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Purpose : To assess the association of age-related macular degeneration AMD progression and statins, connected with AMD genetic risk, and if there is an interplay between statins and genetics. Methods : In this analysis, subjects made two visits 6. Subjects who started taking statins at any time point between the two visits were considered. Time to progression was estimated using unadjusted Kaplan—Meier curves. Multiplicative and additive interactions were assessed. Results : Median survival time was 7. No statistically significant multiplicative or additive interactions were found. Conclusions : Statins seem to be protective against AMD progression, and genetics may play a role in treatment response. Purchase this article with an account. Jump To Methods Results Discussion Acknowledgments References. Open Access. Alerts User Alerts. You will receive an email whenever this article is corrected, updated, or cited in the literature. You can manage this and all other alerts in My Account. This feature is available to authenticated users only. Get Citation Citation. Get Permissions. Age-related macular degeneration AMD is the main cause of irreversible vision loss in developed countries among people 55 years of age or older. Other non-genetic factors, such as age, smoking habits, and unhealthy diet, have also been associated with AMD. Statins, the widely used systemic hypolipemic drugs, have been studied as a possible therapeutic option for AMD. Their use in the protection against the onset or progression of AMD relies on different assumptions. The lipid metabolism pathway, a pathophysiological mechanism in AMD, stands as an important therapeutic target but is still an unexplored strategy. Drusen, the main characteristic of the disease, are lipid-rich deposits, and high serum cholesterol levels have been associated with AMD in several studies, 7 a finding that substantiates the importance of this pathway. Also, cholesterol and phospholipids are present in the outer segments of photoreceptors, and retinal pigment epithelium RPE cells actively participate in the homeostasis and secretion of these lipids. Pharmacogenetics is an important step forward in precision and personalized medicine. To the best of our knowledge, only one study has addressed the question of how statins and genetics may interact to affect AMD onset and progression. The main objectives of the studies were to determine AMD prevalence and the 6. The CES took place in the primary health care units of both towns. Details on the CES can be found elsewhere. Participants went through different ophthalmological exams to allow for image grading. Furthermore, medical histories were recorded based on a standardized questionnaire. Participants were called upon to participate in the study by letter and by phone call. Blood samples were collected from participants who consented to genetic analysis. Participants were graded according to the presence of AMD. Staging was performed in both eyes. The single eye was considered for differential grading if only one eye presented AMD. In case of bilateral disease, the worse eye was considered for AMD staging but both eyes were graded. Progressors were subjects who progressed from grade 0 or 1 as not having AMD at baseline to grades 2, 3, or 4 at the 6. Genotyping of Participants and Genetic Risk Score. The study nurse invited participants to the study by phone call and asked them to bring a list of any medications they were taking at the time of the study visit. Statins were divided into strength categories low, medium, and high , according to Chou et al. High-strength statins include to mg atorvastatin and to mg rosuvastatin. We excluded from the analysis participants with no information on the start date of statin intake, as well as those participants who were already taking statins before the baseline visit. That is, we considered only subjects who started taking statins at any time point between the two visits. Categorical variables are summarized with frequencies and percentages, and numerical variables are presented as median and interquartile range IQR , due to the non-normal distribution of the variables. Normal distribution was tested using the Shapiro—Wilk test and visually verified with histogram plots. To test the association between exposure to statin use and AMD progression, we used a time-to-event analysis or survival analysis. The outcome was defined as the time to progression to occur. Subjects with no progression at the follow-up visit were treated as censoring events in this analysis. First, survival time, or time to progression, was estimated using unadjusted Kaplan—Meier curves and was compared between subjects taking statins and those not taking statins using a log-rank test, taking into account clustering in eyes of the same subjects. Statin intake was not constant over time because the participants started taking these drugs some time from the baseline visit date on, at different time points. To test for the association between statins and the risk of AMD progression, we used two models. Model 1, an extended Cox model with statin intake as a time-dependent variable i. Because we found statistical significance, we designed model 2 similarly to model 1 but included the GRS in the model, in addition to the covariates included in model 1. In order to assess if the use of statins and the GRS per pathway were associated with AMD progression, we used