Diabetic retinopathy (DR) is the most common late complication of diabetes mellitus (DM) in the working-age population and one of the leading causes of blindness in the elderly, accounting for a significant drop in quality of life (QoL) and working ability for the patients [
The lack of oxygen in the retina causes fragile blood vessels to grow into the vitreous body and along the retina, causing an eminent risk of bleeding and formation of fibrovascular/proliferative membranes, leading consequently to tractional retinal detachment. These new blood vessels can furthermore grow into the angle of the anterior chamber and cause neovascular glaucoma [
To date, numerous screening studies have addressed the question of whether DM is a risk factor for primary open angle glaucoma (POAG); however, no converging or uniform conclusions exist to date. Some studies state that POAG is more prevalent in diabetic than in nondiabetic populations [
The aim of the present study was to use data from the entire Danish population using redeemed prescription on antidiabetic and antiglaucoma drugs over a 16-year period and check whether DM is a risk factor for developing glaucoma after adjusting for diabetic complications and several other demographic factors. Furthermore, we wanted to investigate whether any difference exists in glaucoma with regard to medication type, diabetic complications, or concomitant medications such as antihypertensive drugs in patients having DM.
To the best of our knowledge, only one previous cohort study on the topic has been carried out to date, and no study has addressed the association between the medication used within the group of DM patients and patients treated with antiglaucomatous medication. Moreover, the large dataset, amounting to a 16-year follow-up of more than 6 million individuals, constitutes a comprehensive source of data for investigating comorbidities between DM and glaucoma.
The study population comprised all individuals living in Denmark in the period between 1996 and 2012 and without previously diagnosed DM or glaucoma, amounting to 6,343,747 individuals. Data from the National Danish Civil Registration System contain information on vital status of all individuals born in, or migrating to, Denmark [
The information contained in the database contains dates of redemption of antidiabetic or antiglaucomatous medication (if any) for each individual and furthermore data on patients diagnosed with diabetic complications such as DR and/or nephropathy. The diabetic complications were identified based on the diagnostic codes, according to the International Statistical Classification of Diseases and Related Health Problems (ICD-10), and were retrieved from the register accordingly. On the other hand, the incident glaucoma and DM were based upon the pharmacotherapy used, and glaucoma and DM information was retrieved from the Danish Register of Medicinal Product Statistics, which holds data on all prescriptions dispensed in Denmark that are classified according to the Anatomical Therapeutic Classification system; this register is directly linked to the government for reimbursement purposes and is therefore very accurate. All pharmacies in Denmark are required by the government-financed Danish healthcare system to register all redeemed prescriptions at the individual level by the Danish Personal Identification number (the so-called CPR-number). We hereby identify individuals taking antidiabetic therapy through the National Danish Registry of Medicinal Products Statistics. Drugs administered during a hospital admission are, however, not included. Our data contain the dates of all redeemed antidiabetic treatments as well as all antiglaucomatous treatments, excluding those from before 1995, when mixed data on new and old prescriptions was combined in the register. To assure that the data only contain new prescriptions, all prescriptions registered in the database after January 1, 1996, were therefore included in the study.
The ATC codes for antihypertensive drugs used in the analyses are listed here by classes of origin: BB are in the group of C07; RAS inhibitors are in the group of C09; DD are in the group of C03; Ccb are in the group of C08D, and vasoprotectives are in the group of C02. To investigate the effect of pharmacotherapy, the focus was placed on RAS and BB, compared to the rest.
Patients were classified as incident with glaucoma (having their onset of glaucoma) by their first redemption of an antiglaucoma medication and incident with hypertension (having their onset of hypertension) by their first redemption of a second antihypertensive drug.
The selection process for the study population is illustrated in Figure
Flowchart of diabetes mellitus and glaucoma in the Danish population in the period from 1996 to 2012. The National Danish Registry of Medicinal Products Statistics was used to identify all individuals who were treated with glaucoma medication and/or antidiabetic drugs.
DM and glaucoma are most often managed and diagnosed by patients’ primary physicians and an out-of-hospital specialist in ophthalmology, respectively. Therefore, the in-hospital ICD-10 diagnoses for the two diseases are not relevant. Instead, we identify the population of glaucoma patients and those with DM and hypertension using the National Danish Registry of Medicinal Products Statistics as descripted above. With this approach, we are able to identify patients with a redeemed prescription for DM and/or glaucoma. Furthermore, this procedure allows us to identify the onset of the condition.
