Efficacy and safety of morning or evening antihypertensive drug administration on albuminuria in hypertensive patients: an open-label pilot randomized controlled trial

Abstract

To date, little is known regarding the treatment effects of different timed-dosing antihypertensive medications among hypertensive patients with albuminuria. We aimed to investigate whether morning or evening dosing of antihypertensive medication differentially affects early changes in albuminuria.We conducted an open-label, single-center, assessor-masked, parallel-group, pilot randomized controlled trial among adult hypertensive patients with albuminuria (urinary albumin‒creatinine ratio [UACR] ≥ 30 mg/g) receiving at least one antihypertensive medication. The participants were assigned (1:1) to receive antihypertensive medications either in the morning (6:00–10:00 AM) or in the evening (6:00–10:00 PM), with a treatment follow-up at 3 months. The primary outcome was the change in the log UACR. The secondary outcomes were changes in blood pressure and kidney function. Post hoc outcomes included clinically meaningful control of outcomes.Among the 60 participants enrolled (mean age, 65.6 years; proportion of females, 51.7%; median UACR, 116.1 mg/g), 58 patients completed the trial. The absolute changes in log UACR over 3 months were − 0.21 (95% CI, -0.40 to -0.03; n = 31) for morning-dosing and − 0.22 (95% CI, -0.46 to 0.01; n = 27) for evening-dosing, with an adjusted difference of -0.01 (95% CI, -0.32 to 0.30; P = 0.955) between the groups. No statistically significant difference was observed for secondary and post hoc outcomes. No safety profile concerns were identified. Among hypertensive patients with albuminuria, chronotherapy, whether administered in the morning or evening, did not affect early treatment outcomes in terms of the UACR, blood pressure, or kidney function. Trial registration: Thai Clinical Trials Registry (TCTR); TCTR20240930002; Registration date: 30/09/2024; retrospectively registered.

Introduction

Hypertension is a major risk factor for premature death from cardiovascular disease, stroke, and kidney disease, affecting approximately 10.8 million people worldwide¹. Albuminuria is common and occurs in 40% of untreated hypertensive patients^2,3. The link between hypertension and kidney damage is explained by glomerular hypertension and increased selective permeability of the glomerular basement membrane^4,5. Existing studies have also revealed an association between albuminuria and the risk of developing coronary artery disease and chronic kidney disease (CKD)^6,7. Oliveras et al. reported that patients with a reduced estimated glomerular filtration rate (eGFR) were more likely to have microalbuminuria and that elevated nighttime blood pressure was correlated with albuminuria⁸. Moreover, elevated evening blood pressure is also associated with left ventricular hypertrophy, a well-known traditional risk factor for cardiovascular diseases and mortality^9,10.

With respect to circadian variations, the interconnection between circadian blood pressure rhythms and adverse health outcomes has been recognized^11–13. Several mechanisms have been proposed to explain these associations, such as autonomic dysfunction during the night or disruptions in the sleep‒wake cycle. A longitudinal 21-year follow-up study by Lempiäinen (2024) revealed that a nondipping blood pressure pattern—characterized by a nighttime dip and a morning rise—is associated with an increased risk of cardiovascular events (hazard ratio [HR], 4.01; 95% confidence interval [CI], 1.89–8.67; P < 0.001)¹⁴. Moreover, other evidence supports the finding that morning hypertension is associated with an increased risk of acute myocardial infarction, sudden cardiac death, and cardiovascular disease peaks between 6 AM and 12 PM, partially explained by the diminished control of morning-dosing during the nighttime hours^11–13.

To date, evidence among hypertensive patients with or without kidney complications has shown that timed antihypertensive administration mimicking endogenous circadian rhythms might offer a potential benefit for better blood pressure control, particularly for nocturnal blood pressure and improving the circadian rhythm^15–19. To our knowledge, given these circadian patterns, apart from their practicability and convenience, no known clinical trials have established the impact of timed antihypertensive administration on kidney outcomes among hypertensive patients with albuminuria. As such, in this pilot randomized controlled trial (RCT), we aimed to investigate whether morning or evening dosing of antihypertensive medication differentially affects early changes in the urinary albumin-to-creatinine ratio (UACR) and has additional effects on blood pressure and kidney function among hypertensive patients with albuminuria.