an extended Cox model adjusted to the same covariates of interest for each pathway separately. Because the grading of both eyes was potentially available, we used the individual eye as the unit of analysis. To take into account the correlation between the two eyes for the same participant, the standard errors of the results are based on an infinitesimal jackknife estimate. The proportional hazards assumption was tested graphically and using the Schoenfeld residual method. No variables violated this assumption. To evaluate the interactions between the two risk factors—that is, whether one risk factor strengthens the association of another factor with risk for progression to AMD—we used both multiplicative and additive interactions, as suggested by Knol et al. For the multiplicative scale, we evaluated whether the interaction between the two factors statin intake and GRS is multiplicatively associated with increased risk for progression to AMD—that is, if the risk among patients with a high GRS and statin intake is higher than the product of the individual risks due to each condition. Also, as additive measures were developed for risk factors rather than for protective factors, we recoded the statin protective factor to guarantee that the stratum with the lowest risk was the single reference category. Figure 1 shows the flow chart of this analysis. From the original pool of subjects in total, we excluded for different reasons: 73 did not know treatment duration at the 6. Figure 1. View Original Download Slide. Flowchart of the study participants in this analysis. Overall, subjects were eligible for the analysis, The median follow-up time was 6. Between the baseline and the follow-up visit, subjects For these participants, the median of the proportion of years covered by the medication over the follow-up period the drug exposure time was 0. Smoking 6. In the group of non-progressors, the most used statin was atorvastatin In the group of progressors, these statins were also the most prescribed, corresponding to Table 1. View Table. Between non-progressors and progressors, there were significant differences in 1 age at baseline: For patients who progressed, we analyzed the AMD progression stage versus the strength of statin intake. We compared the median time to progression between the two groups of participants taking and those not taking statins. The median survival time was 7. The survival curves using the Kaplan—Meier method are shown in Figure 2. Figure 2. To investigate if the conclusions were maintained regarding exposure statin intake , after including other covariables of interest, we used an extended Cox regression model with statin intake as a time-dependent variable Table 2. Table 2. Results are presented in Table 3. We found no statistically significant differences between subjects with a high lipid-specific GRS when compared to subjects with a low lipid-specific GRS. Table 3. Next, we examined the multiplicative and additive interactions effects on the risk for AMD progression Table 4. We assessed only interaction with the overall GRS because the lipid-specific pathway GRS, the most relevant for this analysis, was not statistically significant. Table 4. The time to progression for participants not taking statins was shorter when compared to time to progression for participants taking statins. The joint effects of not taking statins along with having a high genetic risk for AMD increased the risk for progression fourfold. Additionally, in the group of participants who did not take statins, the risk for progression was significantly higher in those participants with a high GRS compared to those with a low GRS. AMD is a complex and multifactorial disease. Evidence shows that patients do not respond equally to treatment, so different therapeutic targets should be identified for better disease management. In this context, the lipid metabolism pathway has long been subject of research since different pieces of evidence point to its involvement in AMD pathophysiology. Drusen, the deposits that are hallmarks of AMD, are rich in lipids. Statins are used in atherosclerotic disease, with the therapeutic indication of lowering cholesterol levels through the inhibition of hydroxymethylglutaryl-coenzyme A HMG-CoA reductase. This mechanism of action is hinged on cardiovascular disease underlying pathophysiological and biochemical mechanisms, which has been confirmed by genetic studies showing that distinct SNPs are associated with decreased low-density lipoprotein LDL cholesterol levels, 28 , 29 as well as by Mendelian randomization studies that, in, fact, proved causality of high LDL levels being associated with coronary heart disease. Wu and colleagues 9 have shown that statins, particularly lipophilic statins, can inhibit, via cellular cholesterol reduction, the synthesis and secretion of cholesteryl ester—rich apolipoprotein B This is a lipoprotein that can accumulate in Bruch's membrane prior to the onset of AMD; thus, decreasing cholesteryl ester rich apolipoprotein B reduces the development of drusen. A successful topical ophthalmological treatment with statins relies on penetration of the drug into the retina, but most available pharmacological data are based on oral formulations and are particularly related to diffusion through the blood—brain barrier, which depends on the lipophilicity of the statin. Various non-interventional studies have revisited the role of statins in AMD. All of this important evidence