Differential associations of statin treatment and polymorphism in genes coding for HMGCR and PCSK9 to risk for insomnia
Accepted: 20 October 2021 Published: 30 December 2021
Importance: Statins have been linked to an increased risk for insomnia, but the literature is controversial. Moreover, it is unknown, if the potential effects are directly related to the inhibition of the statin target HMGCR, the subsequently lowered cholesterol levels, or other off-target effects of statins. Aims: To investigate the association of statin treatment and genetic proxies of cholesterol lowering drugs with the risk for insomnia and chronotype in a large population-based cohort. Methods: A cross-sectional cohort study based on baseline data collected between 2006–2010 in UK biobank cohort was conducted. European participants without any history of psychiatric/neurological disorders or of stroke and with available genetic data as well as information on statin use were included in the present study. Self-reported measures of insomnia and chronotype were analysed (a) in statin users versus control subjects, (b) subjects carrying single nucleotide polymorphisms (SNPs) in the HMGCR gene, which are associated with reduced enzymatic function and lower cholesterol levels (rs17238484 and rs12916) and (c) subjects carrying a SNP in the PCSK9 gene (rs1159147), which leads to lower cholesterol levels independent of HMGCR. The main analysis were performed using multivariable regression models. Statin treatment and SNPs in HMGCR and PCSK9 genes were used as exposures and main outcomes were insomnia and chronotype. Results: A total of 206,801participants (mean [SD] age, 57.5 [7.9] years; 56% women; 20% statin users) were included in the present study. Statin users had an increased risk of insomnia compared to controls (odds ratio [95% CI], 1.07 [1.03 to 1.11]; p = 1.42
 Cholesterol Treatment Trialists’ (CTT) Collaboration, Baigent C, Blackwell L, Emberson J, Holland LE, Reith C, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. The Lancet. 2010; 376: 1670–1681.
 Istvan ES, Deisenhofer J. Structural mechanism for statin inhibition of HMG-CoA reductase. Science. 2001; 292: 1160–1164.
 O’Regan C, Wu P, Arora P, Perri D, Mills EJ. Statin therapy in stroke prevention: a meta-analysis involving 121,000 patients. The American Journal of Medicine. 2008; 121: 24–33.
 Pencina MJ, Navar-Boggan AM, D’Agostino RB, Williams K, Neely B, Sniderman AD, et al. Application of new cholesterol guidelines to a population-based sample. The New England Journal of Medicine. 2014; 370: 1422–1431.
 Koren MJ, Giugliano RP, Raal FJ, Sullivan D, Bolognese M, Langslet G, et al. Efficacy and safety of longer-term administration of evolocumab (AMG 145) in patients with hypercholesterolemia: 52-week results from the Open-Label Study of Long-Term Evaluation against LDL-C (OSLER) randomized trial. Circulation. 2014; 129: 234–243.
 Robinson JG, Farnier M, Krempf M, Bergeron J, Luc G, Averna M, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. The New England Journal of Medicine. 2015; 372: 1489–1499.
 Ajufo E, Rader DJ. Recent advances in the pharmacological management of hypercholesterolaemia. The Lancet. Diabetes and Endocrinology. 2016; 4: 436–446.
 Awan Z, Seidah NG, MacFadyen JG, Benjannet S, Chasman DI, Ridker PM, et al. Rosuvastatin, proprotein convertase subtilisin/ kexin type 9 concentrations, and LDL cholesterol response: the JUPITER trial. Clinical Chemistry. 2012; 58: 183–189.
 Takada M, Fujimoto M, Yamazaki K, Takamoto M, Hosomi K. Association of statin use with sleep disturbances: data mining of a spontaneous reporting database and a prescription database. Drug Safety. 2014; 37: 421–431.
 Szmyd B, Rogut M, Białasiewicz P, Gabryelska A. The impact of glucocorticoids and statins on sleep quality. Sleep Medicine Reviews. 2021; 55: 101380.
