Bedtime ingestion of hypertension medications reduces the risk of new-onset type 2 diabetes: a randomised controlled trial

Diabetologia. 2016 Feb;59(2):255-65. doi: 10.1007/s00125-015-3749-7. Epub 2015 Sep 23.


Aims/hypothesis: We investigated whether therapy with the entire daily dose of ≥ 1 hypertension medications at bedtime exerts greater reduction in the risk of new-onset diabetes than therapy with all medications upon awakening.

Methods: We conducted a prospective, randomised, open-label, blinded endpoint trial of 2,012 hypertensive patients without diabetes, 976 men and 1,036 women, 52.7 ± 13.6 years of age. Patients were randomised, using a computer-generated allocation table, to ingest all their prescribed hypertension medications upon awakening or the entire daily dose of ≥ 1 of them at bedtime. Investigators blinded to the hypertension treatment scheme of the patients assessed the development of new-onset diabetes.

Results: During a 5.9-year median follow-up, 171 participants developed type 2 diabetes. Patients of the bedtime, compared with the morning-treatment group, showed: (1) significantly lower asleep BP mean, greater sleep-time relative BP decline and attenuated prevalence of non-dipping at the final evaluation (32% vs 52%, p < 0.001); and (2) significantly lower HR of new-onset diabetes after adjustment for the significant influential characteristics of fasting glucose, waist circumference, asleep systolic BP mean, dipping classification and chronic kidney disease (CKD) (unadjusted HR 0.41 [95% CI 0.29, 0.58]; adjusted HR 0.43 [0.31, 0.61]; event-rate 4.8% vs 12.1% with bedtime and morning treatment, respectively; p < 0.001). Greater benefit was observed for bedtime compared with awakening treatment with angiotensin receptor blockers (ARBs) (HR 0.39 [0.22, 0.69]; p < 0.001), ACE inhibitors (0.31 [0.12, 0.79], p = 0.015) and β-blockers (0.35 [0.14, 0.85], p = 0.021).

Conclusions/interpretation: In hypertensive patients without diabetes, ingestion of ≥ 1 BP-lowering medications at bedtime, mainly those modulating or blocking the effects of angiotensin II, compared with ingestion of all such medications upon awakening, results in improved ambulatory BP (ABP) control (significant further decrease of asleep BP) and reduced risk of new-onset diabetes.

Trial registration: NCT00295542.

Funding: This independent investigator-promoted research was supported by unrestricted grants from Ministerio de Ciencia e Innovación (SAF2006-6254-FEDER; SAF2009-7028-FEDER); Xunta de Galicia (PGIDIT03-PXIB-32201PR; INCITE07-PXI-322003ES; INCITE08-E1R-322063ES; INCITE09-E2R-322099ES; 09CSA018322PR); and Vicerrectorado de Investigación, University of Vigo.

Keywords: Ambulatory blood pressure monitoring; Bedtime therapy; Renin–angiotensin blockade; Sleep-time blood pressure; Type 2 diabetes.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antihypertensive Agents / administration & dosage*
  • Arousal / drug effects
  • Arousal / physiology
  • Blood Pressure / drug effects
  • Blood Pressure Monitoring, Ambulatory
  • Diabetes Mellitus, Type 2 / epidemiology
  • Diabetes Mellitus, Type 2 / prevention & control*
  • Drug Chronotherapy*
  • Female
  • Follow-Up Studies
  • Humans
  • Hypertension / complications
  • Hypertension / drug therapy*
  • Hypertension / physiopathology
  • Male
  • Middle Aged
  • Risk Factors
  • Sleep / physiology


  • Antihypertensive Agents

Associated data