has been gathered based on oral statin intake, which may be limiting to treatment success, as eye bioavailability may be decreased due to the blood—aqueous barrier. Also, most analyses are retrospective, with different AMD classification systems and with different statin intakes being investigated, sometimes concomitantly along with other drugs. Meta-analyses are of great interest, but most do not associate the use of statins with protection against AMD or its progression. This has been proven by clinical trials reporting that statins have been associated with a reduction in the risk of progression. In that study, various analyses of the effect of mg simvastatin on the risk of progression of AMD were performed, and, despite not showing statistical significance in all, there was a tendency for simvastatin protection. Similar results were shown by a large retrospective cohort study of an insurance database studying the outcome of statins on progression from non-exudative AMD to exudative AMD. In our study, in the survival analysis, subjects taking statins took longer to progress compared to those not taking statins, which strengthens the association that statins might present in protecting against AMD. Our results also suggest that the strength of statins may be associated with protection against AMD progression. In fact, the use of rosuvastatin and atorvastatin, statins with a higher potency used in secondary prevention, suggests a protective effect against AMD progression Table 1. Our results were not altered by the inclusion of the GRS in the model. We then tested for interactions between statin intake and overall GRS. To the best of our knowledge, no study has yet performed such an analysis comprehensively, with the assessment of combined effects and both multiplicative and additive interactions. Guymer and colleagues 14 assessed multiplicative interaction and stratification between treatment with simvastatin and three SNPs of two susceptibility AMD genes CFH and ApoE that have been associated with inflammation and lipid metabolism, respectively. A statistically significant interaction between simvastatin use and the risk genotype CC of the CFH YH was found, unlike our findings. We did not find a statistically significant multiplicative interaction, and we built upon these results, analyzing the additive interaction as well. This is highly relevant, as it suggests that the treatment response is dependent on the genotype of each patient; thus, its benefit must be considered in a personalized way aimed at achieving personalized medicine. As Guymer et al. This is, obviously, important in both outcomes of hypercholesterolemia treatment and AMD management. Our stratification analysis by intake of statins revealed that people who do not take statins have a statistically significant higher risk of AMD progression if they are carriers of a higher genetic risk for AMD compared to those who have a lower genetic risk. This is in agreement with our combined effects analysis, which found noteworthy significance. The joint effect of having a high genetic risk for AMD and not taking statins increases the risk for AMD progression fourfold when compared to having a low genetic risk for AMD and taking statins. Finally, we acknowledge that other non-genetic factors that were not considered in our analysis may contribute to the role of statins against AMD pathogenesis. We must acknowledge that, out of the subjects in this analysis, few of them progressed , and, of these, only 19 began taking statins between the two visits, which is a small sample. Additionally, we have an unbalanced sample, inherently due to an epidemiologic, population-based study. We also realize that we are assessing statins as a therapeutic family rather than a specific statin. Clinically, it would be preferable to study various statins separately, namely high-strength statins, and considering the best SNPs for a pharmacogenetic approach, in terms of pharmacokinetics and pharmacodynamics, to a better treatment response. Another limitation of this analysis is the fact that, within the 6. Should they have been available, such information would be important to have, as hypercholesterolemia has been associated with AMD 49 and a low-fat diet is also an important protective factor for AMD. We built a time-dependent model, meaning that the treatment duration was considered when assessing the effect of statin intake. Our model was also controlled for most of the variables that could bias the results, and, additionally, we minimized the risk of bias of progression by considering as progressors only those subjects who had no AMD at baseline. A well-designed, randomized clinical trial with a large sample and long follow-up period 43 , 45 to assess genetics, as well as the interaction of statins and genetics, and to compare topical ophthalmological formulations would be important in the study of statins and AMD. Considering their mechanisms of action that involve common pathways with AMD pathophysiology, concomitant medications indicated to treat other pathologies may be an option in the management of AMD. Such an approach would provide protection against the disease, and, ultimately, assessing the treatment response on a genetic-based approach could also serve as an important strategy in precision medicine. Disclosure: P. Barreto , None; C. Coimbra , None; M. Cachulo , None; J. Melo , None; Y. Age-related macular degeneration. Nat Rev Dis Primers. Updates on the