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Parts 1 and 2. Faculty/Presenter Disclosure. Disclosure of Commercial Support. This program has received financial support from AstraZeneca Canada Inc. in the form of an educational grant

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  1. Parts 1 and 2

  2. Faculty/Presenter Disclosure

  3. Disclosure of Commercial Support This program has received financial support from AstraZeneca Canada Inc. in the form of an educational grant This program has received in-kind support from AstraZeneca Canada Inc. in the form of logistical support Potential for conflict(s) of interest: [Faculty/speaker name] has received [payment/funding] from [organization supporting the program AND/OR organization whose product(s) are being discussed in this program] AstraZeneca Canada Inc. markets or benefits from the sale of a product(s) that will be discussed in this program: exenatide (Byetta), saxagliptin(Onglyza)

  4. Mitigating Potential Bias Potential sources of bias identified in the preceding 2 slides have been mitigated as follows: Information presented is evidence-based Recommendations made are evidence- or guidelines-based rather than personal recommendations of the presenter Material has been reviewed by an Educational Committee responsible for overseeing the program’s Needs Assessment and subsequent content development

  5. Learning Objectives After completing this program, participants will be able to: Articulate overall approaches to CV risk reduction in patients with type 2 diabetes (T2DM); Describe the impact of glycemic control on CV risk; and Cite evidence describing CV risks and/or benefits of various antihyperglycemic agents.

  6. Part 1

  7. Case Study 1: Paul • 55-year-old male • Has been seen many times over past years but has been poorly compliant to follow-up • Last visit 3 years ago: – noted to have “pre diabetes” (A1C 6.3%) – dietician follow-up booked; patient did not follow through Today’s visit: wants to “get his heart checked out” after his 59-year-old brother suffered a fatal MI

  8. What investigations would you order in Paul’s case at this point?

  9. Paul: Investigations BP: 152/96 mmHg (confirmed on 2 office visits and HBP log) All other blood parameters: normal Lifestyle: sedentary, non-smoker Family history: mother with T2DM; brother with fatal MI at age 59 Fasting blood sugar: 9.8 mmol/L A1C: 8.6% TC: 5.6 mmol/L, TG: 4.7 mmol/L, HDL-C: 0.7 mmol/L LDL-C: unable to calculate BMI: 34 kg/m2

  10. Discussion Write a “problem list” for Paul. Is his risk for CV events low, medium or high? What tools do you use to establish risk? Do you use any tools to communicate CV risk to patients? What are your treatment priorities for Paul?

  11. Problem List

  12. How would you describe Paul’s risk for CV events?

  13. What are your treatment priorities for Paul?

  14. Metabolic Syndrome ≥ 3 risk determinants are present: • FBG: ≥ 5.6 mmol/L (or receiving treatment of elevated glucose) • BP: ≥ 130/85 mmHg (or receiving treatment of previously diagnosed hypertension) • TG: ≥ 1.7 mmol/L (or receiving treatment) • HDL-C: < 1.0 mmol/L (men) or < 1.3 mmol/L (women) • Abdominal obesity: WC ≥ 102 cm (men) or ≥ 88 cm (women) in Canada/U.S./European populations* • *Otherwaistcircumference (WC) cutoffs: ≥ 94 cm (men) or ≥ 80 cm (women) for Europids, whites, Sub-SaharanAfricans, Mediterranean and Middle East (Arab) populations; ≥ 90 cm (men) or ≥ 80 cm (women) for Asian and ethnic South and Central American populations. • Leiter LA, et al. Can J Cardiol 2011; 27(2):e1-e33.

  15. CV Risk Assessment Patient is at HIGH RISK for CV disease Not necessary to perform Framingham calculation to assess risk…

  16. 2013 CHEP Recommendations: Assessing Cardiovascular Risk to Improve Adherence • Use analogies that describe comparative risk, such as “Cardiovascular Age,” “Vascular Age” or “Heart Age” to inform patients of their risk status Inform patients of their global risk to improve the effectiveness of risk-factor modification

  17. What strategies would you use in discussing Paul’s CV risk with him?

  18. Informing Patients of Their Global Risk Improves the Effectiveness of Risk-factor Modification • GroverSA, et al. J Gen Intern Med 2009; 24(1);33-9.

