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  2483  ORIGINALARTICLE   RelationshipbetweenCoronaryArteryDiseaseandRetinopathyinPatientswithType2DiabetesMellitus Satsuki Kawasaki 1 , Haruo Misawa 1 , Yasushi Tamura 1 , Yoshinobu Kondo 2 , Shinobu Satoh 2 ,Osamu Hasegawa 3 , Satoshi Kato 4 and Yasuo Terauchi 5 Abstract Objective  To examine risk factors for coronary artery disease (CAD) and retinopathy in patients with type2 diabetes mellitus (DM) and assess the relationship between CAD and retinopathy. Methods  A total of 1,003 outpatients with type 2 DM (578 men and 425 women) were classified into twogroups according to the presence (based on ischemic findings on a resting electrocardiogram or a history of angina or myocardial infarction) or absence of CAD and four retinopathy stages based on the InternationalClinical Classification of Diabetic Retinopathy. Results  Stepwise multiple regression analyses showed that independent risk factors for CAD were age, thetriglyceride (TG) level and smoking, while those for retinopathy included age, age of DM diagnosis, theHbA1c level and a female gender. The prevalence of CAD increased in association with the progression of retinopathy (p<0.01). Conclusion  Since it is difficult to distinguish macrovascular and microvascular diseases, diabetic vasculardisorders require comprehensive approaches to assessment and treatment. Keywords:  coronary artery disease, retinopathy, risk factor, type 2 diabetes mellitus (InternMed52:2483-2487,2013)(DOI:10.2169/internalmedicine.52.9444) Introduction Large-scale clinical studies have demonstrated that the de-velopment and progression of diabetic microangiopathy canbe attributed to long-term poor glycemic and/or blood pres-sure control (1-3). Meanwhile, macroangiopathy is associ-ated with various factors in addition to blood glucose, in-cluding lipid profiles, blood pressure and lifestyle factors.Earlier studies have reported that the incidence of coronaryartery events increases in relation to the number of coexist-ing risk factors (4, 5). Macro- and microangiopathy havealso been shown to progress in parallel with the course of the underlying diabetes, with several reports identifying ret-inopathy as a risk factor for coronary artery disease(CAD) (6-8). In this study, we examined risk factors forCAD and retinopathy and assessed the relationship betweenthe major forms of macro- and microangiopathy. MaterialsandMethods This retrospective study included 1,003 outpatients withtype 2 DM (578 men and 425 women) who were treated atthe Diabetes Clinic at Cigasaki Tokushukai Medical Centerbetween 2006 and 2011. The patients were divided into twogroups according to whether they did or did not have CAD(CAD and non-CAD groups, respectively). A patient was di-agnosed as having CAD if there were ischemic findings ona resting electrocardiogram (e.g., abnormal Q waves, STsegment depression or inverted T waves) or a history of an-gina or myocardial infarction. Diabetic retinopathy was as-sessed by ophthalmologists and graded according to the In-  Department of Endocrinology and Metabolism, Shonan Fujisawa Tokushukai Hospital, Japan,   Department of Endocrinology and Metabolism,Chigasaki Municipal Hospital, Japan,   Department of General Medicine, Yokohama City University Medical Center, Japan,   Department of Oph-thalmology, University of Tokyo School of Medicine, Japan and   Department of Endocrinology and Metabolism, Yokohama City UniversityGraduate School of Medicine, JapanReceived for publication December 2, 2012; Accepted for publication June 18, 2013Correspondence to Dr. Satsuki Kawasaki,  Intern Med 52: 2483-2487, 2013 DOI: 10.2169/internalmedicine.52.9444 2484 T a ble   1.   