The Effect of Statins on Ocular Disorders: A Systematic Review of Randomized Controlled Trials

Aim: Statins have been established in the market not only due to their ability to lower plasma cholesterol levels but also due to their pleiotropic effects. In the literature, there is a controversy regarding the role of statins in ophthalmology. We aimed to systematically address the possible effect of statin therapy on ocular diseases and to identify if there is a beneficial relationship. Methods: We searched PubMed and Cochrane Library databases up to 31 December 2022 for studies evaluating the effect of statins on ocular diseases. We included all relevant Randomized Control Trials (RCTs) that have been conducted in the adult population. PROSPERO registration number: CRD42022364328. Results: Nineteen RCTs were finally considered eligible for this systematic review, with a total of 28,940 participants. Ten studies investigated the role of simvastatin, suggesting a lack of cataractogenic effect and a possible protective role in cataract formation, retinal vascular diseases, and especially diabetic retinopathy, age-related macular disease progression, and non-infectious uveitis. Four studies investigated lovastatin, showing no cataractogenic effect. Three studies examined atorvastatin, revealing conflicting results regarding diabetic retinopathy. Two studies examined rosuvastatin, indicating a possibly harmful effect on lenses and a significant protective effect on retinal microvasculature. Conclusions: Based on our findings, we believe that statins have no cataractogenic effect. There are indications that statins may have a protective role against cataract formation, AMD, diabetic retinopathy progression, and non-infectious uveitis. However, our results were insufficient for any robust conclusion. Future RCTs, with large sample sizes, on the current topic are therefore recommended to provide more solid evidence.


Introduction
Nowadays, multiple statins are available in the market, including atorvastatin, rosuvastatin, simvastatin, lovastatin, pravastatin, fluvastatin, and pitavastatin [1,2]. Since 1987, when the first statin was introduced, intensive clinical investigations have proven that statin therapy is well tolerated, with an excellent safety profile, although some adverse events have been reported, with the most common being muscle toxicity and elevation of liver enzymes [3,4]. The occurrence of other adverse effects, such as the slightly elevated risk of newly diagnosed diabetes mellitus and the possible increased risk of hemorrhagic stroke, has limited importance compared to the proven cardiovascular benefits of statin therapy [3,4].

Figure 1 summarizes the results of our extended literature search in a Preferred
Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) chart [9]. We identified 567 publications through PubMed, Cochrane Library, and the relevant studies' reference lists. Of these, 303 publications were duplicates in the database, and an additional 239 records were excluded after reviewing their titles and abstracts. The full texts of the remaining 26 studies were further assessed for eligibility. Studies to be included in this review had to match predetermined criteria according to the Population, Intervention, Comparison, Outcomes, and Study (PICOS) approach. Criteria for inclusion and exclusion are specified in Supplementary Table S1. After reviewing the full texts, seven more studies were excluded for not meeting the inclusion criteria (Supplementary Table S2) [10][11][12][13][14][15][16]. After the final exclusion, 19 RCTs [17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35] fulfilled the criteria to be included in our systematic review.

Study Characteristics
The studies that met the eligibility criteria for inclusion in our systematic review examined a total of 28,940 participants, who were followed up for a mean of 24.4 months. The mean age of all participants was approximately 55 years old, and the male-to-female ratio was similar. We initially searched for seven different statins, but in the included studies, only four were evaluated: simvastatin (10 studies), atorvastatin (3 studies), lovastatin (4 studies), and rosuvastatin (2 studies). Among the studies, ten analyzed the effect of statins in the human lens, and seven studies investigated the role of statins in the progression of retinal vascular diseases focusing mainly on diabetic retinopathy. The remaining studies examined other eye disorders, such as AMD and non-infectious uveitis. The studied population mainly suffered from hyperlipidemia and diabetes mellitus. Other comorbidities that were also reported were non-advanced AMD and asymptomatic aortic stenosis, and a percentage of the participants was considered to be at high risk for coronary heart diseases. A series of ophthalmological tests (slit lamp examination, measurement of visual acuity, fundoscopy) and a biochemical investigation were evaluated in most of the trials. More specific tests were also performed based on the aim of each study. No significant adverse events have been reported except for some minor symptoms that can be attributed as possible side effects of statins, such as muscle pain, weakness, rash, and mild headache. The studies were conducted in different areas around the world, including the US (5 studies), India (3 studies), Australia (3 studies), Europe (4 studies), Turkey (1 study), Russia (1 study), and China (1 study). Table 1 lists the characteristics of each one of the included studies.