Methods

Study design

The Efficacy and Safety of Morning or Evening Antihypertensive Drug Administration on Albuminuria in Hypertensive Patients (MORE) trial is an open-label, single-center, assessor-blinded, pilot randomized controlled trial with parallel groups, with follow-up for 3 months. The study was conducted at Vajira Hospital, Navamindradhiraj University, a tertiary hospital in Thailand. The study protocol was approved by the Vajira Ethics Committee (No. 032/2564; Date of approval: 24/02/2021). Written informed consent was obtained from all participants. The study was conducted in full compliance with the Declaration of Helsinki.

This clinical trial was registered with the Thai Clinical Trial Registry (TCTR20240930002; first registered 30/09/2024; retrospectively registered) and is available at https://www.thaiclinicaltrials.org/show/TCTR20240930002. The study was reported in line with the Consolidated Standards of Reporting Trials (CONSORT) statement²⁰ and its extension for randomized pilot and feasibility trials²¹.

Study population

Eligible participants were ambulatory adult Thai residents aged 18–80 years with hypertension diagnosed for more than one year between March 2021 and March 2022. The inclusion criteria were history of albuminuria, regular daytime activity and nighttime sleep, and treatment with at least one antihypertensive medication for more than 3 months, including an angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB). Eligible patients were prescreened from known hypertensive cases with a history of albuminuria. One UACR measurement was performed at baseline to confirm eligibility, and participants with UACR < 30 mg/g were excluded. No minimum prior duration of albuminuria was specified. The exclusion criteria were end-stage kidney disease (estimated glomerular filtration rate [eGFR] < 15 ml/min/1.73 m²), pregnancy, treatment with more than one dosing time regimen daily of antihypertensive therapy, regular night or rotating shift-work employment, secondary hypertension or resistant hypertension (uncontrolled blood pressure despite the concurrent use of three different antihypertensive classes), severe comorbid conditions (i.e., congestive heart failure, active cancer), current or recent hospitalization (within 3 months before enrollment), a history of psychological illness, nonadherence to treatment, or conditions that interfere with the ability to adhere to the study protocol.

Randomization and masking

On the basis of no restriction, stratification, or minimization approach, eligible participants were randomly assigned (1:1) to receive antihypertensive medications either in the morning (6:00–10:00 AM) or evening (6:00–10:00 PM) via a permuted block of four. Randomization was conducted by a blinded member of the research team. The allocation process was concealed via opaque envelopes, which were opened only upon enrollment, and informed consent was obtained from the participants. For practicability in routine care, participants and investigators were not masked; however, assessors of outcomes were masked.

Intervention and study procedures

All participants were treated with the maximum dose or tolerated dose of ACEIs or ARBs for more than 3 months before enrollment. The maximum or tolerated dose of ACEIs/ARBs was defined as the highest approved or clinically maintainable daily dose without symptomatic hypotension, hyperkalemia, or a clinically significant rise in serum creatinine, according to the treating physician’s judgment. Participants who were randomized to the evening-dosing group received all their antihypertensive medications once daily at 6:00–10:00 PM. Those who were treated with diuretics as part of the antihypertensive regimens were advised to take their dosing time at 6:00 PM to avoid the effects of nocturia. However, if nocturia persisted, the dosing time was adjusted to the morning. Participants taking diuretics were counseled at randomization by the treating investigator or study physician regarding the assigned dosing window. They were also counseled at baseline regarding the assigned dosing time and the possibility of nocturia. Because the medication taken in the morning was employed as the conventional time (6:00–10:00 AM), no change was recommended for participants who were randomized to the morning-dosing group.

