Introduction
Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly.1 AMD pathogenesis is unclear, but pathology focuses on the retinal pigment epithelium (RPE), which develops abnormal morphology and ultimately dies.2 Numerous biological pathways have been implicated in AMD pathogenesis, including lipid homeostasis,3 oxidative stress,4 and inflammation,5 all of which could be targeted by therapy.
In an earlier study, we found that history of cholelithiasis was protective against AMD.6 While the mechanism behind this association is unknown, alterations in bile acids could explain the protective effect. Hydrophilic bile acids, such as ursodeoxycholic acid (UDCA; ursodiol), can solubilize cholesterol in gallstones and may also promote dissolution of extracellular lipid deposits in AMD.7 In addition to its effect on cholesterol solubility, UDCA has anti-apoptotic,8 antioxidant,9 anti-inflammatory,10 and neuroprotective effects, as demonstrated in clinical trials for neurodegenerative disease.11 UDCA therefore targets many of the pathways disrupted in AMD and could be a promising treatment.
To test this hypothesis, we performed a retrospective cohort study to examine an association between oral UDCA supplementation and AMD.
Methods
Database
Data was derived from the Optum de-identified Clinformatics® Data Mart database, which includes all outpatient medical claims (office visits, procedures, medications), demographic data, and some laboratory values for patients enrolled in commercial and Medicare Advantage insurance plans. Data from all patients between January 1, 2000 and June 30, 2022 were included in this study. The University of Pennsylvania Institutional Review Board exempted this study from review due to the de-identified nature of the data. The study adhered to the Declarations of Helsinki and followed the STROBE guidelines for reporting observational studies.
Cohorts
Two cohorts were created; the exposed cohort consisted of patients who were prescribed oral UDCA, while the control cohort consisted of patients with no exposure to UDCA. The exposed cohort was matched 1:3 to control patients based on age (±3 years), sex, race, and medical coverage start and end date (±4 months). Due to our previous analysis in the same dataset that showed a reduced risk of AMD in those with gallbladder disease,6 to be included in the study, all patients (exposed and controls) were required to have a diagnosis of cholelithiasis, cholecystitis, or cholecystectomy, and we matched patients on disease severity (i.e. cholelithiasis exposed to UDCA with a cholelithiasis control without UDCA). All patients were required to be age 55 years or older for inclusion based on the significantly greater prevalence of AMD in older individuals.12 The index date was the first date when UDCA was prescribed (exposed cohort). The same index date for controls was assigned based on the index date of the matched exposed patients. Exclusion occurred if there was lack of two years of complete, uninterrupted data prior to the index date or any history of AMD. Using a two year look back period has been shown to greatly improve incident ocular disease identification.13 See Supplementary Table 1 for the full list of ICD9/ICD10 and CPT codes used during this study.
Outcome of Interest, Covariates, and Statistical Analysis
The primary outcome of interest was progression to AMD, as defined by the addition of an ICD code for macular degeneration that was not present on or before the index date. To reduce confounding at baseline between comparison cohorts, inverse probability of treatment weighting (IPTW) was applied using a multivariable logistic regression model. In addition to age and sex, other demographic and clinical characteristics were included in the analysis. These included variables like race, education, household income, and geographic location; smoking; healthcare usage; and preexisting comorbidities, including history of hypertension, diabetes, peripheral arterial disease, heart failure, ischemic stroke, chronic kidney disease, chronic pulmonary disease, chronic liver disease, among others (see Table 1 for full list of covariates used). Cox proportional hazard regression modeling with IPTW was used to compare the UDCA to control cohorts. Censoring occurred if a patient left the insurance plan or for controls if UDCA was initiated. Next, we also ran an age-stratified secondary analysis to determine if certain age groups benefited from UDCA exposure more than others. Lastly, since neovascular AMD takes longer to develop, we also ran a sensitivity analysis that excluded this from the outcome to be sure that undiagnosed latent cases of dry AMD that progressed were not impacting the results. Statistical analyses were performed with SAS version 9.4 (SAS Institute Inc., Cary, NC). Tests were considered statistically significant at a two-tailed p-value of 0.05.
