this topic are beyond the scope of this systematic
review. It is however important to stress here that the RAAS is a
complex system in which angiotensin II acts through two main receptor
subtypes, the AT1 and the AT2 receptor. 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 dysfunction, vascular
remodelling and end organ damage. On the other hand, AT2 receptors
elicits antithrombotic, ant inflammatory and natriuretic effects
[23]. Thus, the activation of the RAAS could have complex actions
according to the balance of the activation between the two types of
receptors which counteract each other in their biological actions on the
cardiovascular system [24,25].
Whilst there is evidence that PRA is helpful in selecting patients who
will benefit from diuretic therapy [26], 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 [27].
In that respect, a biomarker would be suitable for that use depending on
whether a change can be detected in response to diuretic treatment and
whether this relates to BP response. In our analysis the change in SBP
with that of PA suggests that change in PA, as opposed to pre-treatment
could be a useful marker to guide diuretic therapy (for example by
increasing diuretic dose if there is inadequate rise in PA). To confirm
this hypothesis, further studies are warranted. On the other hand it
could be also speculated that the use of a concomitant medication might
play a role in limiting the raise in PA which in turn could have a
beneficial effects per se since it has been suggested that aldosterone
could facilitate cardiac remodelling without affecting arterial pressure
[28–30]. To elucidate this point, dedicated investigations would
need to be designed and conducted.
We did not identify any correlation between change in serum potassium
and PA. Apart from RAAS, the other major factor regulating aldosterone
secretion is potassium. In man and in experimental animals, alterations
in potassium balance as well as acute increments in serum potassium can
stimulate aldosterone production. For example, in 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 hr can also substantially modify the secretion of aldosterone from
the adrenal glands induced by acute potassium administration: high
dietary potassium intake enhances responsiveness, while low potassium
intake reduces it [11]. Our results seem to suggest that variation
of serum concentration of potassium per se might have a limited effect
in regulating PA although there are suggestions that the mechanism could
be relevant in specific populations [31].
Finally, the sub-analysis investigating MRA showed similar effects of
these agents on PA compared to other diuretic classes. It has been
reported that similarly to other inhibitory drugs of the RAAS
[32,33], after an initial suppression/blockade of aldosterone, the
PA level often returns to normal or even rises above pre-treatment
levels for the so-called escape mechanism [34,35].
This review is subject to several limitations. We were unable to
stratify results by ethnicity (since well-established difference in RAAS
activity 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.
In conclusion, this systematic review and meta-analysis demonstrates
that diuretic therapy in hypertension leads to an increase in PA which
does not differ between classes of diuretics and which is related to the
fall in SBP in previously untreated subjects .