Study Characteristics
The studies that met the eligibility criteria for inclusion in our systematic review ex amined a total of 28,940 participants, who were followed up for a mean of 24.4 months The mean age of all participants was approximately 55 years old, and the male-to-femal ratio was similar. We initially searched for seven different statins, but in the included studies, only four were evaluated: simvastatin (10 studies), atorvastatin (3 studies), lovas tatin (4 studies), and rosuvastatin (2 studies). Among the studies, ten analyzed the effec of statins in the human lens, and seven studies investigated the role of statins in the pro gression of retinal vascular diseases focusing mainly on diabetic retinopathy. The remain ing studies examined other eye disorders, such as AMD and non-infectious uveitis. Th studied population mainly suffered from hyperlipidemia and diabetes mellitus. Othe comorbidities that were also reported were non-advanced AMD and asymptomatic aorti stenosis, and a percentage of the participants was considered to be at high risk for coro nary heart diseases. A series of ophthalmological tests (slit lamp examination, measure ment of visual acuity, fundoscopy) and a biochemical investigation were evaluated in most of the trials. More specific tests were also performed based on the aim of each study No significant adverse events have been reported except for some minor symptoms tha can be attributed as possible side effects of statins, such as muscle pain, weakness, rash and mild headache. The studies were conducted in different areas around the world, in cluding the US (5 studies), India (3 studies), Australia (3 studies), Europe (4 studies), Tur key (1 study), Russia (1 study), and China (1 study). Table 1 lists the characteristics of each

Outcomes of the Included Studies
The results are summarized in Table 1. According to our analysis, 10 studies investigated the role of simvastatin, suggesting a lack of cataractogenic effect and a possible protective role in cataract formation, retinal vascular diseases, and especially diabetic retinopathy, age-related macular disease progression, and non-infectious uveitis. In addition, four studies investigated lovastatin, showing no cataractogenic effect. Furthermore, three studies examined atorvastatin, revealing conflicting results regarding diabetic retinopathy, while two studies examined rosuvastatin, indicating a possibly harmful effect in lenses and a significant protective effect on retinal microvasculature.

Quality Appraisal
The bias risk was assessed using version 2 of the Cochrane risk of bias tool for randomized trials (RoB2) [36] (Figures 2 and 3). Out of the 19 studies assessed, only two studies were judged to have "high" bias risk, while six were judged to have "some concerns". All the 11 remaining trials were judged to have a "low" bias risk. thy, while two studies examined rosuvastatin, indicating a possibly harmful effect in lenses and a significant protective effect on retinal microvasculature.

Quality Appraisal
The bias risk was assessed using version 2 of the Cochrane risk of bias tool for randomized trials (RoB2) [36] (Figures 2 and 3). Out of the 19 studies assessed, only two studies were judged to have "high" bias risk, while six were judged to have "some concerns". All the 11 remaining trials were judged to have a "low" bias risk.

