1. Part 1

2. Faculty/Presenter Disclosure Faculty/Presenter:[insert name here] Relationships with commercial interests: Grants/research support:[insert company/organization name(s) here] Speaker’s bureau/honoraria:[insert company/organization name(s) here] Consulting fees:[insert company/organization name(s) here] Other:[insert company/organization name(s) here]

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 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

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

8. 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/m 2

9. Discussion 1.Write a “problem list” for Paul. 2.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? 3.What are your treatment priorities for Paul?

10. Problem List

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

12. What are your treatment priorities for Paul?

13. Metabolic Syndrome *Other waist circumference (WC) cutoffs: ≥ 94 cm (men) or ≥ 80 cm (women) for Europids, whites, Sub-Saharan Africans, 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. 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* FBG: ≥ 5.6 mmol/L (or receiving treatment of elevated glucose) BP: ≥ 130/85 mmHg (or receiving treatment of previously diagnosed hypertension) ≥ 3 risk determinants are present:

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

15. 2013 CHEP Recommendations: Assessing Cardiovascular Risk to Improve Adherence Inform patients of their global risk to improve the effectiveness of risk-factor modification Use analogies that describe comparative risk, such as “Cardiovascular Age,” “Vascular Age” or “Heart Age” to inform patients of their risk status

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

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

18. 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?

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

20. CDA 2013 Guidelines: Vascular Protection Checklist CDA: Canadian Diabetes Association. CDA 2013 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. Can J Diabetes 2013;37(suppl 1):S1-S212. A A1C – optimal glycemic control (usually ≤7%) B BP – optimal blood pressure control (<130/80) C Cholesterol – LDL ≤ 2.0 mmol/L if decided to treat D Drugs 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 S Smoking cessation

21. CHEP Hypertension Recommendations: Vascular Protection 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. 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

22. 2012 CCS Dyslipidemia Guidelines Update: Recommendations in High Risk Anderson TJ, Gregoire J, et al. Can J Cardiol 2013; 29(2):151-67. 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)

23. STEP 2: What is the patient’s age? ≥ 55 years OR 40-54 years STEP 3: Does the patient… Have diabetes > 15 years AND age > 30 years? Warrant statin therapy based on the 2012 CCS Lipid Guidelines? 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 Statin + ACEi or ARB Statin Does This Patient Require Vascular Protective Medications? Canadian Diabetes Association. guidelines.diabetes.ca YES NO Statin + ACEi or ARB + ASA Clopidogrel if ASA-intolerant YES

24. CDA 2013 Guidelines: Individualizing Antihyperglycemic Agents After Metformin 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. CDA: Canadian Diabetes Association. CDA 2013 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. Can J Diabetes 2013;37(suppl 1):S1-S212.

25. Individualizing Antihyperglycemic Agents After Metformin (1) Class Example medications A1C- lowering Effect on weight Risk of hypo- glycemia Leave blank Alpha-glucosidase inhibitor Biguanides DPP-4 inhibitors GLP-1 agonists Insulin Insulin secretagogues TZDs

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

27. 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. Class* Relative A1C lowering HypoglycemiaWeightOther therapeutic considerationsCost Alpha-glucosidase inhibitor (acarbose) ↓RareNeutral to ↓Improved postprandial control, GI side effects$$ Incretin agents: DPP-4 inhibitors GLP-1 agonists ↓↓ ↓↓ to ↓↓↓Rare Neutral to ↓ ↓↓GI side effects $$$ $$$$ Insulin↓↓↓Yes↑↑No dose ceiling, flexible regimens$ to $$$$ Insulin secretagogue: Meglitinide Sulfonylurea↓↓Yes↑ Less hypoglycemia in context of missed meals but usually requires tid to qid dosing Gliclazide and glimepiride associated with less hypoglycemia than glyburide $$ $ TZD↓↓Rare↑↑CHF, edema, fractures, rare bladder cancer (pioglitazone), cardiovascular controversy (rosiglitazone), 6-12 weeks required for maximal effect $$ Weight loss agent (orlistat) ↓None↓GI side effects$$$

