Figures
Abstract
Objective
To evaluate the incidence of diabetic retinopathy in patients with Type 2 Diabetes Mellitus, to identify the risk factors associated with the incidence of retinopathy and to develop a risk table to predict four-year retinopathy risk stratification for clinical use, from a four-year cohort study.
Design
The MADIABETES Study is a prospective cohort study of 3,443 outpatients with Type 2 Diabetes Mellitus, sampled from 56 primary health care centers (131 general practitioners) in Madrid (Spain).
Results
The cumulative incidence of retinopathy at four-year follow-up was 8.07% (95% CI = 7.04–9.22) and the incidence density was 2.03 (95% CI = 1.75–2.33) cases per 1000 patient-months or 2.43 (95% CI = 2.10–2.80) cases per 100 patient-years. The highest adjusted hazard ratios of associated risk factors for incidence of diabetic retinopathy were LDL-C >190 mg/dl (HR = 7.91; 95% CI = 3.39–18.47), duration of diabetes longer than 22 years (HR = 2.00; 95% CI = 1.18–3.39), HbA1c>8% (HR = 1.90; 95% CI = 1.30–2.77), and aspirin use (HR = 1.65; 95% CI = 1.22–2.24). Microalbuminuria (HR = 1.17; 95% CI = 0.75–1.82) and being female (HR = 1.12; 95% CI = 0.84–1.49) showed a non-significant increase of diabetic retinopathy. The greatest risk is observed in females who had diabetes for more than 22 years, with microalbuminuria, HbA1c>8%, hypertension, LDL-Cholesterol >190 mg/dl and aspirin use.
Conclusions
After a four-year follow-up, the cumulative incidence of retinopathy was relatively low in comparison with other studies. Higher baseline HbA1c, aspirin use, higher LDL-Cholesterol levels, and longer duration of diabetes were the only statistically significant risk factors found for diabetic retinopathy incidence. This is the first study to demonstrate an association between aspirin use and diabetic retinopathy risk in a well-defined cohort of patients with Type 2 Diabetes Mellitus at low risk of cardiovascular events. However, further studies with patients at high cardiovascular and metabolic risk are needed to clarify this issue.
Citation: Salinero-Fort MÁ, San Andrés-Rebollo FJ, de Burgos-Lunar C, Arrieta-Blanco FJ, Gómez-Campelo P, on behalf of MADIABETES Group (2013) Four-Year Incidence of Diabetic Retinopathy in a Spanish Cohort: The MADIABETES Study. PLoS ONE 8(10): e76417. https://doi.org/10.1371/journal.pone.0076417
Editor: Guoying Wang, Johns Hopkins Bloomberg School of Public Health, United States of America
Received: November 9, 2012; Accepted: August 27, 2013; Published: October 17, 2013
Copyright: © 2013 Salinero-Fort et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This study has been funded by the Spanish Ministry of Science and Innovation via the Instituto de Salud Carlos III(PI05/0681, PI10/02796, PI12/01806). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
Introduction
Diabetic Retinopathy (DR) is the most common microvascular complication in diabetes mellitus (DM). Worldwide, it remains a significant cause of acquired visual loss and blindness in the 20 to 60 years-old age group [1]–[3].
In an effort to detect DR at an optimal stage for intervention, the American Diabetes Association (ADA) recommends that, after the diagnosis of Type 2 DM (T2DM), patients should receive an initial dilated and comprehensive eye examination by an ophthalmologist, and subsequent annual examinations. Less frequent exams, every 2 or 3 years, may be considered following one or more normal eye exams [4]. However, initial data from the Health Plan Employer Data and Information Set (HEDIS) indicate that, in reality, only 35% to 50% of patients between 30 and 64 years-old receive the annual eye examination [5].
Presence of DR is not only linked to an increased risk of vision loss, but also a two to three-fold excess risk of coronary disease [6]–[9] and ischemic stroke [10].
Identifying individuals at risk of DR in order to establish preventive and therapeutic strategies is a highly important public health issue. Risk scores for DR, based on simple anthropometric and demographic variables, have been set to identify type 1 diabetes patients with high risk of DR [11]. Recently, cross-sectional studies with the same aim have also been published [12], but to our knowledge, no studies have been carried out in patients with T2DM.
We conducted a cohort study with a Spanish population with T2DM at 56 primary health care centers in Madrid, in order to evaluate the incidence of DR over four years, to identify the risk factors associated with incidence of DR, and to develop a risk table to predict four-year DR risk stratification for clinical use.
Materials and Methods
Study Population and Design
The Madrid Diabetes Study (MADIABETES Study) is a prospective cohort study of 3,443 T2DM outpatients, sampled from 56 primary health care centers in the metropolitan area of Madrid (Spain). Study participants were selected by simple random sampling by participating general practitioners (n = 131), using the list of patients with a T2DM diagnosis in their computerized clinical records. Using diabetes diagnosis in computerized clinical records for epidemiological studies has been validated in our setting [13].
Data were collected by general practitioners at baseline visit (2007) and annually during the follow-up period (2008–2011). These data were recorded in electronic Case Report Forms. The flow diagram of participants is shown in Figure 1. Last observation carried forward (LOCF) was used to impute missing values for patients with incomplete data during follow-up period.
Inclusion criteria were: age >30 years-old, a previous diagnosis of T2DM and provision of written informed consent to take part in the study. Exclusion criteria were: type 1 DM and homebound patients. Patients without an eye examination at baseline visit were excluded from follow-up (n = 403), as were patients who had been previously diagnosed with DR (n = 292), leaving a final sample size of 2,748 patients. Three hundred and forty-three patients were excluded from the final analysis for not having a second eye examination during the follow-up period.
After collection, all data were internally audited to ensure quality. This involved the random selection of 50 participating general practitioners and the review of the clinical records they produced. There was a strong data consistency (higher than 88% for all variables).
We examined DR incidence (DR at visits 1 to 4 among individuals without DR at baseline visit). The median follow-up period for patients was 47.97 months (Interquartile range [IQR] = 11.99).
The study was approved by the Institutional Review Board of the Ramón y Cajal Hospital (Madrid), and conducted in accordance with the principles of the Declaration of Helsinki.
