Purpose
To determine whether an association exists between dry eye disease (DED) and statin use and/or dyslipidemia.
Design
Retrospective, case-control study.
Methods
Setting : University of North Carolina (UNC)-affiliated healthcare facilities. Study population : 72,931 patients seen at UNC ophthalmology clinics over a 10-year period. Main Outcome Measures : Odds ratios (ORs) calculated between DED and a history of low, moderate, or high-intensity statin use; and ORs calculated between DED and abnormal lipid panel values.
Results
Total of 39,336 individuals (53.9% female) were analyzed after exclusion of individuals with confounding risk factors for DED. Of these, 3,399 patients (8.6%) carried a diagnosis of DED. Low-, moderate-, and high-intensity statin regimens were used by 751 subjects (1.9%), 2,655 subjects (6.8%), and 1,036 subjects (2.6%). Lipid abnormalities were identified as total cholesterol >200 mg/dL, 4,558 subjects (11.6%); high-density lipoprotein (HDL) <40 mg/dL, 2,078 subjects (5.3%); low-density lipoprotein (LDL) >130 mg/dL, 2,756 subjects (7.0%); and triglycerides (TGs) >150 mg/dL, 2,881 subjects (7.3%). The odds ratios (OR) of carrying a diagnosis of DED given the presence of low-, moderate-, and high-intensity statin use were 1.39 (95% confidence interval [CI]: 1.13-1.72); OR 1.47 (95% CI: 1.30-1.65), and OR 1.46 (95% CI: 1.21-1.75), respectively. The OR of carrying a diagnosis of DED given the presence of total cholesterol >200 mg/dL, HDL <40 mg/dL, LDL >130 mg/dL, and TGs >150 mg/dL were 1.66 (95% CI: 1.52-1.82), 1.45 (95% CI: 1.26-1.67), 1.55 (95% CI: 1.39-1.74), and 1.43 (95% CI: 1.27-1.61), respectively.
Conclusions
A history of statin use or dyslipidemia is associated with an increased odds of having a DED diagnosis. Further studies are needed to determine whether statin use and/or dyslipidemia increases the risk of DED.
Dry eye disease (DED) affects a significant proportion of the general population, with an estimated prevalence ranging from 7% to 33%. The incidence and severity of DED increases with age and female sex. This multifactorial condition is characterized by decreased tear production and/or increased evaporation and can lead to symptoms of ocular discomfort, visual disturbances, and a diminished quality of life. , Meibomian gland dysfunction (MGD) is the most common cause of evaporative dry eye and involves abnormalities in the quantity and/or composition of tear film lipids, including excess free cholesterol. The relationship between systemic lipid abnormalities and those of the tear film has not been clearly established. However, prior studies, although conflicting, suggest an association between MGD/DED and dyslipidemia.
Dyslipidemia is a significant risk factor for cardiovascular disease, affecting an estimated 12% of adults. It is most often treated with “statin” medications. This drug class is composed of β-hydroxy β-methylglutaryl-co-enzyme A (HMG-CoA) reductase inhibitors, which block the rate-limiting step in the biosynthesis of cholesterol. HMG-CoA reductase expression has been identified within the sebaceocytes of meibomian glands in human eyelid tissue. Thus, it is possible that statin use could alter cholesterol synthesis and lipid homeostasis within the meibomian glands, leading to destabilization of the tear film and subsequent DED.
To investigate a potential association between DED and each of a history of statin use or dyslipidemia, this study examined a large number of patients seen at University of North Carolina (UNC)-affiliated healthcare facilities over a 10-year period.
Subjects and Methods
This was a retrospective case-control study with approval obtained from the institutional review board of UNC. All methods described herein adhered strictly to the tenets of the Declaration of Helsinki and Health Insurance Portability and Accountability Act regulations. The dataset was acquired from the Carolina Data Warehouse for Health (CDWH), a repository of de-identified patient information collected from patient visits at UNC-affiliated hospitals and outpatient clinics. Use of an online interface linked to the CDWH identified 72,931 unique patients older than 18 years of age, with prior lipid panel results, and seen at UNC ophthalmology clinics between May 1, 2008, and May 31, 2018.
