Timing of statin dose: a systematic review and meta-analysis of randomized clinical trials 

Statins are one of the most commonly prescribed medications, and it is surprising that the timing of statin administration is controversial—society guidelines are also silent on this issue.^1–3 The trials conducted on the efficacy of statin administration timing have heterogeneous outcomes. Our objective was to compare the efficacy and safety of statin morning vs. evening dose by a meta-analysis of randomized controlled trials (RCTs).

A time-limited search from inception until 30 October 2021 was conducted using PubMed and EMBASE databases. The following Medical Education Subject Headings were used for this search: ‘chronotherapy’, ‘conventional therapy’, ‘statins’, ‘hyperlipidemia’, ‘morning dose’, and ‘evening dose’. The inclusion criteria were RCTs that compared the effect of morning vs. evening dosing of statins on changes in at least one lipid profile parameters [LDL cholesterol (LDL-C), HDL cholesterol (HDL-C), total cholesterol (TC), and triglycerides] or adverse events. The two authors (M.H.M. and S.B.) independently selected studies based on titles, abstracts, and full-text studies, extracted data, and appraised the methodological quality of included trials using Cochrane Risk of Bias Tool (see Supplementary material online, AppendixTable S1 and Figure S1).

Mean difference (MD) and odds ratio (OR) with 95% confidence intervals (CIs) were calculated using random effects model using DerSimonian–Laird method. Sub-group analyses were considered based on statin half-life and simvastatin use. Sensitivity analyses were conducted using leave-one-out and including trials with dyslipidemic patients alone. Study size effect was evaluated using cumulative meta-analysis. Funnel plots were used to assess publication bias. Analyses were conducted using Stata version 17.0. We did not register study protocol.

The initial search yielded 671 reports, and finally 13 RCTs were included in the final meta-analysis (see Supplementary material online, Figure S2). The studies enrolled a total of 1129 patients (621 were randomized to evening dosing and 631 to morning dosing group; four cross-over trials), with similar doses of statin between morning and evening doses (Table 1).

Evening dosing of a statin led to greater reduction in LDL-C [MD = −6.27 mg/dl (95% CI: −9.92 to −2.63), I² = 37%; 12 trials] compared with morning dosing (Figure 1). The effect was more pronounced in the subgroup of trials testing short half-life statins (−11.6 mg/dl vs. −4.3 mg/dl), with a significant heterogeneity of treatment effect (P_{heterogeneity} = 0.06). Subgroup analysis stratified by trials of simvastatin vs. non-simvastatin (P_{heterogeneity} = 0.48) showed a similar effect, but without significant heterogeneity (Figure 1 and see Supplementary material online, Figure S3). Sensitivity analysis by including trials enrolling patients with dyslipidaemia only [MD = −7.17 mg/dl (95% CI: −11.46 to −2.88), I² = 37%; 11 trials], and leave-one-out analysis resulted in no apparent difference (see Supplementary material online, Figure S3).

Figure 1

LDL-C, HDL-C, total cholesterol, and triglyceride change based on statin half-life.

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There was no significant difference in HDL-C reduction between evening and morning dosing with main [MD = 0.97 mg/dl (95% CI: −0.54 to 2.47), I² = 72%; 11 trials], sub-group, and sensitivity analyses (Figure 1 and see Supplementary material online, Figure S4).

TC reduction was significantly greater with evening dosing [MD = −6.09 mg/dl (95% CI: −10.80 to −1.38), I² = 54%; 11 trials] compared with morning dosing (Figure 1). The effect was more pronounced in the subgroup of trials testing short half-life statins (−13.0 mg/dl vs. −3.6 mg/dl), with a significant heterogeneity of treatment effect (P_{heterogeneity} = 0.05). Subgroup analysis stratified by trials of simvastatin vs. non-simvastatin (P_{heterogeneity} = 0.30) showed similar effect, but without significant heterogeneity (Figure 1 and see Supplementary material online, Figure S5). Sensitivity analysis including trials that enrolled patients with dyslipidaemia alone did not show any difference from the main analysis, but leave-one-out analysis had significant difference when Fauler et al. was removed (see Supplementary material online, Figure S5).

There was no significant difference in triglyceride reduction between evening and morning dosing in main analysis [MD = −2.51 mg/dl (95% CI: −7.92 to 2.90), I² = 27%; 11 trials], sub-group and sensitivity analyses, but leave-one-out analysis had significant difference when Scharnagl et al. was removed (Figure 1 and see Supplementary material online, Figure S6).

Adverse events were similar between evening and morning dosing in main [OR = 1.22 (95% CI: 0.79–1.88), I² = 0%; 7 trials], sub-group, and sensitivity analyses (see Supplementary material online, Figure S7). Overall, there was no evidence of small study effect or publication bias (see Supplementary material online, Figures S4–S7).

This meta-analysis showed significant reduction of LDL-C and TC in patients randomized to evening compared with morning dosing despite identical statin dose strength. However, there was no significant difference in triglycerides and HDL-C. The results were consistent regardless of statin half-life or statin type used although there was a greater magnitude of benefit with short half-life statins.

This is the largest meta-analysis to evaluate the efficacy of statin morning vs. evening dose. Prior trials and meta-analysis have shown heterogeneous outcomes, and as such, the guidelines have been silent on this subject.⁴ According to Cholesterol Treatment Trialists’ Collaborators, a 1 mmol/l reduction in LDL-C reduces relative risk of CV events by 22%.⁵ Reduction of 6.27 mg/dl is extrapolated to reduce the relative risk of CV events by 3.6%, a not so trivial reduction for a simple intervention. Real-world statin efficacy, however, does not have same LDL reduction effect as expected attributed to individual variability such as genetic polymorphism, LDL levels, and medication compliance.⁶ Evening dose is thought to increase compliance by increasing time to administer and, hence, could be assessed in future studies.

The circadian rhythm of liver has highest activity over the night time and lower during the day. As such, 3-hydroxy-3-methylglutaryl coenzyme A reductase, the rate-limiting enzyme in cholesterol biosynthesis, has higher expression and hence biosynthesis at night.^7–9 Evening dose statins reach plasma level peak simultaneously with HMG-CoA reductase peak expression, potentially explaining greater statin efficacy in LDL-C reduction compared with morning dose.^9–11

This meta-analysis is limited by the following: (i) small RCTs in specific geographical areas limits generalizability; (ii) the duration of follow-up of included trials was short; (iii) statin adherence was not reported in most of these trials and it is unclear if night-time dosing was based on post-prandial status; and (iv) not all statins that are commercially available were represented in this meta-analysis.

Evening dosing of statins significantly reduces LDL-C when compared with morning dosing regardless of statin half-life. This simple intervention should be considered in the management of patients with hypercholesterolaemia.

Authors’ contributions

M.H.M. was involved in (i) conception and design or analysis and interpretation of data, or both; (ii) drafting of the manuscript or revising it critically for important intellectual content; and (iii) final approval of the manuscript submitted. F.H.M., D.W., A.H.S., and D.J.M. were involved in (i) drafting of the manuscript or revising it critically for important intellectual content and (ii) final approval of the manuscript submitted. S.B. was involved in (i) conception and design or analysis, interpretation of data and supervision, or both; (ii) drafting of the manuscript or revising it critically for important intellectual content; and (iii) final approval of the manuscript submitted.

Supplementary material

Supplementary material is available at European Journal of Preventive Cardiology online.

Acknowledgements

There is no relevant acknowledgement to declare.

Funding

The authors declare that they did not receive funding for this research project and publication.

Data availability

All manuscript data is included in the manuscript and supplementary material.

References

Author notes