Glaucoma is the leading cause of blindness worldwide

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1 ORIGINAL STUDY Relationship Between Serum Glucose Levels and Intraocular Pressure, a Population-based Cross-sectional Study Eytan Cohen, MD,*wz Michal Kramer, MD,zy Tzippy Shochat, MSC,8 Elad Goldberg, MD,*z and Ilan Krause, MD*z Purpose: The purpose of this study is to assess the relationship between serum glucose levels and intraocular pressure (IOP) both in subjects with impaired fasting glucose (IFG) as well as in subjects with diabetes mellitus (DM). Materials and Methods: Data of a cross-sectional sample of 18,406 subjects who underwent routine annual screening at a tertiary medical center in 2000 to 2013 were analyzed. Results: Mean (SD) age of the subjects was 46 (10) years; 68% were male. Mean (95% confidence interval) IOP measured 13.1 ( ) mm Hg in subjects with normal glucose levels, 13.7 ( ) mm Hg in subjects with IFG, and 14.3 ( ) mm Hg in subjects with diabetes. The difference in IOP between subjects with normal and abnormal (DM or IFG) serum glucose levels were significant, even after adjusting for age, body mass index, and hypertension (P < ). There was a positive linear correlation between serum glucose levels and IOP in both men (r = 0.12; P < ) and women (r = 0.17; P < ). For every 10 mg/dl increase in fasting serum glucose, IOP increased by 0.09 mm Hg in men and by 0.11 mm Hg in women. Conclusions: This study demonstrated that similar to subjects with DM, subjects with IFG also have IOP levels that are higher than those with normal serum glucose. Moreover, there is a direct correlation between fasting serum glucose levels and changes in IOP. These findings highlight another end-organ effect of uncontrolled glucose levels. Key Words: impaired fasting glucose, diabetes mellitus, intraocular pressure, glaucoma (J Glaucoma 2017;26: ) Glaucoma is the leading cause of blindness worldwide after cataracts 1 and the main reason for blindness among African Americans. 2,3 Elevated intraocular pressure (IOP) is a major risk factor for the development of openangle glaucoma in addition to older age, black race, and positive family history. 4,5 It has been associated with progression of open-angle glaucoma, and lowering IOP is the major focus of glaucoma treatment. 6 8 Factors that affect IOP per se include older age, high blood pressure, 9 and elevated BMI. 10 Received for publication December 14, 2016; accepted April 27, From the *Department of Medicine F Recanati; wclinical Pharmacology Unit; ydepartment of Ophthalmology; 8Statistical Counseling Unit, Rabin Medical Center, Beilinson Hospital, Petach Tikva; and zsacklerfaculty of Medicine, Tel Aviv University, Tel Aviv, Israel. Disclosure: The authors declare no conflict of interest. Reprints: Eytan Cohen, MD, Department of Medicine F Recanati and Clinical Pharmacology Unit, Rabin Medical Center Beilinson Hospital, Petach Tikva , Israel ( dreytancohen@gmail.com). DOI: /IJG Diabetes mellitus (DM) may lead to an increase in IOP as well as to progression to glaucoma. Despite earlier inconsistencies, a recent large meta-analysis of 47 studies assessed the relationship between DM and glaucoma and yielded a pooled relative risk of 1.48 for glaucoma in diabetic patients compared with nondiabetic patients. In 10 of the 47 studies that assessed the relationship between DM and IOP, patients with DM had an overall mean increase in IOP of 0.18 mm Hg. 11 Moreover, a recent study has shown the correlation between duration of diabetes and risk of developing glaucoma. Patients with Z5 years of diabetes duration had an OR for glaucoma of 3.90 [95% confidence interval (CI), ] compared with patients with <5 years of diabetes duration. 12 The mechanism of the association between hyperglycemia and elevated IOP is not clear. Sato and Roy 13 suggested that high glucose levels may affect IOP by inducing an increase in fibronectin expression and cell proliferation in trabecular meshwork cells in the eye. Another suggested mechanism is an osmotic gradient created by hyperglycemia that draws excess aqueous humor into the anterior chamber of the eye. 14 Glucose levels even within the impaired fasting glucose (IFG) range may have these effects although data on IOP levels in patients with IFG are lacking. Also lacking are comprehensive data on the degree of IOP increase in relation to increases in serum glucose levels. The first aim of the present study was to compare IOP levels among subjects with normal glucose levels, IFG, or established DM. The second aim was to assess the correlation between IOP levels over the entire spectrum of fasting serum glucose levels. Since some studies have reported differences between adult men and women as to the prevalence of