The MAPEC study is the first, and thus far only, reported trial to assess prospectively the hypothesis that bedtime treatment with the entire daily dose of ≥1 hypertension medications exerts not only better BP control but better protection against new-onset diabetes than conventional therapy with all such medications ingested upon awakening. The results document, first, greater ABP control in hypertensive patients randomised to the bedtime-treatment group. The main differences between the bedtime vs morning-time treatment groups in terms of ABP control were achievement in the former of: (1) significantly lower asleep BP mean; and (2) greater sleep-time relative BP decline, without loss of awake BP-lowering efficacy (Table 2). The ingestion-time-dependent effects on asleep BP control were strongly associated with attenuated risk of new-onset diabetes. Indeed, in the MAPEC study the progressive decrease in the asleep BP mean during follow-up was the most significant predictor of reduced risk of new-onset diabetes, independent of other conventional variables associated with increased risk such as older age, larger waist circumference, elevated fasting glucose, and CKD diagnosis [20]. As documented in a series of prospective controlled trials extensively reviewed elsewhere [7, 8], bedtime hypertension treatment is the most cost-effective and simplest strategy of successfully achieving the therapeutic goal of adequate asleep BP reduction and control. One could thus conclude that the significant 57% reduction in the risk of new-onset diabetes by ingestion of the entire daily dose of ≥1 BP-lowering medications at bedtime, compared with ingestion of all such medications upon-waking (Fig. 2), is linked to better achievement of this novel hypertension therapeutic goal through therapeutic targeting of the underlying biological mechanisms. The total new-onset diabetes event-rate was somehow intermediate between that reported in the HOPE [5] and DREAM trials [6]; both of these trials had a lower follow-up than MAPEC, but in DREAM was restricted to patients with impaired fasting glucose and thus at higher risk for new-onset diabetes.

The randomisation for this trial, independently done for each of the allowed choices of hypertension medications, and the so-far unique approach of systematic periodic (at least annual) patient evaluation by highly reproducible 48 h ABPM to guide required changes in therapy, allowed prospective comparative investigation of the influence of different classes of hypertension medications on the risk of new-onset diabetes. The findings summarised in Figs 3, 4 document significant differences in risk of new-onset diabetes between individual classes of hypertension medications when treatment-time is taken into consideration. The adjusted HR of new-onset diabetes across all six classes of the tested hypertension medications was equivalent in those patients randomised to ingest all of them as full daily doses upon awakening (Fig. 3a). However, among patients randomised to the bedtime regimen, ingestion of an ARB, ACEI or β-blocker was associated with significantly lower HR of new-onset diabetes compared with ingestion of any other class of medication also at bedtime. We wish to emphasise that nebivolol was the β-blocker most participants were treated with, in fact, the only one allowed for first randomisation among untreated patients. Nebivolol is a third generation, long acting β-blocker medication that exerts endothelium-dependent vasodilation through activation of the l-arginine/nitric oxide pathway, significant reduction of glucose and lipids in patients with diabetes [35], and regulatory effect on the RAAS [36]. Accordingly, our findings might not be extrapolated to all β-blockers as a class, an issue that requires future investigation. With these considerations notwithstanding, the results depicted in Fig. 4 indicate that reduced risk of new-onset diabetes is significantly associated with RAAS blockade therapy ingested at bedtime. Since the RAAS activates during night-time sleep [9], the results also suggests, in keeping with the hypotheses for this trial, that bedtime, rather than upon awakening, RAAS inhibition or blockade and the corresponding potential improved control of impaired glucose and insulin tolerance might be among the factors associated with reduced risk of new-onset diabetes.

Our study has some potential limitations. First, sample size of the single-centre MAPEC study is limited to evaluate the potential predictive value of different hypertension medications within each therapeutic class. Second, the reported findings require validation in other ethnic groups. Finally, the use of a PROBE design might also be considered a limitation; however, the PROBE design was specifically developed for the conduct of long-term outcome trials, though it is also frequently used for the conduct of short-term efficacy clinical studies in patients evaluated in a blinded manner by ABPM. The design of the MAPEC Study also has several strengths [21], mainly being the first trial yet to: (1) provide results based on systematic periodic, at least annual, multiple evaluations by ABPM and wrist actigraphy throughout the median 5.9 years of follow-up; (2) define hypertension as an inclusion criterion based solely on ABP measurements; (3) prescribe changes in therapeutic intervention during follow-up to improve control of ABP, instead of daytime clinic BP; and (4) randomise patients either to ingest all BP-lowering medications upon awakening or the complete daily dose of ≥1 of them at bedtime, thus according to the individualised rest/activity cycle that synchronises the documented predictable-in-time 24 h changes in RAAS activation and BP patterning [9].

In conclusion, according to this prospective evaluation, in hypertensive patients without diabetes, ingestion of the entire daily dose of ≥1 BP-lowering medications at bedtime compared with ingestion of all such medications upon-awakening, results in significantly improved asleep ABP control and prevention of new-onset diabetes. Moreover, the safety of bedtime- and morning-treatment regimens was similar, a finding consistent with previous publications reporting bedtime compared with morning BP therapy significantly improves ABP reduction without any increase in adverse effects [37]. Finally, antagonism of the RAAS by reduction of angiotensin II formation and blockade of its receptors achieved either by a bedtime ACEI or ARB ingestion strategy is superior to any other treatment strategy for reducing risk of new-onset diabetes. Future prospective intervention trials that incorporate periodic, annually or more frequent, ABPM assessments during long-term follow-up evaluation, as done in the MAPEC study and the currently ongoing multicentre Hygia project [38, 39], are necessary to confirm the reduced risk of new-onset diabetes by bedtime hypertension chronotherapy.