 Broncel M, Gorzelak-Pabiś P, Sahebkar A, Serejko K, Ursoniu S, Rysz J, et al. Sleep changes following statin therapy: a systematic review and meta-analysis of randomized placebocontrolled polysomnographic trials. Archives of Medical Science. 2015; 11: 915–926.
 Morin CM, Drake CL, Harvey AG, Krystal AD, Manber R, Riemann D, et al. Insomnia disorder. Nature Reviews. Disease Primers. 2015; 1: 15026.
 Caap-Ahlgren M, Dehlin O. Insomnia and depressive symptoms in patients with Parkinson’s disease. Relationship to healthrelated quality of life. an interview study of patients living at home. Archives of Gerontology and Geriatrics. 2001; 32: 23–33.
 Daley M, Morin CM, LeBlanc M, Grégoire JP, Savard J. The economic burden of insomnia: direct and indirect costs for individuals with insomnia syndrome, insomnia symptoms, and good sleepers. Sleep. 2009; 32: 55–64.
 Ward NC, Watts GF, Eckel RH. Statin Toxicity. Circulation Research. 2019; 124: 328–350.
 Barth JD, Kruisbrink OA, Van Dijk AL. Inhibitors of hydroxymethylglutaryl coenzyme a reductase for treating hypercholesterolaemia. British Medical Journal. 1990; 301: 669.
 Grundy SM. HMG-CoA reductase inhibitors for treatment of hypercholesterolemia. The New England Journal of Medicine. 1988; 319: 24–33.
 Eckernäs SA, Roos BE, Kvidal P, Eriksson LO, Block GA, Neafus RP, et al. The effects of simvastatin and pravastatin on objective and subjective measures of nocturnal sleep: a comparison of two structurally different HMG CoA reductase inhibitors in patients with primary moderate hypercholesterolaemia. British Journal of Clinical Pharmacology. 1993; 35: 284–289.
 Sinzinger H, Mayr F, Schmid P, Granegger S, O’Grady J, Peskar BA. Sleep disturbance and appetite loss after lovastatin. The Lancet. 1994; 343: 973.
 Black DM, Lamkin G, Olivera EH, Laskarzewski PM, Stein EA. Sleep disturbance and HMG CoA reductase inhibitors. Journal of the American Medical Association. 1990; 264: 1105.
 Sierra S, Ramos MC, Molina P, Esteo C, Vázquez JA, Burgos JS. Statins as neuroprotectants: a comparative in vitro study of lipophilicity, blood-brain-barrier penetration, lowering of brain cholesterol, and decrease of neuron cell death. Journal of Alzheimer’s disease. 2011; 23: 307–318.
 Alsehli AM, Olivo G, Clemensson LE, Williams MJ, Schiöth HB. The Cognitive Effects of Statins are Modified by Age. Scientific Reports. 2020; 10: 6187.
 Power MC, Weuve J, Sharrett AR, Blacker D, Gottesman RF. Statins, cognition, and dementia—systematic review and methodological commentary. Nature Reviews. Neurology. 2015; 11: 220–229.
 Schirris TJ, Renkema GH, Ritschel T, Voermans NC, Bilos A, van Engelen BG, et al. Statin-Induced Myopathy is Associated with Mitochondrial Complex III Inhibition. Cell Metabolism. 2015; 22: 399–407.
 Niedzielski M, Broncel M, Gorzelak-Pabiś P, Woźniak E. New possible pharmacological targets for statins and ezetimibe. Biomedicine and Pharmacotherapy. 2020; 129: 110388.
 Murphy C, Deplazes E, Cranfield CG, Garcia A. The Role of Structure and Biophysical Properties in the Pleiotropic Effects of Statins. International Journal of Molecular Sciences. 2020; 21: 8745.
 Nelson CP, Lai FY, Nath M, Ye S, Webb TR, Schunkert H, et al. Genetic Assessment of Potential Long-Term on-Target Side Effects of PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) Inhibitors. Circulation. Genomic and Precision Medicine. 2019; 12: e002196.