Assessment of DR
Eye examinations were conducted by ten experienced ophthalmologists, through dilated pupils with a slit lamp biomicroscopy examination, with a 90-D handheld magnifier lens. DR was diagnosed by the presence of any of the following lesions: microaneurysm, intraretinal hemorrhage, venous beading, neovascularization, vitreous/preretinal hemorrhage, cotton wool spots, retinal thickening, and hard exudates. The stage of DR was based in the severity scale proposed by Wilkinson et al. [14]. This scale has the following categories: no retinopathy, nonproliferative DR (mild, moderate and severe), proliferative DR and Diabetic Macular Edema (retinal thickening and hard exudates in the posterior pole). This DR severity scale is based on the results of the ETDRS [15] and, therefore, relies on scientific evidence, pretending not to displace the original classification, but only to provide a basis for simple operation and adequate clinical practice [16]. In the absence of photographic records, it was difficult to determine the number of microaneurysms per quadrant, so we decided to simplify the category of nonproliferative DR in two gradations mild and moderate/severe.
Clinical Examination and Biochemistry
All patients were subjected to anamnesis, a physical examination, and biochemical tests. The following variables were collected at baseline visit: age, gender and duration of DM (years). Further data was collected at baseline and each follow-up visit: fasting plasma glucose (FPG), glycated haemoglobin (HbA1c), systolic (SBP) and diastolic blood pressure (DBP), total cholesterol, triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), albuminuria, smoking status (current smoker, former smoker, non-smoker), use of hypoglycemic and cardiovascular medications (antihipertensyve agents, statins, aspirin), body mass index (BMI), and history of cardiovascular events (myocardial infarction or stroke) and hypertension.
BMI was calculated as weight/height2 (Kg/m2), and patients with a BMI ≥30 were considered obese. Blood pressure was measured using a checked, calibrated sphygmomanometer. History of hypertension was defined as BPS ≥140 mmHg or BPD ≥90 mmHg or via the use of antihypertensives. After a 5 minutes rest period, a first reading was taken, followed by a second reading 5 minutes later. The mean result was then calculated; a value of <140/90 mm Hg was taken to reflect good control of blood pressure. A baseline FPG level of <126 mg/dL and a HbA1c level of <7% were considered to represent good control of these variables, as were values of <150 mg/dL for TG, <200 mg/dL for total cholesterol, and <100 mg/dL for LDL-C. In females, HDL-C was considered under control when values >50 mg/dL were recorded; in males, values >40 mg/dL were considered satisfactory. Persistent microalbuminuria was defined as a urinary albumin excretion of 30–300 mg/24 in at least two of three consecutive samples. HbA1c was measured using high performance liquid chromatography (Diabetes Control and Complications Trial [DCCT]-aligned) [17].
Cardiovascular risk was calculated following the REGICOR formula (a calibration of the Framingham algorithm adapted for Spain) for each patient [18]. Patients with a cardiovascular risk of 10% over 10 years were considered moderate or high risk [19].
Statistical Analysis
Descriptive data were expressed as mean and standard deviation, and median and IQR. Comparison of continuous variables between two groups was performed with Student’s t-test for data that were normally distributed, The Mann–Whitney U-test for non-normal distributions, and the chi-square test for categorical variables.
Incident DR was analyzed using adjusted hazard ratios (HR) and corresponding 95% Confidence Intervals (CI) were estimated using an extension of Cox proportional hazards models for time-dependant variables. The variables HbA1c, microalbuminuria, LDL-C, blood pressure and use of aspirin were included as time-dependant variables, while gender and duration of diabetes were included as fixed variables. Possible confounding factors, such as use of insulin or aspirin, were checked.
The predictive accuracy of multivariable Cox model was evaluated by the C-index, which is equivalent to the area under the receiver operating characteristic curve for binary dependent variables.
Finally, a probability table of DR risk [20] was obtained with the regression coefficients. A lower DR probability (5%) was calculated in the absence of risk variables and a higher one was calculated in the presence of all of them (98.3%). Between these extremes, a total of 576 combinations of DR probabilities were obtained.
The analysis of the results with hierarchical or multilevel models was unnecessary, as there is no evidence of the variance between the primary health care centers for the HbA1c variable being different from zero (p = 0.34); in addition, the Coefficient Correlation Intraclass has a value of 0.036.
All calculations were performed using SPSS v.19.0 software for Windows. Significance was set at p value <0.05 for differences with a probable type I error.
Results
Table 1 shows the socio-demographic and clinical characteristics at baseline visit of the MADIABETES DR Cohort, including the follow-up patients (with second eye examination; n = 2,405) and the lost to follow-up patients (without second eye examination; n = 343). Mean age in this patient cohort was 67.8 years-old (SD = 10.6) and mean duration of DM was 7.7 years (SD = 7.1). The vast majority (91.3%) had a low risk (less or equal to 10 percent) of developing coronary events within 10 years.
Follow-up patients and lost to follow-up patients do not differ statistically in socio-demographic and clinical baseline variables except in age, proportion of former smokers and mortality rate during the 2008–2011 period. None of these factors was of a magnitude likely to affect the generality of the results.
For follow-up patients, data at baseline visit showed that individuals who developed DR (n = 194) had a higher duration of DM, higher HbA1c levels, and greater use of insulin and aspirin versus non incidence cases (n = 2,211) (Table 2).
The cumulative incidence of DR at four-years was 8.07% (95% CI = 7.04–9.22) and the incidence density was 2.03 (95% CI = 1.75–2.33) cases per 1,000 patient-months or 2.43 (95% CI = 2.10–2.80) cases per 100 patient-years.
Moreover, considering the stage of DR, 30 out of 194 cases (15.5%) were patients with diabetic macular edema; 96 (49.5%) and 68 (35.1%) had non-proliferative and proliferative DR, respectively. Of the 96 cases of non-proliferative DR, 85 cases were mild and 11 moderate or severe.
Additionally, no significant differences were seen in stage DR between patients treated with or without aspirin (p = 0,954). Also, there were significant differences in the duration of DM between strata formed by stage of DR. Thus, patients with macular edema (12.7 years, SD = 7.40) or non-proliferative DR (11.4 years, SD = 10.6) presented higher duration of DM than proliferative DR (6.9 years, SD = 6.9) (p<0.001). However, there were no significant differences between the HbA1c level and the stage of DR (p = 0.081).
