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Dry eyes in patients with diabetes mellitus
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Brief report
Dry eyes in patients with diabetes mellitus Gabriela Roncholeta De Freitas, Giovana Aparecida Moura Ferraz, Marcelo Gehlen, Thelma L. Skare ∗ Faculdade Evangélica Mackenzie de Curitiba, PR, Brazil
a r t i c l e
i n f o
Article history: Received 3 September 2019 Received in revised form 28 December 2019 Accepted 31 January 2020 Available online xxx Keywords: Diabetes Mellitus Dry eye Metformin Quality of life
a b s t r a c t Dry eyes may be caused by impairment in the tear production or excessive tear evaporation and are associated with photophobia, red eyes, vision impairment, local pain and pruritus. It has been described that patients with Diabetes Mellitus (DM) may have a higher prevalence of dry eyes than normal population. This is a case control study of 120 patients with Diabetes Mellitus (DM) and 120 paired controls aiming to compare their prevalence of dry eyes (by the Schirmer test) and its severity (measured by OSDI or Ocular Surface Disease Index) as well as their association with diseases’ clinical variables. We found that 38.3% of DM patients had dry eyes, a prevalence that was higher than controls (p = 0.02). At univariate analysis, they were found to be more common in older individuals (p = 0.001) with type 2 diabetes (p = 0.001) and in those using metformin (p = 0.001). A multivariate linear regression showed that metformin use was the only independent variable associated with dry eyes. When patients with dry eyes with and without DM were compared, no differences in the symptom’s intensity were found. © 2020 Primary Care Diabetes Europe. Published by Elsevier Ltd. All rights reserved.
1. Introduction The eyes are affected in Diabetes Mellitus (DM) and diabetic retinopathy is one of the most feared complications of this disease [1]. Dry eyes may also occur in these patients and it contributes to loss of quality of life [2]; they cause blurred vision, photophobia and pruritus favoring the appearance of corneal ulcers [2]. Human tears are sophisticated structures that support corneal nutrition and protection. They are formed by mucin elaborated by the goblet cells and by an aqueous component, produced by the lacrimal glands [3]. The mucin layer helps to reduce friction and protects the cornea during blinking; the aqueous component contains enzymes, vitamins, electrolytes, antibodies, etc. and are important for lubrication and local defense. Externally to them there is a hydrophobic lipid layer that avoids tear evaporation and that is produced by the eyelid sebaceous glands [3]. An eye may become dry either for inadequate tear production or by excessive tear evaporation [3]. The former is usually secondary to lacrimal gland dysfunction while the second is seen more commonly with Meibomian gland malfunctioning or with blepharitis [3]. Reducing the tear production results in tear-film hyperosmolarity and local inflammation [3,4].
∗ Corresponding author at: Travessa Luís Leitner, 50, 80730 000, Curitiba, PR, Brazil. E-mail address: [email protected] (T.L. Skare).
Dry eyes, also known as keratoconjunctivitis sicca, are commonly seen in normal population affecting from 5% to 34% of the population around the world [4] and may be triggered by environmental factors associated with low-humidity ambient, use of contact lenses, excessive use of computers, etc. [3]. Some authors state that they are more common in DM than controls although the reasons for this finding are not completely clear [2,5,6]. The prevalence of dry eye syndrome in DM varies from 15 to 53% [2,5]. Such variability may be caused by intervening factors as this syndrome suffers influence of patient’s age (being more common in those with older age); used medications (such as isotretinoin, tricyclic antidepressants, selective serotonin reuptake inhibitors, antihistamines), previous eye surgery (that damages tearing somatosensory reflex) [7] and, according to certain authors, diabetes control [5,6]. Kaiserman et al. [6] observed that poor glycemic control correlates with increased artificial tear use in diabetic patients. Animal studies showed that diabetic mice have significant decrease in aqueous tear production when compared to the non-diabetic ones [8]. Also, the methods for searching this entity have great variability and this may help to explain the variability found [3]. Herein, we studied a sample of Brazilian patients with DM for dry eye syndrome comparing its prevalence and severity with normal population. We also aimed to see if diabetes variables do influence on its appearance.
https://doi.org/10.1016/j.pcd.2020.01.011 1751-9918/© 2020 Primary Care Diabetes Europe. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: G.R. De Freitas, et al., Dry eyes in patients with diabetes mellitus, Prim. Care Diab. (2020), https://doi.org/10.1016/j.pcd.2020.01.011
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Table 1 Comparison of epidemiological data and dry eye features in DM (Diabetes Mellitus) patients and controls.
