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 .