  19. Case Study 1: Paul (cont’d) • Paul agrees to see the diabetes nurse educator and start on lifestyle changes • Adamant that he wants to reduce his CV risk, and comfortable with whatever therapies are necessary to achieve this What evidence-based medical therapies would you recommend?

  20. What evidence-based medical therapies would you recommend in Paul’s case?

  21. CDA 2013 Guidelines: Vascular Protection Checklist • CDA: Canadian Diabetes Association. • CDA 2013 ClinicalPractice Guidelines for the Prevention and Management of Diabetes in Canada. Can J Diabetes 2013;37(suppl 1):S1-S212. AA1C – optimal glycemic control (usually ≤7%) BBP – optimal blood pressure control (<130/80) CCholesterol – LDL ≤ 2.0 mmol/L if decided to treat DDrugs to protect the heart A – ACEi or ARB │S – Statin │A – ASA if indicated E Exercise / Eating healthily – regular physical activity, achieve and maintain healthy body weight SSmoking cessation

  22. CHEP Hypertension Recommendations: Vascular Protection • Male gender • 55 years or older • Smoking • T2DM • TC:HDL-C ratio ≥ 6 • Family history of premature CV disease • Previous stroke or TIA • LVH • ECG abnormalities • Microalbuminuria or proteinuria • Peripheral vascular disease Statins are recommended in high-risk hypertensive patients based on having established atherosclerotic disease or at least 3 of the following: • Hackam DG, et al. Can J Cardiol 2013; 29(5):528-42.

  23. 2012 CCS Dyslipidemia Guidelines Update: Recommendations in High Risk • High risk: clinical atherosclerosis; all persons with diabetes aged > 40 years as well as younger persons with diabetes with additional sources of risk (e.g., diabetes > 15 years duration and age > 30 years); or adjusted Framingham Risk Score ≥ 20% (Strong Recommendation, High-Quality Evidence) • now included in this category: abdominal aortic aneurysm, high-risk kidney disease (eGFR < 45) and high-risk hypertension (Strong Recommendation, Moderate-Quality Evidence) • Treatment target for LDL-C: ≤ 2.0 mmol/L or ≥ 50% reduction for optimal risk reduction (Strong Recommendation, Moderate-Quality Evidence) • ApoB (≤ 0.80 g/L) or non-HDL-C (≤ 2.6 mmol/L) considered as alternatives (Strong Recommendation, High-Quality Evidence) • Anderson TJ, GregoireJ, et al. Can J Cardiol2013; 29(2):151-67.

  24. Does This Patient Require Vascular Protective Medications? Statin + ACEi or ARB + ASA Clopidogrel if ASA-intolerant YES YES Statin + ACEi or ARB NO STEP 2: What is the patient’s age? ≥ 55 years OR 40-54 years YES YES Statin NO STEP 3: Does the patient… Have diabetes > 15 years AND age > 30 years? Warrant statin therapy based on the 2012 CCS Lipid Guidelines? YES STEP 1: Does this patient have end-organ damage? Macrovascular disease Cardiac ischemia (silent or overt) Peripheral arterial disease Cerebrovascular/carotid disease OR Microvascular disease Retinopathy Nephropathy (ACR ≥ 2.0) Neuropathy • Canadian Diabetes Association. guidelines.diabetes.ca

  25. CDA 2013 Guidelines: Individualizing Antihyperglycemic Agents After Metformin • CDA: Canadian Diabetes Association. • CDA 2013 ClinicalPractice Guidelines for the Prevention and Management of Diabetes in Canada. Can J Diabetes 2013;37(suppl 1):S1-S212. The CDA guidelines suggest individualization of therapy based on patient characteristics Complete the following table, looking at important characteristics of each class of antihyperglycemic agents.

  26. Individualizing Antihyperglycemic Agents After Metformin (1)

  27. What would be your approach to individualizing antihyperglycemic therapy in Paul’s case?

  28. Individualized T2DM Treatment Options After Metformin (CDA 2013) • *In alphabetical order. • CDA 2013 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. Can J Diabetes 2013;37(suppl 1):S1-S212.

