Ppscme Clinical Insights In Diabetes October 2008

Professional Postgraduate Services®

CLINICAL INSIGHTS® IN

Diabetes

Release Date: October 2007 Valid Through: February 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.

VOLUME 10, NUMBER 10 • OCTOBER 2007 †

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

The Association of Nonalcoholic Fatty Liver Disease With CVD Event Risk in Patients With Type 2 Diabetes

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ecent data suggest that the presence of nonalcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes may lead to increased risk of cardiovascular disease (CVD) independent of components of the metabolic syndrome. To test this hypothesis, Targher and colleagues assessed whether an ultrasound diagnosis of NAFLD predicted the risk of incident CVD events in a large cohort of adults with type 2 diabetes. Study subjects were outpatients with type 2 diabetes (n=2,103) in the Valpolicella (Italy) Heart Diabetes Study. During 6.5 years of follow-up (range: 5 to 84 months), 384 patients developed CVD events (151 nonfatal myocardial infarctions [MI], 68 coronary revascularizations, 44 cases of nonfatal ischemic stroke, and 121 cardiovascular deaths). These patients were older, had higher A1C levels and liver enzymes, a greater prevalence of metabolic syndrome, and a higher frequency of NAFLD than those without CVD events. Diabetes duration, LDL cholesterol, sex, smoking, and treatment did not differ between the groups. In multivariate regression analysis, NAFLD was significantly associated with an almost doubling of incident CVD events (hazard ratio [HR], 1.96; 95% confidence interval [CI], 1.4-2.7; P<0.001) after adjusting for age, A1C, diabetes duration, smoking, sex, LDL cholesterol, and medications. Surprisingly, further adjustment

for metabolic syndrome had little effect on the association (HR, 1.87; 95% CI, 1.2-2.6; P<0.001). Adjusting for individual components of the metabolic syndrome and/or liver enzymes produced nearly identical results. Normal liver enzyme measurements showed little diagnostic or prognostic value when assessing patients for NAFLD; 86% of participants with NAFLD had liver enzyme measurements within the reference range. The study’s limitations included a lack of direct measurements of abdominal visceral fat and insulin resistance, precluding the ruling out of possible independent contributions of these factors to accelerated CVD in NAFLD. Also, the diagnosis of NAFLD was based on ultrasonography without a confirmatory biopsy. While this perhaps may cause the overlooking of some diagnoses of underlying NAFLD, this would make the study’s estimates of the association conservative. The authors concluded that NAFLD is significantly associated with increased risk of CVD events, independent of numerous additional CVD risk factors.

Targher G et al. Nonalcoholic fatty liver disease is independently associated with an increased incidence of cardiovascular events in type 2 diabetic patients. Diabetes Care. 2007;30:2119-2121.

COMMENTARY SILVIO E. INZUCCHI, MD. Professor of Medicine, Yale University School of Medicine, and Clinical Director, Section of Endocrinology, Yale-New Haven Hospital, New Haven, Connecticut. This is a very important study. Fatty liver disease, which may progress to frank cirrhosis, is enormously common in our patients with diabetes and may also occur in those with obesity, insulin resistance, and/or prediabetes as well. A near doubling of the hazard ratio for cardiovascular events in patients with steatosis is quite striking. Even more impressive is the fact that controlling for other metabolic syndrome features attenuates this relationship, but only minimally. One can only speculate about the potential mediators of this apparent link between fatty liver disease and atherosclerosis. Clearly, aggressive scientific inquiry will be required to elucidate the mechanisms involved. For the practicing clinician, the finding of abnormal liver function tests in a patient with diabetes should prompt further evaluation to determine the cause. If steatosis is present, more aggressive cardiovascular risk-factor modification would appear to be in order. * 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.

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.

† Dr Inzucchi is a Professor of Medicine at Yale University School of Medicine and Clinical Director, Section of Endocrinology, YaleNew Haven Hospital, New Haven, Connecticut. He has indicated the following relevant financial relationships: retained consultant, Merck & Co., Inc., Novartis, Novo Nordisk, 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.

Professional Postgraduate Services is a business unit of KnowledgePoint360 Group, LLC, Secaucus, NJ.

‡ PPS staff members Managing Editor Terrence Fagan, Senior Medical Writer Ching-Ling Chen, PhD, Program Manager Sydel Cohen, and CME Program Manager Wadee’ah Terry have indicated no relevant financial relationships.