The adjusted HR of associated risk factors for incidence of DR is shown in Table 3. The highest HR was LDL-C>190 mg/dl (HR = 7.91; 95% CI = 3.39–18.47). Furthermore, the other variables with the highest HR were duration of DM longer than 22 years (HR = 2.00; 95% CI = 1.18–3.39), HbA1c>8% (HR = 1.90; 95% CI = 1.30–2.77) and use of aspirin (HR = 1.65; 95% CI = 1.22–2.24). Being female (HR = 1.12; 95% CI = 0.84–1.49) and microalbuminuria (HR = 1.17; 95% CI = 0.75–1.82) were not significant. After adjustment for gender, duration of diabetes, hypertension and HbA1c levels, insulin was not significantly associated with DR.
Finally, the development of a probability table of DR risk can be seen in Table 4. A lower DR probability is observed in men with DM for less than 7 years, without microalbuminuria, with HbA1c<7%, no hypertension, LDL-C between 100–190 mg/dl and who did not use aspirin regularly. The greatest risk is observed in females, with a duration of DM of more than 22 years, with microalbuminuria, HbA1c>8%, hypertension, LDL-C>190 mg/dl, and regular aspirin use.
The C-index for the DR model was 0.654 (95% CI = 0.609–0.699), reflecting moderate ability to discriminate between patients who did and did not have a DR outcome. However, the C-index must be interpreted with great caution, as it is not often constructed with time-dependent variables.
Discussion
Incidence of DR
In the MADIABETES Cohort, the incident rate (2.43 cases per 100 patients/year) and the cumulative incidence of DR (8.07%) were relatively low. This could answer to the routine clinical practice conditions of the study and not having a specially selected study population. The Rochester study [21], performed under routine conditions, shows a four-year cumulative incidence similar to that found in our study (6.1%). However, previous findings, as seen in the LALES study [22] and the San Luis Valley Diabetes Study [23], report higher rates of DR, between 3 and 3.5 times higher than our study. Both these studies had a higher proportion of patients with elevated glucose levels and who were being treated with insulin, what is important due to the relationship insulin and glucose levels have with DR [24].
In Spain, a T2DM cohort of 130 patients attending Alcañiz Hospital (Teruel, Spain) [25] and followed for a mean of 5.2 years, reported a DR cumulative incidence of 36.2%. However, patients had elevated baseline levels of HbA1c (HbA1c = 7.9) and the duration of DM was also high (9.2 years). The MADIABETES cohort had an optimal baseline glycemic control (mean HbA1c = 7%; 55.5% patients with HbA1c<7%), which is in contrast with other studies that report only 17% of patients having HbA1c levels under 7% [26]. Similarly, in a cross sectional study, Brown et al. [27] observed that patients with T2DM had lower prevalence rates of DR compared to patients in the WESDR cohort [28], which may reflect lower mean HbA1c levels (7.9% vs. 10.%). Also, in the Australian Diabetes Obesity and Lifestyle study [29], the baseline HbA1c was close to 6.5% and the 5-year cumulative incidence DR was 13.9%, which are similar results to our findings.
The estimated crude annual incidence of DR in population based studies ranges from 2.2/100 patient-years to 8.6/100 patient-years [22], [23], [25], [30]–[33]. This discordance among various studies could respond to differences in study populations, methods, and definitions. Studies in which DR was identified by grading of seven stereoscopic fundus photographs [28] reached higher rates of DR than those carried out with the use of 45 degree nonstereoscopic, nonmydriatic photographs [34]. Our study was carried out with the use of mydriatic ophthalmoscopy examination through dilated pupils with indirect ophthalmoscopy. The crude annual incidence of DR was 2.4/100 patient-years, which is very similar to results found in the Melbourne Visual Impairment study, performed with two 30 degrees stereoscopic fundus photographs [33].
Moreover, when comparing incidence rates in the various studies, it is important to keep in mind the known duration of DM at the time of inclusion. The mean baseline duration of DM in our patients was 7.7 years, which is lower than in other studies [25], [35]–[38].
The stage distribution of DR was different to that found in other studies conducted in Spain, where there was a lower prevalence of proliferative DR [39]–[40]. This might be due to differences in methodology (prevalence versus incidence) and different methods to detect DR. No significant differences were seen in HbA1c levels among the retinopathy groups as other studies have observed [41].
Risk Factors
In our Cohort, the main variable associated with development of DR was LDL-C. Thus, high LDL-C levels (>190 mg/dl) have a significant association with DR incidence, which is similar to findings in earlier studies [12], [42], [43]. Additionally, LDL-C levels between 100 and 190 mg/dl have no significant protector effect over incidence of DR. However, other studies have demonstrated an increase of DR incidence with low LDL-C levels [44], [45].
Patients who developed DR have used aspirin in a higher percentage than patients who did not develop it (60.1% vs. 50.8%; p<0.001). A possible explanation could be the increased history of ischemic heart disease in those who developed DR. However, too many patients in both groups were taking aspirin, a factor that is not common in other T2DM cohorts [46], and there is not sufficient evidence of its use in primary prevention of cardiovascular events [46].
An unexpected finding has been aspirin as an independent predictor of DR. This could be due to an increased risk of retinal hemorrhage with aspirin use, but our data show that intraretinal hemorrhages were observed in non-proliferative diabetic retinopathy and vitreous/preretinal hemorrhage in proliferative diabetic retinopathy. Also, the patients with a higher use of aspirin had similar incidence of non-proliferative diabetic retinopathy than patients with a lower use of aspirin or without it.
Our findings are not consistent with randomized controlled clinical trials included in a systematic review [47], and we have not found cohort studies evaluating the effect of aspirin on the incidence of DR. Moreover, the long-term use of aspirin (10 years) has recently been associated with a small but statistically significant increase in the risk of incidence late and neovascular Age-related Macular Degeneration [48]. However, a recent meta-analysis has not confirmed these findings [49]. Nevertheless, aspirin is effective for the prevention of cardiovascular events in patients with a history of vascular disease and it is reasonable to consider aspirin as one of the potential therapies for cardiovascular disease risk reduction in patients with DM and elevated cardiovascular disease risk [50].
Our findings are consistent with other studies that have found the predictive value of HbA1c and duration of DM on the incidence of DR [12], [28], [30], [37], [38], [44], [51]–[61]. In this respect, the Barbados study demonstrated that, for each 1% increase in mean HbA1c level at baseline, the incidence of DR increased 30% (RR = 1.3; 95% CI = 1.2–1.5) [62]. In our study, results are even higher: when HbA1c increases from 7% to 8% DR incidence is 38%, when HbA1c increases from 7% to >8% DR incidence is 86%.