  29. Key Messages Insulin resistance is progressiveand care should be taken to not lose patients with pre-diabetes to follow up. 2. Evaluate and treat all vascular risk factors in patients with DM. 3. Individualize the choice of antihyperglycemic agents based on patient characteristics 4. Recent evidence with saxagliptin and alogliptin reinforces the CV safety of DPP-4 Inhibitors

  30. Part 2

  31. Case Study 2: Russell • Now has gained weight and reports a consistent elevation in fasting and 2-hour postprandial glucometer values • Physical exam: negative (except for obesity) • Routine evaluations ordered 64-year-old male T2DM for 10 years Presents for annual health review and medication renewal Previously adequate A1C control

  32. What investigations would you order in Russell’s case at this point?

  33. Russell: Investigations A1C: 7.5% ECG: inferior changes consistent with previous MI (subsequent cardiac echo confirms inferior MI) All other blood parameters: normal or “at target”

  34. Russell: Current Medications Simvastatin 40 mg od EC-ASA 81 mg od Ramipril10 mg od Metformin 1000 mg bid Omeprazole 20 mg bid

  35. Question 1 What is the evidence for improving vascular outcomes by reducing A1C in patients with T2DM? What new evidence exists?

  36. Is there evidence with traditional antihyperglycemic agents to help guide your choice of therapy for reducing CV risk in T2DM?

  37. What We Know: Glycemic Control Prevents Microvascular Complications Final A1C values Eye ADVANCE 6.5% vs. 7.3% Renal * Major Micro * Retinopathy 3-step * 6.4% vs. 7.5% ACCORD Macroalbuminuria * Microalbumin * Metformina UKPDS 7.0% vs. 7.9% Insulin/SUa * 0 10 20 30 40 50 60 70 80 Percent reduction compared with control • aUKPDS results shown are for cumulative microvascular endpoints (renal failure or death; vitreous hemorrhage; retinal photocoagulation) in the respective treatment arms of the glucose control study. • *Statistically significant.

  38. Conflicting Evidence: Glycemic Control and Reductions in Risk for CVD Evidence of Benefit No Evidence of Benefit • Original UKPDS study • ACCORD • ADVANCE • VADT • CVD = cardiovascular disease. • 1. UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998; 352:837-53. 2. The ACCORD Study Group. N Engl J Med 2011; 364:818-28. 3. The ADVANCE Collaborative Group. N Engl J Med 2008; 358:2560-72. 4. Duckworth W, et al. N Engl J Med 2009; 360:129-39. 5. Holman RR, et al. N Engl J Med 2008; 359:1577-89. 6. Boussageon R, et al. BMJ 2011; 343:d4169. 7. Hemmingsen B, et al. BMJ 2011; 343:d6898. • Long-term follow-up of the UKPDS study • benefit of metformin > SU / insulin • Meta-analyses of individual studies

  39. Effect of More- vs. Less-intensive Glycemic Control on CV Outcomes and Death in Patients with Diabetes: A Meta-analysis of Randomized, Controlled Trials No. of events (annual event rate, %) More intensive Less intensive ΔA1C(%) Favors more intensive Favors less intensive Hazard ratio(95% CI) Trials Major cardiovascular event ACCORD ADVANCE UKPDS VADTOverall 352 (2.11)557 (2.15)169 (1.30)116 (2.68)1,194 371 (2.29)590 (2.28)87 (1.60)128 (2.98)1,176 -1.01-0.72-0.66-1.16-0.88 0.90 (0.78 – 1.04)0.94 (0.84 – 1.06)0.80 (0.62 – 1.04)0.90 (0.70 – 1.16)0.91 (0.84 – 0.99)(Q = 1.32, p = 0.72, I2= 0.0%) Myocardial infarction ACCORD ADVANCE UKPDS VADTOverall 198 (1.18)310 (1.18)150 (1.20)72 (1.65)730 245 (1.51)337 (1.28)76 (1.40)87 (1.99)745 -1.01-0.72-0.66-1.16-0.88 0.77 (0.64 – 0.93)0.92 (0.79 – 1.07)0.81 (0.62 – 1.07)0.83 (0.61 – 1.13)0.85 (0.76 – 0.94)(Q = 2.25, p = 0.52,I2= 0.0%) All-cause mortality ACCORD ADVANCE UKPDS VADTOverall 257 (1.41)498 (1.86)123 (0.13)102 (2.22)980 203 (1.14)533 (1.99)53 (0.25)95 (2.06)884 -1.01-0.72-0.66-1.16-0.88 1.22 (1.01 – 1.46)0.93 (0.83 – 1.06)0.96 (0.70 – 1.33)1.07 (0.81 – 1.42)1.04 (0.90 – 1.20)(Q = 5.71, p = 0.13,I2= 47.5%) 0.5 1.0 2.0 Hazard ratio (95% CI) • Adapted from: Turnbull FM, et al. Diabetologia 2009; 52(11):2288-98.