During follow-up, both study groups were allowed to adjust antihypertensive medications on the basis of the office target blood pressure of 130/80 mmHg. Office blood pressure measurements were obtained via a calibrated approach as recommended by guidelines²². After the participants had rested in a seated position for 10 min, blood pressure was measured three times, and the mean office blood pressure of the last two values was calculated. Blood pressure measurements were performed at baseline and at 3 months of follow-up via a validated automatic oscillometric device with upper arm-cuff devices (HBP-9020; Omron Healthcare, Kyoto, Japan, or ES-P302; Terumo, Tokyo, Japan) according to the standard procedures recommended by the guidelines²³. All participants were instructed to record their daily logs at the time they took their antihypertensive medications.

Assessment of outcomes, post hoc outcomes, and adverse events

The primary outcome measured in this study was the difference in the mean logarithm of UACR reduction from baseline to 3 months between the morning-dose and evening-dose groups. The secondary outcomes were the differences in the changes in the mean office blood pressure (systolic and diastolic) and eGFR between the two groups from baseline to 3 months. For clinically meaningful outcome measurements, post hoc outcomes, including treatment responses and unfavourable outcomes, were classified as follows: (1) a decrease in the UACR of 30% or more from baseline, (2) blood pressure control (systolic blood pressure < 130 mmHg and diastolic blood pressure < 80 mmHg), and (3) kidney deterioration (a decrease in the eGFR of 15% or more from baseline). Additionally, any adverse events were documented in detail throughout the study period. During follow-up, nocturnal urination and sleep-related tolerability were monitored by patient self-report during routine follow-up visits and adverse-event assessment. To ensure data accuracy and reliability, information was meticulously collected via a standardized case report form and validated by trained clinical investigators.

Sample size consideration and statistical analysis

This study was planned on the basis of a pilot trial designed to assess the effect of timed antihypertensive administration on early changes in the UACR from baseline to 3 months. However, as of the time the trial was conducted, no direct studies were available. As such, we assumed a detectable difference in the logarithm of 1.47 (equivalent to a UACR of 30 mg/g) between the study groups, with an assumed standard deviation (SD) of 2.0 (equivalent to a UACR of 100 mg/g), at a significance level of P < 0.05 and 80% power. As a result, 29 participants were needed in each group.

All analyses were performed according to an intention-to-treat approach and included all participants who were randomly assigned to treatment intervention groups. Statistical analyses were performed via Stata version 16.0 (StataCorp LLC, TX). A two-tailed test with P < 0.05 was considered statistically significant. Baseline characteristics are described according to treatment intervention groups as the number (%), mean (SD), or median (interquartile range [IQR]), as appropriate.

For the primary outcome and secondary outcomes (change in log UACR, office blood pressure, and eGFR from baseline to 3 months), absolute unadjusted and adjusted (accounting for age, sex, and baseline values of UACR, blood pressure, and eGFR) changes with 95% CIs were compared between groups via t tests and linear regression, respectively. To explore treatment effects on post hoc outcomes (treatment responses and unfavourable outcomes), unadjusted and adjusted (accounting for age, sex, and baseline values of UACR, blood pressure, and eGFR) relative risks (RRs) with 95% CIs were estimated via modified Poisson regression models with robust standard errors. The study protocol specified that the adjusted models would include age, sex, and baseline values of the study outcomes, and no additional covariates were planned for adjustment.

Results

Characteristics of participants at baseline

A total of 160 potential participants were initially assessed for recruitment (Fig. 1). After excluding participants whose UACR was less than 30 mg/g (n = 61), those who were taking antihypertensive medications at more than one dosing time daily (n = 34), and those with evidence of nonadherence to treatment (n = 5), 60 participants met the inclusion criteria and were included in the study. Among the 60 participants randomized, 31 were assigned to the morning-dosing group, 29 were assigned to the evening-dosing group, and both groups were included in the intention-to-treat analysis.

Fig. 1.

Study flowchart.

During the 3-month follow-up period, the overall trial completion rate was 97.7%. Two participants in the evening-dosing group did not complete the trial. Of these, one participant was lost to follow-up, and the other participant withdrew from the study.

