Table 2.

Effects of time-dependent dosing for treatment of HTN: reviewed studies (2013-2017) of populations with specific comorbid conditions (obstructive sleep apnea, chronic kidney disease, or diabetes).

Obstructive Sleep Apnea
Reference	Country	Study Design	Participants details	HTN definition	Follow up (month)	Morning anti- hypertensive medications	Evening anti- hypertensive medications	Measures of BP	Ancillary Measures	Results
Crippa et al. 2016 (138).	Italy.	Post-hoc analysis of observational study; current drug regimen (baseline [group 1]) vs. addition of bedtime antihypertensive medication to current drug regimen (group 2); no blinding.	56% male; aged 69 ± 17 y; 100% untreated moderate-to-severe OSA; 78% non-dippers; 22% reverse-dippersb. (n=41).	Mean daytime ABPM >135/85 mmHg and mean nighttime ABPM >120/70 mmHg.	3.	Group 1 and 2: ACEI, ARB, β-blockers, early distal tubule diuretics.	Group 1: none. Group 2: Addition of 10 mg CCB at 10-11 PM.	24 h ABPM.	Adverse effects.	Group 2 compared to group 1 ↓ in daytime and nighttime BP; dipping BP was normalized in 78% of participants; 3 developed mild symptomatic diurnal hypotension; and 6 showed mild-to-moderate leg oedema.
Kario et al. 2014 (141).	Japan.	Prospective, parallel-group, Crossover, RCT; comparison of nighttime single-dose administration of a CCB vs. β-blocker on sleep BP in OSA patients. Analysis blinded to treatment group.	73% male; aged 65±13 y; 100% AHI ≥15; untreated by CPAP; no prior bedtime hypertensive drugs, renal failure, or severe liver dysfunction. (n=11).	Sleep BP (measured by ABPM) ≥120/70 mm Hg.	0.03.	3±1aincluding: 54% CCB, 18% ACEI, 73% ARB, and 36% diuretics.	CCB or β-blocker administered at 6PM.	Sleep SBP surge (hypoxia-peak SBP), mean sleep BP, morning BP.	Polysomnography parameters (i.e. AHI/hour)	CCB and β-blocker ↓mean sleep and morning SBP and DBP compared to baseline; CCB had more extensive lowering effect than β-blocker. β-blocker ↓ sleep BP surge and pulse rates.
Kasiakogias et al. 2015 (137).	Greece.	Prospective, open label, fixed-dose, cross-over study; morning vs. bedtime dosing, BP measures taken by physician blinded to study protocol.	78% male; aged 52 ± 9 y; BMI 34 ± 6 kg/m2; AHI mean 31 (21-45) events/hour; 61% severe OSA (AHI ≥ 30 events/hour); 49% treated with CPAP; without daytime somnolence, ESS 6 ± 3. Patients were without secondary HTN; diabetes; established CVD; CKD or pulmonary disease. (n=41).	Office SBP/DBP ≥140/90 mmHg recorded following 5 min of rest in quiet place, average of 2nd and 3rd readings taken in 2 minute intervals and confirmed by mean 24 h ABPM >130/80 mmHg.	2.	ARB or fixed combination of ARB/CCB in a single dose before breakfast; 8-9 AM.	Same as morning (crossover design); 2 hours before bedtime.	Office BP (measured 8-9 AM before morning pill) and 24h ABPM.	N/A.	Morning and evening dosing ↓office and 24 h ABPM SBP/DBP compared to baseline; evening dosing ↓ office and nighttime SBP/DBP compared to morning dosing. Prevalence of nighttime dippers ↑from 24% at baseline to 34% with morning dosing and 61% with bedtime dosing. No interaction with CPAP treatment.
