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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:
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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.
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Cataracts and statins. A disproportionality analysis using data from VigiBase
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Diego Macías Saint-Gerons 1,2, Francisco Bosco Cortez3, Giset Jiménez López4, José Luis
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Castro2 and Rafael Tabarés-Seisdedos1
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(1) Department of Medicine, University of Valencia; INCLIVA Health Research Institute
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and CIBERSAM, Valencia, Spain
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(2) Unit of Medicines and Health Technologies (MT); Dep. of Health Systems and Services
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(HSS). Pan American Health Organization (PAHO/WHO)
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(3) Dirección Nacional de Medicamentos. Gobierno de El Salvador, Cd Merliot, El
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Salvador
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(4) CECMED Departamento de Vigilancia Postcomercialización, La Habana, Cuba
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Corresponding author:
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Diego Macías Saint-Gerons. ORCID ID: https://orcid.org/0000-0002-2572-2160
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Department of Medicine, University of Valencia/INCLIVA Health Research Institute and
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CIBERSAM, Valencia, Spain ([email protected])
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Abstract
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The basis of the association between statin use and cataract has been explored using the
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World Health Organization (WHO) global database of individual case safety reports
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(ICSRs) for drug monitoring (VigiBase) through January 2019. The reporting odds ratios
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(RORs) as a measure of disproportionality for reported cataracts and individual statins
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have been calculated. Subgroup analyses according statin lipophilicity, sex, and age
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groups have been performed. Moreover, RORs have been calculated for non-statin lipid
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lowering drugs. An increased disproportionality have been found for most individual statins
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lovastatin: [ROR: 14.80, 95% confidence interval (CI): 13.30, 16.46)], atorvastatin (ROR:
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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:
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2.03, 95% CI: 1.33-3.08) and statins (overall) ROR: 3.66, 95% CI:3.46-3.86). Increased
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disproportionality for cataract and statins (drug-class) have been found regardless of statin
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lipophilicity, sex and group age (more or less than 65 years old). No disproportionality was
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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.
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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,
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Hydroxymethylglutaryl-CoA Reductase Inhibitors, statins, anticholesteremic agents,
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cataract, pharmacovigilance
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1. Introduction
2
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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
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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
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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
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use, while others have found a protective effect on the cataract risk (Desai et al., 2014).
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We present an updated disproportionality analysis performed in the World Health
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Organization (WHO) global database of individual case safety reports (ICSRs) for drug
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monitoring to analyze the relation between cataract and statins.
3
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2. Material and methods
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We searched in World Health Organization (WHO) global database of individual case
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safety reports (VigiBase) for ICSRs in which the following MedDRA preferred terms (PTs):
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“Cataract”, “Cataract cortical”, “Cataract nuclear” and “Cataract subcapsular” were
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reported for HMG-CoA reductase inhibitors according to the anatomical therapeutic
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chemical classification (ATC: C10AA) between inception on Nov 14, 1967, and Jan 15,
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2019. Fixed-dose combinations of statins with other drugs were not considered. We also
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searched for ICSRs for the PTs mentioned above and prednisolone as a positive control –
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a drug previously known to cause cataract- and paracetamol/acetaminophen which served
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as a negative control -a drug not likely to be related with the occurrence of cataracts.
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Furthermore, we searched ICSRs of cataracts related to other lipid-lowering drugs classes
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different from statins: fibrates (ATC: C10AB), ezetimibe (ATC: C10AX09) and proprotein
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convertase subtilisin/kexin type 9 (PCSK9) antibodies (ATC C10AX13, C10AX14).
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VigiBase is maintained and developed on behalf of WHO by the Uppsala Monitoring
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Centre (UMC), situated in Uppsala, Sweden. A de-duplicated dataset version of VigiBase
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including over 18 million ICSRs was used to minimize the risk of identifying duplicate
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reports. The ICSRs were accessed using VigiLyze through the subscription available in
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Cuba and El Salvador as member countries of the WHO Programme for International Drug
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Monitoring. The main characteristics of the ICSRs were described including reporting
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source, patient gender, sex, and type of cataract. When available, daily doses were
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calculated from the information statin prescribed dose and the regimen indicated the
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ICSRs. The induction period was calculated as the time between the start of statin
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treatment and clinical diagnosis of cataract in the ISCRs.
