The prevalence of retinopathy in subjects with and without type 2 diabetes mellitus

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1 The prevalence of retinopathy in subjects with and without type 2 diabetes mellitus Eydis Olafsdottir, 1,2,3 Dan K. G. Andersson, 4 Inger Dedorsson 3 and Einar Stefa nsson 1,2 1 Department of Ophthalmology, The National University Hospital, Reykjavik, Iceland 2 University of Iceland, Reykjavik, Iceland 3 Department of Ophthalmology, O rebro University Hospital, O rebro, Sweden 4 Department of Public Health and Caring Sciences, Family Medicine and Clinical Epidemiology Section, Uppsala University, Uppsala, Sweden ABSTRACT. Purpose: To evaluate the prevalence of and risk factors for, retinopathy in a geographically defined population with type 2 diabetes mellitus compared with a control group of subjects without diabetes, matched by age, sex and residence in order to find the retinopathy attributable to type 2 diabetes. Methods: The study populations are, on one hand, a prevalence cohort of subjects with type 2 diabetes resident in the community of Laxa, Sweden, and on the other a control group, matched by age, gender and residence with those with a diagnosis of type 2 diabetes mellitus. Retinopathy was graded from fundus photographs using a modification of the Early Treatment Retinopathy Study (ETDRS) adaptation of the modified Airlie House classification of diabetic retinopathy (DR). Results: Any retinopathy was found in 34.6% in the type 2 diabetes cohort and in 8.8% in the control group without diabetes. Among the diabetic patients, any retinopathy was significantly associated with duration of diabetes (p = ), HbA1c (p = ), systolic blood pressure (p = ) and lower serum cholesterol (p = ) in multivariate logistic regression analyses. Having retinopathy in the control group was associated only with systolic blood pressure (p = ) in logistic regression analysis. Conclusions: The prevalence of retinopathy among patients with type 2 diabetes in Laxa, Sweden, was similar or somewhat lower compared with other studies in the Nordic countries. The prevalence of retinopathy in a control group without diabetes equalled numbers from population studies worldwide. Our study indicates that the retinopathy that can be attributed to hyperglycaemia in the diabetic state is less common than is usually accounted for. A considerable fraction of retinopathy in subjects with diabetes may instead be due to other factors such as hypertension and should thus be treated correspondingly. Key words: diabetic retinopathy duration hyperglycaemia hypertension nondiabetic retinopathy Type 2 diabetes Acta Ophthalmol. 2014: 92: ª 2013 The Authors Acta Ophthalmologica ª 2013 Acta Ophthalmologica Scandinavica Foundation. Published by Blackwell Publishing Ltd. doi: /aos Introduction Retinopathy is prevalent in between 10 and 30% of diabetes subjects (Klein et al. 1984b; Eggertsen et al. 1993; Henricsson et al. 1996a; Kohner et al. 1998; van Leiden et al. 2002) already at the time of diabetes diagnosis. This may indicate a 4 7 years delay in the diagnosis of diabetes (Harris et al. 1992), based on the assumption that diabetic retinopathy can not exist before the start of the diabetes disease itself. Shortening the diagnostic delay can make activities against risk factors for different diabetes complications such, as for instance retinopathy and progression of retinopathy, possible at an earlier stage and at its best before clinically evident complications have occurred. The number of diabetes patients with visual impairment could then be reduced. Population-based studies indicate, however, that retinopathy in people without diabetes is not uncommon, is associated with hypertension and may predict cardiovascular events and in some cases subsequent risk of diabetes (Yu et al. 1998; Wong et al. 2001, 2005, 2006; Liew et al. 2009). This kind of retinopathy is usually included in and labelled as diabetic retinopathy when prevalence figures are given for patients with diabetes, due to the fact that they look alike. As the nondiabetic and the diabetic retinopathy most likely have different causes and also demand different strategies for prevention and treatment, it is of interest to determine their respective magnitude and their risk factors. In this study, we have estimated the occurrence of retinopathy in a prevalence cohort with type 2 diabetes, and in an age- and gender-matched control group without diabetes. Our first aim was to find the prevalence of retinopathy that could be attributed to 133