Table 1.
Demographics/medical history in controls and patients taking UDCA
| Characteristic | Before IPTW Weighting | After IPTW Weighting | |||||
|---|---|---|---|---|---|---|---|
| Controls (N=17164) | UDCA (N=5863) | SMD | Controls (N=17322) | UDCA (N=5705) | SMD | ||
| Gallbladder Disease (n, %) | Cholelithiasis | 9598 (55.9) | 3241 (55.3) | 0.029 | 9717 (56.1) | 3182 (55.8) | 0.000 |
| Cholecystitis | 2606 (15.2) | 933 (15.9) | 2719 (15.7) | 912 (16.0) | |||
| Cholecystectomy | 4960 (28.9) | 1689 (28.8) | 4887 (28.2) | 1611 (28.2) | |||
| Age | [Mean (SD)] | 70.1 (9.67) | 70.2 (9.42) | 0.012 | 70.3 (9.59) | 70.5 (9.54) | 0.020 |
| Sex (n, %) | Female | 10051 (58.6) | 3425 (58.4) | −0.003 | 9941 (57.4) | 3341 (58.6) | 0.024 |
| Male | 7113 (41.4) | 2438 (41.6) | 7381 (42.6) | 2364 (41.4) | |||
| Race (n, %) | White | 11866 (69.1) | 3986 (68.0) | 0.055 | 11972 (69.1) | 3937 (69.0) | 0.000 |
| Black | 1463 (8.5) | 518 (8.8) | 1519 (8.8) | 501 (8.8) | |||
| Hispanic | 2521 (14.7) | 872 (14.9) | 2469 (14.3) | 813 (14.2) | |||
| Asian | 663 (3.9) | 252 (4.3) | 698 (4.0) | 233 (4.1) | |||
| Unknown | 651 (3.8) | 235 (4.0) | 664 (3.8) | 222 (3.9) | |||
| Education Level (n, %) | Less than 12th Grade | 118 (0.7) | 57 (1.0) | 0.073 | 127 (0.7) | 46 (0.8) | 0.065 |
| High School Diploma | 4629 (27.0) | 1600 (27.3) | 4632 (26.7) | 1565 (27.4) | |||
| Less than Bachelor Degree | 9405 (54.8) | 3082 (52.6) | 9466 (54.6) | 3072 (53.8) | |||
| Bachelor Degree Plus | 2510 (14.6) | 940 (16.0) | 2570 (14.8) | 844 (14.8) | |||
| Unknown | 502 (2.9) | 184 (3.1) | 527 (3.0) | 179 (3.1) | |||
| Household Income (n, %) | <$40K | 4744 (27.6) | 1508 (25.7) | 0.056 | 4684 (27.0) | 1604 (28.1) | 0.055 |
| $40K - $49K | 1424 (8.3) | 487 (8.3) | 1416 (8.2) | 466 (8.2) | |||
| $50K - $59K | 1449 (8.4) | 510 (8.7) | 1618 (9.3) | 475 (8.3) | |||
| $60K - $74K | 1887 (11.0) | 627 (10.7) | 1895 (10.9) | 638 (11.2) | |||
| $75K - $99K | 2484 (14.5) | 838 (14.3) | 2453 (14.2) | 806 (14.1) | |||
| $100K+ | 3576 (20.8) | 1303 (22.2) | 3608 (20.8) | 1169 (20.5) | |||
| Unknown | 1600 (9.3) | 590 (10.1) | 1648 (9.5) | 549 (9.6) | |||
| Geographic Location (n, %) | Upper Midwest | 3629 (21.1) | 1031 (17.6) | 0.137 | 3422 (19.8) | 1112 (19.5) | 0.052 |
| Southern Midwest | 3128 (18.2) | 1174 (20.0) | 3164 (18.3) | 1077 (18.9) | |||
| Northeast | 1908 (11.1) | 826 (14.1) | 2238 (12.9) | 703 (12.3) | |||
| Mountain | 1877 (10.9) | 622 (10.6) | 1856 (10.7) | 616 (10.8) | |||
| Pacific | 2507 (14.6) | 948 (16.2) | 2624 (15.2) | 874 (15.3) | |||
| South Atlantic | 4097 (23.9) | 1258 (21.5) | 4002 (23.1) | 1319 (23.1) | |||
| Unknown | 18 (0.1) | 4 (0.1) | 16 (0.1) | 5 (0.1) | |||