elevated IOP and as to the prevalence of glaucoma, 15,16 all analyses conducted for this study were stratified by sex. MATERIALS AND METHODS Study Population The study population consisted of a cross-sectional sample of all men and nonpregnant women aged 20 to 80 years who were referred by their employers for a routine medical screen at a tertiary medical center in Israel between 2000 and None of the subjects were hospitalized at the time of screening. The screen in each case consisted of a thorough medical history evaluation and complete physical examination along with a broad series of blood and urine tests, chest x-ray, electrocardiogram, exercise stress test, respiratory function test, and full ophthalmology examination. Subjects may return once a year for a repeated J Glaucoma Volume 26, Number 7, July 2017

2 J Glaucoma Volume 26, Number 7, July 2017 Relationship of Serum Glucose and IOP investigation. For the purpose of this study, we used data from each subject s most recent visit. All ophthalmology examinations were performed by an experienced ophthalmologist. IOP measurements using Goldmann applanation tonometry with fluorescein staining were measured in both eyes, in the sitting position, between 8:00 AM and 11:00 AM. All IOP measurements were performed on the same tonometer and were conducted most of the times by the same physician. For the study assessment, we chose only the right eye IOP measurements. Serum glucose levels were measured after an overnight 12-hour fast. Normal serum glucose level was defined as <100 mg/dl, IFG, as 100 to 125 mg/dl, and DM as Z126 mg/dl and/or a known diagnosis of DM. Subjects with glucose serum levels of 100 to 125 mg/dl who had been treated for DM were included in the DM group. Hypertension was defined as systolic blood pressure >140 mm Hg and/or diastolic blood pressure >90 mm Hg. Subjects in this group were those with self-reported hypertension treated mostly by antihypertensive medications. Data regarding the subjects smoking habits and alcohol consumption came from direct questioning on the day of examination in the screening center. Glaucoma was diagnosed in subjects with characteristic nerve damage on fundus examination and visual field testing. Subjects with glaucoma regardless whether they were receiving IOP-lowering medications as well as those scheduled for glaucoma surgery, were excluded from the study. All other subjects with previous ocular surgeries, including cataract surgery, were also excluded. A computer program was created to transfer all data from each visit into a spreadsheet Excel file. The statistical analysis was performed on this file. The study was approved by the Helsinki Ethics Committee of Rabin Medical Center. Statistical Analysis Baseline characteristics were compared between men and women using Student t test for continuous variables and w 2 test for categorical variables. Patients were divided into 3 groups by serum glucose levels: normal (reference group), IFG, and DM, and compared for mean IOP (95% CI) using multivariate analysis of variance with Tukey adjustment. The Pearson correlation index was used to assess the correlation between serum glucose level and IOP in all subjects. Multivariate linear regression analysis was performed to determine the unadjusted and adjusted coefficients of the relationship between continuous serum glucose levels and IOP. Univariate analyses were performed in model 1. Model 2 was adjusted for age, and model 3 was adjusted for age, body mass index (BMI), presence of hypertension, and actual systolic blood pressure. All analyses were conducted using SAS 9.4. Statistical significance was set as a P value of < RESULTS Baseline Characteristics From 2000 to 2013, 18,406 subjects underwent screening at Rabin Medical Center. All data components relevant for this assessment were available in all cases. The clinical characteristics of the subjects are presented in Table 1. Mean (SD) age of the study sample was 46.0 (10) years; 68% were men and 32% were women. Mean IOP (SD) measured 13.4 (2.5) mm Hg in men and 13.0 TABLE 1. Baseline Characteristics of the Study Population (18,406) Mean (SD)/n (%) Males (N = 12,586) (68%) Females (N = 5820) (32%) P Age (y) 45.8 (10.1) 46.1 (10.3) IOP (mm Hg) 13.4 (2.4) 13.0 (2.2) < Normal glucose (82.8%) 5278 (90.7%) < levels Impaired fasting 1661 (13.2%) 384 (6.6%) < glucose Diabetes mellitus 503 (4.0%) 157 (2.7%) < BMI (kg/m 2 ) 27.2 (4.0) 25.5 (4.9) < Hypertension (%) < Smoker (%) Alcohol < consumption (%) egfr (CKD-EPI) 97.3 (14.0) (14.1) < (ml/min/1.73 m 2 ) HDL cholesterol 47.1 (10.1) 59.8 (13.5) < (mg/dl) LDL cholesterol (30.8) (31.2) < (mg/dl) Triglycerides (90.9) (61.0) < (mg/dl) TSH (miu/l) 1.87 (1.82) 2.09 (3.13) < BMI indicates body mass index; CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; egfr, estimated glomerular filtration rate; HDL, high-density lipoprotein; IOP, intraocular pressure; LDL, low density lipoprotein; TSH, thyroid stimulation hormone. (2.2) mm Hg in women (P < 0.001). There were no significant sex differences in age distribution (P=0.126) or smoking patterns (P = 0.291). Men had higher rates than women of IFG and DM in addition to higher BMI, higher rates of hypertension and alcohol consumption, and higher levels of low-density lipoprotein cholesterol and triglycerides (P < for all). They also had lower values for estimated glomerular filtration rate, serum thyroid stimulating hormone level, and high-density lipoprotein cholesterol level (P < ). Mean IOP by Serum Glucose Level (Normal vs. Abnormal) Mean (95% CI) IOP values were in 13.1 ( ) mm Hg in the subjects with normal glucose levels, 13.7 ( ) mm Hg in the subjects with IFG, and 14.3 ( ) mm Hg in the subjects with DM. The difference between those with normal and abnormal (DM or IFG) levels were significant (P < ). Corresponding values for men only were 13.2 ( ), 13.8 ( ), and 14.3 ( ) mm Hg (P < 0.001), and for women, 12.8 ( ), 13.6 ( ), and 14.1 ( ) mm Hg (P < ). Figure 1 shows the above data as means ± SD of the mean. All differences remained significant after adjusting for age, BMI, and hypertension (P < ). Relationship Between Increasing Serum Glucose Levels and IOP As shown in Figure 2, there was a positive linear correlation between serum glucose and IOP over the whole spectrum of serum glucose levels in both men (r = 0.12; P < ) and women (r = 0.17; P < ). On univariate 653

3 Cohen et al J Glaucoma Volume 26, Number 7, July 2017 Sex Effect A positive significant interaction was found looking at the impact of serum glucose on IOP comparing men to women (P = ). FIGURE 1. Mean (SD) intraocular pressure by fasting serum glucose level: normal, impaired fasting glucose, and diabetes mellitus. The black bar represents all subjects; the half shaded bar represents the male population; and the white bar represents the female population (*P < ). Comparing mean intraocular pressure of subjects with impaired fasting glucose or diabetes mellitus to mean intraocular pressure of subjects with normal fasting serum glucose. linear regression analysis, the coefficient (95% CI) for fasting glucose affecting the level of IOP was ( ) for men (P < ) and ( ) for women (P < ). Following multivariate adjustment for age, BMI, presence of hypertension and measured systolic blood pressure, the coefficient (95% CI) for fasting glucose was ( ) for men (P < ) and ( ) for women (P < ). Thus, for subjects of the same age with the same BMI and blood pressure, for every 10 mg/dl increase in fasting serum glucose, IOP increased by 0.09 mm Hg in men and by 0.11 mm Hg in women (Table 2). DISCUSSION In addition to supporting the known association between DM and IOP, our findings add new information on the association between IFG and IOP, showing that subjects with IFG also have significantly higher IOP values than subjects with normal serum glucose levels. These results remained significant after adjustment for other factors that can affect IOP, namely, age, BMI, and hypertension, indicating an independent association between glucose serum levels and IOP even at the IFG level. This study also provides important information on the nature of the effect of serum glucose level on IOP. A positive correlation over the spectrum of glucose levels and IOP was found, showing that the higher the serum glucose level, the higher the IOP. After multivariate adjustment for age, BMI, presence of hypertension, and actual systolic blood pressure, the direct change in IOP associated with a 10 mg/dl increase in fasting serum glucose was 0.09 mm Hg in men and 0.11 mm Hg in women. This finding suggests that subjects with uncontrolled glucose levels could be at higher risk of increased IOP, supporting the importance of DM control. Although the incremental in IOP level was small, the trend toward a higher value with a higher serum glucose level was consistent and significant. Comparison of the subjects with serum glucose level >200 mg/dl with subjects with normal serum glucose levels revealed a difference in IOP of up to 2 mm Hg. To put this into perspective, Medeiros et al 17 assessed the risk of conversion from increased ocular pressure to glaucoma and found that the hazard ratio for progression to glaucoma fore very 1mm Hg increase in ocular pressure was1.16 (95% CI, ; FIGURE 2. Correlation between fasting serum glucose and IOP in men and women. Dashed lines represent 95% confidence intervals. IOP indicates intraocular pressure

