Diabetes MAYER B. DAVIDSON, MD,* CO-EDITOR-IN-CHIEF; HENRY N. GINSBERG, MD, REVIEWER; TERRENCE F. FAGAN, MANAGING EDITOR; CHING-LING CHEN, PhD, WRITER

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1 Professional Postgraduate Services Release Date: March 14, 2008 Valid Through: July 14, 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 post-test and evaluation 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 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. CLINICAL INSIGHTS IN Diabetes MAYER B. DAVIDSON, MD,* CO-EDITOR-IN-CHIEF; HENRY N. GINSBERG, MD, REVIEWER; TERRENCE F. FAGAN, MANAGING EDITOR; CHING-LING CHEN, PhD, WRITER Sex-Specific General Cardiovascular Risk Profile for Use in Primary Care: The Framingham Heart Study T he major risk factors for developing cardiovascular disease (CVD), including age, sex, high blood pressure, smoking, dyslipidemia, and diabetes status, often converge and interact multiplicatively to promote cardiovascular risk. CVD, as defined by the Framingham Heart Study, is a composite of coronary heart disease (CHD), cerebrovascular disease, peripheral vascular disease, and heart failure. Several validated risk prediction algorithms are commonly used for assessment of risk of specific components of CVD and for treatment of risk factors. Their use in primary care, however, is less frequent mainly because of the multiplicity of these prediction models, each algorithm predicting an individual CVD component. The purpose of the present study is to develop a single multivariable risk prediction tool incorporating all the risk factors for CVD that would enable primary care physicians to identify high-risk candidates for any and all initial atherosclerotic CVD events using measurements routinely available in the primary care setting. D Agostino and colleagues used Cox proportional-hazards regressions to evaluate the risk of developing a first CVD event during a maximum follow-up period of 12 years. Sex-specific multivariable risk functions, referred to as general CVD algorithms, were derived with incorporation of covariates, including age, total and highdensity lipoprotein cholesterol, systolic blood pressure, treatment for hypertension, smoking, and diabetes status. A total of 8,491 participants in the Framingham Heart Study (mean age, 49 years; 4,522 women) who attended a routine examination when aged between 30 and 74 years and were free of CVD events were included for evaluation of the performance of the newly developed sex-specific general CVD algorithms for predicting all and individual CVD events. Over 12 years of follow-up, 1,174 participants (456 women) developed a first CVD event. Highly statistically significant relations were observed between all risk factors evaluated and incident CVD, indicating that these risk factors predict CVD risk (multivariable-adjusted P<0.0001). The sex-specific general CVD VOLUME 11, NUMBER 2 FEBRUARY 2008 algorithms demonstrated good discrimination (C statistic, [men] and [women]) and calibration for predicting CVD risk. (See Tables, page 2.) An excellent goodness of fit was seen in the calibration plots by comparing model-based predicted risk and actual observed risk in men and women. The new CVD prediction models also performed better than the Framingham CHD risk functions in the prediction of CVD risk. Furthermore, the new general CVD risk formulation permits the prediction of the risk of individual CVD components by providing discrimination and calibration that are as good as those using individual disease-specific multivariable risk formulations. Simpler CVD risk prediction models were established from simple adjustments to the general CVD risk algorithms for estimation of the risks of each CVD component. Two such simple risk scores were presented: one based on all traditional risk factors, and the other based on nonlaboratory-based predictors. The simple office-based nonlaboratory CVD risk prediction function, which incorporated body mass index instead of laboratory measurements such as total and HDL cholesterol, performed reasonably well with good discrimination and calibration. The strength of the present study is the inclusion of a large community-based sample that is under continuous surveillance using the same standardized criteria for CVD events and the assessment of model performance measures with disease-specific profiles. Possible limitations of this study include transportability of the CVD risk function. D Agostino and associates concluded that a simple sex-specific multivariable risk factor algorithm can be conveniently used to assess general CVD risk as well as risk of individual CVD events in an office-based nonlaboratory, primary care office or clinic. Moreover, the estimated absolute CVD event rates can be used to identify risk and also to guide prevention of CVD events. D Agostino RB Sr et al. General cardiovascular risk profile for use in primary care. The Framingham Heart Study. Circulation. 2008;117: * 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, and Daiichi Sankyo, Inc., and speakers bureau member with Amylin Pharmaceuticals, Eli Lilly and Company, and Merck & Co., Inc. Dr Ginsberg is the Irving Professor of Medicine, College of Physicians and Surgeons of Columbia University, New York, New York. He has indicated the following relevant financial relationships: grant research support, Isis Pharmaceuticals, Inc., and Takeda Pharmaceuticals North America, Inc.; retained consultant, Merck & Co., Inc., Pfizer Inc., and Takeda Pharmaceuticals North America, Inc. PPS staff members Managing Editor Terrence F. Fagan, Senior Medical Writer Ching-Ling Chen, PhD, Program Director Jorge Mojena, and CME Program Manager Wadee ah Terry have indicated no relevant financial relationships.