In patients who redeemed antidiabetic medication, comorbidity with hypertension was then identified using a validated algorithm based on the use of at least two classes of antihypertensive drugs. This algorithm is shown to have a tremendous sensitivity of 94.7% and a positive predictive value of 80.0% [
The Danish Civil Registration System contains information about dates of birth and death of all Danish citizens since 1972 [
To describe the evolution of the incidence of DM, DR, and glaucoma, the incidence rates were calculated in 5-year age strata, as a function of time, and then summarized as events per 1,000 person-years at risk. Furthermore, duration analysis models, based on the Poisson distribution, were employed to investigate the associations between DM treatments and DR, as well as the risk of developing glaucoma, adjusted for a range of potentially confounding factors.
The baseline characteristics are presented as means with standard deviations or frequencies and percentages accordingly. DM was considered to be a time-dependent variable and thus subjects who developed DM contributed risk time in the reference group until the time of diagnosis. Comorbidity was updated continuously throughout the follow-ups. Hazard ratios (HRs) for the study endpoint were estimated using Cox proportional hazards models adjusted for confounding factors including age, sex, comorbidity with DR, hypertension (concomitant medications with antihypertensive drug(s)), and diabetic nephropathy.
The primary analysis was not adjusted for medications used for the treatment of hypertension. An additional analysis was carried out with inclusion of antihypertensives when investigating all patients redeemed with antidiabetic medication to estimate its impact on the HRs of glaucoma. All statistical analyses were performed using SAS 9.4. Heteroscedasticity-robust standard errors were used in the duration model and cluster-robust standard errors, clustered on the individual level, were used in the regression discontinuity models. A significance level of 0.05 was applied, meaning that estimated coefficients with
The
The primary outcome in the present study was glaucoma (as inferred by antiglaucomatous drug prescriptions used).
The Danish Data Protection Agency approved the study (2007-58-0015, int. ref: GEH-2010-001). Retrospective register-based studies do not require ethical approval in Denmark.
The study comprised a total of 6,343,747 subjects within a sixteen-year follow-up. During the study period, 275,078 subjects with incident DM, 75,022 subjects with incident glaucoma, and 18,170 subjects with DR were identified, as shown in the flowchart of the study population selection (Figure
The incidence of DM, DR, and glaucoma in the Danish population over the period from 1996 to 2012 is depicted in Figure
Incidence of diabetes mellitus, diabetic retinopathy, and glaucoma in the Danish population, in the period from 1996 to 2012, per 1000 individuals (
The results showed an association between DM and the increased risk of new-onset glaucoma (Table
Hazard ratios for glaucoma development in patients treated with antidiabetic drugs. A range of confounding factors, comorbidity, concomitant medications factors, age, and gender are being adjusted for. The underlying data represents patients ≥ 40 years of age. For data on the total diabetic population, see Table
To exclude that increased incidence of glaucoma among patients treated with antidiabetic medication is simply caused by a common association with age or other potentially confounding factors, a duration model was implemented.
Table
Duration analysis. The table shows the relative risk for developing glaucoma in patients treated with antidiabetic drugs in the Danish population (1996–2012). The model controls for complication with DR and age as well as calendar year fixed effects (omitted from the table). RR: relative risk; CI: confidence interval; anti-DM drug: antidiabetic drug.
Model | 1 | 2 | 3 | 4 | 5 | 6 |
---|---|---|---|---|---|---|
Anti-DM drug | | | | | | |
DR | | | | | | |
Gender | | | | |||
| ||||||
Age | No | No | No | No | Yes | Yes |
Calendar year | No | No | No | No | No | Yes |
Multivariable Cox regression model analyses showing the hazard ratios for glaucoma by antidiabetic drugs used in patients with DM. The effect of complications such as diabetic retinopathy and nephropathy was investigated, as well as the concomitant medications used, such as antihypertensive drugs. RAS: renin-angiotensin system; PE: parameter estimate; SE: standard error; HR: hazard ratio.