The relative contribution HbA1c levels have to the risk of DR in populations is known to range from 9% [63] to 11% [53]. Consequently, improvements in glycemic control reduce the substantial burden of DR in T2DM patients. Direct evidence to test this hypothesis is available from the U.K. Prospective Diabetes Study, which demonstrated that a 1% decrease in HbA1c equated to a 31% reduction in DR [64], and an intensive blood-glucose control by either sulphonylureas or insulin substantially decreased the risk of retinal photocoagulation by 37% [65]. Also, the Wisconsin Epidemiologic Study [36] showed that decreases in HbA1c over the first four-years of follow-up were associated with improvements in DR.
Numerous studies have shown that the longer duration of T2DM is statistically significantly associated with the incidence of DR [22], [29], [32], [36], [37], [58], [60], [66]–[69]. However, other studies have not found this relationship [23], [30], .
A causal relationship between DR and hypertension was strongly suggested from studies carried out in the 1980s [70] and from the results of the UKPDS 38 study [71]. However, the Appropriate Blood Pressure Control in Diabetes Trial (ABCD) [72] revealed no relationship between blood pressure and incidence of DR. Our results support this conclusion as other recent studies do [12], [35], [73].
Microalbuminuria has been described as an independent predictor of DR [43], [58], [70], [74]–[86]. However, our study did not note a significant increase of DR, only a slight trend towards DR (HR = 1.17, 95% CI = 0.75–1.82). Additionally, older age, raised blood pressure, and poor glycemic control, have been identified as predictors of microalbuminuria [81]. In our study, the prevalence of microalbuminuria is low compared with other published studies [87]–[90]. This low prevalence, good blood pressure and HbA1c control could be explained, in part, by the lack of association between microalbuminuria and DR.
Risk Table
To our knowledge, this is the first study that has developed a simple risk table to predict four-year DR in patients with T2DM.
Taking a high-risk person as an example: female, hypertension, microalbuminuria positive, LDL-C>190 mg/dl, use of aspirin, duration of DM 9 years, and HbA1c>8%, the risk of developing DR at four-year follow-up is 91.7%. However, in the same patient, with HbA1c<7%, the risk is 73.1%. Thus, after changes in HbA1c from <7% to >8%, the increased risk is nearly 19%.
This risk table enables to calculate individual risk estimates and risk reduction strategies to identify, for example, controlling certain parameters such as HbA1c or LDL-C, or stopping treatment with aspirin. Therefore, it is particularly useful for general practitioners caring for patients with T2DM in our setting, as it allows the monitoring of risk over time.
Strengths and Limitations
The strengths of our study include the use of a population based cohort, the prospective ascertainment of end points, and assessment of information on potentially confounding variables, which reduces the potential selection and confusion bias. We believe our results are applicable to other patients with T2DM. This is an essential issue considering the accuracy of predictive models tends to be lower when applied to other data different from the used to develop those models. We addressed this issue by penalizing model complexity and by choosing models that generalized best to cohorts omitted from the estimation procedure. Our database included patients from many primary health care centers in Madrid. The range of patients was broad: male and female, aged from 30 years to the elderly, and the major exposure categories were well represented. The severity of T2DM at baseline ranged from not measurable to very severe.
It is necessary to validate the multivariate model in a longer sample in order to be able to make accurate, reliable predictions, which is a limitation of the study. Also, concerning the assessment of DR, the distribution of patients in ten different clinics for ophthalmologic care, made no ??possible sharing the non-mydriatic retinal camera. Moreover, the ETRDRS scale classification was not commonly used by ophthalmologists working in Primary Health Care Setting.
Conclusions
In summary, the cumulative incidence, after four-year follow-up, of developing DR lesions in our cohort of patients with T2DM was 8.07% (95% CI = 7.04–9.22) and the incidence density was 2.03 (95% CI = 1.75–2.33) cases per 1,000 patient-months or 2.43 (95% CI = 2.10–2.80) cases per 100 patient-years.
In this study, higher baseline HbA1c, aspirin use, higher LDL-C levels, and longer duration of diabetes were the only statistically significant risk factors found for DR incidence after four-year follow-up.
This is the first study to demonstrate an association between aspirin use and DR risk in a well-defined cohort of patients with T2DM at low risk of cardiovascular events. However, further studies with patients at high cardiovascular and metabolic risk are needed to clarify this issue.
Supporting Information
Figure S1.
Receiver operating characteristic (ROC) curve in risk prediction of DR, using the Cox model.
https://doi.org/10.1371/journal.pone.0076417.s001
(TIFF)
Table S1.
Hazard ratio of Diabetic Retinopathy in each stratum variables identified in multivariable analysis (n = 2,405).