  40. What key features would you look for in evaluating the meaningfulness of CV outcome studies in T2DM?

  41. Recent FDA Guidance for Phase 2/3 T2DM Studies in Planning Stage Establish independent committee to prospectively adjudicate CV events in a blinded fashion Include major events (CV mortality, MI, stroke) Can also include ACS hospitalization, urgent revascularization, etc. Design and conduct studies to enable future meta-analyses Include patients at higher risk of CV events Phase 3 trials should provide data on longer-term CV risk (e.g., minimum 2 years) Collect pre-specified CV outcomes data to exclude 80% increase in relative risk of the new agent • FDA. Guidance for Industry: Diabetes Mellitus — Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes. December 2008. Available at: www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071627.pdf.

  42. Two New Trials Released:SAVOR and EXAMINE

  43. SAVOR: Baseline Characteristics and Medications SAVOR: n = 16,492 patients (mean age 65 years) with type 2 diabetes (mean duration 10.3 years) and established CVD (78-79%) or multiple risk factors (21-22%). Median duration of follow-up: 2.1 years. • Scirica BM, et al. N Engl J Med 2013; 369(14):1317-26.

  44. SAVOR: Primary Efficacy Results* 8 4 12 6 2 14 10 0 • HR 1.00 • 95% CI 0.89-1.12 • p (non-inferiority) < 0.001 • p (superiority) = 0.99 • Saxagliptin % of patients • Placebo Months 18 24 12 6 0 • *Primaryendpoint: composite of CV death, non-fatal MI or non-fatal ischemicstroke. • Scirica BM, et al. N Engl J Med 2013; 369(14):1317-26.

  45. SAVOR:Individual Endpoints • Scirica BM, et al. N Engl J Med 2013; 369(14):1317-26.

  46. SAVOR: Rates of Risk of Hospitalization for Heart Failure Over Time Overall HR 1.27 (1.07 – 1.51) p = 0.007 Saxagliptin HR 1.48 (1.14 – 1.87) p = 0.003 0 2 4 6 8 HR 1.80 (1.29 – 2.54) p = 0.001 • Hospitalization for HF (%) 3.5% Placebo n = 16,492 1.9% 2.8% 1.1% HR = hazard ratio 1.3% 0.6% Days • Saxagliptin neither increased nor decreased the risk of the 1° and 2° endpoints in these high-risk populations. • There were no specific subgroups in which the RR associated with saxagliptin was particularly high or low. • The absolute risk with saxagliptin was smallest in patients at low risk of HF and correspondingly larger in patients at highest risk. 900 180 720 540 360 0 • Scirica BM, et al. Presented at AHA 2013, Dallas.

  47. How can the data on CHF hospitalization from SAVOR be put into context, also taking into account the overall CV safety demonstrated in the trial?

  48. EXAMINE: Baseline Characteristics and Medications EXAMINE: n = 5,380 patients (median age 61 years) with type 2 diabetes (mean duration 7.1 to 7.3 years) and acute coronary syndrome within 15-90 days of randomization. Median duration of follow-up: 18 months. White WB, et al. N Engl J Med 2013; 369(14):1327-35.

  49. EXAMINE: Primary Efficacy Endpoint* 6 18 24 12 0 • HR 0.96 • (upper boundary of the one-sided repeated CI: 1.16) • Placebo Cumulative incidence of primary end-point events (%) • Alogliptin Months 24 30 18 12 6 0 *Primaryendpoint: composite of CV death, non-fatal MI or non-fatal ischemicstroke. White WB, et al. N Engl J Med 2013; 369(14):1327-35.

  50. EXAMINE: Other Endpoints *Secondary endpoint: composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or urgent revascularization due to unstable angina within 24 hours after hospital admission. †Upper boundary of the one-sided repeated CI, at an alpha level of 0.01. White WB, et al. N Engl J Med 2013; 369(14):1327-35.

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