| Smoking (n, %) | 6419 (37.4) | 2523 (43.0) | 0.115 | 6797 (39.2) | 2285 (40.0) | 0.017 | |
| Healthcare Usage Days [Mean (SD)] | 8.5 (7.68) | 13.1 (9.71) | 0.584 | 11.5 (15.99) | 10.1 (7.78) | 0.088 | |
| Preexisting Comorbidities (n, %) | Hypertension | 14034 (81.8) | 5000 (85.3) | 0.095 | 14408 (83.2) | 4761 (83.5) | 0.007 |
| Hypercholesterolemia | 14060 (81.9) | 4792 (81.7) | −0.005 | 14273 (82.4) | 4696 (82.3) | −0.002 | |
| Diabetes Mellitus | 7365 (42.9) | 2808 (47.9) | 0.100 | 7701 (44.5) | 2585 (45.3) | 0.017 | |
| Peripheral Arterial Disease | 4382 (25.5) | 1624 (27.7) | 0.049 | 4551 (26.3) | 1554 (27.2) | 0.022 | |
| Peripheral Vascular Disease | 4705 (27.4) | 1675 (28.6) | 0.026 | 4831 (27.9) | 1656 (29.0) | 0.025 | |
| Ischemic Heart Disease | 6624 (38.6) | 2522 (43.0) | 0.090 | 6946 (40.1) | 2341 (41.0) | 0.019 | |
| Heart Failure | 3677 (21.4) | 1552 (26.5) | 0.119 | 4043 (23.3) | 1403 (24.6) | 0.029 | |
| Congestive Heart Failure | 3957 (23.1) | 1649 (28.1) | 0.116 | 4326 (25.0) | 1499 (26.3) | 0.030 | |
| Myocardial Infarction | 2454 (14.3) | 944 (16.1) | 0.050 | 2555 (14.7) | 879 (15.4) | 0.018 | |
| Coronary Artery Bypass Graft | 291 (1.7) | 93 (1.6) | −0.009 | 283 (1.6) | 94 (1.7) | 0.002 | |
| Arrhythmia | 5333 (31.1) | 2155 (36.8) | 0.120 | 5668 (32.7) | 1883 (33.0) | 0.006 | |
| Atrial Fibrillation/Flutter | 3037 (17.7) | 1158 (19.8) | 0.053 | 3215 (18.6) | 1113 (19.5) | 0.024 | |
| Ischemic Stroke | 3722 (21.7) | 1336 (22.8) | 0.027 | 4000 (23.1) | 1316 (23.1) | −0.001 | |
| Intracerebral Hemorrhage | 284 (1.7) | 128 (2.2) | 0.039 | 312 (1.8) | 104 (1.8) | 0.002 | |
| Chronic Kidney Disease | 5439 (31.7) | 2241 (38.2) | 0.207 | 5800 (33.5) | 1941 (34.0) | 0.022 | |
| End-Stage Renal Disease | 1713 (10.0) | 821 (14.0) | 1945 (11.2) | 680 (11.9) | |||
| Chronic Pulmonary Disease | 7311 (42.6) | 2695 (46.0) | 0.068 | 7645 (44.1) | 2550 (44.7) | 0.012 | |
| Chronic Liver Disease | 779 (4.5) | 1567 (26.7) | 0.642 | 1824 (10.5) | 589 (10.3) | −0.007 | |
Results
A total of 5,863 patients taking UDCA and 17,164 matched controls were analyzed after inclusion and exclusion criteria were applied. The baseline characteristics of these cohorts, before and after IPTW, are provided in Table 1. After IPTW, all covariates were balanced (standardized mean difference [SMD] < 0.1). All patients had either cholelithiasis (UDCA: 55.8% vs controls: 56.1%), cholecystitis (UDCA: 16.0% vs controls: 15.7%), or cholecystectomy (UDCA: 28.2% vs controls: 28.2%). The mean age (±standard deviation, SD) was 70.5 (±9.54) years in patients taking UDCA and 70.3 (±9.59) years in controls (SMD=0.02). Women comprised 58.6% and 57.4% of the UDCA and control cohorts, respectively (SMD=0.02).
