Age-related macular degeneration (AMD) is the leading cause of blindness above age 65 in industrialized countries [1]. While early-stage (nonexudative) AMD is characterized by drusenoid deposits that typically do not affect vision, late-stage AMD consists of geographic atrophy (GA) or choroidal neovascularization (CNV, also known as exudative AMD) which can cause significant vision loss.
While antioxidant AREDS vitamins are currently most commonly prescribed for nonexudative AMD, no standard treatment has been established [2]. However, AMD shares several risk factors with atherosclerosis and may have similar pathophysiology [1]. Therefore, statins (β-hydroxy β-methylglutaryl-CoA [HMG-CoA] reductase inhibitors) have been hypothesized as a potential treatment. Research thus far on this topic has been contradictory. CNV in particular is not well understood with fewer relevant trials and observational studies [3, 4]. In a recent prospective cohort of 26 patients on high-dose atorvastatin (80 mg), 10 showed drusen regression, while none progressed to CNV [4]. Large-scale retrospective studies are needed to investigate this further, a gap our study addresses.
Using the Stanford University Medical Center (SUMC) Clinical Data Warehouse, we performed a cross-sectional study of patients with nonexudative AMD seen at SUMC since 2008. Subjects were identified using ICD-9/ICD-10 codes 362.51/H35.31. The influence of statin exposure and covariates age, gender, race, and presence of comorbidities (ICD-9/ICD-10 codes for hypercholesterolemia, hypertension, cardiovascular disease, or cerebrovascular disease) on development of CNV (ICD-9/ICD-10 362.52/H35.32) were examined using crude bivariate analyses (chi-squared) and multivariate logistic regression. Statistical assumptions were met. The protocol was approved by the Stanford University Institutional Review Board.
The study population included 3090 patients (Table 1). Approximately half (49.7%) were on statins and 26.3% developed CNV. Those on statins tended to be older (67.8% ≥80), White (77.5%), and have more comorbidities (84.4%). A larger proportion of statin users developed CNV (29.3%) compared to non-statin users (23.3%). Multivariate logistic regression analysis adjusting for age, sex, race, and comorbidity status revealed statin users have increased odds of CNV (OR 1.27, CI 1.06–1.51) (Table 2). Subjects aged ≥80 (OR 2.82, CI 2.32–3.44) and White (Reference Non-White: OR 0.50, CI 0.40–0.61) were also more likely to develop CNV after controlling for covariates. Interestingly, comorbidity effects disappeared after multivariate adjustment (OR 1.02, CI 0.84–1.25).
Table 1.
Demographics of nonexudative age-related macular degeneration patients by statin exposure
| Characteristic | All patients (n = 3090) | Statins (n = 1535) | No statins (n = 1555) | p-value |
|---|---|---|---|---|
| n (%) | n (%) | n (%) | ||
| Age | ||||
| <80 | 1105(35.8) | 495(32.2) | 610(39.2) | <0.0001 |
| ≥80 | 1985(64.2) | 1040(67.8) | 945(60.8) | |
| Sex | ||||
| Female | 1905(61.7) | 840(54.7) | 1065(68.5) | <0.0001 |
| Male | 1185(38.3) | 695(45.3) | 490(31.5) | |
| Race | ||||
| White | 2320(75.1) | 1190(77.5) | 1130(72.7) | 0.0018 |
| Non-White | 770(24.9) | 345(22.5) | 425(27.3) | |
| Comorbid conditions | ||||
| None | 1035(33.5) | 240(15.6) | 795(51.1) | <0.0001 |
| Hypercholesterolemia | ||||
| Hypertension | ||||
| Cardiovascular disease | ||||
| Cerebrovascular disease | 2055(66.5) | 1295(84.4) | 760(48.9) | |
| Statin use | ||||
| No statins | 1555(50.3) | – | – | |
| Statins | 1535(49.7) | – | – | |
| CNV | ||||
| No CNV | 2278(73.7) | 1085(70.7) | 1193(76.7) | 0.0001 |
| CNV | 812(26.3) | 450(29.3) | 362(23.3) | |
CNV choroidal neovascularization
Table 2.
Characteristics associated with choroidal neovascularization in nonexudative age-related macular degeneration patients
| Characteristic | Unadjusted | Adjusted | ||
|---|---|---|---|---|
| Odds ratio | 95% CI | Odds ratio | 95% CI | |
| Age | ||||
| <80 | 1.00 [Reference] | 1.00 [Reference] | ||
| ≥80 | 2.97 | 2.45 to 3.61 | 2.82 | 2.32 to 3.44 |
| Sex | ||||
| Female | 1.00 [Reference] | 1.00 [Reference] | ||
| Male | 0.87 | 0.74 to 1.03 | 0.85 | 0.71 to 1.01 |
| Race | ||||
| White | 1.00 [Reference] | 1.00 [Reference] | ||
| Non-White | 0.47 | 0.38 to 0.58 | 0.50 | 0.40 to 0.61 |
| Statin use | ||||
| No statins | 1.00 [Reference] | 1.00 [Reference] | ||
| Statins | 1.37 | 1.16 to 1.61 | 1.27 | 1.06 to 1.51 |
| Comorbid conditions | ||||
| None | 1.00 [Reference] | 1.00 [Reference] | ||
| Hypercholesterolemia | ||||
| Hypertension | ||||
| Cardiovascular disease | ||||
| Cerebrovascular disease | 1.38 | 1.16 to 1.65 | 1.02 | 0.84 to 1.25 |
This cross-sectional study adds to the growing literature around the therapeutic potential of statins in preventing AMD progression. Advanced AMD prevalence estimates for GA vs. CNV range from 1:1 to 2:1; however, GA currently has no treatment [5]. As suggested by Miller et al. statins may allow for drusen regression potentially circumventing GA [4]. Therefore, if statins are associated with CNV as indicated in our study, this is a small exchange given vision can be well preserved in these patients with existing therapies like anti-VEGF (vascular endothelial growth factor) [1]. Our study is a preliminary exploration of statin effect on CNV. The observed association is likely complicated by treatment and risk factors unavailable in our database and could be subject to residual confounding. Large cohort studies and randomized controlled trials incorporating risk and treatment factors (dose, class, course length, hydrophilicity) are necessary [4]. In conclusion, given the global disease burden and grave implications of advanced AMD, novel treatment with statins deserves further study and consideration.
Funding
This work was supported by a Medical Scholars Grant, a medical student research grant awarded from the School of Medicine at Stanford University.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
References
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