Median age-years (IQR) Gender — male/female Post menopausal women Median Schirmer (mm) (IQR) Individuals with dry eye (n) OSDI
Diabetes N = 120
Controls N = 120
P
59 (47.2–67.0) 51/69 (42.5%/57.5%) 53/69 (76.8%) 10.5 (7.0–15.0) 46/120 (38.3%) Normal = 28/46 (60.8%) Light = 10/46 (21.7%) Moderate = 4/46 (8.6%) Severe = 4/46 (8.6%)
57 (46.2–67.0) 54/66 (45.0%/55.0%) 44/66 (66.6%) 12 (9.25–15.0) 30/120 (25.0%) Normal = 15/30 (50.0%) Light = 4/30 (13.3%) Moderate = 5/30 (16.6%) Severe = 6/30 (20.0%)
0.832 (*) 0.696 (**) 0.190 (**) 0.124 (*) 0.026 (**) 0.282 (**)
(*) Mann Whitney test; (**) chi squared test; N = number; IQR = interquartile range; OSDI = Ocular Surface Disease Index. Table 2 Comparison of clinical and epidemiological data of diabetic population with and without dry eye.
Males (n) Median age-years- (IQR) Women at menopausa (n) Current smockers (n) Metformin users (n) Insuline users (n) Type 1 DM/type2 DM (n) Median disease duration-years- (IQR)
With dry eye N = 46
Without dry eye N = 74
P
18/46 (39.1%) 63.0 (57.0–71.0) 25/28 (89.2%) 4/46 (8.6%) 38/46 (82.6%) 25/46 (54.3%) 4/46 (8.6%) 12.5 (4.7–20.0)
33/74 (44.5%) 54.5 (37.7–66.2) 28/41 (68.2%) 4/74 (5.4%) 40/74 (54.0%) 53/74 (71.6%) 25/74 (33.7%) 10.0 (6.0–15.5)
0.876 (**) 0.001 (***) 0.673 (*) 0.480 (*) 0.001 (**) § 0.053 (*) 0.001 (*) §§ 0.464(***)
(*) Fisher test; (**) chi squared test; (***) Mann Whitney test; n = number; DM = diabetes mellitus; IQR = interquartile range. § - OR = 4.0 (95%CI = 1.6–9.8); §§ - OR = 5.3 (95% CI = 1.7–16.6).
2. Methods This study was approved by the Committee of Ethics in Research from Sociedade Evangélica Beneficente de Curitiba, PR, Brazil, under protocol number 2.642.669 and all participants signed consent. This is a case-control study with a relation of 1:1 patient/control that included two hundred and forty individuals (120 with DM; 120 controls). DM patients were recruited from a single Endocrinology outpatient clinic of a university hospital and controls from Dermatology Clinic seeking consultation for cosmetic reasons. Patients with chronic inflammatory diseases, ophthalmologic inflammatory complications, contact lenses users, with prior eye surgery and taking medications associated with dryness, were excluded. Controls followed the same exclusion criteria as patients and had no personal or familial history of DM. This is a convenience sample that included all patients that agreed to participate in the study for the period of one year (April 2018 to March 2019). Patients and controls had Schirmer I test, without anesthetics done according to standard recommendations [9]. Dry eye was present when Schirmer values were equal or under 10 mm in at least one eye [9]. For statistical purpose the Schirmer value considered was the worst result from both eyes. Those with dry eyes were submitted to OSDI (Ocular Surface Disease Index) that evaluates the symptoms of ocular irritation consistent with dry eye and their impact on vision-related functioning [10]. OSDI is a 12-item questionnaire that scores the dryness symptoms on a scale from 0 to 100, with higher scores representing greater disability. According to this toll values of 0–12 are considered normal, from 13 to 22 with light, from 23 to 32 with moderate and values >32 with severe symptoms [10]. Treatment data, diabetes type, disease duration, fasting glycemia and HbA1c were collected simultaneously with the Schirmer test realization. Fasting glycemia was measured by dry chemistry and HbA1c by liquid chromatography and these laboratory tests have been done, at most, fifteen days prior to data collection. The distribution of collected data was judged by Shapiro Wilk test. We used chi-squared and Fisher tests to compare gender, number of smokers and post-menopausal women, DM subsets, treatment data and OSDI classification between patients and con-