 Swerdlow DI, Preiss D, Kuchenbaecker KB, Holmes MV, Engmann JEL, Shah T, et al. HMG-coenzyme a reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials. The Lancet. 2015; 385: 351–361.
 Bycroft C, Freeman C, Petkova D, Band G, Elliott LT, Sharp K, et al. The UK Biobank resource with deep phenotyping and genomic data. Nature. 2018; 562: 203–209.
 Benn M, Nordestgaard BG, Grande P, Schnohr P, Tybjaerg-Hansen A. PCSK9 R46L, low-density lipoprotein cholesterol levels, and risk of ischemic heart disease: 3 independent studies and meta-analyses. Journal of the American College of Cardiology. 2010; 55: 2833–2842.
 Jansen PR, Watanabe K, Stringer S, Skene N, Bryois J, Hammerschlag AR, et al. Genome-wide analysis of insomnia in 1,331,010 individuals identifies new risk loci and functional pathways. Nature Genetics. 2019; 51: 394–403.
 Lane JM, Jones SE, Dashti HS, Wood AR, Aragam KG, van Hees VT, et al. Biological and clinical insights from genetics of insomnia symptoms. Nature Genetics. 2019; 51: 387–393.
 Ference BA, Robinson JG, Brook RD, Catapano AL, Chapman MJ, Neff DR, et al. Variation in PCSK9 and HMGCR and Risk of Cardiovascular Disease and Diabetes. The New England Journal of Medicine. 2016; 375: 2144–2153.
 Roy A, Jana M, Kundu M, Corbett GT, Rangaswamy SB, Mishra RK, et al. HMG-CoA Reductase Inhibitors Bind to PPARα to Upregulate Neurotrophin Expression in the Brain and Improve Memory in Mice. Cell Metabolism. 2015; 22: 253–265.
 Andreazza AC, Andersen ML, Alvarenga TA, de-Oliveira MR, Armani F, Ruiz FS, et al. Impairment of the mitochondrial electron transport chain due to sleep deprivation in mice. Journal of Psychiatric Research. 2010; 44: 775–780.
 Murillo-Rodríguez E, Guzmán K, Arankowsky-Sandoval G, Salas-Crisóstomo M, Jiménez-Moreno R, Arias-Carrión O. Evidence that activation of nuclear peroxisome proliferatoractivated receptor alpha (PPARα) modulates sleep homeostasis in rats. Brain Research Bulletin. 2016; 127: 156–163.
 Mijangos-Moreno S, Poot-Aké A, Guzmán K, Arankowsky-Sandoval G, Arias-Carrión O, Zaldívar-Rae J, et al. Sleep and neurochemical modulation by the nuclear peroxisome proliferator-activated receptor α (PPAR-α) in rat. Neuroscience Research. 2016; 105: 65–69.
 Murillo-Rodriguez E. The Role of Nuclear Receptor PPARα in the Sleep-wake Cycle Modulation. a Tentative Approach for Treatment of Sleep Disorders. Current Drug Delivery. 2017; 14: 473–482.
 Noordam R, Bos MM, Wang H, Winkler TW, Bentley AR, Kilpeläinen TO, et al. Multi-ancestry sleep-by-SNP interaction analysis in 126,926 individuals reveals lipid loci stratified by sleep duration. Nature Communications. 2019; 10: 5121.
 Botti RE, Triscari J, Pan HY, Zayat J. Concentrations of pravastatin and lovastatin in cerebrospinal fluid in healthy subjects. Clinical Neuropharmacology. 1991; 14: 256–261.
 Vuletic S, Riekse RG, Marcovina SM, Peskind ER, Hazzard WR, Albers JJ. Statins of different brain penetrability differentially affect CSF PLTP activity. Dementia and Geriatric Cognitive Disorders. 2006; 22: 392–398.
 M.P.A. Report, Statins: Updates to Product Safety Information. November 2009. Available at: https://assets.publishing.service.gov.uk/government/uploads/system/uploads/ attachment_data/file/852414/Statins_update_to_product_safety_information.pdfon15/07/2021 (Access: 15 July2021).