Clinic a l Ch a r a cteri s tic s  of the T yp e 2 DM P a tient s   a ccor d ing to the Pre s ence or Ab s ence of CAD CAD Non-CAD p valuen 387 616Age (years) 66.4±11.0 61.9±12.8 <0.01Age at diagnosis of DM (years) 53.3±1.3 51.7±4.0 0.15Male/female 247/140 331/285 <0.01Duration of DM (months) 158.4±116.9 122.1±106.0 <0.01Body mass index (kg/m 2 ) 25.0±12.5 23.8±3.9 0.07Waist circumference (cm) 88.5±11.7 86.5±10.4 <0.05Systolic blood pressure (mmHg) 137±19 134±19 <0.05Diastolic blood pressure (mmHg) 77±13 77±13 0.55anti-hypertensive agents (Yes/No) 294/93 283/333 <0.01Hb A1c (%) (NGSP) 8.3±2.2 8.1±2.3 <0.05Total cholesterol (mg/dL) 200±39 204±39 0.18Triglycerides (TG) (mg/dL) 181±118 156±104 <0.01log TG 5.03±0.57 4.88±0.59 <0.01HDL cholesterol (mg/dL) 52±21 59±37 <0.01LDL cholesterol (mg/dL) 115±33 117±34 0.27lipid-lowering agents (Yes/No) 248/139 325/291 <0.01Microalbuminuria (mg/gCr) 311.9±809.2 150.7±491.9 <0.01log microalbuminuria 3.93±1.77 3.45±1.47 <0.01Smoking (Yes/No) 196/128 272/278 <0.01Insulin therapy (Yes/No) 98/288 129/469 0.18Retinopathy(Yes/No) 138/217 131/410 <0.01 T a ble   2.   Multi p le Regre ss ion An a l ys e s  for the Pre s ence of CAD Independent factor Odds ratio 95% confidence interval p value     1.82 1.34–2.48 <0.01log TG 1.   1.20–2.14 <0.01Smoking 1.70 1.25–2.31 <0.01retinopat   1.98 1.44–2.74 <0.01 ternational Clinical Classification of Diabetic Retinopa-thy (9) into four stages: no diabetic retinopathy, mild ormoderate non-proliferative diabetic retinopathy, severe non-proliferative diabetic retinopathy and proliferative diabeticretinopathy. Data for the CAD and retinopathy status andclinical characteristics [age, age of DM diagnosis, durationof DM, BMI, waist circumference, blood pressure, HbA1c(NGSP) (10), lipid profile, microalbuminuria, gender, smok-ing status and use of insulin] were collected to evaluate risk factors for CAD and retinopathy. The relationship betweenCAD and the stage of retinopathy was also examined. Statistical analysis The results are expressed as the mean ± SD. The datawere compared between the CAD and non-CAD groups us-ing Student’s  t  -test. The data were compared among the pa-tients with the four retinopathy stages using one-way analy-sis of variance (ANOVA). For the multivariate analysis, mul-tiple regression models were developed based on a stepwiseprocedure in which significant factors for CAD and retino-pathy identified using univariate analyses were included. Amultiple logistic regression analysis was then performed toassess the relationships between the presence or absence of CAD and retinopathy to the individual variables. The rela-tionship between CAD and retinopathy was analyzed usingthe chi-square test. The statistical analyses were performedusing the JMP software program, version 9. A value of p<0.05 was considered to be statistically significant. Results The characteristics of the 1,003 patients with type 2 DMwere as follows: age, 63.7±12.3 (SD) years; duration of DM, 136±112 months; age of DM onset, 52.3±3.0 years;BMI, 24.3±8.4 kg/m 2 ; waist circumference, 87.3±11.0 cm;blood pressure (BP), 135±19/77±13 mmHg (577 patientswere receiving antihypertensive agents); Hb A1c, 8.2±2.3 %;total cholesterol (Tcho), 202±39 mg/dL; triglycerides (TG),166±110 mg/dL; HDL cholesterol (HDL-C), 56±32 mg/dL;LDL cholesterol (LDL-C), 116±34 mg/dL (573 patientswere receiving lipid-lowering agents); and urinary albumin,213.7±640.0 mg/g Cr.Coronary artery disease: A total of 387 patients (39%)were included in the CAD group and 616 (61%) patientswere included in the non-CAD group. Compared with thosein the non-CAD group, the patients in the CAD group weresignificantly older, had a significantly longer duration of DM and exhibited higher values of waist circumference,systolic blood pressure, HbA1c, TG and urinary albuminand lower HDL-C levels, in addition to significantly higherpercentages of men and smokers (Table 1). When using thepresence of CAD as an objective variable, the stepwise mul-tiple regression analysis identified age, the TG level andsmoking as independent risk factors. Table 2 shows the re-sults of the logistic regression analyses of the presence orabsence of CAD.Retinopathy: The patients were divided into four groupsaccording to whether they had no diabetic retinopathy (n=627, 70%), mild or moderate non-proliferative diabetic ret-inopathy (119, 13%), severe non-proliferative diabetic ret-inopathy (52, 6%) or proliferative diabetic retinopathy (102,11%). An analysis of variance revealed that patients withretinopathy