2 the diabetes state per se, that is, the differences in prevalence between subjects with and subjects without diabetes. A second aim was to find factors associated with retinopathy among the studied subjects. Methods The study was undertaken in Laxa, a rural municipality in the central parts of southern Sweden. The diabetes population and the control population have been described elsewhere (Olafsdottir et al. 2007, 2012). In short, the diabetes population included all subjects in Laxå with type 2 diabetes mellitus, as of 1 January The control group was found through the national population register wherefore each diabetes patient, one nondiabetic subject, living in Laxa, of the same sex and closest in age to the diabetic patient was sampled. The nondiabetic status of these subjects, at the time of the eye examination, was secured by means of measurements of fasting whole blood glucose (FBG) and HbA1c. If in doubt, oral glucose tolerance tests were performed. Repeat glucose measurements were performed during a 5-year follow-up period. Fundus photographs were taken after dilatation of the pupil with mydriacyl. Five 45 fields including a stereo pair of the macula were taken with a Topcon fundus camera, TRC- 50 VT. Two 30 photographs were also taken of the optic disc. An experienced ophthalmologist (ID) graded the fundus photographs. Diabetic retinopathy was graded using a modification of the ETDRS adaptation of the modified Airlie House classification of DR (Klein et al. 1994a, 1998). Eyes were graded according to the following criteria: 0. No DR (levels 10 13) 1. Non-proliferative DR: Mild (levels 14 20) 2. Moderate (levels 31 43) 3. Severe (levels 47 53) 4. Proliferative DR (levels 60 85) Any DR was defined as levels Diabetic macular oedema was defined as the presence of hard exudates and or retinal thickening within one disc diameter of the centre of the macula. Macular oedema was graded as present or not present. When data from both eyes were used, all the gradings of a patient were based on the worst eye. If only one eye could be evaluated, this was considered to be the worst eye. The ophthalmologist grading the photographs was not aware of the patient s identity or clinical situation. Systolic and diastolic blood pressure and heart rate were measured in a lying position after five minutes of rest. The mean of three measurements was registered. Height was measured without shoes and weight with light clothing on. Body mass index (BMI) was calculated as weight in kg divided by height in metre, squared (kg m 2 ). All participants of the study were asked to answer a questionnaire. Among the questions asked were smoking habits. Blood samples, including FBG, HbA1c, cholesterol, triglycerides, HDL-cholesterol, creatinine, uric acid and gamma glutamyl transferase, were taken and analysed at the laboratory of the nearby local county hospital of Karlskoga. Enzymatic methods were used for cholesterol, triglycerides, HDL-cholesterol and uric acid. Creatinine was analysed using the Jaffe method and gamma glutamyl transferase according to Szasz-Persijn. These analyses were made on a Hitachi 911 instrument. HbA1c was analysed with a low-pressure chromatography method on Glycomat MTC. The research ethics committee at the Örebro County Council gave the study its approval. All examinations were carried out from July 1996 to June Table 1 shows the characteristics of the type 2 diabetic and the control participants. Two hundred and seventy-six type 2 diabetic patients, all of white Caucasian origin, were enrolled in the study. They included all known type 2 diabetes patients in Laxa, representing a crude 3.9% prevalence of type 2 diabetes. One patient with type 2 diabetes declined participation in the eye examination. Four patients could not participate in taking fundus photographs because of high age combined with severe disease such as dementia, terminal malignant disease or sequel to cerebrovascular disease. In another eight subjects photographs were taken, but could not be graded because