Cholesterol Screening To Aid In Glaucoma Detection
Although intraocular pressure is the primary risk factor for glaucoma, additional risk factors should also be considered. This systematic review and meta-analysis summarize the evidence of the association between cholesterol parameters (total cholesterol, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) levels) and glaucoma and serves to examine the role of cholesterol screening in the diagnosis of glaucoma.
Glaucoma and Cholesterol
Glaucoma is the primary cause of irreversible blindness around the globe. The critical risk factor is intraocular pressure (IOP). Lowering of IOP is found to maintain an individual’s visual field in glaucoma cases making it the most important treatment strategy in glaucoma. However, in some patients, IOP lowering does not seem sufficient to stop the progression of visual field loss.
A common risk factor is hypothesized to be lipid levels as polymorphisms in genes encoding proteins important for lipid metabolism such as ABCA1, GAS7 and ATXN2 have been associated with glaucoma. Since a large case-control study found that long-term statin use was associated with a reduced risk of glaucoma interest in lipid levels as an additional risk factor has risen. However, statins do not only lower lipid levels but also seem to have an anti-inflammatory and consequently neuroprotective effect. This further obscures the relationship between glaucoma, lipid levels, and lipid-lowering drugs.
A lot of data from available studies on the association between cholesterol and glaucoma are conflicting. Therefore, the researchers conducted a systematic review and meta-analysis to summarize the evidence regarding the association between cholesterol parameters (total cholesterol, low-density lipoprotein, and high-density lipoprotein levels) and glaucoma.
Four electronic databases were used in this study. Two independent reviewers screened abstracts and potentially full texts of identified articles for eligibility. The risk of bias was assessed with the Newcastle–Ottawa Scale. A random-effects meta-analysis was used to investigate the differences in total cholesterol, LDL, and HDL levels between patients with and without glaucoma.
The researchers registered the systematic review in the International prospective register of systematic reviews (PROSPERO registration number CRD42017067748). The reporting in this publication follows the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement.
Study eligibility criteria
All observational studies (cross-sectional, case-control, cohort, survey, and surveillance reports) reporting the association between glaucoma and cholesterol screening data including cross-sectional, case-control, cohort, survey, and surveillance reports were included. Studies had to report on adult patients (≥18 years) and had to be published in English.
Abstracts and conference proceedings that are not published in peer-reviewed journals were not included. Furthermore, any publication without original data for the quantitative analysis was excluded for the quantitative meta-analysis. Studies had to ascertain the diagnosis of glaucoma by any one or more of the following: fundus photo, fundus examination, retinal nerve fiber layer (RNFL) thickness evaluation, visual field defects, medical records, self-report, and/or glaucoma treatment.
An experienced medical information specialist (BW) systematically searched the electronic databases: MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and Science Citation Index Expanded for all publications from database inception until October 2020. Additionally, all bibliographies of identified articles were scanned to identify potentially relevant manuscripts missed by our search in the databases. Using free term and controlled term formulations the following keywords were searched for in the databases: ‘glaucoma’ AND ‘cholesterol’, ‘glaucoma’ AND ‘low-density lipoprotein’, ‘glaucoma’ AND ‘high-density lipoprotein’, ‘glaucoma’ AND ‘dyslipidemia’ and ‘glaucoma’ AND ‘lipoprotein’. We limited our search to articles published in English.
Two reviewers (LP, MM) independently screened references for inclusion. After pilot testing, we performed dual abstract screening based on the eligibility criteria. Included references underwent subsequent dual full-text review to decide on the final inclusion or exclusion of the study. Disagreements were resolved by consensus. The online software ‘Covidence’ was used for abstracts and full-text screening.
Two investigators (LP, MM) independently extracted the title, name of authors, year of publication, study design, sample size, type of glaucoma, the definition of glaucoma and control patients, demographic data, and outcome variables (i.e. total cholesterol screening, LDL, HDL). These data were recorded in a Microsoft Excel (Microsoft Cooperation) spreadsheet.
Risk of bias assessment
The Newcastle–Ottawa Scale (NOS) was used to assess the potential risk of bias in each individual study (Hartling et al. 2013). The NOS was developed to assess the quality of nonrandomized studies. Two reviewers (LP, MM) independently assessed the included studies. Disagreements were solved by consensus.
Differences in total cholesterol, LDL, and HDL levels between patients with and without glaucoma were analyzed using a random-effects meta-analysis. The researchers extracted means and standard deviations from the studies whenever available. For one study reporting only the range, the standard deviation was estimated as (max−min)/6 due to a sufficiently large sample size.
For studies with more than one glaucoma study arm (e.g. normal-tension glaucoma (NTG)), the researchers used the weighted mean and pooled standard deviation to combine the arms. For studies with a healthy control group as well as a control group consisting of patients with PEX syndrome without glaucoma, only the healthy controls were considered. Mean differences (MD) between glaucoma and non-glaucoma patients are displayed in forest plots together with their 95% confidence intervals (CI). Possible publication bias was assessed using Egger’s linear regression test and Begg’s rank correlation test.
The study search yielded 1496 references after the removal of duplicates. After the abstract screening, 167 full-text articles were assessed for eligibility. Most were deemed unfit due to different outcome parameters or study populations as well as ‘ineligible type of publication. Finally, the researchers included 29 studies in the qualitative synthesis, and out of those 26 studies contained relevant information for the quantitative analysis.
Overall, 29 observational studies were included in the systematic review, and 26 reported quantitative information to investigate differences in cholesterol parameters between patients with glaucoma (N = 7196) and patients without glaucoma (N = 350 441). Patients with glaucoma had significantly higher total cholesterol levels than patients without glaucoma (Mean Difference (MD) 7.9 mg/dl, 95% CI 3.3 to 12.5, p = 0.001) and lower mean HDL levels (MD −2.0 mg/dl, 95% CI: −3.1 to −0.9, p = 0.001). Patients with glaucoma had higher mean LDL levels than patients without glaucoma, albeit not statistically significant (MD 6.1 mg/dl, 95% CI: −4.3 to 16.4, p = 0.251).
This systematic review and meta-analysis of observational studies found an association between glaucoma and high total cholesterol and low HDL levels, respectively. Although this supports the hypothesis that lipid levels pose an additional risk for glaucoma development, heterogeneity was substantial and causality cannot be presumed from identified observational studies.
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