Out of 5,705 patients taking UDCA, 384 (6.74%) were diagnosed with AMD. Amongst the 17,322 control cohort patients, 1,559 (9.00%) were diagnosed with AMD. Figure 1 shows the Kaplan-Meier curve for the analysis. Cox proportional hazard regression modeling demonstrated that UDCA exposure corresponded to a significantly decreased hazard of AMD (adjusted hazard ratio [aHR]=0.65, 95% CI: 0.58–0.74, p<0.0001). Age-stratified analysis did not show a clear pattern between age groups as all groups benefited (age 60–69 HR=0.51, 95%CI: 0.39–0.68; age 70–79 HR=0.72, 95%CI: 0.60–0.86; age 80+ HR=0.62, 95%CI: 0.49–0.79, p<0.001 for each comparison). Removing neovascular AMD as an outcome for the sensitivity showed very little change to the results, with the UDCA cohort having 359 outcomes and the control cohort having 1,525. The resultant hazard ratio from this analysis was 0.66 (95% CI: 0.58–0.74, p<0.0001).
Figure 1.
Probability of developing AMD in patients taking UDCA vs controls. Blue and red numbers along the bottom of the graph indicate the number of patients in each cohort at risk of developing AMD.
Discussion
In this study, we analyzed 5,863 patients taking UDCA and 17,164 matched controls, finding that exposure to UDCA conferred a 35% reduction in the hazard of AMD. To our knowledge, this represents the first investigation exploring the association of UDCA with AMD.
In a prior study, we found that cholelithiasis conferred a reduced risk for AMD.6 Higher disease severity, approximated by a diagnosis of cholecystitis and history of cholecystectomy, was associated with greater reductions in the risk. While the mechanism for this protective relationship is unknown, we postulated that patients with cholelithiasis may have altered composition or quantity of serum bile acids. Patients with cholelithiasis are known to have increased hepatic and serum bile acids;14 given the ability of some bile acids, such as UDCA, to solubilize cholesterol,15 increased serum bile acids could also facilitate the dissolution of drusen and other extracellular lipid deposits that are characteristic of AMD. A recent study of blood metabolites in AMD patients showed significantly deregulated primary (taurocholate) and secondary (deoxycholic acid glucuronide) bile acid metabolism.16 Our current finding that oral UDCA is also associated with a reduced risk of AMD provides further evidence that altered serum or RPE bile acid metabolism may contribute to AMD pathogenesis. This is particularly notable because all patients in this study had a diagnosis of cholelithiasis, cholecystitis, or cholecystectomy. UDCA was associated with additional protection against AMD in a population already at lower risk, perhaps by further increasing the concentration of serum or RPE bile acids and promoting the dissolution of lipid deposits around the RPE and at Bruch’s membrane.