Table 1 describes the baseline demographic and clinical characteristics according to the antihypertensive treatment-time regimen. Generally, participant characteristics were well balanced between the two groups, except for the mean age. The participants in the evening-dosing group were younger than those in the morning-dosing group were (61.2 [12.0] vs. 69.8 [10.0]). In addition, baseline systolic blood pressure and eGFR also showed numerical differences between groups.

Table 1.

Baseline demographic and clinical characteristics according to antihypertensive treatment regimen.

Characteristic	Total (n = 60)	Morning administration (n = 31)	Evening administration (n = 29)	P value
Age, years	65.6 ± 11.7	69.8 ± 10.0	61.2 ± 12.0	0.004
Sex
Male	29 (48.3)	16 (51.6)	13 (33.8)	0.617
Female	31 (51.7)	15 (48.4)	16 (55.2)
BMI, kg/m2†	25.4 ± 4.1	25.3 ± 3.8	25.4 ± 4.4	0.947
Smoking history†
Never	45 (76.3)	23 (74.2)	22 (78.6)	1.000
Former	11 (18.6)	6 (19.4)	5 (17.9)
Current	3 (5.1)	2 (6.4)	1 (3.6)
Office systolic blood pressure, mmHg	141.1 ± 16.1	144.9 ± 15.2	137.0 ± 16.3	0.057
Office diastolic blood pressure, mmHg	76.3 ± 10.2	77.0 ± 10.6	75.5 ± 9.9	0.586
Medical history
Cardiovascular disease	11 (18.3)	8 (25.8)	3 (10.3)	0.184
Type 2 diabetes	24 (40.0)	15 (48.4)	9 (31.0)	0.197
Chronic kidney disease (stage 3–4)	34 (56.7)	20 (64.5)	14 (48.3)	0.297
Obesity (BMI ≥ 25.0 kg/m2)	32 (54.2)	20 (64.5)	12 (42.9)	0.121
Clinical laboratory test values
Creatinine, mg/dL; median (Q1–Q3)	1.1 (0.9–1.7)	1.1 (1. 0–1.7)	1.0 (0.8–1.6)	0.322
Fasting plasma glucose, mg/dL	112.9 ± 27.1	111.2 ± 27.6	115.0 ± 26.9	0.621
Hemoglobin A1c, %	6.2 ± 0.8	6.4 ± 0.8	6.0 ± 0.9	0.090
HDL cholesterol, mg/dL; median (Q1–Q3)	52 (46–63)	56 (47–66)	50 (40–59)	0.684
LDL cholesterol, mg/dL	94.1 ± 25.9	99.4 ± 25.8	88.5 ± 25.4	0.128
Triglycerides, mg/dL; median (Q1–Q3)	128 (92–162)	132 (92–157)	124 (96–171)	0.840
eGFR, mL/min/1.73 m2	60.2 ± 26.9	55.6 ± 20.6	65.2 ± 31.9	0.174
UACR, mg/g; median (Q1–Q3)	116.1 (61.0–300.2)	124.2 (52.2–371.7)	104.5 (65.2–266.5)	0.684
UACR category
Microalbuminuria (UACR, 30 to < 300 mg/g)	45 (75.0)	23 (74.2)	22 (75.9)	1.000
Macroalbuminuria (UACR, ≥ 300 mg/g)	15 (25.0)	8 (25.8)	7 (24.1)
Concomitant medication
Number of antihypertensive medications; median (Q1–Q3)	2 (2–3)	2 (2–3)	2 (2–3)	0.510
Angiotensin-converting enzyme inhibitor or angiotensin-II receptor blocker	60 (100.0)	31 (100.0)	29 (100.0)	NA
Beta-blocker	24 (40.0)	13 (41.9)	11 (37.9)	0.797
Calcium-channel blocker	41 (68.3)	22 (71.0)	19 (65.5)	0.783
Diuretic	16 (26.7)	9 (29.0)	7 (24.1)	0.774
Mineralocorticoid receptor antagonist	3 (5.0)	1 (3.2)	2 (6.9)	0.606
Statin	49 (81.7)	25 (80.6)	24 (82.8)	1.000
Sodium-glucose cotransporter-2 inhibitor	6 (10.0)	2 (6.4)	4 (13.8)	0.417

Note: Data are presented as the means ± SDs or n (%) of participants unless otherwise indicated.