28. Key Messages 1.Insulin resistance is progressive and 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

29. Support Slides Additional resources for program facilitators

30. 2012 CCS Dyslipidemia Guidelines Update Canadian Cardiovascular Society, 2013. PointsAgeHDL-CTotal cholesterolSBP not treatedSBP treatedSmokerDiabetic -2> 1.6< 120 1.3-1.6 030-341.2-1.3< 4.1120-129< 120No 10.9-1.24.1-5.2130-139 235-39< 0.95.2-6.2140-159120-129 36.2-7.2160+130-139Yes 4> 7.2140-159Yes 540-44160+ 6 745-49 850-54 9 1055-59 1160-64 12 1365-69 1470-74 1575+Total points Points allotted Estimation of 10-year risk of total CVD in men (Framingham Heart Study)

31. Multiplied by 2 when family history of premature CVD is positive PointsRiskPointsRiskPointsRisk -3 or less< 1 %53.9 %1315.6 % -21.1 %64.7 %1418.4 % 1.4 %75.6 %1521.6 % 01.6 %86.7 %1625.3 % 11.9 %97.9 %1729.4 % 22.3 %109.4 %18+> 30 % 32.8 %1111.2 % 43.3 %1213.3 % 2012 CCS Dyslipidemia Guidelines Update Estimation of 10-year risk of total CVD in men (Framingham Heart Study) Canadian Cardiovascular Society, 2013.

32. Cardiovascular Age Tables: Male Patients WITHOUT Diabetes Total Cholesterol:HDL Ratio 3456734567 120/8028.128.428.929.530.2 Age 30 33.133.734.735.736.8120/80 130/8529.129.430.030.831.534.234.936.037.138.3130/85 140/9030.030.431.232.032.935.336.037.338.539.7140/90 150/9531.031.432.333.234.236.437.238.539.841.1150/95 120/8037.337.638.138.839.5 Age 40 42.242.843.844.845.9120/80 130/8538.238.639.240.040.843.343.945.146.247.3130/85 140/9039.239.640.341.242.144.345.146.347.548.7140/90 150/9540.140.641.542.443.445.446.247.548.850.0150/95 120/8047.147.347.948.549.2 Age 50 51.752.353.254.255.1120/80 130/8547.948.348.949.650.452.753.354.455.456.4130/85 140/9048.849.250.050.851.753.754.455.556.657.6140/90 150/9549.750.251.051.952.954.655.456.657.758.7150/95 120/8057.457.658.158.659.2 Age 60 61.562.062.763.564.3120/80 130/8558.258.559.059.660.362.462.963.764.565.3130/85 140/9059.059.360.060.661.463.263.864.665.466.2140/90 150/9559.860.260.961.662.464.064.665.566.266.9150/95 120/8068.268.468.769.169.5 Age 70 71.471.772.272.773.2120/80 130/8568.869.069.469.970.372.172.472.973.473.9130/85 140/9069.569.770.170.671.172.773.073.674.074.4140/90 150/9570.170.470.871.371.873.373.674.174.574.9150/95 Blood Pressure (mmHg) Non-smokersSmokers