4
99
Disproportional reporting was investigated through the calculation of the Reporting Odds
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Ratio with their 95% Confidence Interval using Woolf’s method (Woolf, 1955). Results >
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1.0 indicate a higher than expected reporting rate (Rothman et al., 2004). To test the
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consistency of the disproportionality over time, we calculated the cumulative RORs per
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year were during the period 1988-2018. Additionally, we explored differences in
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disproportionality according to statin lipophilicity. Statins where classified in two groups:
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hydrophilic statins (pravastatin, rosuvastatin) and lipophilic (rest) (Fong et al., 2014).
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Subgroup analysis of the ROR were performed by sex and by age groups (more or less
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than 65 years old). All analyses were conducted using Stata version 14 (StataCorp LP,
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College Station, Texas, USA),
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3. Results
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Following our search 26885 ICSRs of cataract were found. From these 1402 ISCRs
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reported a statin and cataract. For 38 (2.7 %) reports there was more than one suspected
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statin. The median age of the patients in the reports was 62 years old (range 12-95). The
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reports involved 471 (33.59%) men and 845 (60.27%) women; sex was not specified in 86
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(6.13%) reports. Of the 1402 ISCRs, 327 (23.36%) were reported by health professionals,
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420 (29.96%) by consumers or lawyers; reporting source was not specified in 655
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(46.72%) reports. By Regions, the reports originated in America 1145 (81.67%), Europe
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193 (13.77%), Asia 31 (2.21%), Oceania 27 (1.93 %) and Africa 6 (0.43 %). The most
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frequent reported PT was cataract 1387 (98,93%), followed by subcapsular cataract 11
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(0.78%), nuclear cataract 6 (0.43%) and cortical cataract 1 (0.07%). Statin daily doses and
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induction period for cataract onset are shown in table 1. Disproportionality was found for all
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individual statins except pitavastatin and cerivastatin (table 2). Disproportionality was
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found for statins as a drug-class but not for other lipid-lowering pharmacological groups
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(table 3). Cumulative RORs for statins and cataract ranged from 30.9 [95% confidence
5
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interval (CI): 19.0-50.14)] in 1988 to 3.63 (95% CI: 3.44-3.84) to in 2018 (figure 1).
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Disproportionality was found for both hydrophilic and lipophilic statins, 2.97 (95% CI: 2.65-
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3.33) and 3.81 (95% CI:3.59- 4.05) respectively. Increased disproportionality was found for
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both males (ROR: 3.41, 95% CI: 3.11-3.73) and females (ROR: 3.63, 95% CI: 3.39-3.89).
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Age groups less than 65 years and over 65 years shown also increased disproportionality,
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RORs: 7.13 (95% CI: 6.58-7.73) and 2.12 (95% CI: 1.94-2.33) respectively.
130 131
4. Discussion
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In our study, we were able to find statistically significant disproportionality for the drug-
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class and consistently also for most of the marketed individual statins except for
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pitavastatin the newest statin which accumulates less exposure and for cerivastatin
135
withdrawn
136
disproportionality for statins was similar to prednisolone a drug with a well-established
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causal association with cataract (Black et al.,1960; Jobling and Augusteyn, 2002). Isolated
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case reports of cataract associated with statins have been published (Bousquet, 1998), but
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this is to our knowledge, the first analysis applying disproportionality methodology to a
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large pharmacovigilance database of individual case reports (ICSRs).
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Cataracts have been observed in experimental animals during the early development of
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several statins. The recommendation of yearly "slit-lamp" exams was included in the label
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of lovastatin –the first marketed statin- due to cataracts detected in experimental animals
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(Fraunfelder, 1988). Cataracts have been also observed in dogs and rats after three
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months and two years of treatment with simvastatin at high doses, respectively and in
146
dogs exposed to high doses of fluvastatin (Cenedella et al., 2003; Hartman et al., 1996).
147
The following post authorization surveillance did not provide convincing evidence to
from
the
global
market
due
to
drug-related
rhabdomyolysis-.
The
6
148
support the recommendation of ocular examination for lovastatin and it was dropped from
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the label. In our study disproportionality of cataracts and statins was statistically significant
150
during the whole study period. Nevertheless, a greater disproportionality peak was found
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in the early 90s consistent with the awareness at the moment of lovastatin authorization.
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The putative biological mechanism for cataractogenesis is not yet fully understood.