Serinel et al. 2016 (142).	Australia.	Double-blind, placebo-controlled, crossover RCT followed by open-label in final study phase; effects of morning vs. evening antihypertensive administration with placebo at opposite time point; treatment sequence performed by independent company by block design with results stored in sealed envelopes.	81% male, aged 52 ± 9 y; BMI, 34 ± 7 y; 48 ± 23 AHI, events/hours; 9% T2D; 1% stroke, 7% heart disease; on <3 antihypertensive medications not including ACEI or ARB at randomization (49% on 0; 42% on 1; and 8% on 2 antihypertensive medications); participants were free from serve OSA (minimum oxygen saturation ≤65% or respiratory disturbance index >80), excessive sleepiness, and CKD. (At randomization n=85; 92% completed study-results not presented in an intention to treat format).	Office SBP 140-179 mmHg and/or DBP 90-109 mmHg AND 24 h ABPM with awake SBP ≥135 and/or DBP ≥85 mmHg OR asleep SBP ≥120 and/or DBP ≥70 mmHg; excluded if office SBP ≥180 and/or DBP ≥110 mmHg.	1.5 dosing; 2 dosing + CPAP.	9 AM administration of ACEI + 9 PM placebo + previously prescribed medication regimen; final 8 weeks addition of CPAP.	Same drug dosing (crossover study) at 9 PM + 9 AM placebo; final 8 weeks addition of CPAP.	24h ABPM-sleep and 24h BP, BP dipping ratios, and office BP.	Sleep and wake times (Actigraphy, sleep diary); adverse events.	Sleep SBP and DBP ↓from baseline with both evening and morning dosing of ACEI, no difference between dosing groups; wake SBP and DBP ↓more with morning than evening dosing. CPAP ↓sleep SBP and DBP with morning and evening dosing, no difference between dosing time.
Yoshida et al. 2017 (139).	Japan.	Case report; use of bedtime antihypertensive dosing to improve hypoxia-triggered nocturnal SBP surge and early-morning BP.	Young adult male with severe OSA with BP surge during sleep measured by TSP followed by sleep onset stroke 3x, CPAP intolerance.	N/A.	24.	N/A.	Bedtime dosing of selective α-1 blocker (time not specified).	Overnight TSP.	N/A.	↓In hypoxia-triggered nocturnal SBP surge and early-morning BP.
Chronic Kidney Disease
Reference	Country	Study Design	Participants details	HTN definition	Follow up (month)	Morning anti- hypertensive medications	Evening anti- hypertensive medications	Measures of BP	Ancillary Measures	Results
Crespo et al. 2013 (162).	Spain.	Cross-sectional study; all medications upon awakening (group 1), ≥1 medications at bedtime (group 2) in hypertensive patients with CKD.	60% male; aged 65±13 y; 100% CKD with eGFR <60 mL/min/1.73 m2 and/or albuminuria. (n=2659; group 1, n=1446).	Uncontrolled HTN: awake SBP/DBP mean ≥135/85 mm Hg and/or asleep SBP/DBP mean ≥120/70 mm Hg.	N/A.	Group 1: 3†±1 including 74% ARB, 21% ACEI, 72% CCB, 41% α-blocker, 30% β-blocker, and 69% diuretics. Group 2: Varied.	Group 1: none. Group 2: 2†±1 including 59% ARB, 13% ACEI, 33% CCB, 13% α-blocker, 11% β-blocker, and 23% diuretics.	48h ABPM, office BP (2x seated BP after 10 min rest).	Clinical laboratory test including: fasting glucose, serum creatinine, uric acid, cholesterol, triglycerides, and eGFR.	Group 2 significantly ↓mean sleep SBP/DBP, prevalence of non-dippingb pattern, total cholesterol, LDL vs. group 1. Prevalence of non-dipping and glucose, creatinine, and uric acid further ↓with all medications taken at bedtime. Riser BP significantly ↑with morning medication, than ≥1 medications at bedtime, or than all medications at bedtime with significant difference between all groups.
Sakai et al. 2013 (238).	Japan.	Observational; comparison of twice daily ARB (morning and evening) vs. once daily (morning only) ARB.	58% male; aged 70±12 y; 100% CKD; mean eGFR 49±18 mL/min/1.73 m2. (n=39).	N/A.	2.	Pre-study: 20 mg ARB. Study dose: 40 mg ARB.	Pre-study: 20 mg ARB. Study dose: None.	Average of 2x office and morning at-home BPs after 5 min rest.	Renal function/preoteinuria: eGFR, urinary albumin-to-creatinine ratio.	No significant change in BP. ↑ eGFR with morning-only dose.