Model | Age ≥ 40 years | All ages | ||||||
---|---|---|---|---|---|---|---|---|
1 | 2 | 3 | 4 | |||||
PE | HR | PE | HR | PE | HR | PE | HR | |
DR | | | | | | | | |
Diabetic nephropathy | −0.02 | 0.98 | | | 0.03 | 1.03 | | |
Hypertension | 0.06 | 1.06 | | | ||||
Gender | −0.01 | 0.99 | −0.01 | 0.99 | 0 | 1 | 0 | 1 |
Nephropathy × DR | | | | | ||||
Nephropathy × hypertension | 0.05 | 1.05 | 0.01 | 1.01 | ||||
DR × hypertension | 0.1 | 1.1 | 0.08 | 1.08 | ||||
| ||||||||
Biguanides | 0.17 | 1.18 | 0.17 | 1.19 | 0.24 | 1.27 | 0.24 | 1.28 |
Combination | | | | | | | | |
GLP-1-analogues and DDP-IV-inhibitors | −0.05 | 0.95 | −0.05 | 0.96 | 0.26 | 1.3 | 0.27 | 1.31 |
Glitazones | | | | | | | | |
Insulin and insulin analogues (slow) | 0.55 | 1.74 | 0.57 | 1.77 | 0.47 | 1.59 | 0.48 | 1.62 |
Insulin and insulin analogues (slow combined with rapid) | | | | | | | | |
Insulin and insulin analogues (intermediate) | 0 | 1 | 0.01 | 1.01 | 0.12 | 1.13 | 0.13 | 1.14 |
Meglitinides | 0.27 | 1.31 | 0.27 | 1.31 | | | | |
Sulphonylurea | 0.29 | 1.34 | 0.3 | 1.35 | | | | |
0.21 | 1.24 | 0.21 | 1.24 | 0.33 | 1.4 | 0.34 | 1.4 | |
| ||||||||
RAS + | | | −0.09 | 0.92 | ||||
RAS + antiadrenergic | | | | | ||||
RAS + Ccb | | | | | ||||
RAS + Diu | | | | | ||||
RAS + Vas | 0.23 | 1.26 | | | ||||
RAS | −0.03 | 0.97 | 0.01 | 1.01 | ||||
RAS + (other ≥ 2) | 0.11 | 1.12 | | | ||||
−0.03 | 0.97 | 0.03 | 1.03 | |||||
Other antihyp. drugs ≥ 2 | 0.09 | 1.09 | | 1.16 | ||||
| ||||||||
Age 50–59 years | | | | | ||||
Age 60–69 years | | | | | ||||
Age 70–79 years | | | | | ||||
Age > 80 years | | | | | ||||
| ||||||||
Age 21–40 years | | | | | ||||
Age 41–60 years | | | | | ||||
Age 61–80 years | | | | | ||||
Age > 80 years | | | | | ||||
| ||||||||
Number of individuals | 238,671 | 238,671 | 277,266 | 277,266 |
Using multivariate Cox regression model analyses, all individuals treated with antidiabetic drugs were investigated for the HR and adjusted for age, sex, comorbidity, concomitant medications, all being factors which can potentially affect the risk of glaucoma.
In Table
To the best of our knowledge, the present study is one of the largest studies investigating the association between glaucoma and DM, using data for an entire population over a sixteen-year period. We find an overall increased risk of glaucoma among patients with DM. This association remains evident when controlling for age, gender, retinopathy, and year-specific fixed effects.
Furthermore, we find that, in patients with DM, comorbidity with hypertension as well as presence of DR and/or joint complications with DR and nephropathy increases the risk of glaucoma. However, treatment with the antihypertensive combination of
Other large population-based studies have also demonstrated an association between glaucoma and DM [
Among studies which supported the association, the Wisconsin study [
A number of studies have pointed to the possibility that DM may affect the vascular autoregulation of retina and the optic nerve and thereby promote the risk of DR and glaucoma [
Although our results indicate a strong association between use of DM drugs and the use of antiglaucomatous drugs, we cannot rule out the possibility that the observed association is affected by the fact that patients with DM may get eye diseases detected more often by routine clinical care compared to healthy individuals.
As an additional finding, the present study finds an increased risk of glaucoma among DM patients with DR and/or joint complications with DR and nephropathy. The mechanisms behind this association could simply be that these patients suffer from a more severe DM disease. Both DR and nephropathy are serious conditions that need intensive treatment. Furthermore, diabetic nephropathy is often treated with ACE inhibitor as well as lipid lowering treatment and aspirin.
A possible increased risk of glaucoma in patients with concomitant hypertension and DM was further investigated. Overall, we show that antihypertensive medication is associated with an increased risk of glaucoma in patients with DM. However, the combination of
The main strength of our study is the use of comprehensive data resources covering a large population base, namely, the entire Danish population followed over 16 years. In particular, the National Danish Registry records 100% of all dispensed prescriptions in all pharmacies in Denmark, and, furthermore, all births, deaths, emigrations, and immigrations in Denmark. However, a limitation of the study is that we use prescriptions as the indicator of glaucoma and DM. In this matter, we are not able to conclude anything concerning the etiology or severity of the conditions.
In conclusion, this study reports an increased risk of glaucoma among patients treated with antidiabetic drugs. Furthermore, comorbidity with DR and the joint comorbidity with DR and/or diabetic nephropathy increase the hazard of getting glaucoma. Concomitant medications such as antihypertensive drugs can also increase the hazard for developing glaucoma. However, particular treatment with BB decreases the risk of glaucoma, while combination of BB and RAS conversely increases the risk.
Anna Horwitz had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
No conflicting relationship exists for any author.
The authors would like to thank Henrik Horwitz and Marc Klemp for valuable comments to the manuscript and their statistical support. This study was supported by Fight for Sight, Denmark, and the NORDEA Foundation Grant to the Center for Healthy Aging at the University of Copenhagen, Denmark.