33. Cardiovascular Age Tables: Male Patients WITH Diabetes Total Cholesterol:HDL Ratio 3456734567 120/8033.333.734.335.035.8 Age 30 38.439.140.141.142.1120/80 130/8534.334.735.436.237.139.540.241.342.443.4130/85 140/9035.335.736.637.538.440.641.342.543.644.7140/90 150/9536.236.837.738.739.741.642.443.644.845.9150/95 120/8042.342.743.344.144.8 Age 40 47.347.948.949.950.8120/80 130/8543.343.744.445.346.148.349.050.151.152.0130/85 140/9044.244.745.546.447.449.350.051.152.253.1140/90 150/9545.145.746.647.648.650.351.052.153.254.2150/95 120/8051.852.252.853.454.1 Age 50 56.356.957.858.659.4120/80 130/8552.753.153.854.555.357.357.958.859.660.3130/85 140/9053.554.054.855.656.458.258.859.760.561.3140/90 150/9554.454.955.856.657.559.059.660.561.462.2150/95 120/8061.661.962.462.963.5 Age 60 65.465.966.567.167.6120/80 130/8562.462.763.363.864.466.266.667.267.868.3130/85 140/9063.163.564.164.765.466.967.367.968.569.0140/90 150/9563.864.264.965.666.267.567.968.569.169.6150/95 120/8071.671.872.172.472.8 Age 70 74.474.675.075.375.6120/80 130/8572.172.472.773.173.574.975.175.575.876.1130/85 140/9072.772.973.373.774.175.375.575.976.276.5140/90 150/9573.273.573.974.374.775.776.076.376.676.9150/95 Blood Pressure (mmHg) Non-smokersSmokers

34. Total Cholesterol:HDL Ratio 3456734567 120/8033.333.734.335.035.8 Age 30 38.439.140.141.142.1120/80 130/8534.334.735.436.237.139.540.241.342.443.4130/85 140/9035.335.736.637.538.440.641.342.543.644.7140/90 150/9536.236.837.738.739.741.642.443.644.845.9150/95 120/8042.342.743.344.144.8 Age 40 47.347.948.949.950.8120/80 130/8543.343.744.445.346.148.349.050.151.152.0130/85 140/9044.244.745.546.447.449.350.051.152.253.1140/90 150/9545.145.746.647.648.650.351.052.153.254.2150/95 120/8051.852.252.853.454.1 Age 50 56.356.957.858.659.4120/80 130/8552.753.153.854.555.357.357.958.859.660.3130/85 140/9053.554.054.855.656.458.258.859.760.561.3140/90 150/9554.454.955.856.657.559.059.660.561.462.2150/95 120/8061.661.962.462.963.5 Age 60 65.465.966.567.167.6120/80 130/8562.462.763.363.864.466.266.667.267.868.3130/85 140/9063.163.564.164.765.466.967.367.968.569.0140/90 150/9563.864.264.965.666.267.567.968.569.169.6150/95 120/8071.671.872.172.472.8 Age 70 74.474.675.075.375.6120/80 130/8572.172.472.773.173.574.975.175.575.876.1130/85 140/9072.772.973.373.774.175.375.575.976.276.5140/90 150/9573.273.573.974.374.775.776.076.376.676.9150/95 Blood Pressure (mmHg) Non-smokersSmokers 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 43.6 Cardiovascular Age Tables: Male Patients WITH Diabetes

35. Cardiovascular Age Tables: Female Patients WITHOUT Diabetes Total Cholesterol:HDL Ratio 3456734567 120/8028.829.029.229.529.9 Age 30 32.633.133.734.435.2120/80 130/8529.529.730.030.430.833.434.034.735.636.6130/85 140/9030.230.530.831.331.834.234.935.836.938.0140/90 150/9530.931.231.732.232.835.035.936.938.139.4150/95 120/8038.138.238.538.839.1 Age 40 41.842.242.943.644.4120/80 130/8538.739.039.239.640.142.543.143.944.845.8130/85 140/9039.439.740.040.541.143.344.045.046.047.1140/90 150/9540.140.440.941.442.144.145.046.147.348.5150/95 120/8047.647.848.048.348.6 Age 50 51.251.652.252.853.6120/80 130/8548.348.548.849.149.551.952.453.153.954.8130/85 140/9048.949.249.550.050.552.653.354.155.056.0140/90 150/9549.649.950.350.851.453.454.155.156.157.2150/95 120/8057.657.757.958.158.4 Age 60 60.861.161.562.062.6120/80 130/8558.258.358.558.859.261.461.862.362.963.6130/85 140/9058.858.959.259.660.062.062.563.163.864.5140/90 150/9559.359.659.960.360.862.763.363.964.765.5150/95 120/8067.9 68.168.268.4 Age 70 70.570.771.071.371.6120/80 130/8568.468.568.668.869.071.071.371.672.072.3130/85 140/9068.969.069.269.469.671.571.872.272.673.0140/90 150/9569.469.569.770.070.372.172.472.873.273.7150/95 Blood Pressure (mmHg) Non-smokersSmokers