Rahman et al. 2013 (170).	United States.	Open-label, multicenter, 3 period, crossover, RCT; standard morning medication regimen vs. ≥1 medication moved to bedtime, OR an additional medication added to drug regimen at bedtime; no blinding.	64% male; aged 65 ± 10 y; 100% African American; 60% BMI > 30 kg/m2; HTN mean 30 years; 45% non-dipper; 29% reverse dipperb. Participants had not suffered a MI or cerebrovascular accident within 3 months prior to study enrollment and had an EF >40%. (n=147).	Office BP ≤140/90 mm Hg based on 2 BP values measured >1 week apart and currently prescribed 1 antihypertensive medication taken 1x daily, 2 antihypertensive medications with >1 taken 1x daily, or ≥3 antihypertensive medications with >2 taken 1x daily.	1.5.	All participants-all medications 4a.	In 49% of participants 1 antihypertensive medication moved to bedtime (72.5% ACEI; 15% ARB; and 12.5% CCB) In 48% of participants >2 antihypertensive medication moved to bedtime. For add-on schedule, 49.5% received hydralazine; 18.1% diltiazem; 7.6% ramipril; and 24.8% received another medication.	Nocturnal SBP; 24h ABPM, office BP.	N/A.	Nocturnal, 24h, nor daytime SBP significantly differed by treatment timing.
Wang et al. 2013 (239).	China.	Prospective, RCT; comparison of awakening dose in dipping (group 1) vs non-dipping BP (group 2), or bedtime dose in non-dipping BP (group 3) of an ARB; no blinding.	67% male; aged 36±9 y; 100% CKDb and free from CV disorders.	Standard ABPM dipping criteriab.	3.	Group 1: ARB BP dippers. Group 2: ARB BP non-dippers. Group 3: none.	Groups 1/2: none. Group 3: ARB non-dippers.	24h ABPM.	Cardiac ultrasound; urinary protein, creatinine, and sodium excretion.	Group 3 ↓ nocturnal SBP ↑renal protection (slower decline in eGFR) and target organ protection, and ↓proteinuria, vs. group 2.
Diabetes
Reference	Country	Study Design	Participants details	HTN definition	Follow up (month)	Morning anti- hypertensive medications	Evening anti- hypertensive medications	Measures of BP	Ancillary Measures	Results
Ciobanu et al. 2015 (189).	Romania.	Cross-sectional; no medication (group 1) vs. ≥1 antihypertensive medications at morning (group 2) or ≥1 antihypertensive medications at bedtime (group 3).	44% male; T2D; no unstable CV conditions, severe infections, malignancies, or eGFR <30ml/min/1.73m3. (n=144; bedtime, n=60; morning, n=56; no medications, n=28).	SBP and DBP were measured at least 2x after 10 minutes of sitting rest, measures were obtained and averaged from both arms.	N/A	Medications included ACEI, ARB, B-blocker, Diuretic, and CCB.	ACEI (n=38); ARB (n=17); β-blocker (n=45); Diuretic (n=39); CCB (n=25); α-antagonist (n=4).	24h ABPM, dipping index.	HTN duration, CVD, T2DM duration.	↑dipping BP in group 3 compared to group 1 or 2. Bedtime medication use (group 3) associated with ↑ presence of CVD.
Hermida et al. 2016 (191).	Spain.	Prospective, open-label, blinded endpoint, single-center RCT; replacement of one antihypertensive medication with a new one ingested upon awakening (group 1) vs. at bedtime (group 2).	48% male; aged 52±13 y; no diabetes at baseline; no secondary HTN or CVD. Groups had similar distributions of OSA (8-9%); metabolic syndrome (47-50%); obesity (38-39%); previous CV events (6-7%); and non-dipping BPb (44-45%). (Total participants, n=2012; group 1, n=1029).	Awake SBP/DBP mean ≥135/85 mmHg or asleep SBP/DBP mean ≥120/70 mmHg.	70.8 (12-107).	Group 1: all medications (n=2 ±1): 62% ARB, 21% ACEI; 35% CCB; 21% alpha-blocker; 20% beta-blocker; 36% diuretic. Group 2: varied	Group 1: none. Group 2: ≥1 medications (n=2 ±1): 60% ARB, 19% ACEI; 37% CCB; 22% alpha-blocker; 22% beta-blocker; 36% diuretic. Unspecified which drugs were taken at bedtime.	48h ABPM recorded annually (or quarterly if treatment was adjusted).	New-onset diabetes	Bedtime medication (group 2) ↓mean sleep SBP/DBP and HR of new-onset diabetes, ↑ dipping and ABPM control vs. morning medication group. Ingesting ACEIs, β-blocker, or ARB at bedtime compared to morning ↓ risk of new-onset diabetes; non-significance with other drug classes, but may be due to limited sample size of individual treatment-class.