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Increased opacification due to drug accumulation in the lens has been observed in
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lipophilic antipsychotic drugs (Kamei, 1994). Statins have also been found deposited in the
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lens [Gerson et al., 1990; Grosser et al., 2004) and differences in the lipophilicity across
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the drug-class have been described (Fong, 2014). However, in our study, we found
157
disproportionality for statins regardless of its lipophilic profile consistent with a drug-class
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effect. Currently, no information at all on cataract can be obtained in summary of the
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product characteristics of pravastatin and atorvastatin, whereas for simvastatin and
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rosuvastatin findings in animal studies are mentioned but cataract is not included as an
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adverse reaction in the clinical section.
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Triparanol, a cholesterol-lowering agent was withdrawn from the market by the Food and
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Drugs Administration (FDA) in 1962 after several reports of induced cataracts in patients
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(Laughlin and Carey, 1962). Lipid- lowering drugs might affect the functionality of the lens
165
membranes by reducing its content in cholesterol (Cenedella et al., 2003). In our study, we
166
did not detect disproportionality for other non-statin lipid- lowering drugs such as
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ezetimibe, PCSK9 antibodies or fibrates that can achieve similar or greater reductions than
168
statins in serum lipid levels (Sabatine et al., 2015; Sahebkar et al., 2017). However,
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triparanol and statins –to a lesser degree- can inhibit the cholesterol biosynthesis (Risé et
170
al., 2003). This de novo synthesis of cholesterol could play a critical role in the
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maintenance of transparency of the lens since the predominantly avascular structure of the
7
172
lens depends more on endogenous cholesterol synthesis than on serum lipids to meet its
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cholesterol demands (Beri et al., 2009; de Vries et al., 1993).
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Maturity-onset and progression of cataracts have been associated with the damage in the
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lens caused by oxidative stress (Spector et al., 1995). Statins have been claimed to show
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different pleiotropic effects, including decreasing oxidative stress in vascular tissues (Liao
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and Laufs, 2005). Conversely increasing evidence suggests that statin toxicity is caused
178
by augmented oxidative stress in other tissues such as hepatic, kidney and muscle cells
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(Liu, 2018). Moreover, high potency statins or high doses (intensive therapy) have been
180
suggested to increase statin-induced oxidative stress (Golomb and Evans, 2008).
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Furthermore, intensive therapy has also been associated with an increased risk of new-
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onset diabetes which is a known risk factor for cataract formation (Preiss et al., 2011). In
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our study, no clear dose pattern could be identified from the information available in the
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ICSRs.
185
Clinical studies have found conflicting results regarding a possible link between statin use
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and the risk of cataracts. Meta-analysis found results ranging from protective effects in
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preventing cataracts (Kostis and Dobrzynski, 2014) to modest risk increases in the pooled
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estimates of observational studies or no risk differences in the pooled estimates of
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Randomized Clinical Trials (RCTs) (Dobrzynski et al., 2018; Shandong et al., 2017). The
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suggested long induction period for cataract formation, and the presumably modest size
191
risk effect may explain that only RCTs of considerable population size and follow-up offer
192
adequate statistical power to detect differences in this presumably modest size risk effect.
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The Heart Protection Study has led the inconclusive results of pooled RCTs. In this 2x2
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factorial design trial, 20,536 high-risk individuals were allocated to simvastatin 40mg or
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placebo but also to antioxidant vitamin supplementation or placebo found no differences in
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the risk of incident cataract associated with simvastatin were found (risk ratio 0.97
8
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CI95%:0.85- 1.12) (Heart Protection Study Collaborative Group 2002a, 2002b). It is
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unclear whether the cataract risk associated with statins would be independent of the
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effects of the antioxidants (Mathew et al., 2012; Zhao et al., 2014). Conversely, an
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increased risk of cataract surgery was found in other large RCT in which 12,705 patients
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were randomly assigned to rosuvastatin 10 mg or placebo followed a median of 5.6 years
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(risk ratio: 1.24 [95%CI: 1.03-1.49]) (Yusuf et al., 2016).
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Our study also has several limitations. Reports of cataract lack on details about the
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procedure used for the diagnosis (i.e.: slit-lamp examination). The cataract location was
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rarely reported and limited the analysis by cataract subtype. Furthermore, although we
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excluded the preferred term “diabetic cataract” from the searches, some degree of
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misclassification is expected for the broader preferred term “cataract”. Moreover, data on
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known risk factors for cataract such as smoking or UV radiation exposure was not
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available. The possibility of duplicate reporting cannot be excluded notwithstanding a de-
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duplicated dataset version of VigiBase was used. Lastly, spontaneous reporting databases
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have other inherent limitations including the underreporting of long latency ADRs.