trols and/or DM patients with and without dry eye. To compare age, disease duration and Schirmer values, the Mann Whitney test was used. Correlation studies of Schirmer values with glycemic control were done with Spearman test. Data that associated with dry eye with p < 0.1 were studied with multiple linear regression using the measurement of Schirmer test as a dependent variable, to test their independency. The statistical studies were done with help of the software Medcalc® and the adopted significance was 5%. 3. Results Table 1 shows the epidemiologic characteristics of studied sample and pairing data of patients and controls. It also shows the comparison of Schirmer test and OSDI between these two populations. The sample with diabetes had 78/120 (65.0%) of insulin users, 81/120 (67.5%) using oral hypoglycaemic drugs (78/120 or 65% metformin users); 29/120 (24.1%) with type 1 DM and 91/120 (75.8%) with type 2 DM. The median disease duration was of 10 years (IQR = 5.0–18.0), the median fasting glucose of 137.9 md/dL (IQR = 11.2–203.8 mg/dL) and the median HbA1c of 8.1% (IQR = 6.8–9.6%). Table 2 shows the comparison of diabetes sample with and without dry eye. Correlation studies of Schirmer values with fasting glucose and HbA1c were non-significant (p > 0.05). Data that associated with dry eye with p < 0.1 (DM type, age, insulin and metformin use) were studied by multiple regression to test independence of the variables. Only metformin use remained significant with p = 0.04. 4. Discussion Our findings showed that patients with DM have drier eyes than controls with a prevalence of 38.3%. This result is on agreement with those from Ozdemir et al. [5] that studied 40 DM patients comparing than with controls. Hom and De Land [11] found higher prevalence than us, in 53% of their sample. However, these authors diagnosed this entity using a self-reported instrument. On the other hand, the prevalence found in a Chinese study [12] was lower than ours, with only 17.5% of dry eyes. In this latter study the sample
Please cite this article in press as: G.R. De Freitas, et al., Dry eyes in patients with diabetes mellitus, Prim. Care Diab. (2020), https://doi.org/10.1016/j.pcd.2020.01.011
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ARTICLE IN PRESS G.R. De Freitas et al. / Primary Care Diabetes xxx (2020) xxx–xxx
had only type 2 DM from a community-based population, that may have had a milder disease. Some explanations for the presence of dry eye in DM were offered. One of them states that insulin is essential for the acinar lacrimal gland and cornea epithelial cells proliferation [13]. Another is that the tearing reflex is impaired due to corneal insensitivity caused by diabetic corneal neuropathy [14]. It has been also verified that the content of glucose and advanced glycation endproduct (AGEs) may be increased in tears favoring hyperosmolarity and inflammation [15,16]. In this context some authors have found an association of glycemic control with dry eye findings [5,9]. This idea could not be supported by our findings as neither fasting glucose or HbA1c levels correlated with Schirmer values. Uchino et al. [17], Galor et al. [18] and Schaumberg et al. [19] could not prove association of dry eye with hyperglycemia. Also, a study in 152 patients from UK [20] did not find correlation of dry eye with glucose levels and HbA1c, but a positive association of glycemic control with dryness symptoms and loss of quality of life was found. We also found that dry eye was more common in older individuals, with type 2 diabetes using metformin. Interestingly, the only documented independent factor was the metformin use, although we do not find a good explanation for this link. Chew et al. [21] found that metformin had some anticholinergic action mainly when used in high doses or in frail patients and this could be offered as a possible explanation. Prospective studies evaluating lacrimal production before and after using this drug could be enlightening. Finally, some authors have found association of diabetic retinopathy with dry eye [2]. We did not study retinopathy and this is a limitation of this study. Other limitations are its cross-sectional design, the limited number of the sample and not having glycemic levels in controls. Also, the use of more sophisticated tools for the evaluation of dry eyes, such as measurement of tear osmolarity, would be interesting. Nevertheless, it does highlight the high prevalence of dry eye in patients with DM and the possible participation of metformin on its occurrence. In daily practice, diabetic patients undergo regular fundus examinations but no attention is payed to tear dysfunction. Physicians should be aware of this complication that is easily diagnosed and treated. Dry eyes may result in ocular discomfort, corneal ulcers and even blindness, leading to important loss of life quality [3]. Concluding, our results shows that DM patients have greater risk to develop dry eye than controls. Metformin use was the independent factor associated with its occurrence. Funding None. Ethical approval Approval of Committee of Ethics in Research — 2.642.669, Sociedade Evangélica Beneficente de Curitiba, PR, Brazil.