^†Number of participants without baseline data available: BMI, n = 1; smoking history, n = 1.

BMI, body mass index; eGFR, estimated glomerular filtration rate; HDL, high-density lipoprotein; LDL, low-density lipoprotein; NA, not applicable; SD, standard deviation; UACR, urine albumin‒creatinine ratio.

Effects of antihypertensive treatment time regimens on the primary outcome

Overall (Fig. 2), no significant differences between groups were observed: the median UACR reduction at 3 months was − 22.2 mg/g (95% CI, −166.1 to 26.5) for the morning-dosing group and − 15.7 mg/g (95% CI, −66.4 to 44.3) for the evening-dosing group. At the 3-month follow-up, the absolute change in the mean log UACR was − 0.22 mg/g in the evening-dosing group and − 0.21 mg/g in the morning-dosing group (adjusted difference from baseline between groups, −0.01 mg/g [95% CI, −0.32 to 0.30; P = 0.955]; Table 2).

Fig. 2.

Distribution of the change in log UACR from baseline to 3 months according to antihypertensive treatment-time regimen.UACR, urine albumin‒creatinine ratio.

Table 2.

Primary and prespecified secondary outcomes at 3 months.

Outcome measures	Morning antihypertensive treatment-administration				Evening antihypertensive treatment-administration				Change from baseline: Adjusted mean difference (95% CI) †	P value
	Baseline, mean ± SD	3 months			Baseline, mean ± SD	3 months
		Adjusted mean (95% CI)	Unadjusted, mean ± SD	Absolute change (95% CI)		Adjusted mean (95% CI)	Unadjusted mean ± SD	Absolute change (95% CI)
Primary outcome
Log UACR, mg/g	2.2 ± 0.5	2.00(1.78 – 2.23)	2.0 ± 0.7	-0.21 (-0.40 to -0.03)	2.1 ± 0.5	1.91 (1.67 – 2.15)	1.9 ± 0.6	-0.22 (-0.46 to 0.01)	-0.01 (-0.32 to 0.30)	0.955
Secondary outcomes
Office systolic blood pressure, mmHg	144.9 ± 15.2	139.84 (133.47 – 146.20)	143.1 ± 19.0	-1.81 (-9.87 to 6.25)	138.4 ± 15.8	144.04 (137.18 – 150.90)	140.3 ± 18.3	1.92 (-5.40 to 9.25)	4.20 (-5.77 to 14.17)	0.401
Office diastolic blood pressure, mmHg	77.0 ± 10.6	74.26 (70.60 – 77.92)	74.8 ± 12.2	-2.16 (-6.38 to 2.06)	75.4 ± 10.2	78.66 (74.72 – 82.61)	78.0 ± 9.2	2.59 (-2.25 to 7.44)	4.40 (-1.33 to 10.14)	0.129
eGFR, mL/min/1.73 m2	56.3 ± 21.4	56.21 (53.26 – 59.16)	55.6 ± 21.3	-0.66 (-3.75 to 2.43)	58.5 ± 32.0	60.71 (57.27 – 64.16)	61.5 ± 31.2	2.95 (-0.64 to 6.54)	4.50 (-0.37 to 9.38)	0.069

Adjusted for age, sex, and baseline value of outcomes (UACR, systolic and diastolic blood pressure, and eGFR).

CI, confidence interval; eGFR, estimated glomerular filtration rate; SD, standard deviation; UACR, urine albumin–creatinine ratio.