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However, statins are among the most consumed drugs in the world and the capacity to
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identify potential ADRs of statins is also increased in a global pharmacovigilance database
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covering all the marketed statins.
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In conclusion, our results support the hypothesis of cataract occurrence as a drug-class
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effect of statins. Potential differences in risk for specific cataract subtypes and considering
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drug level factors (i.e.: statin potency or dose) merit further investigation. Eye examination
218
and reporting cataracts should be considered in future RCTs involving statins. Benefits
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and potential harms should be considered before starting treatment with statins.
220
Declaration of interests
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The authors declare that they have no conflict of interest. The opinions expressed in this
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article are those of the authors and do not necessarily reflect the views of the Pan
223
American Health Organization (PAHO), its Board of Directors, or the countries they
224
represent.
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Funding.
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None.
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Acknowledgements
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We thank the Uppsala Monitoring Centre (Uppsala, Sweden) and the Pan American
229
Network of Pharmacovigilance for their valuable support.
230
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Persons
without
Cardiovascular
Disease.
N
Engl
J
Med.
15
Table 1. Reported daily dose and induction period for individual statins in the ICSRs. Statin Daily dosea Induction period (days)b N
Dose (%)
N
Median [range]
727
5 mg (1.10) 10 mg (29.02) 20 mg (38.10) 30 mg (0.41) 40 mg (22.15) 50 mg (0.14) 60 mg (0.28) 80 mg (8.80)
60
214 [0-1155]
Atorvastatin
215
10 mg (0.93) 165 218 [0-4383] 20 mg (72.09) Lovastatin 40 mg (20.00) 60 mg (4.65) 80 mg (2.33) 179 2.1 mg (0.56) 11 221 [0-1216] 2.5 mg (3.35) 3 mg (1.12) 5 mg (18.44) Rosuvastatin 10 mg (43.02) 20 mg (18.99) 30 mg (0.56) 40 mg (13.97) 111 5 mg (4.50) 65 243 [0-7445] 10 mg (33.33) Simvastatin 20 mg (36.04) 40 mg (22.52) 80 mg (3.60) 23 5 mg (4.35) 18 207.5 [0-1155] 10 mg (8.70) Pravastatin 20 mg (43.48) 40 mg (39.13) 80 mg (4.35) 8 0.1 mg (37.50) 11 107 [1-518] Cerivastatin 0.2 mg (37.50) 0.3 mg (25.0) 15 20 mg (40.0) 8 134 [0-1539] Fluvastatin 40 mg (46.67) 80 mg (13.33) 10 2 mg (90.00) 3 53 [12-155] Pitavastatin 4 mg (10.00) a More than one suspected statin and/or dose can be reported in the same ISCR; b Time to the outcome from the starting date of the first statin reported.
Table 2. Reporting Odds Ratio (ROR) values for individual statins, control drugs and cataracts. Drug Cataracts ROR (95% CI) Atorvastatin
Exposed 514/26371
Non- exposed 102774/ 18362363
Lovastatin
349/26536
16396/18448741
Rosuvastatin
216/2669
51506/18413631
14.80 (13.3016.46) 2.90 (2.53-3.31)
Simvastatin
215/26670
65270/18399867
2.27 (1.99-2.60)
Pravastatin
85/26800
18593/18446544
3.15 (2.54-3.90)
Cerivastatin
27/26858
13980/18451157
1.33 (0.91-1.94)
Fluvastatin
22/26863
7460/18457677
2.03 (1.33-3.08)
Pitavastatin
12/26873
5219/18459918
1.58 (0.90-2.78)
Prednisolone (positive control) Acetaminophen (negative control)
302/26583
44984/18420153
4.65 (4.15-5.21)
15/26870
123148/18341989
0.08 (0.05-0.14)
3.48 (3.19-3.80)
Table 3. Reporting Odds Ratio (ROR) values for lipid lowering drugs and cataracts. Lipid lowering Cataracts ROR (95% CI) drugs Exposed Non- exposed Statins 1402/25483 273715/18191422 3.66 (3.46-3.86) Fibratesa
45/26840
26287/18438850
1.18 (0.88-1.58)
PCSK9 inhibitorsb
48/26837
51271/18413866
0.64 (0.48-0.85)
Ezetimibe
11/26874
15763/18459918
0.48 (0.27-0.87)
a
ISCRs reported for fibrates included gemfibrozil, fenofibrate and clofibrate; b ISCRs reported for PCSK9 inhibitors included evolocumab and alirocumbab
RESEARCH HIGHLIGHTS
•
Animals models have documented lens opacities associated with statin exposure
•
Clinical evidence has found conflicting results regarding a possible link between statin use and risk of cataracts Data from VigiBase was examined to calculate reporting odds ratios (RORs) as a
•
measure of disproportionality
•
Statins were associated with elevated disproportionality for reporting of cataract relative to other medications
Funding. None
Declaration of interests ☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. ☐The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:
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 Cortez3, Giset Jiménez López4, José Luis
5
Castro2 and Rafael Tabarés-Seisdedos1
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). Disproportionality was
122
found for statins as a drug-class but not for other lipid-lowering pharmacological groups
123
(table 3). Cumulative RORs for statins and cataract ranged from 30.9 [95% confidence
5
124
interval (CI): 19.0-50.14)] in 1988 to 3.63 (95% CI: 3.44-3.84) to in 2018 (figure 1).