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References [1] G. Liew, V.W. Wong, I.V. Ho, Mini review: changes in the incidence of and progression to proliferative and sight-threatening diabetic retinopathy over the last 30 years, Ophthalmic Epidemiol. 24 (2017) 73–80, http://dx.doi.org/10. 1080/09286586.2016.1259638. [2] X. Zhang, L. Zhao, S. Deng, et al., Dry eye syndrome in patients with diabetes mellitus: prevalence, etiology, and clinical characteristics, J. Ophthalmol. 2016 (2016), 8201053, http://dx.doi.org/10.1155/2016/8201053. [3] J.A. Clayton, Dry eye, N. Engl. J. Med. 378 (2018) 2212–2223, http://dx.doi.org/ 10.1056/NEJMc1808906. [4] E.M. Messmer, The pathophysiology, diagnosis, and treatment of dry eye disease, Dtsch. Arztebl. Int. 112 (2015) 71–81, http://dx.doi.org/10.3238/arztebl. 2015.0071. [5] M. Ozdemir, M.A. Buyukbese, A. Cetinkaya, G. Ozdemir, Risk factors for ocular surface disorders in patients with diabetes mellitus, Diabetes Res. Clin. Pract. 59 (2003) 195–199, http://dx.doi.org/10.1016/s0168-8227(02)00244-9. [6] I. Kaiserman, N. Kaiserman, S. Nakar, S. Vinker, Dry eye in diabetic patients, Am. J. Ophthalmol. 139 (2005) 498–503, http://dx.doi.org/10.1016/j.ajo.2004. 10.022. [7] J. Vehof, D. Kozareva, P.G. Hysi, C.J. Hammond, Prevalence and risk factors of dry eye disease in a British female cohort, Br. J. Ophthalmol. 98 (2014) 1712–1717, http://dx.doi.org/10.1136/bjophthalmol-2014-305201. [8] H. Liu, M. Sheng, Y. Liu, et al., Expression of SIRT1 and oxidative stress in diabetic dry eye, Int. J. Clin. Exp. Pathol. 8 (2015) 7644–7653, eCollection 2015. [9] N. Li, X.G. Deng, M.F. He, Comparison of the Schirmer I test with and without topical anesthesia for diagnosing dry eye, Int. J. Ophthalmol. 5 (2012) 478–481, http://dx.doi.org/10.3980/j.issn.2222-3959.2012.04.14. [10] A.M. Prigol, M.B. Tenório, R. Matschinske, et al., Translation and validation of ocular surface disease index to Portuguese, Arq. Bras. Oftalmol. 75 (2012) 24–28, http://dx.doi.org/10.1590/s0004-27492012000100005. [11] M. Hom, P. De Land, Self-reported dry eyes and diabetic history, Optometry 77 (2006) 554–558, http://dx.doi.org/10.1016/j.optm.2006.08.002. [12] X. Zou, L. Lu, Y. Xu, et al., Prevalence and clinical characteristics of dry eye disease in community-based type 2 diabetic patients: the Beixinjing eye study, BMC Ophthalmol. 18 (2018) 117, http://dx.doi.org/10.1186/s12886-018-07817. [13] A.C. Dias, T.M. Batista, L.P. Roma, et al., Insulin replacement restores the vesicular secretory apparatus in the diabetic rat lacrimal gland, Arq. Bras. Oftalmol. 78 (2015) 158–163, http://dx.doi.org/10.5935/0004-2749.20150041. [14] N. Fuerst, N. Langelier, M. Massaro-Giordano, et al., Tear osmolarity and dry eye symptoms in diabetics, Clin. Ophthalmol. 8 (2014) 507–515, http://dx.doi.org/ 10.2147/OPTH.S51514, eCollection 2014. [15] L. Luo, D.Q. Li, R.M. Corrales, S.C. Pflugfelder, Hyperosmolar saline is a proinflammatory stress on the mouse ocular surface, Eye Contact Lens 31 (2005) 186–193, http://dx.doi.org/10.1097/01.icl.0000162759.79740.46. [16] D.Q. Li, L. Luo, Z. Chen, et al., JNK and ERK MAP kinases mediate induction of IL-1beta, TNF-alpha and IL-8 following hyperosmolar stress in human limbal epithelial cells, Exp. Eye Res. 82 (2006) 