What is the difference in efficacy when giving atorvastatin at night compared to in the morning?

Comment by InpharmD Researcher

Data comparing the efficacy of atorvastatin administration at night versus in the morning are primarily limited to prospective, observational studies with conflicting results. Two studies observed similar changes in lipid parameters when atorvastatin was administered at night compared to in the morning. However, one study (see Table 2) observed atorvastatin administered in the evening to significantly reduce total cholesterol, LDL cholesterol, triglycerides and stenosis as well as increase HDL cholesterol levels. Clinical outcomes including target vessel revascularization, unstable angina pectoris, myocardial infarction, cardiac death were also significantly reduced when atorvastatin was administered in the evening. Additionally, pooled data for long half-life statins (e.g, atorvastatin) found evening-dose statins to significantly reduce LDL cholesterol compared to morning-dose statins.

Background

A 2017 meta-analysis evaluated the effects of morning versus evening statin administration on lipid profile. A total of 11 studies with sample sizes ranging from 12 to 299 patients (9 RCTs, 1 non-RCT, and 1 retrospective cohort study; N= 1,034 participants total) were included for analysis. The following statin doses were administered in the included studies: 40 mg/day atorvastatin, 2.5-20 mg/day simvastatin, 10 mg/day rosuvastatin, 20 mg/day lovastatin, 40 mg/day pravastatin and 80 mg/day fluvastatin. The duration of included studies ranged between 4 and 12 weeks. Two studies were included that evaluated morning versus evening administration of atorvastatin (see Tables 1 and 2). Overall, there was no difference in effects of morning versus evening administration of statins on plasma total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and triglycerides. However, evening-dose statins significantly reduced low-density lipoprotein cholesterol (LDL-C) compared to morning-dose statins (mean difference [MD] 3.24 mg/dL; 95% confidence interval [CI] 1.23 to 5.25; p= 0.002). No significant heterogeneity was identified for any outcomes. An analysis was also conducted to determine the impact of statin half-lives on the results. As such, statins were divided into subgroups based on short-half lives below 7 hours (lovastatin, simvastatin, pravastatin, and lovastatin) and long half-lives above 7 hours (atorvastatin, rosuvastatin, controlled-release simvastatin, and extended-release fluvastatin). The pooled analysis for the long half-life statins subgroup did not observe any significant differences for TC, HDL-C, or triglycerides between morning and evening statin administration. However, evening-dose statins significantly reduced LDL-C (MD 2.53 mg/dL; 95% CI 0.41 to 4.64; p= 0.02) compared to morning-dose statins. Again, no significant heterogeneity was noted for any outcomes. [1]

A 2007 review discussed available evidence evaluating the chronobiological effects of morning versus evening statin administration. From available studies at the time (see Tables 1 and 3), atorvastatin demonstrated similar LDL-C reduction regardless of administration time. Due to various limitations with available data, it was determined that rigorous and robust trials are necessary to determine the best administration time to achieve optimal LDL-C lowering for atorvastatin. [2]

References:

[1] Awad K, Serban MC, Penson P, et al. Effects of morning vs evening statin administration on lipid profile: A systematic review and meta-analysis. J Clin Lipidol. 2017;11(4):972-985.e9. doi:10.1016/j.jacl.2017.06.001
[2] Plakogiannis R, Cohen H. Optimal low-density lipoprotein cholesterol lowering--morning versus evening statin administration. Ann Pharmacother. 2007;41(1):106-110. doi:10.1345/aph.1G659
Literature Review

A search of the published medical literature revealed 3 studies investigating the researchable question:

What is the difference in efficacy when giving atorvastatin at night compared to in the morning?

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→


Please see Tables 1-3 for your response.