https://doi.org/10.1371/journal.pone.0076417.s002
(DOC)
Acknowledgments
MADIABETES Group:
JC Abánades-Herranz; AM Alayeto-Sánchez; J Almansa-Sánchez; A Alonso-Menéndez; B Álvarez-Embarba; E Álvarez-Navarro; AM Arias-Salgado-Robsy; A Arnaiz-Kompanietz; M Arnalte-Barrera; G Artiach-Geiser; S Artola-Menéndez; E Barrios-Martos; L Barutell-Rubio; D Beamud-Victoria; MJ Bedoya-Frutos; C Bello-González; A Benítez-Arroyo; F Blanco-Urzaiz; M Caballero-Sánchez; ME Calonge-García; R Calvo-Arregui; E Calvo-García; M Camarero-Shelly; M Canals-Aracil; A Cano-Espín; PP Carreño-Freire; E Carrillo-De Santa Pau; S Casado-González; P Casado-Pérez; C Casella-Barban; S Castellanos-Redondo; MJ Castillo-Lizarraga; J Castro-Martín; MA Cava-Rosado; I Cerrada-Somolinos; C Chamorro-Escobar; RM Chico-Moraleja; R de Felipe-Medina; MC de Hoyos-Alonso; G de la Fuente-de la Fuente; S de la Iglesia-Moreno; O de la Peña-Gutierrez; B de Llama-Arauz; A de Miguel-Ballano; ML De Santiago-De Hernando; L De Vicente-Aymat;M de Vicente-Martínez; MA Díaz-Crespo; M Domínguez-Paniagua; EM Donaire-Jimenez; F Endrino-Gómez; J Escobar-Moreno; R Fernández-Fernández; MI Fernández-Ferrero; J Fernández-García; MR Fernández-García; MR Ferreras-Eleta; E Fonseca-Capdevilla; P Gallego-Gómez; MA García-Alonso; S García-Carmona; MC García-Cubero; F García-García; MI García-García; JN García-Pascual; B García-Serrano;E García-Virosta; P Gil-Díaz; M Gil-Díaz; MJ Gomara-Martínez; MS Gomez-Criado; E Gomez-Navarrro; C González-Benito; C González-Fernández; MI González-García; A González-González; E González-Romero; C Gonzalo-Hernández; I Herreros-Hernanz; P Huelin-Martín; R Iglesias-González; MJ Iglesias-Iglesias; J Innerarity-Martínez; Á Jaime-Siso; A Jiménez-Moreno; BE León-Morales; E López-Burillo; MC López-Gutiérrez; I López-Noguero; E López-Parra; C López-Rodríguez; MB López-Sabater; L López-Sediles; A Maestro-Martín; MJ Mansilla-Bermejo; M Martín-Bun; P Martín-Calvo; MR Martín-Cano; M Martínez-García; J Martínez-Irazusta; C Martín-Madrazo; F Mata-Benjumea; AI Menéndez-Fernández; S Merino-Martin; T Mesonero-Grandes; M Miguel-Garzón; C Montejo-Martínez; MC Montero-García; C Montero-Lizana; A Montilla-Bernabé; A Moran-Escudero; A Muñoz-Cildoz; S Muñoz-Quiros-Aliaga; MA Murchante; E Muro-Díaz; P Nogales-Aguado; S Núñez-Palomo; O Olmos-Carrasco; MC Ortega-Huerta; I Parra-Álvarez; ME Pejenaute-Labari; MA Pellus-Pardines; E Peña-Rodríguez; I Peña-Sainz; C Pérez-de la Campa; FC Pérez-Sánchez; N Pertierra-Galindo; A Pinilla-Carrasco; M Piñera-Tamés; A Pozo-Teruel; MP Puebla-Sanz; S Pulido-Fernández; AB Ramírez-Puerta; G Reviriego-Jaén; C Revuelto-García; C Reyes-Madridejos; P Ríus-Fortea; G Rodríguez-Castro; C Rodríguez-Gallego;MA Rodríguez-Posada; J Roldan-San Juan; MT Rollan-Landeras; A Rosillo-González; C Ruiz-Tuñón; J Sagredo-Pérez; MT Salamanca-Sánchez-Escalonilla; JM San Vicente-Rodríguez; R Santana-Alonso; MT Sanz-de la Fuente; MM Sanz-Pascual; R Sartre-De la Fuente; L Serrano-González; R Serrano-Martín; AM Serrano-Ortíz;ME Serrano-Serrano; P Serrano-Simarro; D Serrano-Tomat; A Siguero-Anguí; AM Sobrado-de Vicente-Tutor; S Soto-Díaz; M Suárez-Baraza; J Suero-Palancar; T Torices-Rasines; P Tovar-García; E Tutor-Pellicer-Palacín; MA Usero-Martín; E Vaquero-Lucas; I Vázquez-Burgos; B Vázquez-Rodríguez; MP Vich-Pérez; R Yehuda-Salama; MM Zamora-Gómez; MP Zazo-Lázaro; C Zúñiga-Bartolomé.
Author Contributions
Conceived and designed the experiments: MSF CBL. Performed the experiments: MSF FJSAR CBL PGC. Analyzed the data: FJSAR MSF PGC. Contributed reagents/materials/analysis tools: CBL. Wrote the paper: MSF FJSAR CBL FJAB PGC.
References
- 1.
Shotliff K, Davies N (2012) Diabetes and the Eye. In: Shaw KM, Cummings MH, editors. Diabetes. Oxford, UK: Wiley-Blackwell. 1–33. doi: 10.1002/9781118405550.ch1
- 2. Moss SE, Klein R, Klein BE (1998) The 14-year incidence of visual loss in a diabetic population. Ophthalmology 105(6): 998–1003.
- 3. Resnikoff S, Pascolini D, Etya’ale D, Kocur I, Pararajasegaram R, et al. (2004) Global data on visual impairment in the year 2002. Bull World Health Organ 82(11): 844–851.
- 4. American Diabetes Association (2011) Standards of Medical Care in Diabetes–2012. Diabetes Care 35(Suppl1): S11–S63.
- 5. Thompson JW, Bost J, Ahmed F, Ingalls CE, Sennett C (1998) The NCQA’s quality compass: evaluating managed care in the United States. Health Aff (Millwood) 17(1): 152–158.
- 6. Juutilainen A, Lehto S, Rönnemaa T, Pyörälä K, Laakso M (2007) Retinopathy predicts cardiovascular mortality in type 2 diabetic men and women. Diabetes Care 30(2): 292–299.
- 7. Tong PCY, Kong AP, So WY, Yang X, Ng MCY, et al. (2007) Interactive effect of retinopathy and macroalbuminuria on all-cause mortality, cardiovascular and renal end points in Chinese patients with Type 2 diabetes mellitus. Diabet Med 24(7): 741–746.
- 8. Targher G, Bertolini L, Zenari L, Lippi G, Pichiri I, et al. (2008) Diabetic retinopathy is associated with an increased incidence of cardiovascular events in Type 2 diabetic patients. Diabet Med 25(1): 45–50.
- 9. Cheung N, Wang JJ, Klein R, Couper DJ, Sharrett AR, et al. (2007) Diabetic retinopathy and the risk of coronary heart disease: the Atherosclerosis Risk in Communities Study. Diabetes Care 30(7): 1742–1746.
- 10. Cheung N, Rogers S, Couper DJ, Klein R, Sharrett AR, et al. (2007) Is diabetic retinopathy an independent risk factor for ischemic stroke? Stroke 38(2): 398–401.
- 11. Zhang L, Krzentowski G, Albert A, Lefebvre PJ (2001) Risk of Developing Retinopathy in Diabetes Control and Complications Trial Type 1 Diabetic Patients With Good or Poor Metabolic Control. Diabetes Care 24(7): 1275–1279.
- 12. Hosseini SM, Maracy MR, Amini M, Baradaran HR (2009) A risk score development for diabetic retinopathy screening in Isfahan-Iran. J Res Med Sci 14(2): 105–110.
- 13. de Burgos-Lunar C, Salinero-Fort MA, Cárdenas-Valladolid J, Soto-Díaz S, Fuentes-Rodríguez CY, et al. (2011) Validation of diabetes mellitus and hypertension diagnosis in computerized medical records in primary health care. BMC Med Res Methodol 11: 146.
