• Jose Manuel Izquierdo-Palomares, Jesus Maria Fernandez-Tabera, Maria N Plana, Almudena Añino Alba, Pablo Gómez Álvarez, Inmaculada Fernandez-Esteban, Luis Carlos Saiz, Pilar Martin-Carrillo, and Óscar Pinar López.
• Subdirección General de Farmacia y Productos Sanitarios, Servicio Madrileño de Salud, Pza. Carlos Trías Beltran 7, Madrid, Spain.
• Cochrane Db Syst Rev. 2016 Nov 26; 11: CD009462.

BackgroundElevated levels of total cholesterol and low-density lipoprotein play an important role in the development of atheromas and, therefore, in cardiovascular diseases. Cholesterol biosynthesis follows a circadian rhythm and is principally produced at night (between 12:00 am and 6:00 am). The adjustment of hypolipaemic therapy to biologic rhythms is known as chronotherapy. Chronotherapy is based on the idea that medication can have different effects depending on the hour at which it is taken. Statins are one of the most widely used drugs for the prevention of cardiovascular events. In usual clinical practice, statins are administered once per day without specifying the time when they should be taken. It is unknown whether the timing of statin administration is important for clinical outcomes.ObjectivesTo critically evaluate and analyse the evidence available from randomised controlled trials regarding the effects of chronotherapy on the effectiveness and safety of treating hyperlipidaemia with statins.Search MethodsWe searched the CENTRAL, MEDLINE, Embase, LILACS, ProQuest Health & Medical Complete, OpenSIGLE, Web of Science Conference Proceedings, and various other resources including clinical trials registers up to November 2015. We also searched the reference lists of relevant reviews for eligible studies.Selection CriteriaWe included randomised controlled trials (RCTs), enrolling people with primary or secondary hyperlipidaemia. To be included, trials must have compared any chronotherapeutic lipid-lowering regimen with statins and any other statin lipid-lowering regimen not based on chronotherapy. We considered any type and dosage of statin as eligible, as long as the control and experimental arms differed only in the timing of the administration of the same statin. Quasi-randomised studies were excluded.Data Collection And AnalysisWe used the standard methodological procedures expected by Cochrane. We extracted the key data from studies in relation to participants, interventions, and outcomes for safety and efficacy. We calculated odds ratios (OR) for dichotomous data and mean differences (MD) for continuous data with 95% confidence intervals (CI). Using the GRADE approach, we assessed the quality of the evidence and we used the GRADEpro Guideline Development Tool to import data from Review Manager to create 'Summary of findings' tables.Main ResultsThis review includes eight RCTs (767 participants analysed in morning and evening arms). The trials used different lipid-lowering regimens with statins (lovastatin: two trials; simvastatin: three trials; fluvastatin: two trials; pravastatin: one trial). All trials compared the effects between morning and evening statin administration. Trial length ranged from four to 14 weeks. We found a high risk of bias in the domain of selective reporting in three trials and in the domain of incomplete outcome data in one trial of the eight trials included. None of the studies included were judged to be at low risk of bias.None of the included RCTs reported data on cardiovascular mortality, cardiovascular morbidity, incidence of cardiovascular events, or deaths from any cause. Pooled results showed no evidence of a difference in total cholesterol (MD 4.33, 95% CI -1.36 to 10.01), 514 participants, five trials, mean follow-up 9 weeks, low-quality evidence), low-density lipoprotein cholesterol (LDL-C) levels (MD 4.85 mg/dL, 95% CI -0.87 to 10.57, 473 participants, five trials, mean follow-up 9 weeks, low-quality evidence), high-density lipoprotein cholesterol (HDL-C) (MD 0.54, 95% CI -1.08 to 2.17, 514 participants, five trials, mean follow-up 9 weeks, low-quality evidence) or triglycerides (MD -8.91, 95% CI -22 to 4.17, 510 participants, five trials, mean follow-up 9 weeks, low-quality evidence) between morning and evening statin administration.With regard to safety outcomes, five trials (556 participants) reported adverse events. Pooled analysis found no differences in statins adverse events between morning and evening intake (OR 0.71, 95% CI 0.44 to 1.15, 556 participants, five trials, mean follow-up 9 weeks, low-quality evidence).Authors' ConclusionsLimited and low-quality evidence suggested that there were no differences between chronomodulated treatment with statins in people with hyperlipidaemia as compared to conventional treatment with statins, in terms of clinically relevant outcomes. Studies were short term and therefore did not report on our primary outcomes, cardiovascular clinical events or death. The review did not find differences in adverse events associated with statins between both regimens. Taking statins in the evening does not have an effect on the improvement of lipid levels with respect to morning administration. Further high-quality trials with longer-term follow-up are needed to confirm the results of this review.

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