Hjortkjaer et al. 2016 (188).	Denmark.	Placebo-controlled, double-blind, two-way cross-over, RCT; comparison between morning and bedtime dosing of an ACEI in patients type 1 diabetes and with cardiac autonomic neuropathy. Double blinded.	42% male; aged 60±7 y; BMI 25±4 kg/m2; diabetes duration 36±11 y; 71% prescribed antihypertensive treatment. (n=24).	N/A.	3.	ACEI + placebo at bedtime + previously prescribed medication regimen.	Same as morning (crossover design) with placebo in the morning.	24h ABPM, nighttime SBP/DBP, BP-dippingb.	Left ventricular function.	Bedtime dose ↑ SBP dipping compared to morning dose. No changes in daytime BP or left ventricular function.
Rossen et al. 2014 (190).	Denmark.	Open-label crossover study, RCT; morning vs. bedtime administration of participants’ 1x daily medication; unclear blinding.	73% male; aged 65 (54-75) y; 100% T2D; no presence of MI, AF, or known HF with EF<45%. (n=41).	Nighttime SBP ≥120 mmHg and daytime SBP: 1) ≤130 mmHg and minimum 1 antihypertensive drug, 2) 131-135 mmHg and minimum 2 antihypertensive drugs, 3) 136-140 mmHg and minimum 3 antihypertensive drugs, or 4) 141-150 mmHg and minimum 4 antihypertensive. Office BP measured 4 times, reported average of the latter 3.	2.	Median # number of once-daily antihypertensive drugs, 3(1-6); median # twice-daily antihypertensive drugs 3 (1-6). Drugs by class included ACEIs, ARBs, β-blockers, CCBs, and Thiazide. All once-daily drugs included a RASI	Same as morning (crossover design).	24 h ABPM, office BP, pre-awakening morning BP surge; sleep-trough morning BP surge; nadir-average.	Arterial stiffness, autonomic dysfunction, creatinine, HbA1c, cholesterol, parameters of RAAS, markers of endothelial dysfunction, markers of inflammation, arginine vasopressin, atrial natriuretic peptide, sleep duration, time of drug intake, nighttime bathroom, and adverse events.	Bedtime administration of antihypertensive drugs ↓nightime and 24h SBP. Urinary sodium/creatine and potassium/creatine ↑, urinary osmolality ↓, and C-reactive protein (inflammation marker) ↓with bedtime administration.
Meta-analysis
Wang et al. 2017 (161).		Meta-analysis comparing evening vs. morning dosing regimen of antihypertensive drugs on BP patterns of CKD patients with HTN.	5 RCTs and 1 comparative study:40-64% male; mean age 36-70 y. (n=3582).	SBP and/or DBP ≥140 and/or ≥90 mmHg.	1-70.					Evening dosing regimen drug therapy ↓percentage of non-dipper BP patterns, nocturnal SBP and DBP.

Inclusive of original studies reviewed from January 2013 to December 2017.

^aMean number of medications taken in total.

^bNon-dipping BP defined as average nocturnal SBP reduction compared to average awake SBP (measured using ABPM) ≥0% but <10%; extreme dipper nocturnal SBP reduction ≥20%; and riser or reverse dipper when reduction <0%. ABPM, ambulatory blood pressure monitoring; ACEI, angiotensin-converting enzyme inhibitors; AF, atrial fibrillation; ARB, angiotensin II receptor blocker; BP, blood pressure; CCB, calcium channel blockers; CKD, chronic kidney disease; CVD, cardiovascular disease; DBP, diastolic blood pressure; EF, ejection fraction; ESS, Epworth sleepiness scale; HF, heart failure; HTN, hypertension; MI, myocardial infarction; OSA, obstructive sleep apnea; RAAS, renin-angiotensin aldosterone system; RASI, renin-angiotensin system inhibitor; RCT, randomized controlled trial; SBP, systolic blood pressure; T2D, type 2 diabetes mellitus; TSP, trigger sleep BP.