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Nonfasting Triglycerides Associated With Increased Risk of Cardiovascular Events You have received this fax because we believe it may be of interest to you. If you would like your name to be removed from the ® Clinical Insights in Diabetes newsletter fax list, please follow these instructions: Call toll-free 1 (866) 860-3439, enter PIN 6114, followed by the # key and fax number.

VISIT OUR WEBSITE www.ndei.org to register for Type 2 Diabetes, Metabolic Syndrome, and CVD: Clinical Implications of Recent Pivotal Trials, A Case-Based CME/CE Dinner Meeting. This unique forum will take place on: Thursday, November 15, 2007 at 6:30 PM The Omni Los Angeles Hotel at California Plaza 251 South Olive Street Los Angeles, California

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lthough the association of triglycerides with cardiovascular disease (CVD) remains controversial, patients with moderate hypertriglyceridemia and other lipid risk factors often develop premature atherosclerosis. It has been suggested that chylomicron remnants and very low-density lipoprotein remnants in the plasma of patients with hypertriglyceridemia penetrate the arterial intima and are trapped within the arterial wall, thereby contributing to the formation of foam cells and promoting the development and progression of atherosclerosis. Since remnant lipoproteins are present in elevated nonfasting triglycerides, atherosclerosis has been considered by some a “postprandial phenomenon.” Although fasting triglycerides are routinely monitored for lipid profile, postprandial triglyceride levels may be an important measure for predicting risk of CV events. Two manuscripts recently published in the Journal of the American Medical Association provide support for the role of nonfasting triglyceride levels as an independent predictor for CV events. Copenhagen City Heart Study To test the hypothesis that very high levels of nonfasting triglycerides predict CV events including myocardial infarction (MI), ischemic heart disease (IHD), and death, Nordestgaard and colleagues conducted a large prospective cohort study involving 13,981 individuals, aged 20 to 93 years, drawn from the general population of Copenhagen, Denmark. Main outcome measures were hazard ratios (HRs) for incident MI, IHD, and death with increased levels of nonfasting triglycerides, which were stratified by 88.5 mg/dL increments into 5 groups vs a referent group of <88.5 mg/dL. During a mean follow-up of 26 years, a total of 1,793 participants (691 women and 1,102 men) developed MI, 3,479 (1,567 women and 1,912 men) developed IHD, and 7,818 (3,731 women and 4,087 men) died from all causes. Assessment of the risk of CV events with 5 categorized nonfasting triglyceride levels indicated that the cumulative incidence of MI, IHD, and death increased with increasing levels of baseline nonfasting triglycerides in both men and women (all log-rank trend tests; P<0.001). For instance, the age-adjusted HRs for incident MI among women for each respective category per 88.5 mg/dL increase in nonfasting triglyceride levels were 2.2, 4.4, 3.9, 5.1, and 16.8 (P for trend <0.001), and among men, the values were 1.6, 2.3, 3.6, 3.3, and 4.6 (P for trend <0.001), compared with triglyceride levels of <88.5 mg/dL. The same trend was observed for age-adjusted HRs for incident IHD and death from all causes in men and women. HRs for CV events were attenuated, but still significant, after further adjustment for various

potential confounders, including obesity, hypertension, diabetes, total cholesterol, smoking, and hormone therapy. A better predictive ability of nonfasting triglyceride levels was seen in women than in men. Moreover, when considered as a continuous variable, nonfasting triglyceride levels were shown to be independently predictive of MI and death in women, and of death in men. Women’s Health Study Bansal and colleagues evaluated the association of fasting and nonfasting triglyceride levels with risk of future CV events in a prospective study of 26,509 healthy women (20,118 fasting and 6,391 nonfasting) in the United States. The major outcome measures for this study were hazard ratios (HR) for incident CV events, which were a composite of confirmed nonfatal MI, nonfatal ischemic stroke, coronary revascularization, or CV death. During a median follow-up of 11.4 years, 1,001 participants experienced an incident CV event (including 276 nonfatal MIs, 265 ischemic strokes, 628 coronary revascularizations, and 163 CV deaths), for an overall rate of 3.46 CV events per 1,000 person-years of follow-up. At baseline, triglyceride levels in fasting and nonfasting women correlated with traditional cardiac risk factors and markers of metabolic syndrome and insulin resistance. Triglyceride levels were divided into tertiles for fasting (≤90 mg/dL, 91-147 mg/dL, ≥148 mg/dL) and nonfasting (≤104 mg/dL, 105-170 mg/dL, ≥171 mg/dL) groups, with the lowest tertile as the referent group. After adjusting for age, blood pressure, smoking, and use of hormone therapy, both fasting and nonfasting triglyceride levels were strongly associated with CV events. Among fasting participants, further adjustment for total and high-density lipoprotein cholesterol and for indicators of insulin resistance substantially weakened this association, rendering it nonsignificant (fully adjusted HR [95% confidence interval (CI)] for increasing tertiles of triglyceride levels with an HR of 1.21 [0.96-1.52] for the second tertile and 1.09 [0.851.41] for the third [P=0.90 for trend]). In contrast, nonfasting triglyceride levels maintained a strong and significant association with CV events in the fully adjusted models (HR [95% CI] for increasing triglyceride levels, with an HR of 1.44 [0.90-2.29] in the second tertile and 1.98 [1.213.25] in the third [P=0.006 for trend]). Additionally, in secondary analyses stratified by postprandial time, women who had eaten 2 to 4 hours prior to phlebotomy showed the strongest association of triglyceride levels with CV events (fully adjusted HR [95% CI] for highest vs lowest tertiles of triglyceride levels, 4.48 [1.98-10.15] [P<0.001 for trend]). Interestingly, this relationship progressively attenuated with longer periods after the meal. Continued

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Nonfasting Triglycerides and CV Events Continued Both studies strongly support the notion that nonfasting triglyceride levels are associated with incident CV events. Nonfasting rather than fasting triglyceride levels might therefore someday be employed in the risk assessment for CV events, particularly in women. This might actually simplify blood sampling for lipid management. Furthermore, the findings by Nordestgaard et al of the relationship of remnant lipoproteins and nonfasting triglycerides may offer options for

designing new trials or new agents that aim at reducing postprandial triglyceride levels or attenuating atherogenic metabolic abnormalities such as remnant lipoproteins. Nordestgaard BG et al. Nonfasting triglycerides and risk of myocardial infarction, ischemic heart disease, and death in men and women. JAMA. 2007;298:299-308. Bansal S et al. Fasting compared with nonfasting triglycerides and risk of cardiovascular events in women. JAMA. 2007;298:309-316.

Higher Mortality in Diabetes Following Acute Coronary Syndromes Biology of Leg Disorders™ (BOLD™) Initiative COMING TO A LOCATION NEAR YOU! A Nationwide Educational Simulcast Differentiating Leg Disorders: Strategies for Diagnosis and Treatment in the Primary Care Setting Broadcast simultaneously to 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. Saturday, November 3, 2007 – 3.0 CME/CE Credits Register on LegDisorders.org

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he rise in worldwide prevalence of type 2 diabetes raises the burden of cardiovascular disease (CVD) as well. The Framingham Heart Study reported a 3-fold increase in age-adjusted CV mortality in patients with diabetes. Approximately two thirds of patients with diabetes in the United States die from CVD. Moreover, diabetes is considered as a risk equivalent of coronary artery disease for myocardial infarction (MI) and CV mortality. It is not clear, however, whether diabetes is an independent predictor for mortality following acute coronary syndromes (ACS). In this report, Donahoe and colleagues assessed the independent effect of diabetes on mortality following ACS from a large clinical trial database covering the full spectrum of ACS and their medical therapies. Patients with ACS were pooled from 11 independent Thrombolysis in Myocardial Infarction (TIMI) Study Group clinical trials from 1997 to 2006. A total of 62,036 patients, which included 46,577 with ST-segment elevation myocardial infarction (STEMI) and 15,459 with unstable angina/non-STEMI (UA/NSTEMI), were evaluated. Among this group, 10,613 (17.1%) had self-reported diabetes. The primary outcome measures were shortterm (30 days) and long-term (1 year) mortality following ACS. Mortality rates were compared among patients with and without diabetes in 3 populations, including all patients with ACS, patients with UA/NSTEMI, and patients with STEMI. A multivariable model was generated to adjust for baseline characteristics, ACS clinical presentations, and ACS medical therapies used. Compared with patients without diabetes, those with the disease at ACS presentation were older, more often women, had a higher body mass index, and were more likely to have a history of hypertension, hyperlipidemia, previous MI, and coronary artery bypass graft surgery. These patients also had a higher TIMI risk score and a higher risk of heart failure. Patients with UA/NSTEMI had a higher prevalence of diabetes than those with STEMI (22.4% vs 15.4%; P<0.001). Additionally, among the 15,574 (25.1%) with available coronary angiography data from the index ACS hospitalization, patients with diabetes had a higher risk of multivessel

coronary disease than patients without diabetes (62.0% vs 48.1%; P<0.001). Thirty-day mortality was substantially higher in patients with diabetes than in those without diabetes following UA/NSTEMI (2.1% vs 1.1%; P<0.001) or STEMI (8.5% vs 5.4%; P<0.001). Patients with diabetes who were older than 75 years, and those with a higher risk of heart failure, decreased creatinine clearance, or increased TIMI risk score had the highest absolute mortality at 30 days regardless of ACS type. After adjusting for baseline characteristics and clinical presentations and treatment of the ACS event by multivariable modeling, diabetes was independently associated with higher 30-day mortality following UA/NSTEMI (odds ratio [OR], 1.78; 95% confidence interval [CI], 1.24-2.56) or STEMI (OR, 1.40; 95% CI, 1.241.57). The independent risk conferred by diabetes at 30 days was higher in patients with UA/NSTEMI than in patients with STEMI. One-year mortality was also significantly higher among patients with diabetes than in those without diabetes following UA/NSTEMI (7.2% vs 3.1%; P <0.001) or STEMI (13.2% vs 8.1%; P<0.001). After adjustments, diabetes remained a significant independent factor associated with all-cause mortality for patients with UA/NSTEMI (hazard ratio [HR], 1.65; 95% CI, 1.30-2.10) or with STEMI (HR, 1.22; 95% CI, 1.08-1.38) at 1 year. Study limitations include data being pooled from several clinical trials, inter-trial variability in care and diagnostic guidelines for diabetes at each site, incomplete collection of fasting glucose measurements, and inability to assess the type and duration of diabetes, features of diabetes management, and degree of glycemic control, as well as unavailability of cause of death. Donahoe and colleagues concluded that diabetes confers a significant independent increase in mortality risk at 30 days and 1 year following ACS. The investigators further suggested that despite a variety of modern therapies available for ACS, development of newer, more aggressive strategies will be needed to address this very high-risk group. Donahoe SM et al. Diabetes and mortality following acute coronary syndromes. JAMA. 2007;298:765-775.

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Clinical Insights in Diabetes Post-Test October 2007 1) Two recent studies examining the impact of nonfasting triglyceride levels on cardiovascular (CV) events showed all but one of the following: a. Nonfasting triglyceride levels are associated with incident CV events b. Nonfasting triglyceride levels showed greater predictive ability in women than in men c. Fasting triglyceride levels showed stronger association with CV events than nonfasting triglyceride levels in models adjusted for multiple variables d. Risk of CV events was greater at higher nonfasting triglyceride levels 2) In a study of patients with type 2 diabetes, the presence of nonalcoholic fatty liver disease was significantly associated with increased risk of cardiovascular disease except after adjusting for which of the following a. Metabolic syndrome b. Diabetes duration c. LDL cholesterol d. None of the above 3) In a study of patients following acute coronary syndromes, diabetes was an independent risk factor for mortality at 30 days and 1 year in patients with ST-segment elevation myocardial infarction (STEMI), but not with unstable angina/non-STEMI. a. True b. False

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c. Fasting triglyceride levels showed stronger association with CV events than nonfasting triglyceride levels in models adjusted for multiple variables. After adjusting for age, blood pressure, smoking, and use of hormone therapy, both fasting and nonfasting triglyceride levels were strongly associated with CV events. Among fasting participants, further adjustment for total and high-density lipoprotein cholesterol and for indicators of insulin resistance substantially weakened this association, making it nonsignificant. In contrast, nonfasting triglyceride levels maintained a strong and significant association with CV events in fully adjusted models. d. None of the above. In multivariate regression analysis, nonalcoholic fatty liver disease was significantly associated with incident CVD events after adjusting for age, A1C, diabetes duration, smoking, sex, LDL cholesterol, and medications. Further adjustment for metabolic syndrome had little effect on the association. b. False. Diabetes was an independent risk factor for mortality at 30 days and 1 year in patients with ST-segment elevation myocardial infarction (STEMI) as well as patients with unstable angina/non-STEMI.

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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Activity Code: T196-7 Issue Date: October 2007 CME Credit Availability: Through February 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