of concomitant eye disease. Hence, 263 patient fundus photographs could be evaluated, in 20 patients only of one eye. Originally 275 control subjects were sampled. Of these 36 subjects declined participation, had no photographs taken or the photographs could not be graded for the same reasons as for the diabetes subjects, leaving 251 control subjects whose fundus photographs could be evaluated (Table 1). In eight subjects, only one eye could be graded. Statistical analyses The data were analysed using the sas software release 9.2 (SAS Institute, Cary. NC, USA). Potential variables associated with any retinopathy were identified in bivariate logistic regression analyses. Then, multivariate logistic regression analyses, providing odds ratios (OR), their 95% confidence intervals (CI), p-values and Wald s chi-square estimates, were performed with any retinopathy as dependent variable and variables significant in bivariate analyses as independent variables. All tests were twotailed. p-values <0.05 were accepted as indicating statistical significance. Results Of the 263 patients with type 2 diabetes, 172 had no retinopathy and 91 (34.6%) had any retinopathy. Of the latter 62 (23.6%) had mild retinopathy, 20 (7.6%) moderate retinopathy, 5 (1.9%) severe retinopathy and four patients (1.5%) had proliferative retinopathy. Seven patients (2.7%) had macular oedema out of which two had moderate, three had severe nonproliferative retinopathy and two had proliferative retinopathy. The prevalence of diabetic retinopathy increased from 11.8% (2 17) in those with a diabetes duration less than 1 year to 68.2% (15 22) in those with a diabetes duration of 20 years or more (Fig. 1). One patient was blind with best visual acuity 0.1, due to proliferative retinopathy. Twenty-two of the 251 control subjects (8.8%) had any retinopathy. Of these, 20 had mild and two had mod- 134

3 Table 1. Characteristics of the study participants. No diabetes Diabetes No retinopathy n = 229 Any retinopathy n =22 p-value (any retinopathy no retinopathy No retinopathy n = 172 Any retinopathy n =91 p-value (any retinopathy no retinopathy Age (year) Sex (female male) Diabetes duration (year) NA NA NA NA NA < Current smoker (%) Fasting whole blood glucose (mm) HbA1c (%) Total cholesterol (mm) HDL-cholesterol (mm) Triglycerides (mm) Creatinine (lm) Uric acid (lm) Gamma glutamyl transferase (lm) Height (cm) Weight (kg) Body mass index (kg m 2 ) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Heart rate (beats per minute) Bold values are statistically significant. erate retinopathy. During a 5-year follow-up time, two subjects in the control group with retinopathy developed type 2 diabetes. They were diagnosed 35 and 43 months after the eye examinations. Both died shortly (3 and 2 months) after the diabetes diagnosis was confirmed. Table 1 also shows associations, from bivariate analyses, between the presence of any retinopathy and variables registered at the cross-sectional examinations. Among the diabetic subjects, any retinopathy was significantly positively associated with diabetes duration (p < ), FBG and HbA1c (p = , p = ), systolic and diastolic blood pressure (p = , p = ) and inversely to total cholesterol (p = 0.098). When these variables were treated in a series of multivariate logistic analyses, duration of diabetes (p = ), HbA1c (p = ), systolic blood pressure (p = ) and lower serum cholesterol (p = ) remained statistically significant for any retinopathy (Table 2). Among the control subjects, having retinopathy was significantly positively related to systolic blood pressure Percent with retinopathy (p = ), diastolic blood pressure (p = ) and to age (p = ). In a multivariate analysis (Table 2), Classes of retinopathy by duration of type 2 diabetes Proliferative DRP Severe DRP Moderate DRP Mild DRP Duration of diabetes (years) Fig. 1. Classes of retinopathy by duration of type 2 diabetes. only systolic blood pressure remained statistically significant (p = , OR 1.030, CI , v 2 = 10.26). 135

