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Cataracts and Statins. a Disproportionality Analysis Using Data from Vigibase

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Cataracts and Statins. a Disproportionality Analysis Using Data from Vigibase Journal Pre-proof Cataracts and statins. A disproportionality analysis using data from VigiBase Diego Macías Saint-Gerons, Francisco Bosco Cortez, Giset Jiménez López, José Luis Castro, Rafael Tabarés-Seisdedos PII: S0273-2300(19)30273-9 DOI: https://doi.org/10.1016/j.yrtph.2019.104509 Reference: YRTPH 104509 To appear in: Regulatory Toxicology and Pharmacology Received Date: 21 June 2019 Revised Date: 3 October 2019 Accepted Date: 24 October 2019 Please cite this article as: Macías Saint-Gerons, D., Cortez, F.B., López, Giset.Jimé., Castro, José.Luis., Tabarés-Seisdedos, R., Cataracts and statins. A disproportionality analysis using data from VigiBase, Regulatory Toxicology and Pharmacology (2019), doi: https://doi.org/10.1016/j.yrtph.2019.104509. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Inc. 1 Cataracts and statins. A disproportionality analysis using data from VigiBase 2 3 4 Diego Macías Saint-Gerons 1,2 , Francisco Bosco Cortez 3, Giset Jiménez López 4, José Luis 5 Castro 2 and Rafael Tabarés-Seisdedos 1 6 7 (1) Department of Medicine, University of Valencia; INCLIVA Health Research Institute 8 and CIBERSAM, Valencia, Spain 9 (2) Unit of Medicines and Health Technologies (MT); Dep. of Health Systems and Services 10 (HSS). Pan American Health Organization (PAHO/WHO) 11 (3) Dirección Nacional de Medicamentos. Gobierno de El Salvador, Cd Merliot, El 12 Salvador 13 (4) CECMED Departamento de Vigilancia Postcomercialización, La Habana, Cuba 14 15 16 17 18 19 20 21 Corresponding author: 22 23 Diego Macías Saint-Gerons. ORCID ID: https://orcid.org/0000-0002-2572-2160 24 Department of Medicine, University of Valencia/INCLIVA Health Research Institute and 25 CIBERSAM, Valencia, Spain ([email protected]) 26 Abstract 1 27 The basis of the association between statin use and cataract has been explored using the 28 World Health Organization (WHO) global database of individual case safety reports 29 (ICSRs) for drug monitoring (VigiBase) through January 2019. The reporting odds ratios 30 (RORs) as a measure of disproportionality for reported cataracts and individual statins 31 have been calculated. Subgroup analyses according statin lipophilicity, sex, and age 32 groups have been performed. Moreover, RORs have been calculated for non-statin lipid 33 lowering drugs. An increased disproportionality have been found for most individual statins 34 lovastatin: [ROR: 14.80, 95% confidence interval (CI): 13.30, 16.46)], atorvastatin (ROR: 35 3.48, 95% CI 3.19-3.80), pravastatin (ROR: 3.15, 95% CI: 2.54- 3.90), rosuvastatin (ROR: 36 2.90, 95% CI: 2.53-3.31), simvastatin (ROR: 2.27, 95%CI: 1.99-2.60), fluvastatin (ROR: 37 2.03, 95% CI: 1.33-3.08) and statins (overall) ROR: 3.66, 95% CI:3.46-3.86). Increased 38 disproportionality for cataract and statins (drug-class) have been found regardless of statin 39 lipophilicity, sex and group age (more or less than 65 years old). No disproportionality was 40 found for other lipid-lowering drugs (ezetimibe, fibrates or PCSK9 inhibitors). These 41 findings suggest an increased risk of cataract associated with statins as a drug-class. 42 Further studies to characterize the risk are advised. Benefits and potential harms should 43 be considered before starting treatment with statins. 44 45 46 Keywords, 47 Hydroxymethylglutaryl-CoA Reductase Inhibitors, statins, anticholesteremic agents, 48 cataract, pharmacovigilance 49 1. Introduction 2 50 Loss of lens transparency, cataract, is the leading cause of visual impairment and 51 blindness worldwide (Bourne et al., 2013). Along with the aging population and extended 52 life expectancy, the number of people with cataract is expected to increase continuously 53 (He, 2017). Therefore, preventable vision loss due to cataract (reversible with surgery) and 54 understanding the modifiable risk factors for developing lens opacities remains a public 55 health priority (Flaxman et al., 2017; Leuschen et al., 2013). 56 Hydroxymethyl glutaryl coenzyme A reductase inhibitors (statins) are among the most 57 prescribed drugs in the world for the prevention of cardiovascular disease, and its use has 58 been expanded to wider populations. According to the Guidelines released by the 59 American Heart Association and the American College of Cardiology up to 56 million 60 adults are currently indicated to receive statins only in the U.S. (Salami et al., 2017). Clear 61 benefits of statins have been found for patients at high risk of cardiovascular disease 62 (CVD), however the potential adverse effects associated with statins should also be 63 considered especially in primary prevention of CVD and the elderly in which the benefits 64 are less evident (Armitage et al., 2019). 