- 14. Wilkinson CP, Ferris FL 3rd, Klein RE, Lee PP, Agardh CD, et al. (2003) Proposed international clinical diabetic retinopathy and diabetic macular edema disease severity scales. Ophthalmology 110(9): 1677–1682.
- 15.
(1991) Grading diabetic retinopathy from stereoscopic color fundus photographs - an extension of the modified Airlie House classification. ETDRS report number 10. Early Treatment Diabetic Retinopathy Study Research Group. Ophthalmology 98(5 Suppl): 786–806.
- 16. López Gálvez MI (2004) International severity scale of diabetic retinopathy and diabetic macular edema. Arch Soc Esp Oftalmol 79(4): 149–150.
- 17. Selvin E, Coresh J, Zhu H, Folsom A, Steffes MW (2010) Measurement of HbA1c from stored whole blood samples in the Atherosclerosis Risk in Communities study. J Diabetes 2(2): 118–124.
- 18. Marrugat J, Solanas P, D’Agostino R, Sullivan L, Ordovas J, et al. (2003) Coronary risk estimation in Spain using a calibrated Framingham function. Rev Esp Cardiol 56(3): 253–261.
- 19. Bosomworth NJ (2011) Practical use of the Framingham risk score in primary prevention: Canadian perspective. Can Fam Physician 57(4): 417–423.
- 20.
Domenech JM, Navarro JB (2008) Análisis de la supervivencia y modelo de riesgos proporcionales de Cox. Barcelona: Signo.
- 21. Dwyer MS, Melton LJ 3rd, Ballard DJ, Palumbo PJ, Trautmann JC, et al. (1985) Incidence of diabetic retinopathy and blindness: a population-based study in Rochester, Minnesota. Diabetes Care 8(4): 316–322.
- 22. Varma R, Choudhury F, Klein R, Chung J, Torres M, et al. (2010) Four-year incidence and progression of diabetic retinopathy and macular edema: the Los Angeles Latino Eye Study. Am J Ophthalmol 149(5): 752–761.
- 23. Tudor SM, Hamman RF, Baron A, Johnson DW, Shetterly SM (1998) Incidence and progression of diabetic retinopathy in Hispanics and non-Hispanic whites with type 2 diabetes. San Luis Valley Diabetes Study, Colorado. Diabetes Care 21(1): 53–61.
- 24. Pugliese G, Solini A, Zoppini G, Fondelli C, Zerbini G, et al. (2012) High prevalence of advanced retinopathy in patients with type 2 diabetes from the Renal Insufficiency And Cardiovascular Events (RIACE) Italian Multicenter Study. Diabetes Res Clin Pract 25 S0168–8227(12)00310-5.
- 25. Gimeno-Orna JA, Castro-Alonso FJ, Boned-Juliani B, Lou-Arnal LM (2003) Fasting plasma glucose variability as a risk factor of retinopathy in Type 2 diabetic patients. J Diabetes Complicat 17(2): 78–81.
- 26. Nathan DM, Zinman B, Cleary PA, Backlund J-YC, Genuth S, et al. (2009) Modern-day clinical course of type 1 diabetes mellitus after 30 years’ duration: the diabetes control and complications trial/epidemiology of diabetes interventions and complications and Pittsburgh epidemiology of diabetes complications experience (1983–2005). Arch Intern Med 169(14): 1307–1316.
- 27. Brown JB, Pedula KL, Summers KH (2003) Diabetic retinopathy: contemporary prevalence in a well-controlled population. Diabetes Care 26(9): 2637–2642.
- 28. Klein R, Klein BE, Moss SE, Davis MD, DeMets DL (1984) 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(4): 527–532.
- 29. Tapp RJ, Tikellis G, Wong TY, Harper CA, Zimmet PZ, et al. (2008) Longitudinal association of glucose metabolism with retinopathy: results from the Australian Diabetes Obesity and Lifestyle (AusDiab) study. Diabetes Care 31(7): 1349–1354.
- 30. Leske MC, Wu S-Y, Hennis A, Nemesure B, Hyman L, et al. (2003) Incidence of diabetic retinopathy in the Barbados Eye Studies. Ophthalmology 110(5): 941–947.
- 31. Klein R, Klein BE, Moss SE, Davis MD, DeMets DL (1989) The Wisconsin Epidemiologic Study of Diabetic Retinopathy. X. Four-year incidence and progression of diabetic retinopathy when age at diagnosis is 30 years or more. Arch Ophthalmol 107(2): 244–249.
- 32. Cikamatana L, Mitchell P, Rochtchina E, Foran S, Wang JJ (2007) Five-year incidence and progression of diabetic retinopathy in a defined older population: the Blue Mountains Eye Study. Eye (Lond) 21(4): 465–471.
- 33. McCarty DJ, Fu CL, Harper CA, Taylor HR, McCarty CA (2003) Five-year incidence of diabetic retinopathy in the Melbourne Visual Impairment Project. Clin Experiment Ophthalmol 31(5): 397–402.
- 34. Liu DP, Molyneaux L, Chua E, Wang YZ, Wu CR, et al. (2002) Retinopathy in a Chinese population with type 2 diabetes: factors affecting the presence of this complication at diagnosis of diabetes. Diabetes Res Clin Pract 56(2): 125–131.
- 35. Tam VHK, Lam EPK, Chu BCY, Tse KK, Fung LM (2009) Incidence and progression of diabetic retinopathy in Hong Kong Chinese with type 2 diabetes mellitus. J Diabetes Complicat 23(3): 185–193.
- 36. Klein R, Knudtson MD, Lee KE, Gangnon R, Klein BEK (2008) The Wisconsin Epidemiologic Study of Diabetic Retinopathy XXII. Ophthalmology 115(11): 1859–1868.
- 37. Leske MC, Wu S-Y, Hennis A, Nemesure B, Schachat AP, et al. (2006) Nine-year incidence of diabetic retinopathy in the Barbados Eye Studies. Arch Ophthalmol 124(2): 250–255.
- 38. Wong TY, Klein R, Islam FMA, Cotch MF, Folsom AR, et al. (2006) Diabetic Retinopathy in a Multi-ethnic Cohort in the United States. Am J Ophthalmol 141(3): 446–455.
- 39.