4 Table 2. Multivariate regression analyses of the effects of significant characteristics of both the control population and type 2 diabetes population on having any retinopathy. No diabetes Diabetes OR 95% CI p-value v 2 OR 95% CI p-value v 2 Age Diabetes duration (years) NA NA NA NA Fasting whole blood glucose (mm) HbA1c (%) Total cholesterol (mm) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Bold values are statistically significant. Discussion We found the prevalence of any retinopathy in our diabetic population to be 34.6%, which is similar to studies in other Nordic countries. Henricsson reported a 36% prevalence of any retinopathy in Helsingborg, Sweden (Henricsson et al. 1996a,b), and Kalm documented 40% in Gothenburg, Sweden (Kalm et al. 1989). In Iceland, the prevalence of any retinopathy was 40% (Kristinsson et al. 1994) and in A rhus, Denmark 32% (Hove et al. 2004). The prevalence found in Wisconsin, USA was somewhat higher than in the Nordic studies, 54% (Klein et al. 1984a). In a study in Kisa, Sweden, the prevalence of any retinopathy was 27% in all type 2 diabetic patients aged 70 years and under (Falkenberg & Finnstrom 1994). A reason for this slightly lower prevalence may be a lower patient age and shorter diabetes duration. The mean age of the Kisa patients and duration of diabetes were 60 ± 9 and 7.5 ± 5.5 years versus 69±12and9±7yearsinourstudy. In contrast to the findings of Hansson-Lundblad et al. (2002), we found no association between patient age and severity level of retinopathy or macular oedema. However, as only eleven patients in our study had severe or proliferative retinopathy or macular oedema, our results should be interpreted cautiously. In accordance with previous studies, duration of diabetes was significantly associated with any retinopathy and increasing grade of retinopathy (Fig. 1). In our study, the frequency of any diabetic retinopathy increased to 68% when the duration of diabetes was more than 20 years. This is similar to what is seen in the other Nordic studies. Glycemic control and blood pressure were also significantly associated with retinopathy, likewise in accordance with previous studies (UK Prospective Diabetes Study (UKPDS) Group. (1998a); UK Prospective Diabetes Study Group., 1998b). Intensifying glucose-lowering therapies as well as blood pressure control can be of value in reducing the risk for retinopathy and other microvascular complications (UK Prospective Diabetes Study (UKPDS) Group. (1998a); UK Prospective Diabetes Study Group., 1998b). We found an inverse association between serum cholesterol and diabetic retinopathy in contrast to some other studies (Diabetes in America 1995). Our finding could not be explained by any drug treatment for dyslipidemia. Although the association was attenuated with increasing severity of diabetic retinopathy, it remained significant and we have so far no reasonable explanation for it. We also found that 8.8% of an ageand gender-matched control group to our type 2 diabetic population had retinopathy and that it was significantly associated with systolic blood pressure, but not to any glucose control measure or to age. To our knowledge, this is the first study where retinopathy has been graded in a control group to a geographically defined diabetes population, but our results are similar to what has been found in other studies in populations without diabetes, where retinal photographs have been used to grade retinopathy. In the Reykjavik Eye Study, the prevalence of retinopathy in a cohort of elderly Icelanders with no diabetes was 10.2% (Gunnlaugsdottir et al. 2012). In the Blue Mountains Eye Study, the prevalence of retinopathy in subjects with no diabetes was 9.8%, in the Beaver Dam Eye Study 7.8%, in the Cardiovascular Health Study 8.3% and in the Hoorn study 9% (Klein et al. 1994b; Yu et al. 1998; van Leiden et al. 2002; Wong et al. 2002a, 2003). In the Icelandic study, associated factors included age and microalbuminuria. In all the other studies, retinopathy was associated with high blood pressure and in some studies to other factors as well, such as age, BMI, serum cholesterol and triglyceride levels. We saw an association with diastolic blood pressure and age in bivariate analyses, but not with BMI or serum lipids possibly because our study is smaller than the others. In diabetic patients, the retinopathy present at the time of diabetes diagnosis has routinely been seen as diabetic retinopathy. However, other pathophysiological processes than hyperglycaemia, like hypertension, might explain some of the retinopathy observed in diabetes patients. If so, the true prevalence of retinopathy that can be attributed to diabetes, both at the time of its diagnosis and during its course, may be overestimated by 8 9%. As the current diabetes, diagnosis, first proposed by the National Diabetes Data Group in 1979 and later by WHO in 1980, 1985 and in 1999 (WHO- Study-Group, 1980, 1985; Report of a WHO consultation. 