Overall, our current results based on a representative Chinese population strongly suggests that glaucoma is a high-risk factor for all-cause mortality in the middle-aged and elderly population, especially among people older than 75 years. In our study, among participants of all ages, the presence of glaucoma is accompanied by an increased risk of mortality resulting from all causes (HR: 2.159, 95% CI: 1.549–3.008), even after considering other conditions that might affect the risk of mortality, such as smoking, drinking, hypertension, dyslipidaemia and diabetes. When stratified by mean age of death, glaucoma significantly increases all-cause mortality in individuals in their mid-70s and above (HR: 1.907, 95% CI: 1.249–2.911). However, among younger individuals, of 45 to 74 years of age, those with glaucoma are not at higher risk compared with their same-age peers.
The results of our study are supported by many previous findings [6, 7, 16–21]. The National Health Interview Survey (NHIS) [21] reported that the probability of death from any cause occurring over a median of seven years of follow-up was higher (HR: 1.35, 95% CI: 1.19–1.53) among participants with glaucoma compared to those without glaucoma, even after adjustment for confounders. The NHIS survey also reported an increased risk of mortality from cardiovascular disease among participants with glaucoma. Similarly, a Taiwanese study [7] demonstrated higher mortality associated with POAG (adjusted HR: 2.11, 95% CI: 1.76–2.54), and it mentioned an association between glaucoma and a higher risk of acute renal failure. Moreover, the Beijing study, which examined 4356 subjects for glaucoma, suggesting that glaucoma, and angle-closure glaucoma in particular, might be associated with an increased rate of mortality among Chinese adults in Greater Beijing [6]. Our study supports and extends these findings reporting an association between glaucoma and mortality, and it enhances the understanding of glaucoma’s impact on the older population.
In contrast to our study, the NHANES study showed no statistical association between increased mortality and glaucoma after adjusting for age and sex [11]. Several studies confirmed an association between glaucoma and mortality in a univariate analysis but disproved the association after adjustment for confounders [8, 22]. In general, the relationship between glaucoma and mortality varies considerably across different studies, but this may have relevance to factors such as race, geography, sampling quantity and method. These factors may explain the differences in results between those studies and ours.
It is worth noting that our results elucidate the association between glaucoma and all-cause mortality in different age groups by showing that, in people older than 75 years, age is an important component of increased all-cause mortality from glaucoma. This may be because aging is one of the main factors that promotes the course of glaucoma and affects its treatment [23]. Aging will aggravate the severity of the disease and promote an increase in all-cause mortality.
Potential mechanisms that may explain the increased risk of mortality in adults with glaucoma include adverse treatment effects and exposure to risk factors known to increase the risk of glaucoma and major cause-specific deaths. First, adverse treatment effects from glaucoma surgery and medications are reported to be associated with high all-cause mortality rates: A retrospective cohort study from Korea indicated that all-cause mortality due to surgery for glaucoma was statistically significant (adjusted HR: 1.31, 95% CI: 1.05–1.62), both for open angle glaucoma and for angle closure glaucoma [24]. The risk of death from neurological disease was 2.7 times higher in older patients who underwent glaucoma surgery than in those who only received a diagnosis of glaucoma. Glaucoma medications can also cause severe side effects, including congestive heart failure (topical cholinergic agonists), increased blood pressure and tachyarrhythmias (topical adrenergic agonists) [25]. Topical administration of beta-blockers is one of the most common treatments for glaucoma, however, this is revealed to be associated with increased mortality. An Australia study in 2006 (relative risk [RR]: 2.14, 95% CI: 1.18–3.89) and research conducted in American in 2008 (RR: 1.91, P = 0.04) both showed higher mortality among glaucoma patients treated with topical timolol [26, 27]. This could be attributed to the drug’s effect on blood lipid levels, such as a 20% reduction in HDL and a 20–40% increase in triglycerides [28]. However, the conclusions were contradictory. An American retrospective cohort analysis indicated that use of any type of glaucoma medication had a statistically significant association with a 7% reduction of mortality (adjusted HR: 0.93, 95% CI: 0.90–0.95) [29]. Another American study, from the same year, showed similar results (HR: 0.26, 95% CI: 0.16–0.40) [25]. Use of topical beta-blockers did not seem to be associated with excess mortality [30]. Second, exposure to risk factors known to increase the risk of both glaucoma and major cause-specific deaths (e.g., neurological disease, cardiovascular disease) also possibly contribute to glaucoma-associated high levels of mortality. The association between neurologic diseases and glaucoma can be interpreted through the mechanisms that cause haemodynamic changes in the cerebral arteries and pathological substances, such as protein tau and amyloid-beta, that cause neurotoxicity and are also strongly associated with optic nerve damage in glaucoma [31]. It is suggested that stroke [32–34], Alzheimer’s disease [35–37] and Parkinson’s disease [38–40] are neurological diseases related to glaucoma. There was evidence that mortality in glaucoma patients was closely associated with cardiovascular events. A study in Australia indicated that cardiovascular mortality was 14.6% in patients with glaucoma as compared to 8.4% in non-glaucoma individuals, while further stratified analyses showed that cardiovascular mortality was higher among those previously diagnosed with glaucoma (RR: 1.85, 95% CI: 1.12–3.04) [26].
In addition, our study has suggested other independent risk factors associated with mortality, which include comorbidities, such as hypertension and diabetes, lifestyle factors, such as smoking and alcohol consumption, and social status, including marital and educational status. Regarding the relationship between hypertension and mortality, a meta-analysis in Japan of 13 cohort studies and a prospective cohort study in Shanghai (HR: 1.26, 95%CI: 1.02–1.55) suggested that high blood pressure increased the risk of all-cause mortality, and that this trend was more pronounced among younger individuals [41, 42], which was consistent with our study. This might be due to elevated blood pressure being associated with a range of cardiovascular outcomes including ischemic heart disease, myocardial infarction, ischemic stroke, sudden cardiac death, heart failure, atrial fibrillation and pulmonary embolism [43–45]. Our results indicate that diabetes significantly increase all-cause mortality, but only in the younger age group. This view is supported by several studies that pointed out that young-onset diabetes led to premature death, possibly due to an increase in complications such as heart disease, stroke and chronic kidney disease [46, 47]. In addition, low educational attainment, a non-married status, smoking and excessive alcohol consumption were also shown to be associated with higher mortality, which were consistent with our findings [21, 22, 48].
The strengths of our study include its nationwide representativity, the large elderly cohort with a high participation rate, the objective quality standards and the complete, adjudicated registry of deaths. As a nationally representative longitudinal survey, middle-aged and older population groups were included, with a high response rate. Moreover, matching using the global positioning system, data checking, recording and checking interviews, and calling participants back, were implemented at every stage of the study to ensure data quality and reliability.
Several study limitations should also be noted. First, we used self-reported measures of glaucoma, which, while subjective, had the advantage of feasibility at a low cost. To some extent, this avoided ambiguous diagnoses relating to elevated intra-ocular pressure or cup-to-disc-ratio, while ignoring other ophthalmic indicators, as occurred in some studies [11]. Second, we did not collect information on the use of antiglaucoma medication, which might have explained the increased risk of mortality. Therefore, there is a lack of data on the causes of death with the possibility that the findings might be explicable by confounders as yet unknown.
To summarize, the present study suggests that glaucoma may be associated with an increased rate of mortality in middle aged and elderly people in China. This provides an important reference for the design and evaluation of glaucoma treatment and for resolving patient management issues.