Teruel Maicas C, Fernández-Real J, Ricart W, Valent Ferrer R, Vallés Prats M (2005) Prevalencia de la retinopatía diabética en la población de diabéticos diagnosticados en las comarcas de Girona: Estudio de los factores asociados. Archivos de la Sociedad Española de Oftalmología [Internet] 80(2). Scielo website. Available: http://scielo.isciii.es/scielo.php?script=sci_arttext&pid=S0365-66912005000200006&lng=en&nrm=iso&tlng=en Accessed 2013 Feb 25.
- 40.
Santos-Bueso E, Fernández-Pérez C, Macarro A, Fernández-Vigo J (2007) Prevalencia de retinopatía diabética en la ciudad de Badajoz 2002 (Proyecto Extremadura para prevención de la ceguera). Archivos de la Sociedad Española de Oftalmología [Internet] 82(3). Scielo website. Available: http://scielo.isciii.es/scielo.php?script=sci_arttext&pid=S0365-66912007000300007&lng=en&nrm=iso&tlng=en Accessed 2013 Mar 29.
- 41. Güven D, Ozdemir H, Hasanreisoglu B (1996) Hemodynamic alterations in diabetic retinopathy. Ophthalmology 103(8): 1245–9.
- 42. Wang S, Xu L, Jonas JB, Wang YX, You QS, et al. (2012) Dyslipidemia and Eye Diseases in the Adult Chinese Population: The Beijing Eye Study. Federici M, editor. PLoS ONE 7(3): e26871.
- 43. Benarous R, Sasongko MB, Qureshi S, Fenwick E, Dirani M, et al. (2011) Differential association of serum lipids with diabetic retinopathy and diabetic macular edema. Invest Ophthalmol Vis Sci 52(10): 7464–7469.
- 44. Romero-Aroca P, Baget-Bernaldiz M, Reyes-Torres J, Fernandez-Ballart J, Plana-Gil N, et al. (2012) Relationship between diabetic retinopathy, microalbuminuria and overt nephropathy, and twenty-year incidence follow-up of a sample of type 1 diabetic patients. J Diabetes Complications 26(6): 506–512.
- 45. Lyons TJ, Jenkins AJ, Zheng D, Lackland DT, McGee D, et al. (2004) Diabetic retinopathy and serum lipoprotein subclasses in the DCCT/EDIC cohort. Invest Ophthalmol Vis Sci 45(3): 910–918.
- 46. Simpson SH, Gamble J-M, Mereu L, Chambers T (2011) Effect of aspirin dose on mortality and cardiovascular events in people with diabetes: a meta-analysis. J Gen Intern Med 26(11): 1336–1344.
- 47. Bergerhoff K, Clar C, Richter B (2002) Aspirin in diabetic retinopathy. A systematic review. Endocrinol Metab Clin North Am 31(3): 779–793.
- 48. Klein BE, Howard KP, Gangnon RE, Dreyer JO, Lee KE, et al. (2012) Long-term use of aspirin and age-related macular degeneration. JAMA 308(23): 2469–78.
- 49. Zhu W, Wu Y, Xu D, Li YH, Jun B, et al. (2013) Aspirin use and risk of age-related macular degeneration: a meta-analysis. PLoS One 8(3): e58821.
- 50. Pignone M, Williams CD (2010) Aspirin for primary prevention of cardiovascular disease in diabetes mellitus. Nat Rev Endocrinol 6(11): 619–28.
- 51. Klein R, Klein BE, Moss SE, Linton KL (1992) The Beaver Dam Eye Study. Retinopathy in adults with newly discovered and previously diagnosed diabetes mellitus. Ophthalmology 99(1): 58–62.
- 52. van Leiden HA, Dekker JM, Moll AC, Nijpels G, Heine RJ, et al. (2003) Risk factors for incident retinopathy in a diabetic and nondiabetic population: the Hoorn study. Arch Ophthalmol 121(2): 245–251.
- 53. Hirsch IB, Brownlee M (2010) Beyond hemoglobin A1c–need for additional markers of risk for diabetic microvascular complications. JAMA 303(22): 2291–2292.
- 54. Liu QZ, Pettitt DJ, Hanson RL, Charles MA, Klein R, et al. (1993) Glycated haemoglobin, plasma glucose and diabetic retinopathy: cross-sectional and prospective analyses. Diabetologia 36(5): 428–432.
- 55. Klein R, Klein BE, Moss SE, Davis MD, DeMets DL (1988) Glycosylated hemoglobin predicts the incidence and progression of diabetic retinopathy. JAMA 260(19): 2864–2871.
- 56. Klein R, Klein BE, Moss SE, Cruickshanks KJ (1994) Relationship of hyperglycemia to the long-term incidence and progression of diabetic retinopathy. Arch Intern Med 154(19): 2169–2178.
- 57. Stratton IM, Kohner EM, Aldington SJ, Turner RC, Holman RR, et al. (2001) UKPDS 50: risk factors for incidence and progression of retinopathy in Type II diabetes over 6 years from diagnosis. Diabetologia 44(2): 156–163.
- 58. Chen MS, Kao CS, Fu CC, Chen CJ, Tai TY (1995) Incidence and progression of diabetic retinopathy among non-insulin-dependent diabetic subjects: a 4-year follow-up. Int J Epidemiol 24(4): 787–795.
- 59. Kim HK, Kim CH, Kim SW, Park JY, Hong SK, et al. (1998) Development and progression of diabetic retinopathy in Koreans with NIDDM. Diabetes Care 21(1): 134–138.
- 60. Looker HC, Krakoff J, Knowler WC, Bennett PH, Klein R, et al. (2003) Longitudinal studies of incidence and progression of diabetic retinopathy assessed by retinal photography in pima indians. Diabetes Care 26(2): 320–326.
- 61. Tam TKW, Lau CM, Tsang LCY, Ng KK, Ho KS, et al. (2005) Epidemiological study of diabetic retinopathy in a primary care setting in Hong Kong. Hong Kong Med J 11(6): 438–444.
- 62. Leske MC, Wu S-Y, Hennis A, Hyman L, Nemesure B, et al. (2005) Hyperglycemia, blood pressure, and the 9-year incidence of diabetic retinopathy: the Barbados Eye Studies. Ophthalmology 112(5): 799–805.
- 63.
Klein R (2008) The Epidemiology of Diabetic Retinopathy. In: Duh EJ, editor. Diabetic Retinopathy. Totowa, NJ: Humana Press. 67–107. Springer website. Available: http://www.springerlink.com/index/10.1007/978-1-59745-563-3_3 Accessed 2013 Apr 10.
- 64.