Discussion
To the best of our knowledge, this is the first systematic review conducted on RCTs that examined the relation between statin use and ocular diseases in the adult population. Our findings suggested conflicting results regarding the effect of statins on the eyes.
Currently, the treatment options for cataracts, AMD, glaucoma, diabetic retinopathy, dry eye, and uveitis are limited, despite affecting a large percentage of the population worldwide. Further options of medical therapy are required to slow the damage in vision loss and, at the same time, to prevent the disease from occurring [7,8]. Due to their pleiotropic effects, relatively safe profile, and low cost, statins seem to be an up-and-coming option for preventing and managing ocular diseases. Statins have already been recommended to use in chronic inflammatory disorders such as rheumatoid arthritis and systemic lupus erythematosus [5]. However, in the literature, the studies that examined the

Discussion
To the best of our knowledge, this is the first systematic review conducted on RCTs that examined the relation between statin use and ocular diseases in the adult population. Our findings suggested conflicting results regarding the effect of statins on the eyes.
Currently, the treatment options for cataracts, AMD, glaucoma, diabetic retinopathy, dry eye, and uveitis are limited, despite affecting a large percentage of the population worldwide. Further options of medical therapy are required to slow the damage in vision loss and, at the same time, to prevent the disease from occurring [7,8]. Due to their Pharmaceuticals 2023, 16, 711 7 of 12 pleiotropic effects, relatively safe profile, and low cost, statins seem to be an up-andcoming option for preventing and managing ocular diseases. Statins have already been recommended to use in chronic inflammatory disorders such as rheumatoid arthritis and systemic lupus erythematosus [5]. However, in the literature, the studies that examined the association between statin therapy and eye disorders have provided controversial results [8].
The exact mechanism linking statin and ocular diseases has not been clarified yet. Their ability to reduce pro-inflammatory cytokines may minimize the harm of inflammation in tissue damage in wet AMD, diabetic retinopathy, dry eye disease, and uveitis [7]. One of the RCTs that have addressed the anti-inflammatory properties of statins was the PRINCE (pravastatin inflammation/CRP evaluation) trial, which noted that statins were involved in the reduction of C-reactive protein (CRP) in patients suffering from cardiovascular diseases [37]. Moreover, in the JUPITER (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin) study, it was first reported that rosuvastatin administration reduced cardiovascular morbidity and mortality, as well as overall mortality, in apparently healthy subjects without hyperlipidemia, but with elevated high-sensitivity CRP (hs-CRP) levels [38].
Statins also have the ability to reduce transforming growth factor beta (TGF-β) and Rho-kinase inhibitory activity, which may have a beneficial impact on glaucoma by improving the aqueous outflow [7,39]. Furthermore, statins decrease vascular endothelial growth factor (VEGF) expression and nicotinamide adenine dinucleotide phosphate oxidase (NADPH) oxidase inhibition, which allows a significant increase in endothelial structure and function, that may benefit the progression of diabetic retinopathy and AMD [7]. Of note, oxidative stress is a significant risk factor for age-related cataracts, further enhancing a possible connection with statins due to their known antioxidative effects [39,40].
Most trials investigated the reaction of the human lens in statin therapy, although a clear causal association could not be ascertained. A meta-analysis that used data from fourteen clinical trials (eight observational studies and six randomized), including approximately 2,403,644 patients and 25,618 cataracts, showed that statin use was related to a 19% drop in the risk of cataracts (OR 0.81, 95% CI: 0.72-0.92, p = 0.0009) [41]. The effect appeared to be statistically significant for clinical cataracts (19% decrease, OR 0.81, 95% CI 0.71-0.93, p = 0.0022), but it was not statistically significant for the lenticular opacities (OR 0.81, 95% CI 0.59-1.12, p = 0.2106) [41]. Of note, the effect observed in the RCTs had the same importance as the observational studies, but it was not statistically significant (OR 0.84, 95% CI 0.67-1.05, p = 0.1189) [41]. Overall, a clinically relevant and statistically significant protective role of statins was demonstrated by the analysis of the results, which appeared to be more pronounced in younger patients and with a more extended follow-up period [41]. A more recent meta-analysis, conducted by Yu et al., analyzed the results of seventeen studies, including six cohorts, six case controls, and five