A Meta-Analysis of Glaucoma Risk in Hyperlipidemic Individuals: A Critical Problem in Design

Abstract

Because glaucoma is the leading cause of irreversible visual impairment and is usually undetectable until advanced stages, 1 investigations on modifiable factors associated with glaucoma risk are warranted. The recent article by McCann et al., 2 which reported on a meta-analysis of observational studies evaluating the effects of statins on glaucoma, demonstrated that ''shortterm statin use is associated with a reduced incidence of glaucoma.'' This is, to our knowledge, the first comprehensive review of statin use and glaucoma risk, but its implication would be limited because it is uncertain whether hyperlipidemia itself increases the risk of developing glaucoma.We conducted a meta-analysis focused on studies that investigated the association between hyperlipidemia and glaucoma following the Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines. A systematic literature search of PubMed, EMBASE, and the Cochrane Library was performed independently by two investigators. The search terms were ''lipid-related,'' ''glaucoma related,'' and ''outcomerelated.'' The inclusion criteria were obviously defined exposure to lipid abnormalities, reported glaucoma incidence, and reported relative risk or odds ratio. Through a rigorous searching process ( Supplementary Fig. S1), three relevant studies 3-5 were included in the final analysis (Supplementary Table S1). Pooled odds ratios demonstrated that hyperlipidemia did not increase the incidence of glaucoma (relative risk, 1.40; 95% confidence interval [CI], 0.73-2.68; Fig.); there was no evidence of publication bias (Egger's test, P for bias ¼ 0.370).In our analysis, all of the included studies did not refine the effects of hyperlipidemia from those of lipid-lowering drugs (i.e., mixed results as a metabolic component or not considered a drug effect; this may have contributed to the high heterogeneity). This flaw was also the same in the study of McCann et al.2 If the opposite directions in these two metaanalyses are true, the effect sizes would be underestimated in both studies. To understand the role of lipid dysregulation and its control of glaucoma risk, a clear definition of case (hyperlipidemic individuals not taking lipid-lowering drugs) and control groups in the cohort or case-control studies, if not the randomized controlled trials, must be done. In addition, a tight connection to other metabolic abnormalities (e.g., hypertension, type 2 diabetes, or obesity) 6 should be considered when designing a study and/or analyzing the data.Apart from the indirect hypothesis of statin's neuroprotective action, 7 there have been very few basic research studies indicating that lipid abnormalities alone increase intraocular pressure or the risk of glaucoma. A plausible mechanism is that excess intraorbital fat and increased blood viscosity in obesity, usually clustered with lipid abnormalities, may disturb the aqueous outflow capacity, which consequently increases the intraocular pressure. 8,9 Clinically, beyond the simple snapshot association, 10 a recent l...

Association of Statin Use and High Serum Cholesterol Levels With Risk of Primary Open-Angle Glaucoma

“…Carefully determining the association with hyperlipidemia is important to help evaluate the possibility of confounding by indication 37 where associations with cholesterol-lowering drugs, such as statins, have been reported. Consistent with other studies 26,38 (eg, a meta-analysis 26 reported an RR of 1.40 [95% CI, 0.73-2.68] for hyperlipidemia history), we observed a trend of higher risk of POAG with higher serum cholesterol levels. This finding indicates that if (1) statins truly lower the risk of POAG and (2) higher cholesterol levels are associated with elevated POAG risk and (3) higher cholesterol levels were associated with being prescribed more statins, then the confounding bias would have been toward the null.…”

“…24 Furthermore, for some studies, confounding by indication due to hyperlipidemia (and concomitant hypertension and diabetes) has been raised as a concern, 25,26 and the association between hyperlipidemia and POAG has been unclear. 25,26 Our primary a priori hypothesis was that longer duration of statin use is associated with a lower risk of POAG, and our secondary hypothesis was that higher cholesterol levels are associated with a higher risk of POAG. Therefore, we examined the association of hyperlipidemia as well as statin use with risk of POAG among 50 710 women in the Nurses' Health Study (NHS), 62 992 women in the NHS2, and 23 081 men in the Health Professionals Follow-up Study (HPFS) followed up for 15 or more years.…”

“…23 Also, studies reporting inverse associations observed stronger associations with at least 2 years of use, [19][20][21] but data are lacking on the association with longer use of statins. 24 Furthermore, for some studies, confounding by indication due to hyperlipidemia (and concomitant hypertension and diabetes) has been raised as a concern, 25,26 and the association between hyperlipidemia and POAG has been unclear. 25,26 Our primary a priori hypothesis was that longer duration of statin use is associated with a lower risk of POAG, and our secondary hypothesis was that higher cholesterol levels are associated with a higher risk of POAG.…”