2 CVD Points for Women Points Age, years HDL-C Total C SBP (un) SBP (t) -3 < < < < * 160+ *Over age 54, add 7 points, plus 1 point for Add 0 points for nonsmoker or without diabetes. every 5 additional years up to age 75+ years Add 3 points for smoker. (eg, 8 pts for 55 59, 9 pts for 60 64, etc.) Add 4 points for diabetes. Total C = total cholesterol. SBP = systolic blood pressure. (un) = untreated. (t) = treated. CVD Risk for Women* Total Points Risk % < >20 >30 *Risk % incrementally increases in each category. Adapted from RB D Agostino Sr et al. Circulation. 2008;117: Used with permission. CVD Points for Men Points Age, years HDL-C Total C SBP (un) SBP (t) < < < < * 160+ *Over age 44, add 6 points for 45 49, Add 0 points for nonsmoker or without diabetes. 8 pts for 50 54, 10 pts for 55 59, Add 3 points for diabetes. 11 pts for 60 64, 12 pts for 65 69, Add 4 points for smoker. 14 pts for 70 74, and 15 pts for 75+. Total C = total cholesterol. SBP = systolic blood pressure. (un) = untreated. (t) = treated. CVD Risk for Men* Total Points Risk % >30 *Risk % incrementally increases in each category. Adapted from RB D Agostino Sr et al. Circulation. 2008;117: Used with permission. 2

3 COMMENTARY HENRY N. GINSBERG, MD, Irving Professor of Medicine, College of Physicians and Surgeons of Columbia University, New York, New York. The article by D Agostino et al provides a new algorithm for determining 10-year risk for all CVD based on baseline characteristics and follow-up of the combined original and offspring Framingham cohorts. By providing a means to assess risk for all CVD, which includes fatal and nonfatal myocardial infarction, stroke, peripheral vascular disease, and heart failure, the authors hope that practicing physicians, particularly internists and generalists, will achieve a more global sense of the risk of their patients. Of particular note is the demonstration that the new algorithm has equal predictive power when BMI is used instead of total cholesterol and HDL cholesterol; this would allow assessment of total CVD risk without the need for a blood sample and laboratory measurements. However, since the goal of quantitating CVD risk would be to intervene, a lipid profile would be required, as would some measure of glucose or A1C. Thus the utility of the laboratory-independent scoring system is not clear. It would be particularly useful if the algorithm automatically provided, in addition to overall CVD risk, individual risks for the components (CHD, stroke etc), particularly since the authors note that certain risk factors were more closely associated with particular component outcomes. The healthcare professional could then assess both global risk and individual CVD risks. Intensified Multifactorial Intervention Reduces Mortality in Type 2 Diabetes T ype 2 diabetes is known to be linked to a high rate of complications related to cardiovascular (CV) events, and a high rate of death, which is about twice as high as that among individuals without the disease. In the earlier Steno-2 study, a prospective, randomized, open-label trial, Gaede and colleagues demonstrated that intensified multifactorial intervention with the use of renin-angiotensin system blockers, aspirin, and lipid-lowering agents significantly reduced the risk of nonfatal cardiovascular disease (CVD) among patients with type 2 diabetes and microalbuminuria during the mean treatment period of 7.8 years. However, the effect of such intensive therapy on mortality in these patients was not clear. To address this question, Gaede and colleagues conducted the present follow-up study to evaluate whether the intensive therapy has any impact on the rate of death, and whether the reduction of CVD risk by the intensive therapy is maintained during the follow-up study. In the original Steno-2 study, 160 Danish patients with type 2 diabetes and persistent microalbuminuria were randomly selected to receive intensified multifactorial therapy or conventional therapy for an average period of 7.8 years. All patients in the intensive-therapy group received an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin II receptor blocker (ARB), regardless of blood pressure, for treatment of microalbuminuria, a low dose of aspirin, and a lipid-lowering medication such as a statin, in addition to dietary modification, increased activity, and antihyperglycemic medications. Defined targets for the intensive therapy group were based on current guidelines from the American Diabetes Association and included an A1C of <6.5%, blood pressure <130 mm Hg systolic and <80 mm Hg diastolic, fasting serum triglyceride level <150 mg/dl, and fasting serum total cholesterol level <175 mg/dl. Patients were subsequently followed for a mean of 5.5 years until December 31, There were no protocol-mediated differences during this follow-up. All subjects in the original 3 study had returned to their own doctors, and all were informed of that study s results, so treatments during follow-up were at the discretion of the patients and their physicians. The primary endpoint at 13.3 years of follow-up was the time to death from any cause, and the secondary endpoints were death from CV causes and a composite of CVD events. During the entire 13.3 years of study, 24 patients (30%) in the intensive-therapy group died, as compared with 40 patients (50%) in the conventional-therapy group (hazard ratio [HR], 0.54; 95% confidence interval [CI], 0.32 to 0.89; P=0.02). The risk of death from CV causes was also lowered by multiple intensive intervention; 9 patients in the intensive-therapy group died from CV causes, as compared with 19 in the conventional-therapy group (HR, 0.43; 95% CI, 0.19 to 0.94; P=0.04). A total of 209 CV events occurred during the 13.3 years of observation; intensive therapy was associated with a lower risk of these events (HR, 0.41; 95% CI, 0.25 to 0.67; P<0.001). Furthermore, fewer diabetes-related diseases and major side effects were observed in the intensive-therapy group. For instance, only 1 patient in the intensive-therapy group had progression to end-stage renal disease, as compared with 6 patients in the conventionaltherapy group (P=0.04). In addition, fewer patients in the intensive-therapy group vs the conventional therapy group required retinal photocoagulation (relative risk, 0.45; 95% CI, 0.23 to 0.86; P=0.02). From the present study, the authors concluded that intensive intervention with multiple drug combinations and behavior modification to manage blood glucose, blood pressure, and cholesterol had sustained the beneficial effects on the reduction of the risk of CV events as well as the risk of mortality from any cause or from CV causes, and thus prolonged the lives of patients with type 2 diabetes. Gaede P et al. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med. 2008;358:

4 Clinical Insights in Diabetes Post-Test February 2008 For a complete list of additional PPS educational activities log on to the following websites: 1) In a Cardiovascular Risk Profile algorithm devised by RB D Agostino Sr et al, 3 of the 4 factors below actually deduct points from the total risk score. Which does not? a. An untreated systolic blood pressure level below 120 mm Hg b. Patient is a nonsmoker c. A treated systolic blood pressure level below 120 mm Hg (women only) d. An HDL cholesterol level of 50 mg/dl or above 2) A follow-up to the Steno-2 trial of patients with type 2 diabetes compared the group that originally received intensive treatment with multiple drug therapy and behavior modification to the group that originally received conventional diabetes treatment. Which of the following results were observed in this study? a. Risk of death from all causes was significantly lower in the intensive treatment group b. Risk of death from cardiovascular (CV) causes was significantly lower in the intensive treatment group c. Risk of any CV events was significantly lower in the intensive treatment group d. Risk of microvascular complications was significantly lower in the intensive treatment group e. All of the above ANSWER KEY 1. b) Patient is a nonsmoker. Status as a nonsmoker added 0 points to a total risk score, but did not deduct points. 2. e) All of the above. Even years after the original study, an intensive treatment regimen was shown to significantly reduce macrovascular and microvascular complications as well as overall mortality in patients with type 2 diabetes. STARTING IN MARCH 2008: Register online at for NDEI s new CME/CE regional dinner meeting series presenting the latest information on diabetes treatment titled, Managing the Complexities of Type 2 Diabetes: A Road Map for Improving Patient Care A Case-Based, Interactive CME/CE Dinner Program For more information about upcoming NDEI CME and CE activities, visit us at or call 1 (800) , ext Visit for information on other CME or CE activities. Clinical Insights in Diabetes is co-edited by NDEI faculty members Mayer B. Davidson, MD, and Silvio E. Inzucchi, MD. Clinical Insights in Diabetes is available to you via . If you would like to receive future issues via , please visit us online at EM-T PHYCME

5 CME Activity Registration/Evaluation 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) (Date) PLEASE PRINT CLEARLY: Dr Mr Mrs Ms Prof Other (Please specify) First Name Last Name Degree MD PharmD DO NP PA RPh Other (Please specify) Specialty Primary Care Internal Medicine Endocrinology Cardiology Other Profession Activity Code: T Issue Date: March 14, 2008 CME Credit Availability: Through July 14, 2008 PREFERRED MAILING ADDRESS Home Office Practice Academic Dept/Div/Suite/Unit/Affil Street City/State/ZIP Code Country (Please print clearly) Phone: - - Fax: - - Overall Program 1. The activity met the stated objectives in such a way that I am better able to: Strongly Disagree Disagree Agree Strongly Agree 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. 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. EM-T PHYCME