588–596, http://dx.doi.org/10.1016/j. exer.2005.08.019. [17] M. Uchino, Y. Nishiwaki, T. Michikawa, et al., Prevalence and risk factors of dry eye disease in Japan: Koumi study, Ophthalmology 118 (2011) 2361–2367, http://dx.doi.org/10.1016/j.ophtha.2011.05.029. [18] A. Galor, W. Feuer, D.J. Lee, et al., Depression, post-traumatic stress disorder, and dry eye syndrome: a study utilizing the national United States Veterans Affairs administrative database, Am J Opthalmology 154 (2012) 340–346, http://dx. doi.org/10.1016/j.ajo.2012.02.009. [19] D.A. Schaumberg, R. Dana, J.E. Buring, D.A. Sullivan, Prevalence of dry eye disease among US men: estimates from the Physicians’ Health Studies, Arch. Ophtalmol. 127 (2009) 763–768, http://dx.doi.org/10.1001/archophthalmol. 2009.103. [20] M.K. Yazdani-Ibn-Taz, M.M. Han, S. Jonuscheit, et al., Patient-reported severity of dry eye and quality of life in diabetes, Clin. Ophthalmol. 13 (2019) 217–224, http://dx.doi.org/10.2147/OPTH.S184173, eCollection 2019. [21] M.L. Chew, B.H. Mulsant, B.G. Pollock, M.E. Lehman, et al., Anticholinergic activity of 107 medications commonly used by older adults, J. Am. Geriatr. Soc. 56 (2008) 1333–1341, http://dx.doi.org/10.1111/j.1532-5415.2008.01737.x.
Conflict of interest The authors declare no conflict of interests.
Please cite this article in press as: G.R. De Freitas, et al., Dry eyes in patients with diabetes mellitus, Prim. Care Diab. (2020), https://doi.org/10.1016/j.pcd.2020.01.011
ARTICLE IN PRESS
PCD-871; No. of Pages 3
Primary Care Diabetes xxx (2020) xxx–xxx
Contents lists available at ScienceDirect
Primary Care Diabetes journal homepage: http://www.elsevier.com/locate/pcd
Brief report
Dry eyes in patients with diabetes mellitus Gabriela Roncholeta De Freitas, Giovana Aparecida Moura Ferraz, Marcelo Gehlen, Thelma L. Skare ∗ Faculdade Evangélica Mackenzie de Curitiba, PR, Brazil
a r t i c l e
i n f o
Article history: Received 3 September 2019 Received in revised form 28 December 2019 Accepted 31 January 2020 Available online xxx Keywords: Diabetes Mellitus Dry eye Metformin Quality of life
a b s t r a c t Dry eyes may be caused by impairment in the tear production or excessive tear evaporation and are associated with photophobia, red eyes, vision impairment, local pain and pruritus. It has been described that patients with Diabetes Mellitus (DM) may have a higher prevalence of dry eyes than normal population. This is a case control study of 120 patients with Diabetes Mellitus (DM) and 120 paired controls aiming to compare their prevalence of dry eyes (by the Schirmer test) and its severity (measured by OSDI or Ocular Surface Disease Index) as well as their association with diseases’ clinical variables. We found that 38.3% of DM patients had dry eyes, a prevalence that was higher than controls (p = 0.02). At univariate analysis, they were found to be more common in older individuals (p = 0.001) with type 2 diabetes (p = 0.001) and in those using metformin (p = 0.001). A multivariate linear regression showed that metformin use was the only independent variable associated with dry eyes. When patients with dry eyes with and without DM were compared, no differences in the symptom’s intensity were found. © 2020 Primary Care Diabetes Europe. Published by Elsevier Ltd. All rights reserved.
