Diabetes. Diabetic Retinopathy and the Risk of Coronary Heart Disease: The ARIC Study C L I N I C A L I N S I G H T S I N

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1 P r o f e s s i o n a l P o s t g r a d u a t e S e r v i c e s Release Date: August 2007 Valid Until: December 2007 Sponsor This educational activity is a component of the National Diabetes Education Initiative (NDEI ), sponsored by Professional Postgraduate Services (PPS). Professional Postgraduate Services is a business unit of KnowledgePoint360 Group, LLC, Secaucus, NJ. Clinicians who wish to receive CME credit for this educational activity should do the following: (1) read the current issue; and (2) complete the post-test and evaluation form included to conclude this CME activity. You may also complete the post-test andevaluation form on our website, To apply for CME credit,return the completed post-test and evaluation form to: Professional Postgraduate Services CME Dept. T Meadowlands Parkway Secaucus, NJ You may also fax the completed materials to 1 (201) If you have any questions, please call 1 (800) Ext Applicants will receive a certificate of participation from PPS by return mail within 6 to 8 weeks of the date of receipt of the completed evaluation form and post-test. Online applicants will automatically receive their CME credit certificate upon completion of the online post-test and evaluation form. Target Audience This educational activity is designed for primary care physicians, internal medicine specialists, endocrinologists, diabetologists, cardiologists, and other healthcare professionals involved in the care and management of patients with type 2 diabetes, insulin resistance, and cardiovascular disease. Learning Objectives With information from the latest evidencebased studies, participants should be able to: Identify patients with insulin resistance, type 2 diabetes, and/or cardiovascular disease Select the most appropriate therapeutic regimen for patients with type 2 diabetes and its macrovascular and microvascular complications Identify risk factors for cardiovascular disease in patients with type 2 diabetes and select an appropriate therapeutic regimen Accreditation Professional Postgraduate Services is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. Professional Postgraduate Services designates this educational activity for a maximum of.75 AMA PRA Category 1 Credit. Physicians should only claim credit commensurate with the extent of their participation in the activity. Grantor This CME activity is supported by an educational grant from Takeda Pharmaceuticals North America, Inc. Off-Label Disclosure Some of the drug treatments discussed in this issue may note uses not approved by the Food and Drug Administration. Articles containing such uses will be noted at the end of the article. C L I N I C A L I N S I G H T S I N Diabetes V O L U M E 1 0, N U M B E R 8 A U G U S T MAYER B. DAVIDSON, MD,* CO-EDITOR-IN-CHIEF; BERNARD ZINMAN, MD, REVIEWER; TERRENCE F. FAGAN, MANAGING EDITOR AND CO-WRITER; MARK A. PALANGIO, CO-WRITER; MICHELE SALERNITANO, CO-WRITER Diabetic Retinopathy and the Risk of Coronary Heart Disease: The ARIC Study M acrovascular disease is the primary pathogenic mechanism for coronary heart disease (CHD), a leading cause of mortality in patients with type 2 diabetes. Microvascular disease also plays a prominent role in diabetes complications, and diabetic retinopathy is a marker of microvascular disease. To determine if diabetic retinopathy might also be a marker for incident CHD, Cheung and colleagues examined the relation of diabetic retinopathy to incident CHD in a populationbased, prospective cohort of men and women with type 2 diabetes in the Atherosclerosis Risk In Communities (ARIC) Study. The ARIC Study included 15,792 individuals aged 45 to 64 years at first examination between , with a second examination between , and a third between , when retinal photographs were taken of all patients. The 1,524 patients with diabetes in this study had at least 1 retinal photograph gradable according to the Early Treatment of Diabetic Retinopathy Study severity scale, which categorized retinopathy as absent, mild/moderate (nonproliferative), and severe (nonproliferative and proliferative). Patients were free of prevalent CHD and stroke at the time of the retinal photograph. During 7.8 years of follow-up after the retinal photography, the researchers examined incident CHD events in the cohort defined as a fatal CHD event, an incident myocardial infarction (MI), or a myocardial revascularization procedure. They compared unadjusted survival curves by retinopathy levels and determined the hazard rate (HR) ratio for CHD/retinopathy relation using Cox regression, adjusting for sex, race, age, research center, education, diabetes duration and medications, 6-year mean arterial blood pressure, cigarette smoking, antihypertensive treatment, fasting glucose, A1C, body mass index, triglycerides, and total and high-density lipoprotein cholesterol levels. Of the 1,524 participants, 214 (14.7%) had diabetic retinopathy. There were 209 incident CHD events during the 7.8 years of follow-up, including 34 fatal CHD, 110 incident MIs, and 154 cardiac revascularization procedures. After adjusting for multivariate risk factors, diabetic retinopathy was associated with an HR of 2.07 for incident CHD and 3.35 for fatal CHD. CHD risk increased with the severity of retinopathy (HR 1.96 for mild/moderate retinopathy vs HR 2.69 for moderate/severe retinopathy). Diabetic retinopathy was also associated with cardiac revascularization (HR 1.93) and incident MI (HR 1.88), and it remained significant even after adjusting for carotid artery intima-media thickness, inflammatory markers, and nephropathy. The association was significant in men and women with and without hypertension. The authors noted study limitations including the use of one retinal photograph per patient (taken without pharmacologic pupil dilation) for grading, with a high proportion of photographs that couldn t be graded, possibly leading to an underestimation of retinopathy cases. They suggest, however, that a greater number of cases would make the CHD risk stronger in their study. The authors conclude that the study demonstrates an association of diabetic retinopathy with incident CHD independent of diabetes duration and control, cardiovascular risk factors, and large artery atherosclerosis. This supports the concept that microvascular disease may contribute to CHD risk. They suggest that diabetes patients with retinopathy may warrant a more robust cardiovascular assessment and follow-up. Cheung N et al. Diabetic retinopathy and the risk of coronary heart disease: the Atherosclerosis Risk in Communities Study. Diabetes Care. 2007;30: * Dr Davidson is Director, Clinical Center of Research Excellence at Charles R. Drew University, Los Angeles, California. He has indicated the following relevant financial relationships: consultant for Amgen Pharmaceuticals, Amylin Pharmaceuticals, Daiichi Sankyo, Inc. and speaker s bureau member with Amylin Pharmaceuticals, Eli Lilly and Company, and Merck & Co., Inc. Dr Zinman is Director, Leadership Sinai Center for Diabetes, Mt. Sinai Hospital, Toronto, Canada. He has indicated the following relevant financial relationships: grant/research support from Eli Lilly & Company, GlaxoSmithKline, Merck & Co., Inc., Novartis Pharmaceuticals Corporation, and Novo Nordisk A/S; retained consultant for Amylin, Eli Lily & Company, GlaxoSmithKline, Johnson & Johnson, Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Pfizer Inc, and Sanofi-Aventis; speaker s bureau for Eli Lilly & Company, GlaxoSmithKline, Merck & Co., Inc., and Novartis Pharmaceuticals Corporation. PPS staff members Managing Editor Terrence Fagan, Senior Medical Writer Mark Palangio, Writer Michele Salernitano, Program Manager Cynthia Fontan, and CME Program Manager Wadee ah Terry have indicated no relevant financial relationships. 1

2 COMMENTARY BERNARD ZINMAN, MD, Director, Leadership Sinai Center for Diabetes, Mt. Sinai Hospital, Toronto, Canada. The article by Cheung et al clearly demonstrates that there is a relationship between microvascular complications, in this case diabetic retinopathy, and coronary heart disease (CHD). Although possible, there is little evidence that this association represents a cause-and-effect relationship between the microvascular and macrovascular complications of diabetes. Rather, there is robust data in type 1 diabetes studies particularly from the DCCT/EDIC (Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications) study that glycemic control, as assessed by A1C, plays an important pivotal role in the development of both microvascular and macrovascular diabetes complications. In type 2 diabetes, the traditional cardiovascular risk factors are clearly important determinants of CHD and need to be actively targeted. It is indeed interesting that Cheung et al were able to demonstrate that, after adjusting for traditional risk factors, retinopathy was still associated with CHD. Thus it is conceivable that other nontraditional metabolic determinants are contributing to this association. On-Demand CME Activity at A 54-Year-Old Taxi Driver Who Presents for Reassessment of His Type 2 Diabetes and New Dyspnea on Exertion. For primary care physicians and other healthcare professionals involved in the care of patients with type 2 diabetes. Earn.75 AMA PRA Category 1 Credit Free. On-Demand CME Activity at Incretins and Glycemic Control: Understanding the Science for Better Diabetes Management. For primary care physicians, endocrinologisits, and nurse practitioners. Earn 2.5 AMA PRA Category 1 Credits and 2.4 AANP contact hours Free. Incretin Levels and Effect Are Markedly Enhanced 1 Month After Roux-en-Y Gastric Bypass Surgery in Obese Patients With Type 2 Diabetes S tudies have shown that the majority of patients who undergo bariatric surgery lose 50% to 70% of excess body weight, and 77% of patients who test positive for diabetes before surgery are free of diabetes after surgery. Laferrère and colleagues designed a study to determine the role of incretins in insulin improvement in patients with diabetes who undergo Roux-en-Y gastric bypass surgery (RY-GBP). They selected 8 women patients with a mean age of 45 years with type 2 diabetes of 20.1±12.9 months duration, with a body mass index (BMI) >35 kg/m 2 (obese) and an A1C of 6.9%±0.7%. These patients were not taking insulin, thiazolidinediones, or β-blockers before RY- GBP, or any diabetes medications after surgery. Seven obese women without diabetes and taking no medications were recruited as control subjects, with similar age, body weight, and BMI. Only the women in the diabetes group underwent RY-GBP surgery. Liver enzymes, thyroid function, and blood pressure were measured both at baseline and 1 month after RY-GBP surgery. Baseline measurements showed that fasting and glucose-stimulated levels of glucagon-like peptide-1 (GLP-1) and gastric inhibitory peptide (GIP) were approximately equivalent between patients with diabetes and control subjects before surgery. GIP is secreted by the K cells in the proximal small intestine, and GLP-1 is secreted by the L cells of the distal small intestine. These 2 incretins affect postprandial insulin secretion and are impaired in patients with diabetes. One month after RY-GBP surgery, a substantial reduction in both body weight (9.2±7.0 kg; P=0.008) and BMI (3.5±3.6 kg/m 2 ; P=0.029) was observed, along with reductions in both fasting glucose (1.60±1.45 mmol/l; P=0.017) and 120-min glucose (4.10±1.62 mmol/l; P<0.0001) levels, which brought the 8 patients with presurgery diabetes into the nondiabetic range. In addition, a substantial increase in insulin levels was shown. During the 1 month directly following the RY-GBP surgery, investigators administered an oral glucose tolerance test (OGTT) and an isoglycemic intravenous glucose test (IsoG IVGT), both consisting of 50 g of glucose, in the morning on 2 separate occasions less than 5 days apart, following a 12-hour overnight fast. Blood was sampled periodically during the 3-hour testing period. OGTT blood samples were compared with those of the IsoG IVGT, and the difference in β-cell responses (measured as insulin total area under the curve [INS area under the curve {AUC} min]) was considered the incretin effect. Analysis found that GLP-1 AUC and peak GIP increased significantly after RY-GBP surgery by 24.3±7.9 pmol 1 1- min -1 (P<0.0001) and 131±85 pg/ml (P=0.007), respectively. A significant increase in the blunted incretin effect, from 7.6%±28.7% to 42.5%±11.3% (P=0.005), was also observed. Investigators concluded that RY-GBP surgery had a very rapid effect on incretin production and activity, occurring less than 1 month after surgery. This incretin effect greatly increased glucose-induced insulin secretion, which resulted in a substantial improvement in diabetes management. Although promising, this study was conducted on a very small group of women with similar ethnic backgrounds. Further testing should be conducted to assess these effects on a larger and more diverse group of participants. Laferrère B et al. Incretin levels and effect are markedly enhanced 1 month after Roux-en-Y gastric bypass surgery in obese patients with type 2 diabetes. Diabetes Care. 2007;30:

3 NDEI Breakfast Symposium Diabetes Expert Forum The Role of Incretin Therapy in Your Practice Friday, October 5, 2007 Chicago, Illinois 6:00 AM-7:45 AM CME Credit: 1.25 AMA PRA Category 1 Credits TM and 1.25 Prescribed credits. Free registration online at CME/CE Dinner Meeting in Orange ange,, CA for Managed Care Providers Type 2 Diabetes, Metabolic Syndrome, and CVD: Clinical Implications of Recent Pivotal Trials. Date: Wednesday, September 26, 2007 at 6:30 PM. Speaker: Steven V. Edelman, MD. Free registration online at No Impact on All-Cause Mortality With Various Oral Antihyperglycemic Agents Relative to Sulfonylurea P revious work has not revealed a definitive relationship between oral antihyperglycemic drug therapy and mortality. With this in mind, Kahler and colleagues evaluated the impact of several classes of oral antihyperglycemic agents relative to sulfonylurea monotherapy on allcause mortality among a cohort of patients with diabetes from the Veterans Health Administration (VHA). This retrospective cohort study used data obtained from the VHA Diabetes Epidemiology Cohort, which is an ongoing study of virtually all VHA patients with diabetes since October Individuals using oral antihyperglycemic agents were stratified into the following groups: sulfonylurea monotherapy, metformin monotherapy, metformin plus sulfonylurea, thiazolidinedione (TZD) alone or in combination with other oral agents, and no drug therapy. Drug effects on all-cause mortality were estimated using multivariate mixed models. The analysis was restricted to individuals who responded to the 1999 Large Health Survey of Veteran Enrollees (LHSVE) between April 1999 and April Sensitivity analysis odds ratios were adjusted for propensity score plus age, diabetes duration, A1C, creatinine level, diabetes-related physician visits, and utilization of lipid-lowering and hypertension medications. A total of 39,721 patients with diabetes who responded to the LHSVE and received care from 125 US medical facilities were included in the study. Among this study population, 48.0% of patients were in the reference (sulfonylurea monotherapy) group, 7.5% were in the metformin group, 34.8% were in the metformin in combination with sulfonylurea group, 1.7% were in the TZD group, and 8.0% were in the no-drug-therapy group. Mortality rates were 5.3% with sulfonylurea monotherapy, 2.7% with metformin monotherapy, 3.4% with metformin plus sulfonylurea, 7.1% with TZD alone or in combination with other oral agents, and 4.1% with no drug therapy. Adjusted odds ratios and 95% confidence intervals for all-cause mortality were 0.87 ( ) for metformin monotherapy, 0.92 ( ) for metformin plus sulfonylurea, and 1.04 ( ) for TZD, relative to sulfonylurea monotherapy. Adjusting odds ratios without A1C yielded similar findings, indicating the robustness of the original results. This analysis did not reveal any significant drug effect on all-cause mortality for any oral antihyperglycemic therapy relative to oral sulfonylurea monotherapy. The investigators pointed out that this study had the distinctive ability to control for various variables that are usually not available in database studies. Limitations of the study included use of administrative databases and short duration of the follow-up period. Additional study is needed to evaluate whether long-term use of oral antihyperglycemic drug therapy reduces all-cause and cause-specific mortality. Kahler KH et al. Impact of oral antihyperglycemic therapy on all-cause mortality among patients with diabetes in the Veterans Health Administration. Diabetes Care. 2007;30: AOA/ACOFP 112th Annual Convention & Scientific Seminar Joint ACOFP/AOA Scientific Lecture and Dinner ner Sunday, September 30, 2007 San Diego, California 5:30 PM 9:00 PM CME Hours: 3.5 Extra Credit Register online at: 3 3

4 Clinical Insights in Diabetes Post-Test August ) In the ARIC Study, results showed that diabetic retinopathy was associated with increased risk of: a. Stroke b. Nephropathy c. Coronary heart disease d. Neuropathy 2) In a sub-study focusing on incretin levels in 8 obese women with diabetes, which of the following was an effect in the participants 1 month following Roux-en-Y gastric bypass surgery? a. Significant increase in incretin effects b. Significant decrease in body weight c. Reduction in glucose levels to nondiabetic range d. All of the above 3) Relative to sulfonylurea oral monotherapy, Kahler and colleagues found a significant drug effect on all-cause mortality with: a. Metformin monotherapy b. Thiazolidinedione monotherapy c. Metformin plus sulfonylurea therapy d. No significant drug effect was found ANSWER KEY NDEI MISSION STATEMENT The National Diabetes Education Initiative (NDEI ) is a multicomponent educational program on type 2 diabetes designed for endocrinologists, diabetologists, cardiologists, primary care physicians, and other healthcare professionals involved in the care and management of patients with type 2 diabetes and insulin resistance. NDEI programs address issues concerning insulin resistance and type 2 diabetes, from the epidemiology and pathophysiology of the disease and its associated complications to the therapeutic options for treatment and prevention. National Diabetes Education Initiative, NDEI, and Clinical Insights are trademarks used herein under license. Copyright 2007 Professional Postgraduate Services. All rights reserved. For more information about upcoming NDEI CME and CE activities, visit us at or call 1 (800) Visit for information on other CME or CE activities. Clinical Insights in Diabetes, Monthly is co-edited by NDEI faculty members Mayer B. Davidson, MD, and Silvio E. Inzucchi, MD. Clinical Insights in Diabetes monthly CME e-newsletter is available at no cost to you via . To subscribe to receive future issues via , please visit us online at or insert your name and address below and fax this page back to 1 (800) Name: (Please print) Specialty: Address: You have received this because we believe it may be of interest to you. If you would like your name to be removed from the Clinical Insights newsletter list, please click on the following link EM-T196-5-PHYCME

5 Activity Code: T196-5 Issue Date: August 2007 CME Credit Availability: Through December 2007 CME Activity Evaluation/Registration Form Participants who wish to obtain CME credit for this educational activity, please complete the contact information below, sign this form, and fax it with the completed post-test to 1 (201) or mail to: Professional Postgraduate Services, CME Dept. T196, 150 Meadowlands Parkway, Secaucus, NJ You may download previous issues of Clinical Insights in Diabetes e-newsletters by visiting us online at I have completed this activity as designed: (Signature) PLEASE PRINT CLEARLY: Name: Address: City: Phone: Address: State: ZIP Code: - - Fax: - - Professional Classification: MD DO PharmD RN NP Other Specialty: Endocrinology Cardiology Internal medicine Family medicine Other 1. The activity met the stated objectives in such a way that I am better able to: a. Identify patients with insulin resistance, type 2 diabetes, and/or cardiovascular disease b. Select the most appropriate therapeutic regimen for patients with type 2 diabetes and its macrovascular and microvascular complications c. Identify risk factors for cardiovascular disease in patients with type 2 diabetes and select an appropriate therapeutic regimen Strongly Disagree Disagree Agree Strongly Agree 2. Overall, the activity was presented in a fair-balanced manner. Yes No* * If you checked No, please explain. 3. Overall, the activity was free from commercial bias. Yes No* * If you checked No, please explain. 4. In reflecting on your practice, what type of impact will this educational activity have? This program has validated my practice in the treatment of type 2 diabetes and its cardiovascular complications. Need more information before making a change. (Please specify what information you would require.) 5. What is the largest challenge or unmet educational need in your practice? 6. What other clinical issues are you and your colleagues challenged by that could be addressed in a CME activity? (Please specify.) Thank you for your participation. 5 5