1999), is based on an evaluation of the risk of future microangiopathic complications, mainly retinopathy, due to elevated blood glucose levels at a 2-h oral glucose tolerance test (OGTT), our findings may also question the validity of the 2-h glucose level as the gold standard for the diabetes diagnosis and prompt future research on how to separate diabetic from other types of retinopathy. 136

5 From the UKPDS, we know that for persons having type 2 diabetes mellitus, it is important to control blood glucose as well as blood pressure in order to minimize the risk of developing sightthreatening retinopathy (Stratton et al. 2001). Isolated retinal micro-aneurysms and haemorrhages are the earliest signs of retinopathy in people with diabetes mellitus, and their presence has a high predictive value for worsening retinopathy (Kohner et al. 1999). The significance of retinopathy and the natural course of this phenomenon in persons not having diabetes is, however, less well known, although new studies signal its importance and connection with stroke and coronary heart disease (Wong et al. 2001, 2002b, 2005). In conclusion, our study shows a 34.6% prevalence of retinopathy in our type 2 diabetic prevalence cohort, which is similar to many other Nordic studies. The retinopathy attributed to the diabetes disease itself may, however, be overestimated by 8.8% as this was the prevalence of retinopathy that was found in the control group without diabetes. Acknowledgements This study was supported by the O rebro County Council, O rebro, Sweden, the Research foundation of the National University Hospital, Reykjavik, Iceland and the Helga Jonsdottir and Sigurlidi Kristjansson Memorial Fund, Reykjavik, Iceland. References Diabetes in America (1995): Diabetes in America, 2nd edn. National Institute of Health, National Institute of Diabetes and Digestive and Kidney Diseases. Bethesda, MD: National Diabetes Information Clearinghouse, NIH Publication no , 320. Eggertsen R, Kalm H & Blohme G (1993): The value of screening for retinopathy and microalbuminuria in patients with type 2 diabetes in primary health care. Scand J Prim Health Care 11: Falkenberg M & Finnstrom K (1994): Associations with retinopathy in type 2 diabetes: a populationbased study in a Swedish rural area. Diabet Med 11: Gunnlaugsdottir E, Halldorsdottir S, Klein R et al. (2012): Etinopathy in old persons with and without diabetes mellitus: the Age, Gene Environment Susceptibility Reykjavik Study (AGES-R). Diabetologia 55: Hansson-Lundblad C, Holm K, Agardh CD & Agardh E (2002): A small number of older type 2 diabetic patients end up visually impaired despite regular photographic screening and laser treatment for diabetic retinopathy. Acta Ophthalmol Scand 80: Harris MI, Klein R, Welborn TA & Knuiman MW (1992): Onset of NIDDM occurs at least 4-7 yr before clinical diagnosis. Diabetes Care 15: Henricsson M, Nilsson A, Groop L, Heijl A & Janzon L (1996a): Prevalence of diabetic retinopathy in relation to age at onset of the diabetes, treatment, duration and glycemic control. Acta Ophthalmol Scand 74: Henricsson M, Tyrberg M, Heijl A & Janzon L (1996b): Incidence of blindness and visual impairment in diabetic patients participating in an ophthalmological control and screening programme. Acta Ophthalmol Scand 74: Hove MN, Kristensen JK, Lauritzen T & Bek T (2004): The prevalence of retinopathy in an unselected population of type 2 diabetes patients from Arhus County, Denmark. Acta Ophthalmol Scand 82: Kalm H, Egertsen R & Blohme G (1989): Non-stereo fundus photography as a screening procedure for diabetic retinopathy among patients with type II diabetes. Compared with 60D enhanced slit-lamp examination. Acta Ophthalmol (Copenh) 67: Klein R, Klein BE & Moss SE (1984a): Visual impairment in diabetes. Ophthalmology 91: 1 9. Klein R, Klein BE, Moss SE, Davis MD & DeMets DL (1984b): The Wisconsin