1. Introduction The eyes are affected in Diabetes Mellitus (DM) and diabetic retinopathy is one of the most feared complications of this disease [1]. Dry eyes may also occur in these patients and it contributes to loss of quality of life [2]; they cause blurred vision, photophobia and pruritus favoring the appearance of corneal ulcers [2]. Human tears are sophisticated structures that support corneal nutrition and protection. They are formed by mucin elaborated by the goblet cells and by an aqueous component, produced by the lacrimal glands [3]. The mucin layer helps to reduce friction and protects the cornea during blinking; the aqueous component contains enzymes, vitamins, electrolytes, antibodies, etc. and are important for lubrication and local defense. Externally to them there is a hydrophobic lipid layer that avoids tear evaporation and that is produced by the eyelid sebaceous glands [3]. An eye may become dry either for inadequate tear production or by excessive tear evaporation [3]. The former is usually secondary to lacrimal gland dysfunction while the second is seen more commonly with Meibomian gland malfunctioning or with blepharitis [3]. Reducing the tear production results in tear-film hyperosmolarity and local inflammation [3,4].
∗ Corresponding author at: Travessa Luís Leitner, 50, 80730 000, Curitiba, PR, Brazil. E-mail address: [email protected] (T.L. Skare).
Dry eyes, also known as keratoconjunctivitis sicca, are commonly seen in normal population affecting from 5% to 34% of the population around the world [4] and may be triggered by environmental factors associated with low-humidity ambient, use of contact lenses, excessive use of computers, etc. [3]. Some authors state that they are more common in DM than controls although the reasons for this finding are not completely clear [2,5,6]. The prevalence of dry eye syndrome in DM varies from 15 to 53% [2,5]. Such variability may be caused by intervening factors as this syndrome suffers influence of patient’s age (being more common in those with older age); used medications (such as isotretinoin, tricyclic antidepressants, selective serotonin reuptake inhibitors, antihistamines), previous eye surgery (that damages tearing somatosensory reflex) [7] and, according to certain authors, diabetes control [5,6]. Kaiserman et al. [6] observed that poor glycemic control correlates with increased artificial tear use in diabetic patients. Animal studies showed that diabetic mice have significant decrease in aqueous tear production when compared to the non-diabetic ones [8]. Also, the methods for searching this entity have great variability and this may help to explain the variability found [3]. Herein, we studied a sample of Brazilian patients with DM for dry eye syndrome comparing its prevalence and severity with normal population. We also aimed to see if diabetes variables do influence on its appearance.
https://doi.org/10.1016/j.pcd.2020.01.011 1751-9918/© 2020 Primary Care Diabetes Europe. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: G.R. De Freitas, et al., Dry eyes in patients with diabetes mellitus, Prim. Care Diab. (2020), https://doi.org/10.1016/j.pcd.2020.01.011
G Model PCD-871; No. of Pages 3
ARTICLE IN PRESS G.R. De Freitas et al. / Primary Care Diabetes xxx (2020) xxx–xxx
2
Table 1 Comparison of epidemiological data and dry eye features in DM (Diabetes Mellitus) patients and controls.