progression exhibited higher values of age, ageof DM diagnosis, duration of DM, HbA1c and urinary albu-min and lower values of BMI and diastolic blood pressure,with significantly higher percentages of women, smokersand patients receiving insulin therapy (Table 3). With stageprogression as an objective variable, the stepwise multipleregression analysis identified age, age of DM diagnosis, theHbA1c level and a female gender as independent risk fac-tors. The results of the logistic regression analyses of thepresence or absence of retinopathy are shown in Table 4.Relationship between CAD and retinopathy: The preva-lence of CAD increased as the stage of retinopathy ad-vanced [patients with vs. without CAD: 217 (35%) vs. 410(65%) in the no diabetic retinopathy group, 54 (47%) vs. 61(53%) in the mild or moderate non-proliferative diabetic ret-inopathy group, 26 (50%) vs. 26 (50%) in the severe non-proliferative diabetic retinopathy group and 58 (57%) vs. 44(43%) in the proliferative diabetic retinopathy group; p<0.01]. Despite these differences, the results also indicatedthat CAD was present in 35% of the patients without dia-betic retinopathy and absent in 43% of the patients with  Intern Med 52: 2483-2487, 2013 DOI: 10.2169/internalmedicine.52.9444 2485 T a ble   3.   Clinic a l Ch a r a cteri s tic s  of the P a tient s   a ccor d ing to the Retino pa th y  St a ge  p value<0.01<0.01<0.05<0.050.600.15<0.05<0.01<<0.01<0.01<0.05<0.01<0.01 proliferative diabetic retinopathy10267.2 ±10.848.5±0.841/61224±12023.1±4.086.4±10.4134±2270±1376/268.4±2.0202±43159±11258±31116±3357/45520.3±1030.636/5059/4358/44severe non-proliferative diabetic retinopathy5264.2±11.747.1±2.230/22205±11423.7±4.586.5±11.5139±2075±1141/118.48±2.6211±53183±12255±20121±4535/17570.7±1101.129/1719/3326/26mild or moderate non-proliferative diabeticretinopathy11967.6±10.752.6±1.662/57180±10923.5±4.486.4±11.8137±1775±1395/248.4±2.2197±40172±13559±42111±3281/38408.0±974.351/4944/7154/61 No diabeticretinopathy62763.0±12.453.7±4.3380/247111±9724.3±3.887.6±10.8135±1978±12201/426 8.0±2.2202±38163±10656±32116±33197/43094.9±303.4304/24994/530217/410nAge(years)Age of DM diagnosis (years)Male/femaleDuration(months)Body mass index(kg/m 2 )Waist circumference(cm) Systolic blood pressure(mmHg)Diastolic blood pressure(mmHg)anti-hypertensive agents(Yes/No) HbA1c(%)(NGSP)Total cholesterol(mg/dL)Triglycerides(mg/dL)HDL cholesterol(mg/dL)LDL cholesterol(mg/dL)lipid-lowering agents (Yes/No)Microalbuminuria(mg/gCr)Smoking(+/-)Insulin therapy(+/-)CAD(Yes/No)<0.01 T a ble   4.   Multi p le Regre ss ion An a l ys e s  for the Pre s ence of Retino pa th y Independent factor Odds ratio 95% confidence interval p value     2.58 1.78–3.79 <0.01Age at DM diagnosis (<50  r   3.   2.52–5.37 <0.01Hb   %   8 1.23–2.31 <0.01Female gender 1.   1.   –2.   <0.01CAD 1.97    –2.70 <0.01 proliferative diabetic retinopathy (Figure). Discussion The present study examined risk factors for CAD and ret-inopathy in DM patients and found that age, the TG leveland smoking were independent risk factors for CAD (Ta-ble 2). An epidemiological report from the FraminghamHeart Study (11) showed that multiple lifestyle factors areassociated with the development of ischemic heart disease,and subsequent research has identified relevant risk factors,including hyper-LDL cholesterolemia, diabetes, hypertensionand smoking. The Japan Diabetes Complication Study(JDCS) reported that risk factors for ischemic heart diseaseamong the Japanese study population with diabetes were amale gender, the TG level, age and the LDL-C level (12).These studies demonstrated the LDL-C level to be a risk factor for CAD, a finding that was not confirmed in the cur-rent study. This difference is likely due to the influence of lipid-lowering medications.The current study also identified age, age of DM diagno-sis, the HbA1c level, and a female gender to be independentrisk factors for retinopathy (Table 4). Previous studies haveproposed numerous risk factors for the development andprogression of retinopathy, the most significant of which arethe duration of DM and glycemic control (13-15). In ourstudy population, the patients with advanced retinopathywere older, had an earlier age of DM onset and exhibitedelevated HbA1c levels. Although a number of reports havesuggested that there are no significant correlations between  Intern Med 52: 2483-2487, 2013 DOI: 10.2169/internalmedicine.52.9444 2486 Figure.   