Effects of antihypertensive treatment time regimens on secondary and post hoc outcomes

There was no significant difference in terms of changes in office blood pressure or the eGFR between baseline and the 3-month follow-up (Table 2). The mean systolic blood pressure changed by 1.92 mmHg in the evening-dosing group and − 1.81 mmHg in the morning-dosing group (adjusted difference from baseline between groups, 4.20 mmHg [95% CI, −5.77 to 14.17; P = 0.401]). Similarly, the mean diastolic blood pressure changed by 2.59 mmHg in the evening-dosing group and − 2.16 mmHg in the morning-dosing group (adjusted difference of change from baseline between groups, 4.40 mmHg [95% CI, −1.33 to 10.14; P = 0.129]). Regarding the changes in kidney function from baseline, the mean eGFR changed by 2.95 mL/min/1.73 m² in the evening-dosing group and − 0.66 mL/min/1.73 m² in the morning-dosing group (adjusted difference of change between groups, 4.50 mL/min/1.73 m² [95% CI, −0.37 to 9.38; P = 0.069]).

According to post hoc outcome analyses, the overall percentage of participants who achieved a clinically meaningful UACR reduction of 30% or more from baseline to 3 months was 40.7% in the evening-dosing group and 41.9% in the morning-dosing group (Fig. 3). At 3 months, office blood pressure control was achieved in only 8/31 (25.8%) participants in the morning-dosing group and 7/27 (25.9%) participants in the evening-dosing group. (Table 3)

Fig. 3.

Relative reduction in UACR of 30% or more from baseline to month 3, %.UACR, urine albumin‒creatinine ratio.

Table 3.

Relative risk of achieving clinically meaningful post hoc outcomes at 3 months.

Post hoc outcomes	No./total (%) of achieving clinically meaningful		Absolute risk difference, % (95% CI)	Risk ratio
	Morning antihypertensive treatment-administration	Evening antihypertensive treatment-administration		Unadjusted (95% CI)	P value	Adjusted (95% CI)†	P value
Decreased in UACR of 30% or more from baseline	13/31 (41.9)	11/27 (40.7)	-1.2 (-26.6 to 24.2)	0.97 (0.52 – 1.81)	0.927	0.76 (0.41 – 1.42)	0.386
Blood pressure control (systolic blood pressure <130 mmHg and diastolic blood pressure <80 mmHg)	8/31 (25.8)	7/27 (25.9)	0.1 (-22.5 to 22.7)	1.00 (0.42 – 2.42)	0.992	0.76 (0.34 – 1.68)	0.501
Decreased in eGFR of 15% or more from baseline	4/28 (14.3)	1/21 (4.8)	-9.5 (-25.4 to 6.3)	0.33 (0.04 – 2.83)	0.314	0.12 (0.01 – 2.86)	0.191

Adjusted for age, sex, and baseline value of outcomes (UACR, systolic and diastolic blood pressure, and eGFR).

CI, confidence interval; UACR, urine albumin‒creatinine ratio.

With respect to the stage of CKD status (eGFR > 60 or < 60 mL/min/1.73 m²), there was no substantial difference in the proportion of participants who met the criterion of a reduction in the UACR of 30% or more from baseline to 3 months (Fig. 3). Considering the multivariable modified Poisson regression, at the 3-month follow-up, there was no significant difference between groups in terms of the adjusted RR for treatment response and unfavourable outcomes (Table 3): adjusted RR, 0.76 (95% CI, 0.41–1.42; P = 0.386) for a decrease in the UACR of 30% or more; adjusted RR, 0.76 (95% CI, 0.34–1.68; P = 0.501) for blood pressure control; and adjusted RR, 0.12 (95% CI, 0.01–2.86; P = 0.191) for an eGFR deterioration of 15% or more.

Adverse events and treatment compliance

No serious or significant adverse events were reported during the trial period. However, two participants (6.9%) in the evening-dosing group reported episodes of mild dizziness during the trial follow-up, which were resolved by rest and symptomatic medications. Concerning poor adherence to the assigned dosing time, no such issues were identified throughout the trial investigation.