125
Disproportionality was found for both hydrophilic and lipophilic statins, 2.97 (95% CI: 2.65-
126
3.33) and 3.81 (95% CI:3.59- 4.05) respectively. Increased disproportionality was found for
127
both males (ROR: 3.41, 95% CI: 3.11-3.73) and females (ROR: 3.63, 95% CI: 3.39-3.89).
128
Age groups less than 65 years and over 65 years shown also increased disproportionality,
129
RORs: 7.13 (95% CI: 6.58-7.73) and 2.12 (95% CI: 1.94-2.33) respectively.
130 131
4. Discussion
132
In our study, we were able to find statistically significant disproportionality for the drug-
133
class and consistently also for most of the marketed individual statins except for
134
pitavastatin the newest statin which accumulates less exposure and for cerivastatin
135
withdrawn
136
disproportionality for statins was similar to prednisolone a drug with a well-established
137
causal association with cataract (Black et al.,1960; Jobling and Augusteyn, 2002). Isolated
138
case reports of cataract associated with statins have been published (Bousquet, 1998), but
139
this is to our knowledge, the first analysis applying disproportionality methodology to a
140
large pharmacovigilance database of individual case reports (ICSRs).
141
Cataracts have been observed in experimental animals during the early development of
142
several statins. The recommendation of yearly "slit-lamp" exams was included in the label
143
of lovastatin –the first marketed statin- due to cataracts detected in experimental animals
144
(Fraunfelder, 1988). Cataracts have been also observed in dogs and rats after three
145
months and two years of treatment with simvastatin at high doses, respectively and in
146
dogs exposed to high doses of fluvastatin (Cenedella et al., 2003; Hartman et al., 1996).
147
The following post authorization surveillance did not provide convincing evidence to
from
the
global
market
due
to
drug-related
rhabdomyolysis-.
The
6
148
support the recommendation of ocular examination for lovastatin and it was dropped from
149
the label. In our study disproportionality of cataracts and statins was statistically significant
150
during the whole study period. Nevertheless, a greater disproportionality peak was found
151
in the early 90s consistent with the awareness at the moment of lovastatin authorization.
152
The putative biological mechanism for cataractogenesis is not yet fully understood.
153
Increased opacification due to drug accumulation in the lens has been observed in
154
lipophilic antipsychotic drugs (Kamei, 1994). Statins have also been found deposited in the
155
lens [Gerson et al., 1990; Grosser et al., 2004) and differences in the lipophilicity across
156
the drug-class have been described (Fong, 2014). However, in our study, we found
157
disproportionality for statins regardless of its lipophilic profile consistent with a drug-class
158
effect. Currently, no information at all on cataract can be obtained in summary of the
159
product characteristics of pravastatin and atorvastatin, whereas for simvastatin and
160
rosuvastatin findings in animal studies are mentioned but cataract is not included as an
161
adverse reaction in the clinical section.