 

Effects of morning versus evening administration of atorvastatin in patients with hyperlipidemia

Design

Prospective cohort study

N= 64

Objective

To assess the effects of morning versus evening administration of atorvastatin for four weeks in a sample of hyperlipidemic adults

Study Groups

Morning administration of atorvastatin (n=32)

Evening administration of atorvastatin (n=32)

Inclusion Criteria

Hyperlipidemic patients at the New York Harbor Healthcare System who were prescribed atorvastatin 40 mg by mouth daily; patients taking atorvastatin in the morning (before noon) or in the evening (after 6pm but before midnight)

Exclusion Criteria

Concomitant diseases or conditions affecting serum lipoprotein levels (such as hepatic disease, renal failure, hypothyroidism, diabetes, systemic lupus erythematosus, acromegaly, glycogen storage disease, anorexia nervosa, alcoholism); consumption of >3 alcoholic drinks daily; patients who could not verify the time of atorvastatin administration; patients receiving medications affecting lipid values (such as thiazide diuretics or β-blockers started in the past four months, α-1-blockers started in the past six months, atypical antipsychotics, cyclosporine, isotretinoin, glucocorticoids, oral contraceptives, androgens, protease inhibitors, lipid-lowering agents)

Methods

Eligible patients were instructed to take their prescribed atorvastatin 40 mg by mouth daily in either the morning or the evening. Blood samples were collected at baseline before initiation of atorvastatin after a 12-hour fast to measure total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides. Blood samples were collected again after a 12-hour fast at study completion to measure the same lab values for comparison. Additionally, all patients were counseled to follow the Step II diet described in the National Cholesterol Education Program Adult Treatment Panel (NCEP ATP II) guidelines (<7% saturated fat and <200 mg/day of cholesterol).

Duration

Four weeks

Outcome Measures

Total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides

Baseline Characteristics

  

Morning administration (n= 32)

Evening administration (n= 32)

Male

 32 (100%)  32 (100%) 

Mean age, years

 58.5±7.8 57.8±7.8 

Hypertension

 21 (66%) 25 (78%) 

Coronary artery disease

 18 (56%)  22 (69%) 

Chronic heart failure

  12 (38%) 16 (50%) 

Myocardial infarction

 6 (19%) 9 (28%) 
Atrial fibrillation 2 (6%) 1 (3%) 
Anxiety 2 (6%) 1 (3%) 
Insomnia 3 (9%) 2 (6%) 
 Results

Endpoint

 Morning administration (n= 32) Evening administration (n= 32) p-value

Total cholesterol, mg/dL

Baseline

Follow up

% change

 

321.4 ± 28.0 

210.0 ± 19.4

−34.7%

 

329.2 ± 23.3 

215.4 ± 18.0

−34.6%

0.50

 LDL, mg/dL

Baseline

Follow up

% change

 

188.3 ± 13.0 

99.0 ± 8.1

−47.4%

 

195.0 ± 10.4

104.2 ± 8.8

−46.6%

 0.94 

HDL, mg/dL

Baseline

Follow up

% change

 

46.4 ± 8.9

49.8 ± 10.3

7.3%

 

40.8 ± 5.5 

43.9 ± 6.3

7.6%

 0.33

Triglycerides, mg/dL

Baseline

Follow up

% change

 

434.0 ± 87.2

306.0 ± 59.8

−29.5%

 

468.5 ± 93.0 

337.0 ± 61.2

−28.1%

 0.23

Adverse Events

Common Adverse Events: an assessment of adverse drug events was not conducted.

Serious Adverse Events: N/A

Percentage that Discontinued due to Adverse Events: N/A

Study Author Conclusions

Changes in the levels of total cholesterol, LDL cholesterol, triglycerides, and HDL cholesterol were similar among hyperlipidemic patients receiving atorvastatin calcium 40 mg daily, regardless of the time of day the drug was administered.

InpharmD Researcher Critique

This study had several key limitations, including that it did not utilize a randomized, double-blind design. All the patients in this study were male, so the findings may not be generalizable to female patients. The evening administration group had a greater percentage of patients with cardiovascular comorbidities, and there was a noticeable difference in baseline LDL and HDL between groups. Lastly, patients were not screened for concomitant use of herbal or natural antihyperlipidemic products which may have affected the findings.