Queries were performed to identify unique individuals among this group carrying a diagnosis of DED (International Classification of Diseases, ed. 9 [ICD-9] and ICD-10 codes 370.33, 375.15, H04.12x, and H16.22x). Additional queries were carried out to identify patients with a history of low-intensity, moderate-intensity, and high-intensity statin use as well as those with dyslipidemia. Low-intensity statins included fluvastatin, 20-40 mg daily; lovastatin, 20 mg daily; pitavastatin, 1 mg daily; pravastatin, 10-20 mg daily; and simvastatin, 10 mg daily. Moderate-intensity included statins atorvastatin 10-20 mg daily; fluvastatin, 40 mg twice a day or 80 mg daily; lovastatin, 40 mg daily; pitavastatin, 2-4 mg daily; pravastatin, 40-80 mg daily; rosuvastatin, 5-10 mg daily; and simvastatin, 20-40 mg daily. High-intensity statins included atorvastatin, 40-80 mg daily; and rosuvastatin, 20-40 mg daily. Abnormal lipid values were total cholesterol >200 mg/dL; high-density lipoprotein (HDL) <40 mg/dL; low-density lipoprotein (LDL) >130 mg/dL; and triglycerides (TG) >150 mg/dL. Statin categories were constructed to be unique and not double count individuals.
Upon data acquisition, exclusion of individuals with confounding factors well known to be associated with DED was performed. Individuals were excluded if they used specific medications associated with DED (tricyclic antidepressants, antihistamines, or diuretics); had a history of rheumatoid arthritis, Sjögren’s disease, or lupus (ICD-9 and -10 codes 710.0, 710.2, 714.0, M32.x, M35.x, M05.79, M05.89, M06.09, and M06.89), or a history of cataract or refractive surgery (Current Procedural Terminology codes 66984, S0800, and S0810). Odds ratios (ORs) and their associated 95% confidence intervals (CIs) were calculated between DED and each of the above parameters and further stratified by age. All data were analyzed using SAS version 9.4 software (SAS, Cary, North Carolina).
Results
A total of 72,931 patients were considered for inclusion in the study. After excluding individuals with the confounding factors identified above, the analyzed cohort consisted of 39,336 individuals, of whom 53.9% were female. Demographic characteristics of the analyzed population are outlined in Table 1 . In total, 3,399 patients (8.6%) carried a diagnosis of DED. Low-intensity, moderate-intensity, and high-intensity statin regimens were used by 751 patients (1.9%), 2,655 patients (6.8%), and 1,036 patients (2.6%), respectively. Lipid abnormalities were found in the respective numbers of patients: total cholesterol >200 mg/dL, 4,558 patients (11.6%); HDL <40 mg/dL, 2,078 patients (5.3%); LDL >130 mg/dL, 2,756 patients (7.0%); and TGs >150 mg/dL, 2,881 patients (7.3%).
| Demographic | Number (%) of Patients (N = 39,336) |
|---|---|
| Sex | |
| Males | 18,149 (46.1) |
| Females | 21,187 (53.9) |
| Race | |
| White | 22,701 (57.7) |
| African American | 6,862 (17.4) |
| Asian | 1,194 (3.0) |
| Native American or Alaskan | 177 (0.4) |
| Other or unknown | 8,402 (21.4) |
| Age groups, y | |
| 18-34 | 11,259 (28.6) |
| 35-54 | 10,334 (26.3) |
| 55-64 | 6,070 (15.4) |
| ≥65 | 11,673 (29.7) |
Table 2 and 3 show the calculated odds ratios and their associated 95% CIs for this cohort. The OR of carrying a diagnosis of DED, given the presence of low-intensity, moderate-intensity, and high-intensity statin use, were 1.39 (95% CI: 1.13-1.72), 1.47 (95% CI: 1.30-1.65), and 1.46 (95% CI: 1.21-1.75), respectively, compared to patients not taking statins. The ORs of carrying a diagnosis of DED, given the presence of total cholesterol >200 mg/dL, HDL <40 mg/dL, LDL >130 mg/dL, and TGs >150 mg/dL were 1.66 (95% CI: 1.52-1.82), 1.45 (95% CI: 1.26-1.67), 1.55 (95% CI: 1.39-1.74), and 1.43 (95% CI: 1.27-1.61), respectively.
| Exposure | Age Groups (y) | ||||
|---|---|---|---|---|---|
| 18-34 | 35-54 | 55-64 | ≥65 | All Ages | |
| Low-intensity statin therapy, OR (CI) | NA a | 0.85 (0.44-1.62) | 1.00 (0.62-1.63) | 1.71 (1.33-2.21) | 1.39 (1.13-1.72) |
| Moderate-intensity statin therapy, OR (CI) | 6.96 (2.63-18.42) | 1.13 (0.81-1.58) | 1.37 (1.08-1.74) | 1.57 (1.35-1.82) | 1.47 (1.30-1.65) |
| High-intensity statin therapy, OR (CI) | 17.50 (5.99-51.13) | 1.15 (0.69-1.90) | 1.28 (0.89-1.85) | 1.54 (1.21-1.95) | 1.46 (1.21-1.75) |
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