RAAS blockers: Best taken at bedtime

Hypertension commonly occurs in conjunction with insulin resistance, while activation of the renin–angiotensin–aldosterone system (RAAS) contributes to increased hepatic glucose release and decreased insulin sensitivity. Furthermore, hyperglycaemia increases serum aldosterone levels. Consequently, in addition to its blood pressure (BP)-lowering effects, RAAS blockade might also serve as an effective strategy to control impaired glucose tolerance. This concept has been illustrated by large studies, in which RAAS-blocking therapy was associated with a reduction in new-onset type 2 diabetes (Gillespie et al, 2005; Putnam et al, 2012).

Various clinical trials have suggested that different dose timings may result in different BP-lowering therapeutic effects. This may be particularly relevant in the case of RAAS blockade, as this system is highly circadian and activates during night-time sleep (Portaluppi et al, 2012). There is also a wealth of data to suggest that nocturnal BP may be a particularly important mediator of cardiovascular risk (Hermida et al, 2012), while elevated nocturnal BP has also been identified as a predictor of new-onset diabetes (Hermida et al, 2016). Based on such considerations, the latest study by Hermida and colleagues (summarised alongside) is the first to prospectively investigate whether bedtime administration of the entire daily dose of one or more hypertension medications offers better protection against development of new-onset diabetes than morning therapy, and whether RAAS inhibition or blockade is superior to any other treatment strategy for achieving this objective.

This was a prospective, randomised, open-label, blinded-endpoint trial of 2012 hypertensive people without diabetes: 976 men and 1036 women, with an average age of 52.7±13.6 years. The participants were randomised to ingest their prescribed hypertension medications either upon awakening or at bedtime. Investigators blinded to the treatment scheme assessed the development of new-onset diabetes. During a 5.9-year median follow-up, 171 participants developed type 2 diabetes. Compared with the morning-treatment group, the bedtime group showed the following:

• Significantly lower sleep-time mean BP, greater sleep-time relative BP decline and an attenuated prevalence of non-dipping at the final evaluation.
• A significantly lower risk of new-onset diabetes after adjustment for fasting glucose level, waist circumference, asleep systolic BP, dipping classification and presence of chronic kidney disease (hazard ratio [HR], 0.43; event rate 4.8% vs 12.1%).
• Greater benefit in terms of new-onset diabetes risk with angiotensin receptor blockers (ARBs; HR, 0.39), angiotensin-converting enzyme inhibitors (ACEIs; HR, 0.31) and beta-blockers (HR, 0.35).

Thus, according to this unique study, in hypertensive people without diabetes, ingestion of the entire daily dose of one or more BP-lowering medications at bedtime, compared with ingestion upon waking, results in significantly improved asleep BP control and prevention of new-onset diabetes. Moreover, the safety of the bedtime- and morning-treatment regimens was similar, while RAAS antagonism with bedtime ACEI or ARB treatment was superior to any other treatment strategy for reducing the risk of new-onset diabetes. The results of this study have significant implications for routine practice and strategies to reduce the risk of incident diabetes, particularly in the context of NHS England’s widely publicised objective of reducing the incidence of type 2 diabetes.

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