162
Triparanol, a cholesterol-lowering agent was withdrawn from the market by the Food and
163
Drugs Administration (FDA) in 1962 after several reports of induced cataracts in patients
164
(Laughlin and Carey, 1962). Lipid- lowering drugs might affect the functionality of the lens
165
membranes by reducing its content in cholesterol (Cenedella et al., 2003). In our study, we
166
did not detect disproportionality for other non-statin lipid- lowering drugs such as
167
ezetimibe, PCSK9 antibodies or fibrates that can achieve similar or greater reductions than
168
statins in serum lipid levels (Sabatine et al., 2015; Sahebkar et al., 2017). However,
169
triparanol and statins –to a lesser degree- can inhibit the cholesterol biosynthesis (Risé et
170
al., 2003). This de novo synthesis of cholesterol could play a critical role in the
171
maintenance of transparency of the lens since the predominantly avascular structure of the
7
172
lens depends more on endogenous cholesterol synthesis than on serum lipids to meet its
173
cholesterol demands (Beri et al., 2009; de Vries et al., 1993).
174
Maturity-onset and progression of cataracts have been associated with the damage in the
175
lens caused by oxidative stress (Spector et al., 1995). Statins have been claimed to show
176
different pleiotropic effects, including decreasing oxidative stress in vascular tissues (Liao
177
and Laufs, 2005). Conversely increasing evidence suggests that statin toxicity is caused
178
by augmented oxidative stress in other tissues such as hepatic, kidney and muscle cells
179
(Liu, 2018). Moreover, high potency statins or high doses (intensive therapy) have been
180
suggested to increase statin-induced oxidative stress (Golomb and Evans, 2008).
181
Furthermore, intensive therapy has also been associated with an increased risk of new-
182
onset diabetes which is a known risk factor for cataract formation (Preiss et al., 2011). In
183
our study, no clear dose pattern could be identified from the information available in the
184
ICSRs.
185
Clinical studies have found conflicting results regarding a possible link between statin use
186
and the risk of cataracts. Meta-analysis found results ranging from protective effects in
187
preventing cataracts (Kostis and Dobrzynski, 2014) to modest risk increases in the pooled
188
estimates of observational studies or no risk differences in the pooled estimates of
189
Randomized Clinical Trials (RCTs) (Dobrzynski et al., 2018; Shandong et al., 2017). The
190
suggested long induction period for cataract formation, and the presumably modest size
191
risk effect may explain that only RCTs of considerable population size and follow-up offer
192
adequate statistical power to detect differences in this presumably modest size risk effect.
193
The Heart Protection Study has led the inconclusive results of pooled RCTs. In this 2x2
194
factorial design trial, 20,536 high-risk individuals were allocated to simvastatin 40mg or
195
placebo but also to antioxidant vitamin supplementation or placebo found no differences in
196
the risk of incident cataract associated with simvastatin were found (risk ratio 0.97
8
197
CI95%:0.85- 1.12) (Heart Protection Study Collaborative Group 2002a, 2002b). It is
198
unclear whether the cataract risk associated with statins would be independent of the
199
effects of the antioxidants (Mathew et al., 2012; Zhao et al., 2014). Conversely, an
200
increased risk of cataract surgery was found in other large RCT in which 12,705 patients
201
were randomly assigned to rosuvastatin 10 mg or placebo followed a median of 5.6 years
202
(risk ratio: 1.24 [95%CI: 1.03-1.49]) (Yusuf et al., 2016).
203
Our study also has several limitations. Reports of cataract lack on details about the
204
procedure used for the diagnosis (i.e.: slit-lamp examination). The cataract location was
205
rarely reported and limited the analysis by cataract subtype. Furthermore, although we
206
excluded the preferred term “diabetic cataract” from the searches, some degree of
207
misclassification is expected for the broader preferred term “cataract”. Moreover, data on
208
known risk factors for cataract such as smoking or UV radiation exposure was not
209
available. The possibility of duplicate reporting cannot be excluded notwithstanding a de-
210
duplicated dataset version of VigiBase was used. Lastly, spontaneous reporting databases
211
have other inherent limitations including the underreporting of long latency ADRs.
212
However, statins are among the most consumed drugs in the world and the capacity to
213
identify potential ADRs of statins is also increased in a global pharmacovigilance database
214
covering all the marketed statins.
215
In conclusion, our results support the hypothesis of cataract occurrence as a drug-class
216
effect of statins. Potential differences in risk for specific cataract subtypes and considering
217
drug level factors (i.e.: statin potency or dose) merit further investigation. Eye examination
218
and reporting cataracts should be considered in future RCTs involving statins. Benefits
219
and potential harms should be considered before starting treatment with statins.