Median age-years (IQR) Gender — male/female Post menopausal women Median Schirmer (mm) (IQR) Individuals with dry eye (n) OSDI
Diabetes N = 120
Controls N = 120
P
59 (47.2–67.0) 51/69 (42.5%/57.5%) 53/69 (76.8%) 10.5 (7.0–15.0) 46/120 (38.3%) Normal = 28/46 (60.8%) Light = 10/46 (21.7%) Moderate = 4/46 (8.6%) Severe = 4/46 (8.6%)
57 (46.2–67.0) 54/66 (45.0%/55.0%) 44/66 (66.6%) 12 (9.25–15.0) 30/120 (25.0%) Normal = 15/30 (50.0%) Light = 4/30 (13.3%) Moderate = 5/30 (16.6%) Severe = 6/30 (20.0%)
0.832 (*) 0.696 (**) 0.190 (**) 0.124 (*) 0.026 (**) 0.282 (**)
(*) Mann Whitney test; (**) chi squared test; N = number; IQR = interquartile range; OSDI = Ocular Surface Disease Index. Table 2 Comparison of clinical and epidemiological data of diabetic population with and without dry eye.
Males (n) Median age-years- (IQR) Women at menopausa (n) Current smockers (n) Metformin users (n) Insuline users (n) Type 1 DM/type2 DM (n) Median disease duration-years- (IQR)
With dry eye N = 46
Without dry eye N = 74
P
18/46 (39.1%) 63.0 (57.0–71.0) 25/28 (89.2%) 4/46 (8.6%) 38/46 (82.6%) 25/46 (54.3%) 4/46 (8.6%) 12.5 (4.7–20.0)
33/74 (44.5%) 54.5 (37.7–66.2) 28/41 (68.2%) 4/74 (5.4%) 40/74 (54.0%) 53/74 (71.6%) 25/74 (33.7%) 10.0 (6.0–15.5)
0.876 (**) 0.001 (***) 0.673 (*) 0.480 (*) 0.001 (**) § 0.053 (*) 0.001 (*) §§ 0.464(***)
(*) Fisher test; (**) chi squared test; (***) Mann Whitney test; n = number; DM = diabetes mellitus; IQR = interquartile range. § - OR = 4.0 (95%CI = 1.6–9.8); §§ - OR = 5.3 (95% CI = 1.7–16.6).
2. Methods This study was approved by the Committee of Ethics in Research from Sociedade Evangélica Beneficente de Curitiba, PR, Brazil, under protocol number 2.642.669 and all participants signed consent. This is a case-control study with a relation of 1:1 patient/control that included two hundred and forty individuals (120 with DM; 120 controls). DM patients were recruited from a single Endocrinology outpatient clinic of a university hospital and controls from Dermatology Clinic seeking consultation for cosmetic reasons. Patients with chronic inflammatory diseases, ophthalmologic inflammatory complications, contact lenses users, with prior eye surgery and taking medications associated with dryness, were excluded. Controls followed the same exclusion criteria as patients and had no personal or familial history of DM. This is a convenience sample that included all patients that agreed to participate in the study for the period of one year (April 2018 to March 2019). Patients and controls had Schirmer I test, without anesthetics done according to standard recommendations [9]. Dry eye was present when Schirmer values were equal or under 10 mm in at least one eye [9]. For statistical purpose the Schirmer value considered was the worst result from both eyes. Those with dry eyes were submitted to OSDI (Ocular Surface Disease Index) that evaluates the symptoms of ocular irritation consistent with dry eye and their impact on vision-related functioning [10]. OSDI is a 12-item questionnaire that scores the dryness symptoms on a scale from 0 to 100, with higher scores representing greater disability. According to this toll values of 0–12 are considered normal, from 13 to 22 with light, from 23 to 32 with moderate and values >32 with severe symptoms [10]. Treatment data, diabetes type, disease duration, fasting glycemia and HbA1c were collected simultaneously with the Schirmer test realization. Fasting glycemia was measured by dry chemistry and HbA1c by liquid chromatography and these laboratory tests have been done, at most, fifteen days prior to data collection. The distribution of collected data was judged by Shapiro Wilk test. We used chi-squared and Fisher tests to compare gender, number of smokers and post-menopausal women, DM subsets, treatment data and OSDI classification between patients and con-
trols and/or DM patients with and without dry eye. To compare age, disease duration and Schirmer values, the Mann Whitney test was used. Correlation studies of Schirmer values with glycemic control were done with Spearman test. Data that associated with dry eye with p < 0.1 were studied with multiple linear regression using the measurement of Schirmer test as a dependent variable, to test their independency. The statistical studies were done with help of the software Medcalc® and the adopted significance was 5%. 