Discussion

In this open-label, assessor-masked, pilot randomized controlled trial, we demonstrated that both dosing regimens resulted in modest reductions in the UACR at 3 months; however, there was no significant difference between the groups. When the reduction in albuminuria was adjusted for age, sex, and baseline outcome values, the difference in albuminuria change remained statistically insignificant. Blood pressure and kidney function outcomes, including eGFR, were also comparable between the two groups. These findings suggest that altering the timing of antihypertensive medication intake alone does not provide additional short-term benefits for albuminuria or blood pressure control beyond standard therapy, although both regimens were associated with favourable, albeit modest, improvements.

The amount of albuminuria is closely correlated with cardiovascular risk, chronic kidney disease, and mortality²⁴. Therefore, reducing urine albumin levels is of utmost importance, particularly in hypertensive patients²⁵. A decrease in UACR is an indicator of reduced early kidney injury and endothelial injury²⁶, and serves as an index of cardiovascular disease^27,28, thereby potentially lowering future cardiovascular events.

Recent data show that morning hypertension increases the risk of cerebrovascular accidents^29,30. On the other hand, several studies, including a Spanish prospective trial on ambulatory blood pressure monitoring and cardiovascular events, have reported that taking antihypertensive drugs at bedtime provides better controls BP than morning dosing^31–33. Hermida et al. (2013) reviewed multiple studies across six antihypertensive drug classes and found that ACEI/ARB exert a greater therapeutic effect with bedtime administration³⁴. Similarly, Roush et al. performed a meta-analysis showing a beneficial effect of evening dosing³⁵. In contrast, other studies have not found differences in the efficacy of BP or UACR reduction between morning and evening dosing, which is consistent with our findings^25,36,37. A large United Kingdom–based prospective randomized trial comparing evening versus morning dosing of usual antihypertensives in adults with hypertension also demonstrated no difference in major cardiovascular outcomes between morning and evening administration¹⁵. In addition, the BedMed randomized clinical trial, similar to the TIME trial, did not demonstrate a clear cardiovascular advantage of bedtime versus morning antihypertensive dosing¹⁶.

The inclusion of ACEI/ARB in all patients likely contributed to UACR reductions in both groups, as these drugs have established renoprotective effects³⁷. Concerns about diuretic effects on UACR, due to potential alterations in kidney perfusion, were not supported in our study since eGFR changes were not significant. Additionally, no differences in sleep quality or nocturnal urination were observed, consistent with prior evidence that bedtime dosing is tolerable¹⁵. However, these symptoms were assessed by patient self-report rather than validated sleep-quality instruments or structured voiding diaries; therefore, subtle between-group differences in sleep quality or nocturnal urination cannot be excluded. The modest decreases in UACR in both groups likely reflect the ongoing effects of renin–angiotensin system blockade and overall blood pressure control rather than the timing of administration.

A strength of our study was the use of UACR as a primary surrogate marker for endothelial injury and cardiovascular risk^26–28, along with the mandatory inclusion of ACEI/ARB in all participants, a drug class with proven efficacy in lowering UACR³⁷. Several limitations should be acknowledged. First, as a pilot trial with only 60 participants, this study was underpowered to detect modest between-group differences. Thus, despite adjustment for several covariates, residual confounding and type II error remain possible. Larger adequately powered studies are needed to provide more precise effect estimates and to clarify the effect of antihypertensive dosing time on albuminuria. Second, the 3-month follow-up was likely insufficient to observe robust or sustained effects on albuminuria, as most randomized trials assessing interventions for albuminuria require at least 6–12 months of follow-up³⁸. Third, the study population was exclusively Asian, which may limit generalizability to other ethnic groups due to potential differences in chronopharmacology and risk profiles. Additional limitations include the open-label design, which could introduce bias despite assessor masking, and the absence of objective adherence monitoring. While patients were educated at each visit to enhance compliance, unmeasured differences in adherence or lifestyle may have influenced the results. Furthermore, ambulatory BP monitoring was not performed, limiting the ability to assess circadian BP patterns, such as dipper versus nondipper status. Prior studies, including MAPEC³¹, demonstrated that bedtime dosing may particularly benefit nondippers, an effect we could not evaluate. Concerns about nocturia with evening diuretic use were also minimal, aligning with evidence from larger studies that reported no significant differences in nocturnal symptoms when diuretics are taken at night¹⁵. Another limitation relates to albuminuria eligibility. Albuminuria eligibility was based on UACR at screening, and no minimum prior duration of albuminuria was specified. Therefore, we could not determine whether albuminuria had been persistent for a defined period before study entry. Although most baseline characteristics were generally comparable between groups, the evening-dosing group was younger and also showed numerically lower baseline systolic blood pressure and higher baseline eGFR. While these variables were not statistically significantly different at baseline, some degree of residual confounding cannot be excluded, particularly given the pilot sample size. Moreover, the low rate of blood pressure target attainment in both groups suggests that incomplete BP control may have attenuated any potential effect of dosing time on albuminuria.