RCTs, in more than 313,200 patients, aiming to reach a clear conclusion to the debatable cataractogenic effect of statins [42]. Analysis of the included cohort studies showed that the pooled RR was 1.13 (95% CI, 1.01-1.25), which suggested that statins were responsible for a 13% increased risk of cataract formation or cataract surgery [42]. In contrast, the pooled RRs of case-control studies and RCTs were 1.10 (95% CI, 0.99-1.23) and 0.89 (95% CI, 0.72-1.10), respectively, which indicated that no link was detected between statin use and the risk of cataract development or surgery for cataract extraction [42]. Significant heterogeneity was detected among both cohort studies and case-control studies, although RCTs had low heterogeneity scores [42]. The researchers concluded that there was insufficient data to establish a cataractogenic effect of statins [42].
Concerning the role of statins in the progression of retinal vascular diseases, our results supported that statins may have the ability to minimize diabetic retinal complications either by interfering with retinal vessels or by reducing the hard exudates [26][27][28]31,35]. Miyahara et al. reported that high-dose simvastatin could decrease the expression of vascular endothelial growth factor (VEGF), which has an essential role in the pathogenesis of both diabetic retinopathy and exudative AMD [43]. Additionally, Weis et al. noticed that Pharmaceuticals 2023, 16, 711 8 of 12 endothelial release of VEGF was considerably reduced with high statin concentrations, but no significant difference was detected with low dosages of statins [44].
Regarding the association between statins and AMD risk, Guymer et al. addressed that simvastatin may retard the progression of non-advanced AMD [30]. In support of this notion, a meta-analysis using 15 articles (seven cohort studies, five case-control studies, and three cross-sectional studies), with the number of subjects ranging from 744 to 104,176, indicated no important connection between statin use and the risk of any AMD (RR, 0.95; 95% CI, 0.74-1.15) [46]. Seven studies assessed data on the relationship between statins and early AMD, with a total of 27,308 participants [46]. When the results of these studies were analyzed, the authors found that statins can drop the incidence of early AMD by approximately 17% (RR, 0.83; 95% CI, 0.66-0.99) [46]. The remaining eight studies, with a total of 22,973 participants, reported the role of statins in late AMD [46]. The analysis of the results showed an important protective effect of statins on exudative AMD (RR, 0.90; 95% CI, 0.80-0.99), although no link was detected between statins and geographic atrophy (RR, 1.16; 95% CI, 0.77-1.56) [46]. In general, this meta-analysis supported that statins had a protective role for both early and exudative AMD [46]. However, a recent systematic review and meta-analysis that aimed to link statins and AMD led to a different conclusion [47]. Researchers reviewed a total of 22 studies, with 2,063,195 participants, 15.2% of whom were diagnosed with AMD. The overall OR of AMD in statin-receiving participants was 0.93 (95% CI; 0.83-1.05, p = 0.225). The OR of AMD in those that received statins were 0.92 (95% CI; 0.75-1.13, p = 0.440) in case-control studies, 0.95 (95% CI; 0.82-1.09, p = 0.458) in cohort studies, and 0.951 (95% CI; 0.59-1.53, p = 0.831) in cross-sectional studies. This meta-analysis showed that statin therapy has no positive or negative impact on AMD development [47].
Patients with uveitis usually have to follow an intensive steroid treatment plan for a prolonged time period to avoid any relapse of the disease [39]. Shrinsky et al.'s findings supported the hypothesis that statins have the ability to reduce the extent of ocular inflammation in uveitis due to their anti-inflammatory and immunomodulatory properties [34]. Additionally, a retrospective population-based case-control study selected 108 incident cases of uveitis, with most of them being anterior (81%) and non-infectious (76%) [48]. Comparing the participants with non-infectious uveitis and their respective general population controls, the percentage of those suffering from uveitis was almost 56% less in statin users in contrast to non-statin users (OR: 0.44, 95% CI: 0.22 to 0.88, p = 0.02) when adjusting for multiple factors including age, gender, race, smoking status, and autoimmune diseases [48].
Of note, no RCT has examined the association between statins and glaucoma. However, in a recent systematic review and meta-analysis [49] that included 17 studies, mainly cohort and case-control studies, with a total of 515,788 patients, statin use was associated with a slightly lower risk of open-angle glaucoma onset, while no association between statin use and open-angle glaucoma progression was observed. The use of underpowered studies, however, weakened the overall meta-analysis outcome [49].