36. Cardiovascular Age Tables: Female Patients WITH Diabetes Total Cholesterol:HDL Ratio 3456734567 120/8038.238.739.239.940.6 Age 30 42.543.544.846.147.4120/80 130/8539.039.540.241.041.943.544.746.147.649.1130/85 140/9039.840.441.242.243.244.545.947.549.150.7140/90 150/9540.641.342.343.444.545.547.148.850.552.0150/95 120/8047.247.648.248.949.6 Age 40 51.352.453.654.856.2120/80 130/8547.948.549.250.050.952.353.554.956.357.7130/85 140/9048.749.450.251.152.153.254.656.257.759.3140/90 150/9549.550.251.252.353.454.255.857.559.160.5150/95 120/8056.356.757.257.858.4 Age 50 60.060.961.962.964.0120/80 130/8557.057.458.158.859.560.861.963.064.165.3130/85 140/9057.658.259.059.860.761.762.864.165.366.5140/90 150/9558.459.059.960.861.862.563.865.166.467.5150/95 120/8065.365.566.066.466.9 Age 60 68.469.069.670.371.0120/80 130/8565.966.266.767.267.869.069.770.471.171.8130/85 140/9066.566.967.468.068.669.770.471.271.972.6140/90 150/9567.167.668.168.869.470.371.171.972.673.3150/95 120/8074.374.474.674.975.2 Age 70 76.576.877.177.577.8120/80 130/8574.774.975.275.475.776.977.377.678.078.3130/85 140/9075.175.475.776.076.377.477.778.178.478.7140/90 150/9575.675.876.176.576.877.878.178.578.879.1150/95 Blood Pressure (mmHg) Non-smokersSmokers

37. 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 TrialTherapies#PopulationPrimary endpointEnd Date EXAMINEAlogliptin/Pl acebo 5400ACS 15-90 days before Non-inferiority: time to occurrence of MACE PUBLISHED SAVORSaxagliptin/ Placebo 16,500CVD or ≥ 2 RFSuperiority efficacy, non- inferiority safety: composite CV death, NF MI, NF stroke PUBLISHED CARMELINALinagliptin/P lacebo 8,300High risk of CV events Time to first occurrence of composite CV outcome Jan 2018 CAROLINALinagliptin/ Glimepiride 6000CVD or ≥ 2 RFNon-inferiority: time to first occurrence of any component of MACE composite outcome Sept 2018 TECOSSitagliptin/ Placebo 14,000Established CVDNon-inferiority: time to first occurrence of composite CV outcome Dec 2014

38. Ongoing CV Outcome Trials: GLP-1 Agonists 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 TrialTherapies#PopulationPrimary endpointEnd Date ELIXALixisenatide/ Placebo 6000ACS leading to hosp ≤ 180 days before Non-inferiority: CV death, NF MI, NF stroke, UA hospitalization. Jan 2015 EXSCELExenatide LAR/ Placebo 9500T2DM, A1C of 7.0-10.0% Non-inferiority: Time to primary composite CV endpoint Mar 2017 LEADERLiraglutide/ Placebo 8754CVD, PAD, CKD, CHF or RF if age > 60 years Superiority: Time to composite CV death, NF MI, NF stroke Jan 2016 REWINDDulaglutide/ Placebo 9622CVD or ≥ 2 RF if age ≥ 60 years Superiority: Time to composite CV death, NF MI, NF stroke Apr 2019 SUSTAIN 6Semaglutide/ Placebo 3,260T2DM, CVD or subclinical evidence of CVD if age ≥ 60 years Time to first occurrence of MACE Jan 2016