UDCA supplementation may reduce AMD risk by other mechanisms, in addition to modulating serum/RPE bile acid levels. In the treatment of primary biliary cholangitis, UDCA is used to decrease T cell-mediated hepatocyte destruction,10 reduce oxidative stress,17 and prevent apoptosis.9 These pathways have been implicated in AMD pathogenesis; the RPE cells of AMD patients also incur damage from T cells,18 experience oxidative stress,19 and ultimately die by apoptosis.20 While the effect of UDCA on these pathways has not been studied in the RPE, studies have found protective effects of UDCA in retinal disease. In a mouse model of diabetic retinopathy, UDCA reduced retinal expression of pro-inflammatory cytokines, including TNFα, IL-1β, and IL-6.21 A rat retinal explant model of rhegmatogenous retinal detachment was protected from apoptosis and necrosis by UDCA.22 UDCA-treated retinal explants also upregulated the expression of antioxidant proteins.23 In a mouse model of retinopathy of prematurity, UDCA reduced levels of oxidative stress and pro-inflammatory cytokines.24 These studies suggest that UDCA may similarly protect RPE cells against inflammation, oxidative stress, and cell death.
No clinical trial to date has explored the use of UDCA for the treatment of retinal disease. However, UDCA and similar bile acids, such as tauroursodeoxycholic acid (TUDCA), have been studied in several clinical trials for neurologic disease, in which safety was consistently demonstrated. Patients with ALS given UDCA had slower disease progression,25 and patients with Parkinson’s disease had improvements in midbrain mitochondrial function along with some improvement in gait.26 These clinical trials and aforementioned animal model studies suggest that UDCA could be a well-tolerated, ocularly bioavailable,22 and promising treatment for AMD. However, UDCA is just one example of several bile acids that have shown efficacy in clinical trials. TUDCA has also been well studied and has demonstrated efficacy against many degenerative diseases,11 suggesting the importance of evaluating the efficacy of both UDCA and TUDCA, as well as other bile acids, in treating AMD.
Strengths of this study included the large patient population and IPTW weighting that balanced all measured confounders, e.g. hypertension, diabetes, heart failure, and chronic liver disease. Smoking, the leading environmental risk factor for AMD, was also accounted for in the model.27 However, some potential limitations also need to be noted. Although national in nature, the database used is not a statistical representation of the United States and may not be generalizable to other patient populations. Similarly, given our previous finding that gallbladder disease protected against AMD,6 and because the primary use of UDCA is for gallbladder disease, we performed this study within that population to balance the baseline risk of progression. This could reduce the generalizability of these results to a non-biliary disease population. Also, the data does not contain information about AMD genetic risk, diet, physical activity, or other environmental factors that could be associated with AMD. However, for these to impact the results of the study, they would have to be different between patients with similar gallbladder disease diagnoses, which seems unlikely.
Conclusions
This study provides evidence that UDCA may protect against AMD. This is notable given the paucity of known protective agents for AMD. Assuming our findings are confirmed by other studies, a prospective clinical trial of UDCA may be warranted. Our results additionally build upon our previous analysis that found an association between gallbladder disease and AMD,6 providing further evidence that the pathogenesis of these diseases could be intertwined. Determining the mechanism for the protective effect of UDCA could improve understanding of AMD pathogenesis and lead to the development of additional therapies.
Supplementary Material
Supplementary Table 1. ICD and CPT codes used in this analysis.
a. Funding/Support:
Research to Prevent Blindness unrestricted award, University of Pennsylvania Core Grant for Vision Research (2P30EY001583), the Metzger Family, the FM Kirby Foundation, the Paul and Evanina Mackall Foundation, and a gift in memory of Lee F. Mauger, MD. JLD is a recipient of a Research to Prevent Blindness / Dr. H. James and Carole Free Catalyst Award for Innovative Research Approaches to AMD. KRZ is a recipient of the International Retinal Research Foundation Charles D. Kelman, MD Postdoctoral Scholar Award. Funding from each of the above sources was received in the form of block research grants. The sponsor or funding organization had no role in the design or conduct of this research. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Brian VanderBeek had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Footnotes
b. Financial Disclosures: BVB is a past paid consultant for EyePoint Pharmaceuticals.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supplementary Table 1. ICD and CPT codes used in this analysis.