220
Declaration of interests
9
221
The authors declare that they have no conflict of interest. The opinions expressed in this
222
article are those of the authors and do not necessarily reflect the views of the Pan
223
American Health Organization (PAHO), its Board of Directors, or the countries they
224
represent.
225
Funding.
226
None.
227
Acknowledgements
228
We thank the Uppsala Monitoring Centre (Uppsala, Sweden) and the Pan American
229
Network of Pharmacovigilance for their valuable support.
230
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Table 1. Reported daily dose and induction period for individual statins in the ICSRs. Statin Daily dosea Induction period (days)b N
Dose (%)
N
Median [range]
727
5 mg (1.10) 10 mg (29.02) 20 mg (38.10) 30 mg (0.41) 40 mg (22.15) 50 mg (0.14) 60 mg (0.28) 80 mg (8.80)
60
214 [0-1155]
Atorvastatin
215
10 mg (0.93) 165 218 [0-4383] 20 mg (72.09) Lovastatin 40 mg (20.00) 60 mg (4.65) 80 mg (2.33) 179 2.1 mg (0.56) 11 221 [0-1216] 2.5 mg (3.35) 3 mg (1.12) 5 mg (18.44) Rosuvastatin 10 mg (43.02) 20 mg (18.99) 30 mg (0.56) 40 mg (13.97) 111 5 mg (4.50) 65 243 [0-7445] 10 mg (33.33) Simvastatin 20 mg (36.04) 40 mg (22.52) 80 mg (3.60) 23 5 mg (4.35) 18 207.5 [0-1155] 10 mg (8.70) Pravastatin 20 mg (43.48) 40 mg (39.13) 80 mg (4.35) 8 0.1 mg (37.50) 11 107 [1-518] Cerivastatin 0.2 mg (37.50) 0.3 mg (25.0) 15 20 mg (40.0) 8 134 [0-1539] Fluvastatin 40 mg (46.67) 80 mg (13.33) 10 2 mg (90.00) 3 53 [12-155] Pitavastatin 4 mg (10.00) a More than one suspected statin and/or dose can be reported in the same ISCR; b Time to the outcome from the starting date of the first statin reported.
Table 2. Reporting Odds Ratio (ROR) values for individual statins, control drugs and cataracts. Drug Cataracts ROR (95% CI) Atorvastatin
Exposed 514/26371
Non- exposed 102774/ 18362363
Lovastatin
349/26536
16396/18448741
Rosuvastatin
216/2669
51506/18413631
14.80 (13.3016.46) 2.90 (2.53-3.31)
Simvastatin
215/26670
65270/18399867
2.27 (1.99-2.60)
Pravastatin
85/26800
18593/18446544
3.15 (2.54-3.90)
Cerivastatin
27/26858
13980/18451157
1.33 (0.91-1.94)
Fluvastatin
22/26863
7460/18457677
2.03 (1.33-3.08)
Pitavastatin
12/26873
5219/18459918
1.58 (0.90-2.78)
Prednisolone (positive control) Acetaminophen (negative control)
302/26583
44984/18420153
4.65 (4.15-5.21)
15/26870
123148/18341989
0.08 (0.05-0.14)
3.48 (3.19-3.80)
Table 3. Reporting Odds Ratio (ROR) values for lipid lowering drugs and cataracts. Lipid lowering Cataracts ROR (95% CI) drugs Exposed Non- exposed Statins 1402/25483 273715/18191422 3.66 (3.46-3.86) Fibratesa
45/26840
26287/18438850
1.18 (0.88-1.58)
PCSK9 inhibitorsb
48/26837
51271/18413866
0.64 (0.48-0.85)
Ezetimibe
11/26874
15763/18459918
0.48 (0.27-0.87)
a
ISCRs reported for fibrates included gemfibrozil, fenofibrate and clofibrate; b ISCRs reported for PCSK9 inhibitors included evolocumab and alirocumbab
RESEARCH HIGHLIGHTS
•
Animals models have documented lens opacities associated with statin exposure
•
Clinical evidence has found conflicting results regarding a possible link between statin use and risk of cataracts Data from VigiBase was examined to calculate reporting odds ratios (RORs) as a
•
measure of disproportionality
•
Statins were associated with elevated disproportionality for reporting of cataract relative to other medications
Funding. None
Declaration of interests ☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. ☐The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: