Ppscme Ndei Clinical Insights In Diabetes September 2008

Professional Postgraduate Services®

CLINICAL INSIGHTS® IN

Diabetes

Release Date: September 2007 Valid Until: January 2008 Sponsor This educational activity is a component of the® ® National Diabetes Education Initiative (NDEI ), sponsored by Professional Postgraduate ® Services (PPS). 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 posttest and evaluation form on our website, www.ndei.org. To apply for CME credit,return the completed post-test and evaluation form to: ®

Professional Postgraduate Services CME Dept. T196 150 Meadowlands Parkway Secaucus, NJ 07094-1505

You may also fax the completed materials to 1 (201) 430-1441. If you have any questions, please call 1 (800) 606-6106 Ext. 6014. 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 evidence-based 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. AAFP credit Clinical Insights in Diabetes has been reviewed and is acceptable for up to 9 Prescribed credits by the American Academy of Family Physicians. AAFP accreditation begins 5/1/07. Term of approval is for one year from this date. This issue is approved for .75 Prescribed credit. Credit may be claimed for one year from the date of this issue. 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. Professional Postgraduate Services is a business unit of KnowledgePoint360 Group, LLC, Secaucus, NJ.

VOLUME 10, NUMBER 9 • SEPTEMBER 2007 †

SILVIO E. INZUCCHI, MD,* CO-EDITOR-IN-CHIEF; JAMES W. REED, MD, REVIEWER; ‡ ‡ TERRENCE F. FAGAN, MANAGING EDITOR AND CO-WRITER; CHING-LING CHEN, PhD CO-WRITER

An Analysis of Thiazolidinediones and Heart Failure Risk

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hiazolidinediones (TZDs) play an important role in the treatment of patients with type 2 diabetes. This class of drugs, however, also presents a greater risk for edema and the development of heart failure in some patients. Singh and colleagues performed an analysis to gauge the magnitude and characteristics of the possible role of TZDs in the risk of heart failure. The analysis used data from randomized controlled trials (RCTs) and controlled observational studies to estimate the magnitude of risk; it also used data from published case reports and spontaneous reports from the Canadian Drug Reaction Monitoring Program (CADRMP) to classify specific characteristics of adverse effects. The researchers compiled the results into a teleoanalysis, which combines data from different types of studies to determine the adverse effect of a drug. The RCTs included 3 trials with a total of 10,731 patients. The trials were direct comparisons between a TZD (pioglitazone or rosiglitazone) alone and placebo alone, of at least 6 months’ duration of TZD use for preventing or treating type 2 diabetes, and they were designed to provide numerical data on patients experiencing heart failure. The observational studies included 67,382 patients. The authors also identified 28 published case reports and 1,025 spontaneous reports, reviewing all adverse drug reactions reported to CADRMP for pioglitazone (n=195) or rosiglitazone (n=830). Excluding reports of edema alone, a total of 51 reports of heart failure with pioglitazone and 163 with rosiglitazone were identified. The pooled odds ratio for heart failure in patients randomized to TZDs compared with patients on placebo was 2.10 (95% confidence interval [CI], 1.08-4.08; P=0.03) in the RCTs and 1.55 (95% CI, 1.33-1.80; P<0.00001) in the observational studies. A dose-time susceptibility analysis among 99 analyzable cases showed a

median duration of 24 weeks (range: 1 week– 260 weeks) for the onset of heart failure. An analysis of 162 analyzable cases showed heart failure in subjects ranging in age from 31 to 88 years, with a median age of 67 years; 42 patients (26%) were younger than 60 years. Number needed for heart failure with TZDs was approximately 50 subjects over 2.2 years. No susceptibility factors were identified, with heart failure occurring equally in high and low doses and in men and women. Nine cases were fatal. The authors noted limitations to the analysis. Heart failure diagnosis is often subjective, possibly leading to heterogeneity in some studies. In 2 of the 3 RCTs, however, heart failure information was independently adjudicated, and all 3 RCTs were specifically designed to ascertain heart failure cases. It is noted that diabetes and the use of any treatment is associated with an increased risk of heart failure. The class effect of TZDs is mediated through increased plasma volume rather than any direct effect on the myocardium. Fluid retention from TZDs may trigger clinically apparent episodes of heart failure, or latent heart failure, in susceptible people. The authors concluded that this teleoanalysis confirms the increased magnitude of risk of heart failure with the use of TZDs in patients with diabetes, and suggests existing guidelines and package inserts may need to be revised to incorporate these increased risk characteristics.

Singh S et al. Thiazolidinediones and heart failure: a teleo-analysis. Diabetes Care. 2007;30:2148-2153.

Editor’s Note: In August 2007, the US Food and Drug Administration ordered a boxed warning for heart failure risk to be added to the drug labeling for the entire TZD class of drugs.

* Dr Inzucchi is a Professor of Medicine at Yale University School of Medicine and Clinical Director, Section of Endocrinology, Yale-New Haven Hospital, New Haven, Connecticut. He has indicated the following relevant financial relationships: retained consultant, Daiichi Sankyo, Merck & Co., Inc., Novartis, Novo Nordisk, Pfizer Inc, and Takeda Pharmaceuticals North America, Inc.; speakers bureau, Merck & Co., Inc., and Takeda Pharmaceuticals North America, Inc.; received grant research support from Eli Lilly and Company. † James W. Reed, MD, FACE, FACP is chief of endocrinology at Morehouse School of Medicine in Atlanta, GA; chief of internal medicine at Grady Memorial Hospital and professor of medicine and associate chair of medicine for research at Morehouse School of Medicine, Atlanta, Georgia. Dr Reed is also a medical consultant at Tuskegee Veterans Administration Hospital, Alabama. He has indicated the following relevant financial relationships: retained consultant for Abbott Labs, Eli Lilly and Company, and King Pharmaceuticals; speakers bureau for Abbott Labs and Pfizer, Inc. ‡ PPS staff members Managing Editor Terrence Fagan, Senior Medical Writer Ching-Ling Chen, PhD, Program Manager Cynthia Fontan, and CME Program Manager Wadee’ah Terry have indicated no relevant financial relationships.

CLINICAL INSIGHTS

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IN DIABETES

COMMENTARY JAMES W. REED, MD. Professor of Medicine, Chief of Endocrinology, and Associate Chair of Medicine for Research, Morehouse School of Medicine; Chief of Internal Medicine Service at Grady Memorial Hospital for Morehouse School of Medicine, Atlanta, Georgia.

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On-Demand CME Activity at www.ndei.org: “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 www.ndei.org: “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.

This article analyzed heart failure risk using a type of meta-analysis using the drug reporting system from the Canadian Drug Reaction Monitoring Program for adverse effects. In addition to using clinical trial data, it included spontaneous reports and case reports in a teleo-analysis. It included both pioglitazone and rosiglitazone so it considers heart failure a class effect. It confirms what has been previously known about edema as a side effect of the thiazolidinediones (TZDs). The combined odds ratio from controlled clinical trials is 2.10 for heart failure. It is important to note that there is no sex difference or dose relation difference. The study’s conclusion that the effect of TZDs is mediated through fluid retention rather than a direct effect upon the myocardium is reasonable but will need further investigation to prove. The article does not shed any further light on the coronary artery disease risk that is currently being debated for rosiglitazone.

Mortality Rates Reduced in Men but Not in Women With Diabetes, 1971 to 2000

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he management of diabetes and certain associated cardiovascular disease (CVD) risk factors has substantially improved among US adults with diabetes in recent years. It is, however, unclear whether mortality rates have also declined among these patients. The only nationally representative study designed to examine mortality rates among adults with diabetes between 1971 and 1992 found no improvement. In addition, no national studies of mortality trends in this group have extended through the 1990s, a period with significant advancement in the management of diabetes and CVD. In the present study, Gregg and colleagues reviewed 3 consecutive nationally representative population-based health surveys, the National Health and Nutrition Examination Surveys (NHANES). The surveys were conducted from 1971 to 1975 (NHANES I), 1976 to 1980 (NHANES II), and 1988 to 1994 (NHANES III), and all-cause and CVD mortality rates were determined with a follow-up of 12.2 years through 1986, 1992, and 2000 for the 3 surveys, respectively. Participants were limited to adults aged 35 to 74 years. Diabetes was determined by self-report. In the population without diabetes (both men and women), all-cause mortality rates decreased from 14.4 to 9.5 annual deaths per 1,000 persons (P<0.001) and CVD death rates declined from 7.0 to 3.4 annual deaths per 1,000 persons (P<0.001) between the periods of 1971 to 1986 and 1988 to 2000. In adults with diabetes, however, the decline in mortality rates was limited to men with the disease, and not women. Among the men, the all-cause mortality rate declined from 42.6 to 24.4 annual deaths per 1,000 persons (P=0.03) between 1971 to 1986 and 1988 to 2000. CVD mortality for men with diabetes also declined, from 26.4 to 12.8 annual

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deaths per 1,000 persons between 1971 to 1986 and 1988 to 2000 (P=0.06). Among women with diabetes, however, the all-cause mortality rate increased (18.4 to 25.9 annual deaths per 1,000 persons) and CVD mortality rates barely declined (10.5 to 9.4 annual deaths per 1,000 persons) between 1971 to 1986 and 1988 to 2000. Moreover, the all-cause mortality rate difference between women with and without diabetes more than doubled between 1971 to 1986 and 1988 to 2000, from a difference of 8.3 to 18.2 annual deaths per 1,000 persons (P=0.04). In addition, the differences in all-cause mortality rates by sex in adults with diabetes has evaporated, from a male:female rate of 42.6 vs 18.4 annual deaths per 1,000 persons in 1971-1986 to 24.4 vs 25.9 in 1988 to 2000. The authors concluded that the decline in mortality rates among persons with diabetes has been limited to men, the disparity in mortality rates between women with and without diabetes has worsened, and that the female-to-male advantage in mortality rates among adults with diabetes has been eliminated. They suggest further research to establish the causes for these findings, and recommend increased efforts to reduce excess mortality risk among men and particularly among women with diabetes.

Gregg EW et al. Mortality trends in men and women with diabetes, 1971 to 2000. Ann Intern Med. 2007;147:149-155.

CLINICAL INSIGHTS® IN DIABETES

Decreased Myocardial Reperfusion in Patients With Diabetes Undergoing Percutaneous Coronary Intervention for ST-Segment Elevation Acute Myocardial Infarction: the EMERALD Trial

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Biology of Leg Disorders™ (BOLD™) Initiative COMING TO A LOCATION NEAR YOU! A 25-City Educational Simulcast Differentiating Leg Disorders: Strategies for Diagnosis and Treatment in the Primary Care Setting Broadcast simultaneously to 25 exclusive sites across the country, this certified activity will include an in-depth review of the multiple pathways involved in dozens of leg disorders, focusing on the challenge of differential diagnosis, often complicated by primary and secondary symptoms and comorbid disease, and a critical examination of treatment options.

ype 2 diabetes was shown to increase cardiovascular morbidity and mortality in patients with ST-segment elevation myocardial infarction (MI). To improve the poor prognosis in patients with diabetes and ST-segment elevation MI, Marso and colleagues investigated the effectiveness of primary percutaneous coronary intervention (PCI) in establishing myocardial perfusion in patients with diabetes versus those without diabetes in the Enhanced Myocardial Efficacy and Removal by Aspiration of Liberated Debris (EMERALD) trial. The EMERALD trial was a prospective, randomized, multicenter study evaluating distal embolic protection during primary PCI in ST-segment elevation MI. Using the EMERALD database, the authors compared myocardial perfusion and infarct sizes between patients with and without diabetes undergoing PCI for acute ST-segment elevation MI. Endpoints of this study included final myocardial blush grade (MBG), rates of complete ST-segment resolution (STR) 30 minutes after PCI, and final infarct size as determined by computed tomography measured between days 5 and 14. Of 501 patients enrolled in the EMERALD study, 62 (12%) had type 2 diabetes. A higher incidence of hypertension and dyslipidemia was noted in patients with diabetes. Myocardial perfusion after PCI was significantly decreased in patients with diabetes as measured by MBG 0/1 (34% vs 16%; P=0.002) immediately after the PCI procedure and lower rates of complete STR at 30 minutes (45% vs 65%; P=0.005). Consistent with impaired myocardial reperfusion, final infarct

size was substantially larger in patients with diabetes than those without diabetes (median 20% vs 11%; P=0.005). This was true for left anterior descending and non-left anterior descending infarctions. Additionally, development of new-onset severe congestive heart failure at 6 months (6% vs 1%; P=0.04), and 30-day mortality (10% vs 1%; P<0.001) were also greater in patients with diabetes. After multivariate adjustment, diabetes remained a significant factor associated with incomplete STR at 30 minutes and mortality at 6 months. Use of distal protection devices did not improve outcomes of myocardial reperfusion in patients with or without type 2 diabetes with ST-segment elevation MI. The findings by Marso and associates confirmed the previous observations from the Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) trial demonstrating the deleterious effect of diabetes on myocardial reperfusion after primary PCI. The investigators concluded that diabetes is an independent predictor of decreased myocardial reperfusion, larger infarct, development of congestive heart failure, and decreased survival, in patients with ST-segment elevation MI undergoing primary PCI.

Marso SP et al. Comparison of myocardial reperfusion in patients undergoing percutaneous coronary intervention in ST-segment elevation acute myocardial infarction with versus without diabetes mellitus (from the EMERALD Trial). Am J Cardiol. 2007;100:206-210.

AOA/ACOFP 112th Annual Convention & Scientific Seminar Joint ACOFP/AOA Scientific Lecture and Dinner Achieving Glycemic Control in Type 2 Diabetes: The Role of Incretins in Meeting Old Challenges with New Strategies: An Interactive Case-Based Discussion

Saturday, November 3, 2007 – 3.0 CME/CE Credits

Sunday, September 30, 2007 San Diego, California 5:30 PM–9:00 PM

Register on LegDisorders.org

CME Hours: 3.5 Extra Credit Register online at: www.acofp.org/education/CA_07/index.html

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 TM

CME Credit: 1.25 AMA PRA Category 1 Credits Register online at www.ndei.org

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and 2.25 AAFP Prescribed credits (EB/CME).

CLINICAL INSIGHTS® IN DIABETES

®

Clinical Insights in Diabetes Post-Test September 2007 1) In an analysis of the possible role of thiazolidinedione (TZD) use in the risk of heart failure, Singh and colleagues noted all but one of the following: a. Use of TZDs is associated with an increased magnitude of risk of heart failure in some patients with diabetes b. The class effect of TZDs is mediated through increased plasma volume, not any direct effect on the myocardium c. Diabetes and the use of any treatment is associated with an increased risk of heart failure d. Heart failure was more likely to occur in women taking higher doses of TZDs 2) Which one of the following was not shown in a study by Gregg and colleagues comparing mortality rates in US adults with and without diabetes between 1971 and 2000? a. All-cause mortality rates declined in women with diabetes b. All-cause mortality rates increased in women with diabetes c. CVD mortality rates declined in both men and women with diabetes d. All-cause mortality rates declined in men with diabetes 3) In patients with diabetes and ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention, diabetes is an independent predictor of all but one of the following: a. Larger infarct b. Increased myocardial reperfusion c. Development of congestive heart failure d. Decreased survival

ANSWER KEY

Copyright © 2007 Professional ® Postgraduate Services . All rights reserved.

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National Diabetes Education Initiative, NDEI, and Clinical Insights are trademarks used herein under license.

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d. Heart failure was more likely to occur in women taking higher doses of TZDs. No susceptibility factors were identified, with heart failure occurring equally in high and low doses and in men and women. a. All-cause mortality rates declined in women with diabetes. Among women with diabetes, the all-cause mortality rate increased (18.4 to 25.9 annual deaths per 1,000 persons) between 1971 to 1986 and 1988 to 2000. b. Increased myocardial reperfusion. Myocardial reperfusion after percutaneous coronary intervention (PCI) was significantly decreased in patients with diabetes immediately after the PCI procedure.

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.

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NDEI MISSION STATEMENT

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Clinical Insights® in Diabetes is co-edited by NDEI faculty members Mayer B. Davidson, MD, and Silvio E. Inzucchi, MD.

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CLINICAL INSIGHTS

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Activity Code: T196-6 Issue Date: September 2007 CME Credit Availability: Through January 2008

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) 430-1441 or mail to: Professional Postgraduate Services , CME Dept. T196, 150 ® Meadowlands Parkway, Secaucus, NJ 07094-1505. You may download previous issues of Clinical Insights in Diabetes e-newsletters by visiting us online at www.ndei.org.

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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 2. Overall, the activity was presented in a fair-balanced manner.

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3. Overall, the activity was free from commercial bias. * 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