The p re va lence of CAD incre as e d  in ass oci a tion with the p rogre ss ion of retino pa th y . Bl a ck b a r: p ercent a ge of pa tient s  with CAD. no diabeticretinopathydiabetic retinopathy Non-CADCAD diabetic retinopathysevere proliferative non-proliferativemild or moderatenon-proliferative diabetic retinopathy retinopathy and gender (14), a WHO study (16) and a studyby Constable et al. (17) found a higher prevalence of retino-pathy among women than men, while Schanzlin et al. (18)found a higher prevalence of retinopathy among men. In thepresent study, patients with advanced stages of retinopathyhad an earlier age of DM onset, with a higher prevalence of women.Diabetic retinopathy has been shown to progress duringpregnancy (19, 20). Diabetic retinopathy is aggravated uponsex hormone administration, followed by a return to baselineafter the cessation of therapy (21). Further studies areneeded to evaluate the influence of blood coagulation andsex hormones in relation to gender with regard to the pro-gression of diabetic retinopathy as well as the duration of diabetes and blood glucose control in order to understandthe mechanisms underlying the progression of diabetic ret-inopathy.Regarding the relationship between CAD and retinopathy,our results showed that the prevalence of CAD increased inassociation with the progression of retinopathy (Figure) andthat the affected patients had the following risk factors incommon: age, duration of DM, HbA1c, albuminuria andsmoking. On the other hand, 35% of the CAD patients didnot suffer from retinopathy. Conversely, 43% of the CAD-free patients had proliferative retinopathy. Juutilainen etal. (6) and Cheung et al. (7) linked retinopathy to ischemicheart disease, and Targher et al. (8) reported that severe ret-inopathy is associated with an increased risk of cardiovascu-lar death in type 2 diabetic patients. Myocardial infarction inretinopathy patients is associated with markedly increasedrisks of cardiac failure and death (22, 23), observations thatare supported by a study conducted in Japan by Ono etal. (24). Ono et al. (24) followed up diabetic patients whounderwent coronary artery bypass graft surgery for CADand found that patients with diabetic retinopathy had an ap-proximately four-fold increased risk of postoperative deathand a three-fold increased need for repeat revascularizationand that the presence or absence of diabetic retinopathy wasan important predictor of the treatment outcome forischemic heart disease.The retinal vascular system is known to share variousanatomical and physiological characteristics with the cere-brovascular and cardiovascular systems (25). It is, therefore,highly likely that patients with diabetic retinopathy haveconcomitant arteriolar lesions in the cerebrovascular and car-diovascular systems, suggesting that retinopathy may reflectmacro- as well as microangiopathy. In the present study,some patients were in different stages of CAD and retinopa-thy progression, suggesting that CAD and retinopathy havedistinctive risk factors specific for each condition.We examined the relationship between CAD and retinopa-thy and demonstrated a link between macroangiopathy andmicroangiopathy, i.e., the prevalence of CAD increased withthe progression of retinopathy. The assessment of CAD canbe invasive, while the assessment of retinopathy requiressimple procedures, including ophthalmoscopy.Since it is difficult to distinguish macrovascular and mi-crovascular diseases, diabetic vascular disorders requirecomprehensive approaches to assessment and treatment. TheauthorsstatethattheyhavenoConflictofInterest(COI). References 1.  The Diabetic Control and Complications Trial Research Group.The effect of intensive treatment of diabetes on the development
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