References:

Plakogiannis R, Cohen H, Taft D. Effects of morning versus evening administration of atorvastatin in patients with hyperlipidemia. Am J Health Syst Pharm. 2005;62(23):2491-2494. doi: 10.2146/ajhp050072.

 

Effects of Morning versus Evening Intake of Atorvastatin on Major Cardiac Event and Restenosis Rates in Patients Undergoing First Elective Percutaneous Coronary Intervention

Design

Randomized, prospective study

N= 152

Objective

To investigate the effects of morning versus evening intake of atorvastatin on major cardiac events and restenosis rates and also on serum lipid and high sensitivity C-reactive protein levels in patients with single-vessel disease who underwent first elective percutaneous coronary intervention (PCI)

Study Groups

Morning (n= 73)

Evening (n= 79)

Inclusion Criteria

Adult patients with single-vessel coronary disease who underwent first elective PCI, with successful stenting of 1 lesion in the native coronary arteries and had an indication for lipid-lowering drugs based on the Adult Treatment Panel III guidelines

Exclusion Criteria

Coronary anatomy not suitable for PCI, multivessel coronary artery disease, pre-procedural elevation of creatine kinase, troponin T or troponin I, postprocedural elevation of creatine kinase > 3 times the upper limit of normal, creatinine level > 1.8 mg/dL, other serious medical history or contraindications

Methods

Patients were randomized to receive atorvastatin in the morning after breakfast (group I) or in the evening after dinner (group II). All patients were given atorvastatin 40 mg/day for the first month and 10 mg/day thereafter. Dose of atorvastatin as well as other study medications remained the same throughout the study period.  

Duration

Intervention: 12 months

Follow-up: 12 months

Outcome Measures

Occurrence of ≥ 1 major cardiac event (MACE; cardiac death, unstable angina pectoris, myocardial infarction, or target vessel revascularization) at 12 months, lipid parameters at 6 months, high-sensitivity C-reactive protein (hs-CRP) levels at 24 hours after procedure

Baseline Characteristics

  

Morning (n= 73)

Evening (n= 79)

 p-Value 

Age 

 59 58 0.65

Male

 80.8% 74.7% 0.4 

Smoker

 71.2% 50.6% 0.01 

Comorbidities

Diabetes mellitus

Hypertension

Heart failure

 

27.3%

54.7%

2.7%

 

24%

56.9%

5%

 

0.7

0.87

0.68

Pharmacological treatment 

Beta-blocker

ACEI

Aspirin

Statin

 

100%

68.5%

100%

10.9%

 

100%

64.6%

100%

21.5%

 

1

0.7

1

0.08

Time between index PCI and initiation of atorvastatin, days

8.4

8.6

 –

Lipid parameters, mg/dL

Total cholesterol

Triglyceride

High-density lipoprotein (HDL)

Low-density lipoprotein (LDL)

 

211 ± 26

175 ± 27

35 ± 3

140 ± 14

 

206 ± 18

170 ± 21

37 ± 4

138 ± 13

 

0.08

0.2

0.002

0.4

hs-CRP, mg/dL

0.5 ± 0.3

0.42 ± 0.25

0.08

Results

Endpoint 

Morning (n= 73)

Evening (n= 79)

p-Value

Occurrence of MACE at 12 months

Cardiac death

Unstable angina pectoris

Myocardial infarction

Target vessel revascularization

27 (36.9%)

1 (1.3%)

18 (24.6%)

9 (12%)

24 (46.5%)

7 (8.8%)

1 (1.2%)

7 (8.8%)

0

4 (5%)

0.0002*

1

0.015

0.001

< 0.0001

Lipid parameters at 6 months, mg/dL

Total cholesterol

Triglyceride

HDL

LDL

 

182 ± 11

140 ± 11

37 ± 3

92 ± 13 

 

178 ± 12

134 ± 11

39 ± 3

87 ± 7 

 

0.003

< 0.0001

< 0.0001

0.002

hs-CRP at 24 hours, mg/dL

 0.51 ± 0.32 0.43 ± 0.25 0.07
*Relative risk 0.20, 95% confidence interval 0.89 to 0.47

Adverse Events

 N/A

Study Author Conclusions

The main findings of the present study were that, compared with the intake of atorvastatin in the morning, intake in the evening before PCI was associated with less frequent occurrence of MACEs, a low restenosis rate, a trend toward low pre- and postprocedural hs-CRP levels, a more pronounced decrease in total cholesterol, LDL cholesterol, and triglyceride values, and an increase in HDL cholesterol levels.

