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Part 2

Part 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 This program has received in-kind support from AstraZeneca Canada Inc. in the form of logistical support

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Part 2

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  1. Part 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. 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

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

  8. 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”

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

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

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

  12. 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.

  13. 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

  14. 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.

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

  16. 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.

  17. Two New Trials Released:SAVOR and EXAMINE

  18. 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.

  19. 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.

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

  21. 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.

  22. 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?

  23. 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.

  24. 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.

  25. 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.

  26. SAVOR and EXAMINE: Safety Endpoints of Special Interest1,2 • Incidences of acute and chronic pancreatitis were similar between treatment and placebo groups in these studies.1,2 • Further analysis of SAVOR results3 showed that pancreatitis frequency remained flat over the entire treatment period, suggesting that observed cases were natural history. • *Definite or possible. • 1. SciricaBM, et al. N Engl J Med 2013; 369(14):1317-26. • 2. White WB, et al. N Engl J Med 2013; 369(14):1327-35. • 3. Raz I, Bhatt DL. Presented at EASD 2013, Barcelona.

  27. In terms of efficacy, were A1C levels adequately controlled in the SAVOR and EXAMINE studies?

  28. Question 2 What is the impact of hypoglycemia on CV risk?

  29. Link Between Hypoglycemia and Acute CV Events in T2DM Retrospective, observational study assessing association between hypoglycemia and acute CV events 3.1% patients had hypoglycemia during evaluation period Patients with hypoglycemia had 79% higher odds for acute CV events vs. patients with no hypoglycemia • Johnston SS et al. Diabetes Care 2011; 34:1164-70.

  30. Hypoglycemia May Affect CV Events CRP VEGF IL-6 Neutrophil activation Inflammation Plateletactivation Blood coagulationabnormalities Endothelial dysfunction Hypoglycemia Factor VII Vasodilation Sympathoadrenal response Rhythm abnormalities Hemodynamic changes Heart rate variability Adrenaline Oxygen consumption Contractility Heart workload • Desouza CV, et al. Diabetes Care 2010; 33(6):1389-94.

  31. Acute Complications and Effects of Severe Hypoglycemia Increased Risk of Cardiac Arrhythmia1 Low Plasma Glucose Levels: • Abnormal prolonged cardiac repolarization - QTc • Sudden death? Progressive Neuroglycopenia2 • Cognitive impairment • Unusual behaviour • Seizure • Coma • Brain death? • 1. Landstedt-Hallin L, et al. J Intern Med 1999; 246:299-307. • 2. Cryer PE. J Clin Invest 2007; 117(4):868-70.

  32. Question 3 What is an appropriate A1C target for Russell? What classes of antihyperglycemic agents may increase CV harm? What is the impact on CV risk of various antihyperglycemic classes? (chart completion)

  33. What is an appropriate A1C target for Russell?

  34. CDA 2013 Guidelines: Individualizing A1C Targets ≤7% >7% 7% Most patients with type 1 and type 2 diabetes A target A1C ≤ 6.5% may be considered in some patients with T2DM to further lower the risk of nephropathy and retinopathy, which must be balanced against the risk of hypoglycemia • Consider A1C target 7.1–8.5% if: • Limited life expectancy • High level of functional dependency • Extensive coronary artery disease at high risk of ischemic events • Multiple comorbidities • History of recurrent severe hypoglycemia • Hypoglycemia unawareness • Longstanding diabetes and difficulty achieving A1C ≤ 7%despite effective doses of multiple antihyperglycemic agents, including intensified basal-bolus insulin therapy • 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.

  35. What classes of antihyperglycemic agents might increase CV risk?

  36. Some Antihyperglycemic Therapies May Have Adverse CV Effects • 1. Tzoulaki I, et al. BMJ 2009; 339:b4731. 2. Schramm TK, et al. Circulation 2008; 117:1945-54. 3. Nissen SE, Wolski K. N Engl J Med 2007; 356:2457-71. 4. Home PD, et al. Lancet 2009; 373:2125-35. 5. Dormandy JA, et al. Lancet 2005; 366:1279-89. 6. Wilcox R, et al. Am Heart J 2008; 155:712-17. • Data suggest an increase in CV risk with certain oral antihyperglycemic agents • Certain sulfonylureas,1,2possibly mediated by: • increased CV risks associated with hypoglycemia • effects on cardiac potassium ATP channels (loss of beneficial ischemic pre-conditioning) • Thiazolidinediones3-6 • increased risk of edema, CHF

  37. What do we know about sulfonylureas and CV safety?

  38. Individualizing Antihyperglycemic Agents After Metformin (2)

  39. Question 4 What changes would you make to Russell’s medication regimen?

  40. What changes would you make to Russell’s medication regimen?

  41. Key Messages Evaluate all patients with diabetes for vascular risk Avoid antihyperglycemic agents which put patients with established CV disease at risk for hypoglycemia Individualize the choice of antihyperglycemic agents based on patient characteristics Recent evidence with saxagliptin and alogliptin reinforces the CV safety of DPP-4 Inhibitors

  42. Support Slides Additional resources for program facilitators

  43. 2012 CCS Dyslipidemia Guidelines Update Estimation of 10-year risk of total CVD in men (Framingham HeartStudy) • Canadian CardiovascularSociety, 2013.

  44. 2012 CCS Dyslipidemia Guidelines Update Estimation of 10-year risk of total CVD in men (Framingham HeartStudy) Multiplied by 2 whenfamilyhistory of premature CVD is positive • Canadian CardiovascularSociety, 2013.

  45. Cardiovascular Age Tables: Male Patients WITHOUT Diabetes Non-smokers Smokers Blood Pressure (mmHg) Blood Pressure (mmHg)

  46. Cardiovascular Age Tables: Male Patients WITH Diabetes Non-smokers Smokers Blood Pressure (mmHg) Blood Pressure (mmHg)

  47. Cardiovascular Age Tables: Male Patients WITH Diabetes Non-smokers Smokers 43.6 Example: 30-year-old male with diabetes who smokes, BP 150/95 mmHg, TC:HDL-C ratio 5 • CV age: 43.6 years • CV age vs. same profile but without diabetes: + 5 years • CV age vs. healthy 30-year-old male: + 13.6 years Blood Pressure (mmHg) Blood Pressure (mmHg)

  48. Cardiovascular Age Tables: FemalePatients WITHOUT Diabetes Non-smokers Smokers Blood Pressure (mmHg) Blood Pressure (mmHg)

  49. Cardiovascular Age Tables: FemalePatients WITH Diabetes Non-smokers Smokers Blood Pressure (mmHg) Blood Pressure (mmHg)

  50. Ongoing CV Outcome Trials: DPP-4 Inhibitors • Adapted from:1. Golden SH. Am J Cardiol 2011; 108(Suppl):59B-67B. 2. Fonseca V. Am J Cardiol 2011; 108(Supp):52B–58B. 3. www.clinicaltrials.gov

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