Limitations
This systematic review examined the association between statin therapy and ocular diseases. We believe that through an extensive search of two databases, we were able to detect and analyze all the relevant RCTs. However, certain limitations should be acknowledged. Different classifications for the evaluation of the findings were used in the studies, making it hard to compare them. Additionally, due to high heterogeneity, we were unable to perform a meta-analysis.

Study Design
We performed a qualitative synthesis of published randomized controlled trials (RCTs) to address the possible effect of statin therapy, including simvastatin, lovastatin, atorvastatin, fluvastatin, pravastatin, rosuvastatin, and pitavastatin on ocular diseases, namely, cataracts, AMD, glaucoma, diabetic retinopathy, dry eye, and uveitis, and to identify if there is any beneficial relationship.

Eligibility Criteria
Eligible studies for our systematic review were RCTs in adults (>18 years old) that compared statin therapy (simvastatin, lovastatin, atorvastatin, fluvastatin, pravastatin, rosuvastatin, and pitavastatin) versus placebo, diet, or control group. We excluded any nonrandomized studies, including case controls, cohort, and cross-sectional studies, articles written in a non-English language, articles focusing on the pediatric population (<18 years old), articles with insufficient data, and articles irrelevant to our primary aim.

Data Extraction
Two authors (C.L., A.P.A.) independently scanned the abstract, title, or both, of every record and assessed the full text to determine which studies meet the inclusion criteria in order to be included in the review. During the process, any disagreement between the reviewers was resolved by consensus discussion. Data extraction was done in accordance with the PRISMA model. Because of the study's design, there was no need either for approval by the National Bioethics Committee (CNBC) or for informed permission from the patients. Initially, all the search results to databases were screened for duplications through Zotero software. After removing duplicates, data were extracted using Excel and included the following information: first author, publication year, the country where the trial was conducted, number and characteristics of the participating population, study duration, statin therapy, comparator, and the outcome. Following that, papers were chosen based on a further review of full-text articles to conclude our final selection.

Assessment of Risk of Bias
A Risk of Bias Assessment was performed for each included study to establish transparency of systematic review results and findings, using the RoB2 tool for randomized trials [36]. The assessment is divided into a series of domains through which bias might be introduced into the trial. Within each domain, a number of questions ('signaling' questions) aim to facilitate judgments regarding the risk of bias. Based on the answers to the signaling questions, an algorithm generates a proposed judgment regarding the risk of bias from each domain. Judgment can be expressed as having a "Low" risk of bias, "High" risk of bias, or "Some concerns".

Conclusions
This systematic review found 19 RCTs that assess the effect of statin use (simvastatin, lovastatin, atorvastatin, and rosuvastatin) in eye disorders (cataracts, AMD, retinal vascular disease, and non-infectious uveitis). Based on our findings, we believe that statins have no cataractogenic effect. There are indications that statins may have a protective role against cataract formation, AMD, diabetic retinopathy progression, and non-infectious uveitis. However, our results were insufficient for any robust conclusion. Future research is required to give definite answers regarding the role of statins in ophthalmology.

Supplementary Materials:
The following supporting information can be downloaded at: https: //www.mdpi.com/article/10.3390/ph16050711/s1, Supplementary Table S1. PICOS criteria for inclusion and exclusion of studies; Supplementary Table S2. Table of