InpharmD Researcher Critique

This study incorporated a limited sample size, without a control group. Additionally, the study was not blinded. A significantly higher number of smokers was included in group I. Additionally, patients in group II had a significantly higher HDL at baseline. 



References:

Ozaydin M, Dede O, Dogan A, et al. Effects of morning versus evening intake of atorvastatin on major cardiac event and restenosis rates in patients undergoing first elective percutaneous coronary intervention. Am J Cardiol. 2006;97(1):44-47. doi:10.1016/j.amjcard.2005.07.107

 

Pharmacodynamic Effects and Pharmacokinetics of Atorvastatin after Administration to Normocholesterolemic Subjects in the Morning and Evening 

Design

Randomized, nonblinded, two-way crossover study

N= 16

Objective

To evaluate the pharmacodynamic effects and pharmacokinetics of atorvastatin after administration of 40 mg daily doses for 15 days in the morning or evening

Study Groups

Morning (n= 8)

Evening (n= 8)

Inclusion Criteria

Normal physical examinations, 12-lead electrocardiograms, and clinical laboratory tests

Exclusion Criteria

Significant medical history, recent medication use, or history of adverse reactions to lipid-regulating agents 

Methods

Patients were randomized to one of two groups. Patients in the first group were to receive 40 mg atorvastatin at 6 pm for 15 days, followed by a 28-day washout period, followed by the same dose at 7 am for 15 days. Patients in the other group received the same treatment in reverse. Patients were to fast for 2 hours before and after each dose, as well as for 12 hours before collection of blood samples. 

Duration

Intervention: 15 days

Follow-up: up to 64 days

Outcome Measures

Lipid parameters (low-density lipoprotein [LDL], high-density lipoprotein [HDL], very-low density lipoprotein [VLDL], and total cholesterol) after 15 days

Baseline Characteristics

 See below for baseline lipid parameters.     

Results

 

Morning

Evening

Endpoint

Baseline

 % Change Baseline % Change

Serum lipid parameters

Total cholesterol

LDL cholesterol

HDL cholesterol

VLDL cholesterol

Triglycerides

Apolipoprotein A-1

Apolipoprotein B

 

177

116

48

13

90

146

92

 

-33.1 

-47.2

1.3

-35.1

-22.8

-7.3

-32.7

 

182 

118

49

15

101

146

94

 

-34.3

-48.2

2.3

-37.2

-26.4

-5.0

-34.6

Adverse Events

Common Adverse Events: Atorvastatin was well tolerated, with headache being the most frequently reported adverse event (incidence rate not specified).

Serious Adverse Events: N/A

Percentage that Discontinued due to Adverse Events: one participant withdrew (evening administration) due to asymptomatic transient elevations of LDH, alanine aminotransferase, and aspartate aminotransferase. Elevations resolved within 2-3 weeks after discontinuation of atorvastatin. 

Study Author Conclusions

 Morning and evening administration of 40 mg atorvastatin are equally effective in reducing total and LDL cholesterol levels.

InpharmD Researcher Critique

The study is limited due to its small sample size and applicability since no baseline characteristics were provided for the study population. The study did not provide information on previous medication use or other comorbidities that could affect cholesterol levels or medication absorption. The study did try to account for dietary factors and control meals but did so with only the last meals before the patient would switch from morning to evening dosing.



References:

Cilla DD Jr, Gibson DM, Whitfield LR, Sedman AJ. Pharmacodynamic effects and pharmacokinetics of atorvastatin after administration to normocholesterolemic subjects in the morning and evening. J Clin Pharmacol. 1996;36(7):604-609. doi:10.1002/j.1552-4604.1996.tb04224.x