65 Cataractogenesis, or opacification of the ocular lens of the eyes, is a multifactorial process 66 that may be initiated by oxidative damage from oxygen radicals (Chodick et al., 2010). 67 Investigators have previously hypothesized that statins' so-called antioxidant and anti- 68 inflammatory effects on the lens may slow the aging process of the lens nucleus and 69 epithelium (Fong and Poon, 2012). However clinical studies have reported conflicting 70 results; some studies have found an increased risk for cataract in association with statin 71 use, while others have found a protective effect on the cataract risk (Desai et al., 2014). 72 We present an updated disproportionality analysis performed in the World Health 73 Organization (WHO) global database of individual case safety reports (ICSRs) for drug 74 monitoring to analyze the relation between cataract and statins. 3 75 76 2. Material and methods 77 We searched in World Health Organization (WHO) global database of individual case 78 safety reports (VigiBase) for ICSRs in which the following MedDRA preferred terms (PTs): 79 “Cataract”, “Cataract cortical”, “Cataract nuclear” and “Cataract subcapsular” were 80 reported for HMG-CoA reductase inhibitors according to the anatomical therapeutic 81 chemical classification (ATC: C10AA) between inception on Nov 14, 1967, and Jan 15, 82 2019. Fixed-dose combinations of statins with other drugs were not considered. We also 83 searched for ICSRs for the PTs mentioned above and prednisolone as a positive control – 84 a drug previously known to cause cataract- and paracetamol/acetaminophen which served 85 as a negative control -a drug not likely to be related with the occurrence of cataracts. 86 Furthermore, we searched ICSRs of cataracts related to other lipid-lowering drugs classes 87 different from statins: fibrates (ATC: C10AB), ezetimibe (ATC: C10AX09) and proprotein 88 convertase subtilisin/kexin type 9 (PCSK9) antibodies (ATC C10AX13, C10AX14). 89 VigiBase is maintained and developed on behalf of WHO by the Uppsala Monitoring 90 Centre (UMC), situated in Uppsala, Sweden. A de-duplicated dataset version of VigiBase 91 including over 18 million ICSRs was used to minimize the risk of identifying duplicate 92 reports. The ICSRs were accessed using VigiLyze through the subscription available in 93 Cuba and El Salvador as member countries of the WHO Programme for International Drug 94 Monitoring. The main characteristics of the ICSRs were described including reporting 95 source, patient gender, sex, and type of cataract. When available, daily doses were 96 calculated from the information statin prescribed dose and the regimen indicated the 97 ICSRs. The induction period was calculated as the time between the start of statin 98 treatment and clinical diagnosis of cataract in the ISCRs. 4 99 Disproportional reporting was investigated through the calculation of the Reporting Odds 100 Ratio with their 95% Confidence Interval using Woolf’s method (Woolf, 1955). Results > 101 1.0 indicate a higher than expected reporting rate (Rothman et al., 2004). To test the 102 consistency of the disproportionality over time, we calculated the cumulative RORs per 103 year were during the period 1988-2018. Additionally, we explored differences in 104 disproportionality according to statin lipophilicity. Statins where classified in two groups: 105 hydrophilic statins (pravastatin, rosuvastatin) and lipophilic (rest) (Fong et al., 2014). 106 Subgroup analysis of the ROR were performed by sex and by age groups (more or less 107 than 65 years old). All analyses were conducted using Stata version 14 (StataCorp LP, 108 College Station, Texas, USA), 109 3. Results 110 Following our search 26885 ICSRs of cataract were found. From these 1402 ISCRs 111 reported a statin and cataract. For 38 (2.7 %) reports there was more than one suspected 112 statin. The median age of the patients in the reports was 62 years old (range 12-95). The 113 reports involved 471 (33.59%) men and 845 (60.27%) women; sex was not specified in 86 114 (6.13%) reports. Of the 1402 ISCRs, 327 (23.36%) were reported by health professionals, 115 420 (29.96%) by consumers or lawyers; reporting source was not specified in 655 116 (46.72%) reports. By Regions, the reports originated in America 1145 (81.67%), Europe 117 193 (13.77%), Asia 31 (2.21%), Oceania 27 (1.93 %) and Africa 6 (0.43 %). The most 118 frequent reported PT was cataract 1387 (98,93%), followed by subcapsular cataract 11 119 (0.78%), nuclear cataract 6 (0.43%) and cortical cataract 1 (0.07%). Statin daily doses and 120 induction period for cataract onset are shown in table 1. Disproportionality was found for all 121 individual statins except pitavastatin and cerivastatin (table 2).
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