epidemiologic study of diabetic retinopathy. III. Prevalence and risk of diabetic retinopathy when age at diagnosis is 30 or more years. Arch Ophthalmol 102: Klein R, Klein BE, Moss SE & Cruickshanks KJ (1994a): The Wisconsin Epidemiologic Study of diabetic retinopathy. XIV. Ten-year incidence and progression of diabetic retinopathy. Arch Ophthalmol 112: Klein R, Klein BE, Moss SE & Wang Q (1994b): Hypertension and retinopathy, arteriolar narrowing, and arteriovenous nicking in a population. Arch Ophthalmol 112: Klein R, Klein BE, Moss SE & Cruickshanks KJ (1998): The Wisconsin Epidemiologic Study of Diabetic Retinopathy: XVII. The 14-year incidence and progression of diabetic retinopathy and associated risk factors in type 1 diabetes. Ophthalmology 105: Kohner EM, Aldington SJ, Stratton IM, Manley SE, Holman RR, Matthews DR & Turner RC (1998): United Kingdom Prospective Diabetes Study, 30: diabetic retinopathy at diagnosis of non-insulindependent diabetes mellitus and associated risk factors. Arch Ophthalmol 116: Kohner EM, Stratton IM, Aldington SJ, Turner RC & Matthews DR (1999): Microaneurysms in the development of diabetic retinopathy (UKPDS 42). UK Prospective Diabetes Study Group. Diabetologia 42: Kristinsson JK, Stefansson E, Jonasson F, Gislason I & Bjornsson S (1994): Screening for eye disease in type 2 diabetes mellitus. Acta Ophthalmol (Copenh) 72: van Leiden HA, Dekker JM, Moll AC, Nijpels G, Heine RJ, Bouter LM, Stehouwer CD & Polak BC (2002): Blood pressure, lipids, and obesity are associated with retinopathy: the hoorn study. Diabetes Care 25: Liew G, Wong TY, Mitchell P, Cheung N & Wang JJ (2009): Retinopathy predicts coronary heart disease mortality. Heart 95: Olafsdottir E, Andersson DK & Stefansson E (2007): Visual acuity in a population with regular screening for type 2 diabetes mellitus and eye disease. Acta Ophthalmol Scand 85: Olafsdottir E, Andersson DKG & Stefansson E (2012): The prevalence of cataract in a population with and without type 2 diabetes mellitus. Acta Ophthalmol Scand 90: Report of a WHO Consultation. (1999): Definition, diagnosis and classification of diabetes mellitus and its complications. part 1: diagnosis and classification of diabetes mellitus. Geneva: World Health Organization. Stratton IM, Kohner EM, Aldington SJ, Turner RC, Holman RR, Manley SE & Matthews DR (2001): UKPDS 50: risk factors for incidence and progression of retinopathy in Type II diabetes over 6 years from diagnosis. Diabetologia 44: UK Prospective Diabetes Study (UKPDS) Group. (1998a): Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 352: UK Prospective Diabetes Study Group. (1998b): Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ 317: WHO-Study-Group (1980): Diabetes mellitus: technical report series 646. Geneva: World Health Organization. WHO-Study-Group (1985): Diabetes mellitus: technical report series 727. Geneva: World Health Organization. Wong TY, Klein R, Couper DJ, Cooper LS, Shahar E, Hubbard LD, Wofford MR & Sharrett AR (2001): Retinal microvascular abnormalities and incident stroke: the Atherosclerosis Risk in Communities Study. Lancet 358: Wong TY, Hubbard LD, Klein R et al. (2002a): Retinal microvascular abnormalities and blood pressure in older people: the Cardiovascular Health Study. Br J Ophthalmol 86: Wong TY, Klein R, Sharrett AR, Couper DJ, Klein BE, Liao DP, Hubbard LD & Mosley TH (2002b): Cerebral white matter lesions, retinopathy, and incident clinical stroke. JAMA 288: Wong TY, Klein R, Sharrett AR et al. (2003): The prevalence and risk factors of retinal microvascular abnormalities in older persons: the Cardiovascular Health Study. Ophthalmology 110: Wong TY, Rosamond W, Chang PP, Couper DJ, Sharrett AR, Hubbard LD, Folsom AR & Klein R (2005): Retinopathy and risk of congestive heart failure. JAMA 293: Wong TY, Mohamed Q, Klein R & Couper DJ (2006): Do retinopathy signs in non-diabetic individuals predict the subsequent risk of diabetes? Br J Ophthalmol 90: Yu T, Mitchell P, Berry G, Li W & Wang JJ (1998): Retinopathy in older persons without diabetes and its relationship to hypertension. Arch Ophthalmol 116: Received on June 29th, Accepted on December 8th, Correspondence: Eydis Olafsdottir, MD Department of Ophthalmology Örebro University Hospital Örebro, Sweden Tel: Fax: eydiso@simnet.is 137