Cataracts and Statins. a Disproportionality Analysis Using Data from Vigibase

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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.

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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

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

21 Corresponding author:

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.

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 from the global market due to drug-related rhabdomyolysis-. The

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

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.

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15 Table 1. Reported daily dose and induction period for individual statins in the ICSRs. Statin Daily dose a Induction period (days) b

N Dose (%) N Median [range] 727 5 mg (1.10) 60 214 [0-1155] 10 mg (29.02) 20 mg (38.10) 30 mg (0.41) Atorvastatin 40 mg (22.15) 50 mg (0.14) 60 mg (0.28) 80 mg (8.80)

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) Exposed Non- exposed Atorvastatin 514/26371 102774/ 18362363 3.48 (3.19-3.80)

Lovastatin 349/26536 16396/18448741 14.80 (13.30- 16.46) Rosuvastatin 216/2669 51506/18413631 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 302/26583 44984/18420153 4.65 (4.15-5.21) (positive control) Acetaminophen 15/26870 123148/18341989 0.08 (0.05-0.14) (negative control)

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)

Fibrates a 45/26840 26287/18438850 1.18 (0.88-1.58)

PCSK9 inhibitors b 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: