Diabetes mellitus is associated with a 5-fold higher prevalence of cataracts, which remains a major cause of blindness in the world (Obrosova et al. 2010). In diabetics, cataracts usually develop at an earlier age and progress faster (Machan et al. 2012). An increase in the prevalence of type 2 diabetes results in an increase in cataract-induced vision loss (Li et al. 2014). Despite the safety of cataract surgery due to advances in technology, cataract still poses a threat to vision in an unpredictable manner (Kiziltoprak et al. 2019).

The development of cataracts in diabetes may be due to a number of plausible pathophysiological mechanisms including perturbations in the oxidative stress and polyol pathways (Lee and Chung 1999; Vinson 2006; Elanchezhian et al. 2012). The polyol pathway, via which aldose reductase catalyzes glucose reduction into sorbitol, has been proposed as a central mechanism of cataract formation (Kador et al. 2016). There are numerous publications that describe oxidative stress damage to lens fibers by free radical scavengers in diabetics (Chung et al. 2003; Mulhern et al. 2006). The mechanism can be reflected in risk factors for cataracts and associated blindness related to diabetes, including those that can be targeted for cataract prevention.

Previous studies have shown limited diabetes-related risk factors in cataract development, which include a longer duration of diabetes and poor metabolic control (Pollreisz and Schmidt-Erfurth 2010). However, more clinical features in diabetic patients remain to be investigated. Patients with diabetes have multiple issues to be evaluated prior to the standard surgical treatment, perioperatively, and after surgery. It is important for these patients to be monitored and managed properly in order to minimize the risk of vision loss. We, therefore, examined the associated factors for cataract complications in patients with type 2 diabetes.

Study design and data source

The national health insurance claims database in Korea contains individual beneficiaries and healthcare service information including diagnosis, procedures, and prescriptions. Diagnostic codes are based on the 10th revision of the International Classification of Diseases (ICD-10). The data on senior subjects was derived from stratified samples of insurance claims drawn at random. The size of the cohort was calculated and extracted to improve the representativeness of the socio-demographic characteristics, diagnosis, and healthcare services. In order to protect personal information, medical claims data are encrypted and accompanied by anonymous identification numbers. This study was approved by the Institutional Review Board of Chungbuk National University (CBNU-201703-ETC-425-01).

Defining case and control groups

The index date was the first diagnosis of type 2 diabetes and 365 days before the entry date was applied as a wash out period. Subjects with missing demographic information and cataract diagnoses prior to type 2 diabetes were excluded from the study. Patients with one or more diagnosis of cataract in an inpatient or two or more visits in outpatient were defined as the case group and patients without the diagnosis of cataract were defined as the control group. In order to allow the time for cataract development after diabetes diagnosis, we set a minimum of 365 days prior to the cataract diagnosis. Risk set sampling was used to match each case with one control by age, sex, and duration of follow-up based on a nested case-control study.

Statistical analysis

Baseline characteristics were summarized for the case (cataract) and control groups. Results were presented as numbers and percentages for categorical variables, and differences between groups were estimated according to chi-square tests. Comorbidities and medications reported to be related to cataract were included in the analyses (Supplementary Table 1) (Harding et al. 1993; Klein et al. 1995; Delcourt et al. 2000; Galeone et al. 2010; Yu et al. 2014; Abate and Clarke 2017; Hu et al. 2016; Liu et al. 2017; Becker et al. 2018; Li et al. 2019). Covariates with statistical significance in univariate analysis were entered into the multivariable analysis to estimate adjusted odds ratios. We conducted a conditional logistic regression to determine significant differences between groups. All statistical analyses were done using the SAS Enterprise Guide version 9.4 (SAS Institute Inc, Cary, NC, USA), and a two-tailed confidence interval of 0.05 was considered to indicate statistical significance.

In this study, we included 14,352 patients in both the case (cataract) group and the control group after 1:1 risk set sampling (Fig. 1). The percentage of males (39.6%) and females (60.4%), mean age (69.1 ± 5.0 years), and diabetes duration (46.9 ± 26.8 months) were identical in both groups since we matched the patients by sex, age, and follow-up duration. The majority of patients had 3 or greater Charlson Comorbidity Index in both groups. The percentages of patients with comorbidities, such as liver disease, asthma, and heart failure were statistically significantly lower in the control group. On the other hand, the percentage of dementia, glaucoma, diabetic retinopathy, and cerebrovascular disease was lower in the cataract group (Table 1).

Table 1 . Baseline characteristics of the study subjects.

	Control group N = 14,352 (%)	Cataract group N = 14,352 (%)	p-value
Sex			1.000
Male	5,682 (39.6)	5,682 (39.6)
Female	8,670 (60.4)	8,670 (60.4)
Age, years (mean ± SD)	69.1 ± 5.0	69.1 ± 5.0	1.000
60-69	8,346 (58.2)	8,346 (58.2)
70-79	5,532 (38.5)	5,532 (38.5)
80-89	474 (3.3)	474 (3.3)
Diabetes duration, month (mean ± SD)	46.9 ± 26.8	46.9 ± 26.8	1.000
Charlson comorbidity Index			0.001
0	571 (4.0)	513 (3.6)
1-2	3,251 (22.6)	3,041 (21.2)
≥ 3	10,530 (73.4)	10,798 (75.2)
Comorbidities
Renal disease	900 (6.3)	945 (6.6)	0.278
Liver disease	4,459 (31.1)	4,663 (32.5)	0.010
Gout	941 (6.6)	990 (6.9)	0.248
Hypertensive disease	1,293 (9.0)	1,374 (9.6)	0.100
Hyperlipidemia	9,998 (69.7)	10,137 (70.6)	0.073
Hypocalcemia	1,386 (9.7)	1,389 (9.7)	0.952
Asthma	5,853 (40.8)	6,251 (43.6)	< 0.001
Dementia	1,591 (11.1)	1,273 (8.9)	< 0.001
Glaucoma	3,137 (21.9)	2,483 (17.3)	< 0.001
Diabetic retinopathy	1,827 (12.7)	1,634 (11.4)	0.001
Cerebrovascular disease	3,852 (26.8)	3,382 (23.6)	< 0.001
Heart failure	2,002 (14.0)	2,151 (15.0)	0.012
Co-medication
Diabetes medications	8,635 (60.2)	9,093 (63.4)	< 0.001

Figure 1. Flow chart of patient selection.

After adjusting for comorbidities and diabetic medications, patients with liver disease, asthma, heart failure, and diabetic medications showed a slight increased risk of cataract development with a statistical significance. In contrast, patients with dementia, glaucoma, diabetic retinopathy, and cerebrovascular disease showed a decreased risk of cataract after adjustment (Table 2).

Table 2 . Association of covariates with cataract development.

Variable	Crude odds ratio (95% CI)	Adjusted odds ratio* (95% CI)
Liver disease	1.06 (1.01-1.12)	1.07 (1.02-1.13)
Asthma	1.12 (1.06-1.17)	1.13 (1.08-1.19)
Dementia	0.78 (0.72-0.84)	0.81 (0.73-0.86)
Glaucoma	0.74 (0.70-0.79)	0.75 (0.70-0.80)
Diabetic retinopathy	0.88 (0.82-0.94)	0.89 (0.82-0.96)
Cerebrovascular diseases	0.84 (0.79-0.88)	0.86 (0.82-0.91)
Heart failure	1.08 (1.01-1.16)	1.08 (1.01-1.16)
Diabetes medications	1.14 (1.09-1.20)	1.17 (1.12-1.23)

*Adjusted for sex, age, liver disease, asthma, dementia, glaucoma, diabetic retinopathy, cerebrovascular disease, heart failure, and diabetes medication..

Since diabetes medications revealed statistical significance in association with cataract development, we analysed the relationship according to the specific type of medications. Among the diabetes medications, sulfonylurea and insulin were associated with a slight increased risk of cataract development. As diabetes medications are often used in combination, we also performed an analysis in combination therapy. However, combination therapy did not show statistical significance after adjusting for co-medications (Table 3).

Table 3 . Diabetic medications in association with cataract development.

	Control group N = 14,352 (%)	Cataract group N = 14,352 (%)	Crude OR* (95%CI)	Adjusted OR** (95%CI)
Insulin	3,455 (24.07)	3,785 (26.37)	1.13 (1.07-1.19)	1.07 (1.01-1.14)
DPP4-inhibitor	381 (2.65)	412 (2.87)	1.08 (0.94-1.24)	1.00 (0.86-1.16)
Metformin	5,964 (41.56)	6,394 (44.55)	1.13 (1.07-1.18)	1.05 (0.99-1.12)
Sulfonylurea	7,218 (50.29)	7,688 (53.57)	1.14 (1.08-1.19)	1.08 (1.01-1.15)
a-Glucosidase inhibitor	3,061 (21.33)	3,334 (23.23)	1.11 (1.05-1.18)	1.03 (0.96-1.10)
Thiazolidinedione	674 (4.70)	699 (4.87)	1.03 (0.93-1.15)	0.96 (0.86-1.08)
Metformin + Thiazolidinedione	151 (1.05)	147 (1.02)	0.97 (0.77-1.22)	0.93 (0.74-1.17)
Metformin + Sulfonylurea	1,628 (11.34)	1,754 (12.22)	1.08 (1.01-1.16)	1.01 (0.94-1.10)
Sulfonylurea + Thiazolidinedione	48 (0.33)	45 (0.31)	0.93 (0.62-1.40)	0.87 (0.57-1.31)

*Crude odds ratio..

**Adjusted odds ratio; Adjusted for age, sex and diabetes medications..

Based on an interesting result that dementia was related to the decreased risk of cataract, we performed a sub-analysis of dementia medications. Among patients taking dementia medications, 1,273 patients were found to develop cataract. Dementia medications showed a tendency of decreased the risk of cataract. Especially, memantine was associated with a 62% lowered risk of cataract in diabetes patients (Table 4).

Table 4 . Sub-analysis of dementia medications in association with diabetic cataract.

	Control N = 1,591 (%)	Cataract group N = 1,273 (%)	Crude OR* (95%CI)	Adjusted OR** (95%CI)
Rivastigmine	40 (2.51)	25 (1.98)	0.77 (0.46-1.28)	0.76 (0.43-1.32)
Galantamine	42 (2.64)	36 (2.83)	1.07 (0.64-1.68)	1.10 (0.62-1.94)
Memantine	53 (3.33)	17 (1.34)	0.39 (0.22-0.68)	0.38 (0.20-0.72)
Donepezil	287 (18.04)	162 (12.73)	0.66 (0.53-0.81)	0.65 (0.52-0.82)
Comination therapy	58 (3.65)	33 (2.59)	0.70 (0.45-1.08)	1.47 (0.74-2.93)

*Crude odds ratio..

**Adjusted odds ratio; Adjusted for age, sex and dementia medication..

In this study, we used the national health insurance service - senior cohort database and found that diabetes patients with dementia, glaucoma, diabetic retinopathy, or cerebrovascular disease were significantly less likely to develop cataract than those without such comorbidities. Our sub-analyses showed that memantine or donepezil use was associated with decreased incidence of cataract.

Among the ocular complications of diabetes, diabetic retinopathy has been widely studied. Reported risk factors of diabetic retinopathy include poor metabolic control, hypertension, and hyperlipidemia (Early worsening of diabetic retinopathy in the Diabetes Control and Complications Trial 1998). However, diabetic cataract researches are limited probably due to the difficulty of finding risk factor as it is a degenerative disease. In our study, we used large-scale population data to minimize aging effect by matching method.

We found that dementia was associated with 19% lowered risk of cataract development after adjusting for sex, age, diabetes medications, and other comorbidities. A sub-analysis was conducted to examine the effect of dementia medications treatment rather than the disease itself. Interestingly, patients with memantine and donepezil revealed a significantly lowered risk of cataract. It could be due to the similarities of microvascular changes in diabetes and dementia. Although previous studies are limited to the link between diabetic retinopathy and dementia, it has been reported that vascular changes in the retina mirror those in the cerebral circulation in patients with diabetes. Associations between retinal vascular changes and dementia have been reported in patients with diabetes. The presence of diabetic retinopathy may also indicate an increased risk of developing cognitive dysfunction (Tan and Wong 2023). Retinal vascular changes in diabetes are critical substrates to understand the role of microvascular changes in the pathogenesis of dementia, in particular, new insights into the vascular effects exerted by diabetes (Tan and Wong 2023). Another study by Grauslund et al reported that individuals with diabetes without diabetic retinopathy were less likely to develop Alzheimer’s disease compared to persons without diabetes. However, individuals with diabetic retinopathy had a 34% higher risk of incident Alzheimer’s disease (Pedersen et al. 2022). This might indicate that prevention or treatment of dementia could affect the risk of ocular complications in diabetics.

In a study of memantine on neuroretinal function and retinal vascular changes of diabetic rats, memantine showed possibility in the treatment of ocular diseases, including diabetic retinopathy with neurodegeneration (Kusari et al. 2007). This could support our result of memantine in reducing the risk of cataract in patients taking memantine.

We could not find studies on donepezil in association with cataract prevention or treatment. However, one study showed that donepezil therapy might prevent deterioration of visual field defects, optic nerve head blood flow, and regional cerebral blood flow in the temporal, parietal, and posterior lobes (Yoshida et al. 2010). Previous studies as mentioned above indicate possible repositioning of memantine and donepezil in managing cataract. A large scale prospective randomized controlled studies are needed to confirm the efficacy of dementia medications on cataract prevention or treatment.

Our study was conducted using the national health insurance system database. Since it is based on medical service claims data recorded by doctors, there could be differences between the actual data of medical examination and insurance claim dates. Also, the ICD-10 codes were selected subjectively and were subject to controversies about whether these codes were appropriate for the patient’s symptoms. Furthermore, the clinical data on the laboratory values or the severity of dementia were not available, so we could not measure their impact on the results. In addition, although many variables adjusted the final model, there could be a residual confounding risk.

Despite the above limitations, we used the database with patients representing the total population of Korea. There was no participant left out of this database because it includes all citizens without exception. The control participants were randomly selected and matched for age, sex, and follow-up duration to avoid confounding effects. Another strength is the novel finding of the relationship between cataract and dementia medications using nationwide claims data. The findings of our study can serve as a great basis for further research into dementia medications and cataract.

The authors declare that they have no conflict of interest.