epidemiology of age-related macular degeneration. Asia Pac J Ophthalmol Phila. Global prevalence of age-related macular degeneration and disease burden projection for and a systematic review and meta-analysis. Lancet Glob Health. A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants. Nat Genet. Clinical risk factors for age-related macular degeneration: a systematic review and meta-analysis. BMC Ophthalmol. Dyslipidemia in age-related macular degeneration. Eye Lond. Retinal pigment epithelium possesses both LDL and scavenger receptor activity. Invest Ophthalmol Vis Sci. Apolipoprotein B secretion by cultured ARPE cells is modulated by alteration of cholesterol levels. J Neurochem. Effect of simvastatin on retinal vascular caliber: the age-related maculopathy statin study. Acta Ophthalmol. A case control study of age related macular degeneration and use of statins. Br J Ophthalmol. Effect of statins, metformin, angiotensin-converting enzyme inhibitors, and angiotensin II receptor blockers on age-related macular degeneration. Yonsei Med J. Statin use and the incidence of advanced age-related macular degeneration in the Complications of Age-Related Macular Degeneration Prevention Trial. Proof of concept, randomized, placebo-controlled study of the effect of simvastatin on the course of age-related macular degeneration. PLoS One. Age-related macular degeneration in Portugal: prevalence and risk factors in a coastal and an inland town. The Coimbra Eye Study - Report 2. Incidence of age-related macular degeneration in the central region of Portugal: the Coimbra Eye Study - Report 5. Ophthalmic Res. The prevalence of age-related maculopathy in the Rotterdam Study. Incidence and progression rates of age-related maculopathy: the Rotterdam Study. Preventive Services Task Force. Estimating measures of interaction on an additive scale for preventive exposures. Eur J Epidemiol. Recommendations for presenting analyses of effect modification and interaction. Int J Epidemiol. Li R, Chambless L. Test for additive interaction in proportional hazards models. Ann Epidemiol. Accumulation of cholesterol with age in human Bruch's membrane. Human plasma metabolomics study across all stages of age-related macular degeneration identifies potential lipid biomarkers. Genomic-metabolomic associations support the role of LIPC and glycerophospholipids in age-related macular degeneration. Ophthalmol Sci. Discovery and refinement of loci associated with lipid levels. Biological, clinical and population relevance of 95 loci for blood lipids. Lifelong reduction of LDL-cholesterol related to a common variant in the LDL-receptor gene decreases the risk of coronary artery disease - a Mendelian randomisation study. Mendelian randomization of blood lipids for coronary heart disease. Eur Heart J. A comprehensive Genomes—based genome-wide association meta-analysis of coronary artery disease. Stancu C, Sima A. Statins: mechanism of action and effects. J Cell Mol Med. HMG CoA reductase inhibitors statins : do they have a role in age-related macular degeneration? Surv Ophthalmol. Chen M, Xu H. Parainflammation, chronic inflammation, and age-related macular degeneration. J Leukoc Biol. Anti-inflammatory effects of statins: clinical evidence and basic mechanisms. Nat Rev Drug Discov. Cholesterol in the retina: the best is yet to come. Prog Retin Eye Res. Curcio CA. Soft drusen in age-related macular degeneration: biology and targeting via the oil spill strategies. Efficacy and safety of topical atorvastatin for the treatment of dry eye associated with blepharitis: a pilot study. Pitavastatin loaded nanoparticles: a suitable ophthalmic treatment for Acanthamoeba Keratitis inducing cell death and autophagy in Acanthamoeba polyphaga. Eur J Pharm Biopharm. Atorvastatin-loaded solid lipid nanoparticles as eye drops: proposed treatment option for age-related macular degeneration AMD. Drug Deliv Transl Res. Statins for age-related macular degeneration. Cochrane Database Syst Rev. Memarzadeh E, Heidari-Soureshjani S. The relationship between statin and risk of age-related macular degeneration: a systematic review and meta-analysis. J Ophthalmol. Lipids, lipid genes, and incident age-related macular degeneration: the three continent age-related macular degeneration consortium. Am J Ophthalmol. Use of lipid-lowering agents for the prevention of age-related macular degeneration: a meta-analysis of observational studies. Ophthalmic Epidemiol. Regression of some high-risk features of age-related macular degeneration AMD in patients receiving intensive statin treatment. Statins and the progression of age-related macular degeneration in the United States. Common and rare genetic risk variants in age-related macular degeneration and genetic risk score in the Coimbra eye study. Age-related macular degeneration and coronary heart disease: evaluation of genetic and environmental associations. Eur J Med Genet. Dietary omega-3 fatty acids, other fat intake, genetic susceptibility, and progression to incident geographic atrophy. Dietary fatty acids and the 5-year incidence of age-related maculopathy. Arch Ophthalmol. Copyright The Authors. View Metrics. Related Topics Pharmacology Retina Genetics. Forgot password? To View More Create an Account or Subscribe Now. You must be signed into an individual account to use this feature. This site uses cookies. By continuing to use our website, you are agreeing to our privacy policy.

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