Kohner EM (2008) Microvascular disease: what does the UKPDS tell us about diabetic retinopathy? Diabet Med (Suppl 2): 20–24.
- 65. UK Prospective Diabetes Study (UKPDS) Group (1998) 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(9131): 837–853.
- 66. Thomas RL, Dunstan F, Luzio SD, Roy Chowdury S, Hale SL, et al. (2012) Incidence of diabetic retinopathy in people with type 2 diabetes mellitus attending the Diabetic Retinopathy Screening Service for Wales: retrospective analysis. BMJ 344: e874.
- 67. Manaviat MR, Rashidi M, Afkhami-Ardekani M (2008) Four years incidence of diabetic retinopathy and effective factors on its progression in type II diabetes. Eur J Ophthalmol 18(4): 572–577.
- 68. Younis N, Broadbent DM, Vora JP, Harding SP (2003) Incidence of sight-threatening retinopathy in patients with type 2 diabetes in the Liverpool Diabetic Eye Study: a cohort study. Lancet 361(9353): 195–200.
- 69. Tapp RJ, Zimmet PZ, Harper CA, McCarty DJ, Chitson P, et al. (2006) Six year incidence and progression of diabetic retinopathy: results from the Mauritius diabetes complication study. Diabetes Res Clin Pract 73(3): 298–303.
- 70. Knowler WC, Bennett PH, Ballintine EJ (1980) Increased incidence of retinopathy in diabetics with elevated blood pressure. A six-year follow-up study in Pima Indians. N Engl J Med 302(12): 645–650.
- 71. UK Prospective Diabetes Study Group (1998) Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ 317(7160): 703–713.
- 72.
Estacio RO, Jeffers BW, Gifford N, Schrier RW (2000) Effect of blood pressure control on diabetic microvascular complications in patients with hypertension and type 2 diabetes. Diabetes Care (Suppl 2): B54–64.
- 73. Chew EY, Ambrosius WT, Davis MD, Danis RP, Gangaputra S, et al. (2010) Effects of medical therapies on retinopathy progression in type 2 diabetes. N Engl J Med 363(3): 233–244.
- 74.
Newman DJ, Mattock MB, Dawnay ABS, Kerry S, McGuire A, et al.. (2005) Systematic review on urine albumin testing for early detection of diabetic complications. Health Technol Assess 9(30): iii–vi, xiii–163.
- 75. Raman R, Gupta A, Kulothungan V, Sharma T (2012) Prevalence and risk factors of diabetic retinopathy in subjects with suboptimal glycemic, blood pressure and lipid control. Sankara Nethralaya Diabetic Retinopathy Epidemiology and Molecular Genetic Study (SN-DREAMS, Report 33). Curr Eye Res 37(6): 513–523.
- 76. Perol J, Balkau B, Guillausseau P-J, Massin P (2012) A study of the 3-year incidence of diabetic retinopathy in a French diabetic population seen at Lariboisière Hospital, Paris. Diabetes Metab 38(3): 225–229.
- 77. Chen Y-H, Chen H-S, Tarng D-C (2012) More impact of microalbuminuria on retinopathy than moderately reduced GFR among type 2 diabetic patients. Diabetes Care 35(4): 803–808.
- 78. Vigstrup J, Mogensen CE (1985) Proliferative diabetic retinopathy: at risk patients identified by early detection of microalbuminuria. Acta Ophthalmol (Copenh) 63(5): 530–534.
- 79. Gall MA, Rossing P, Skøtt P, Damsbo P, Vaag A, et al. (1991) Prevalence of micro- and macroalbuminuria, arterial hypertension, retinopathy and large vessel disease in European type 2 (non-insulin-dependent) diabetic patients. Diabetologia 34(9): 655–661.
- 80. Manaviat MR, Afkhami M, Shoja MR (2004) Retinopathy and microalbuminuria in type II diabetic patients. BMC Ophthalmol 4: 9.
- 81. Rani PK, Raman R, Gupta A, Pal SS, Kulothungan V, et al. (2011) Albuminuria and Diabetic Retinopathy in Type 2 Diabetes Mellitus Sankara Nethralaya Diabetic Retinopathy Epidemiology And Molecular Genetic Study (SN-DREAMS, report 12). Diabetol Metab Syndr (1): 9.
- 82. Ajoy Mohan VK, Nithyanandam S, Idiculla J (2011) Microalbuminuria and low hemoglobin as risk factors for the occurrence and increasing severity of diabetic retinopathy. Indian J Ophthalmol 59(3): 207–210.
- 83. Singh SK, Behre A, Singh MK (2001) Diabetic retinopathy and microalbuminuria in lean type 2 diabetes mellitus. J Assoc Physicians India 49: 439–441.
- 84. Potisat S, Srisubat A, Krairttichai U, Jongsareejit A (2008) The relationship between microalbuminuria by using urine dipsticks and diabetic retinopathy in type 2 diabetes. J Med Assoc Thai 91(6): 846–851.
- 85. Voutilainen-Kaunisto RM, Teräsvirta ME, Uusitupa MI, Niskanen LK (2001) Occurrence and predictors of retinopathy and visual acuity in Type 2 diabetic patients and control subjects. J Diabetes Complications 15(1): 24–33.
- 86. Cignarelli M, De Cicco ML, Damato A, Paternostro A, Pagliarini S, et al. (1992) High systolic blood pressure increases prevalence and severity of retinopathy in NIDDM patients. Diabetes Care 15(8): 1002–1008.
- 87. Unnikrishnan RI, Rema M, Pradeepa R, Deepa M, Shanthirani CS, et al. (2007) Prevalence and risk factors of diabetic nephropathy in an urban South Indian population: the Chennai Urban Rural Epidemiology Study (CURES 45). Diabetes Care 30(8): 2019–2024.
- 88. Wirta OR, Pasternack AI, Oksa HH, Mustonen JT, Koivula TA, et al. (1995) Occurrence of late specific complications in type II (non-insulin-dependent) diabetes mellitus. J Diabetes Complicat 9(3): 177–185.
- 89. Bruno G, Cavallo-Perin P, Bargero G, Borra M, Calvi V, et al. (1996) Prevalence and risk factors for micro- and macroalbuminuria in an Italian population-based cohort of NIDDM subjects. Diabetes Care 19(1): 43–47.
- 90. Klein R, Klein BE, Moss SE (1993) Prevalence of microalbuminuria in older-onset diabetes. Diabetes Care 16(10): 1325–1330.