4 J Glaucoma Volume 26, Number 7, July 2017 Relationship of Serum Glucose and IOP TABLE 2. Multivariate Analysis of Intraocular Pressure in Men and Women, Adjusted for Risk Factors Men Women Variable Coefficient 95% CI P Coefficient 95% CI P Age (y) , < , < BMI (kg/m 2 ) , < , < Hypertension (y/n) , , Systolic blood pressure , < , < Fasting glucose (mg/dl)* , < , < *The coefficient is for 10 mg/dl increase in fasting glucose. BMI indicates body mass index; CI, confidence interval. P = 0.010) on univariate analysis and 1.2 (95% CI, ; P = 0.005) on multivariate analysis. The clinical significance may be particularly pronounced in patients who have already experienced glaucomatous optic nerve damage. Tight glucose control may reduce IOP and therefore have a beneficial effect on glaucoma progression. Figure 3 summarizes data from previous studies and ours on the change in IOP in diabetic compared with nondiabetic patients. 14,18 22 Delta IOP ranged between 0.29 and 1.70 mm Hg. It seems that in most studies, in line with the present finding, diabetic women had a higher delta IOP than diabetic men. It is also noteworthy that on analysis by time, delta IOP was higher in the most recent decade than in the previous decade. This might be explained by the contribution of the growing obesity/metabolic syndrome epidemic to an increase in IOP levels. Figure 4 summarizes the data from previous studies and ours on the direct relationship between fasting serum glucose and IOP. 14,23 25 On average, for every 10 mg/dl increase in fasting serum glucose, IOP increased by 0.06 mm Hg in men and 0.12 mm Hg in women. It is of note that this small delta IOP, despite showing significance, may not pose a clinical significance, however, it reflects the association between these parameters. Studies in the general population have shown that women tend to have a higher rate of ocular hypertension (IOP >21 mm Hg) than men. 15 Similar to previous studies, 14,23,24 we found that women had a higher increase in IOP in relationship to serum glucose compared with men. One possible explanation may be that women with diabetes have a higher prevalence of obesity than men. This was the case in our study. However, other metabolic differences may also account for sex differences. This study is notable for the large number of subjects assessed (18,406 men and women). Furthermore, our search of the literature for data on the relationship between fasting serum glucose and IOP yielded only studies from the Far East, whereas ours was conducted in a western population, which may have distinct demographic characteristics. 11,14,23,25,26 Lastly, while previous studies limited their assessment to DM subjects, we examined this relationship across the spectrum of serum glucose levels, from the normal to the abnormally high range. Our study is limited by the use of data drawn from a selected population attending a medical screening center. The center is funded by employers, so the findings may not be generalizable to unemployed populations. Furthermore, our study is cross-sectional and hence causality cannot be determined. It should also be borne in mind that glaucoma can occur in subjects with normal IOP, 27 and it may not develop in some subjects with increased IOP. 28 Hence, we cannot assume a causative association between serum glucose level and glaucoma, and further studies are needed to test to this possibility. FIGURE 3. Summary of studies evaluating the average difference in intraocular pressure (mm Hg) between subjects with and without diabetes mellitus. The size of the box for each study is proportional to the number of subjects included in that study. Horizontal lines represent 95% confidence intervals. *Cohen 2016 is the present study. a indicates men; b, women; IOP, intraocular pressure. Figure 3 can be viewed in color online at

5 Cohen et al J Glaucoma Volume 26, Number 7, July 2017 FIGURE 4. Summary of studies evaluating the change in intraocular pressure (mm Hg) with a 10 mg/dl increase in fasting serum glucose. The size of the box for each study is proportional to the number of subjects included in that study. Horizontal lines represent 95% confidence intervals. *Cohen 2016 is the present study. a indicates men; b, women; IOP, intraocular pressure. Figure 4 can be viewed in color online at In summary, this study shows that similar to subjects with DM, subjects with IFG also have IOP levels that are higher than those with normal serum glucose. Moreover, we show a direct correlation between an increase in fasting serum glucose and an increase in IOP over the entire spectrum of fasting glucose values. These findings point to another end-organ effect of uncontrolled glucose levels. REFERENCES 1. Kingman S. Glaucoma is second leading cause of blindness globally. 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