T2DM, mineralocorticoid receptor antagonist use, and sodium-glucose cotransporter-2 inhibitor use may also influence albuminuria, but these variables were not included in the planned adjustment model. The study protocol specified adjustment for age, sex, and baseline values of the study outcomes, and most baseline characteristics were generally comparable between groups except for age. For this reason, we retained the planned adjustment strategy rather than adding further post hoc covariate adjustment. Nevertheless, some degree of residual confounding cannot be excluded.

In summary, the MORE trial did not demonstrate a clear short-term advantage of evening over morning antihypertensive dosing in reducing albuminuria. This finding adds to the growing evidence that the benefits of chronotherapy may be limited or dependent on patient context. Both dosing schedules were safe and well tolerated, with no serious adverse effects observed. These results suggest that the timing of antihypertensive medication—morning or evening—does not negatively impact outcomes. Therefore, adherence remains the most critical factor in achieving blood pressure control and renal protection. Allowing patients to select a dosing schedule aligned with their daily routine is likely to increase compliance and optimize treatment effectiveness, outweighing any minor differences attributable to dosing time.

Future research should include larger sample sizes, longer follow-up periods, ambulatory BP monitoring, and diverse populations to clarify whether specific subgroups, such as nondippers, derive additional benefit from bedtime dosing.

Conclusion

This pilot study suggested that the timing of antihypertensive medication, whether taken in the morning or evening, has similar effects on short-term albuminuria reduction and does not adversely affect patients. Therefore, medication adherence should be prioritized, and dosing schedules should be individualized to suit each patient’s lifestyle to ensure optimal long-term blood pressure control and renal protection.

Author contributions

Thanphisit Trakarnvanich (ORCID 0000-0001-8788-0730): Conceptualization; Methodology; Investigation; Data curation; Formal analysis; Writing – original draft.Surapon Nochaiwong (ORCID 0000-0003-1100-7171): Supervision; Methodology; Formal analysis; Writing – review & editing. SN conducted major supervised analyses and significantly contributed to the manuscript.Chidchanok Ruengorn (ORCID 0000-0001-7927-1425): Methodology; Formal analysis; Writing – review & editing.Kiatkriangkrai Koyratkoson (ORCID 0000-0002-0335-3069): Data curation; Validation; Writing – review & editing.Tanun Ngamvichchukorn (ORCID 0000-0003-0119-4647): Supervision; Conceptualization; Project administration; Methodology; Resources; Writing – review & editing.

Funding

This work was supported by Navamindradhiraj University Research Fund, Thailand under Grant [no. 79/2564]. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the funder. The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication.

Data availability

The datasets generated and/or analysed during the current study are not publicly available due to participant privacy but are available from the corresponding author on reasonable request for research purposes.

Declarations

Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

The study protocol was approved by the Vajira Hospital Ethics Committee, Faculty of Medicine Vajira Hospital, Navamindradhiraj University, Thailand (approval number 032/2564; Date of approval 24/02/2021). All participants provided written informed consent before enrollment. The study was conducted in accordance with the Declaration of Helsinki and relevant national regulations.