3. Results Table 1 shows the epidemiologic characteristics of studied sample and pairing data of patients and controls. It also shows the comparison of Schirmer test and OSDI between these two populations. The sample with diabetes had 78/120 (65.0%) of insulin users, 81/120 (67.5%) using oral hypoglycaemic drugs (78/120 or 65% metformin users); 29/120 (24.1%) with type 1 DM and 91/120 (75.8%) with type 2 DM. The median disease duration was of 10 years (IQR = 5.0–18.0), the median fasting glucose of 137.9 md/dL (IQR = 11.2–203.8 mg/dL) and the median HbA1c of 8.1% (IQR = 6.8–9.6%). Table 2 shows the comparison of diabetes sample with and without dry eye. Correlation studies of Schirmer values with fasting glucose and HbA1c were non-significant (p > 0.05). Data that associated with dry eye with p < 0.1 (DM type, age, insulin and metformin use) were studied by multiple regression to test independence of the variables. Only metformin use remained significant with p = 0.04. 4. Discussion Our findings showed that patients with DM have drier eyes than controls with a prevalence of 38.3%. This result is on agreement with those from Ozdemir et al. [5] that studied 40 DM patients comparing than with controls. Hom and De Land [11] found higher prevalence than us, in 53% of their sample. However, these authors diagnosed this entity using a self-reported instrument. On the other hand, the prevalence found in a Chinese study [12] was lower than ours, with only 17.5% of dry eyes. In this latter study the sample
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had only type 2 DM from a community-based population, that may have had a milder disease. Some explanations for the presence of dry eye in DM were offered. One of them states that insulin is essential for the acinar lacrimal gland and cornea epithelial cells proliferation [13]. Another is that the tearing reflex is impaired due to corneal insensitivity caused by diabetic corneal neuropathy [14]. It has been also verified that the content of glucose and advanced glycation endproduct (AGEs) may be increased in tears favoring hyperosmolarity and inflammation [15,16]. In this context some authors have found an association of glycemic control with dry eye findings [5,9]. This idea could not be supported by our findings as neither fasting glucose or HbA1c levels correlated with Schirmer values. Uchino et al. [17], Galor et al. [18] and Schaumberg et al. [19] could not prove association of dry eye with hyperglycemia. Also, a study in 152 patients from UK [20] did not find correlation of dry eye with glucose levels and HbA1c, but a positive association of glycemic control with dryness symptoms and loss of quality of life was found. We also found that dry eye was more common in older individuals, with type 2 diabetes using metformin. Interestingly, the only documented independent factor was the metformin use, although we do not find a good explanation for this link. Chew et al. [21] found that metformin had some anticholinergic action mainly when used in high doses or in frail patients and this could be offered as a possible explanation. Prospective studies evaluating lacrimal production before and after using this drug could be enlightening. Finally, some authors have found association of diabetic retinopathy with dry eye [2]. We did not study retinopathy and this is a limitation of this study. Other limitations are its cross-sectional design, the limited number of the sample and not having glycemic levels in controls. Also, the use of more sophisticated tools for the evaluation of dry eyes, such as measurement of tear osmolarity, would be interesting. Nevertheless, it does highlight the high prevalence of dry eye in patients with DM and the possible participation of metformin on its occurrence. In daily practice, diabetic patients undergo regular fundus examinations but no attention is payed to tear dysfunction. Physicians should be aware of this complication that is easily diagnosed and treated. Dry eyes may result in ocular discomfort, corneal ulcers and even blindness, leading to important loss of life quality [3]. Concluding, our results shows that DM patients have greater risk to develop dry eye than controls. Metformin use was the independent factor associated with its occurrence. Funding None. Ethical approval Approval of Committee of Ethics in Research — 2.642.669, Sociedade Evangélica Beneficente de Curitiba, PR, Brazil.
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Conflict of interest The authors declare no conflict of interests.
Please cite this article in press as: G.R. De Freitas, et al., Dry eyes in patients with diabetes mellitus, Prim. Care Diab. (2020), https://doi.org/10.1016/j.pcd.2020.01.011