Content Development Committee - PDF Free Download

Content Development Committee Cardiologists: Family Physicians: Shaun Goodman, MD, MSc, FRCPC, FACC, FESC, FAHA, FCCS (Chair) Associate Head, Division of Cardiology, St. Michael s Hospital Professor, Department of Medicine, University of Toronto Toronto (ON) Richard Choi, MD, FRCPC (Cardiology) Staff Cardiologist, St. Joseph's Health Centre Lecturer, Department of Medicine, University of Toronto Toronto (ON) Maureen Clement, MD, CCFP Clinical Assistant Professor, University of British Columbia Medical Director, Vernon Diabetes Education Centre Vernon (BC) Pierre Filteau, MD Family Physician Founding Member, Master Clinician Alliance Inc. Saint-Marc-des-Carrieres (QC) Jeff Habert, MD, CCFP, FCFP Assistant Professor, Department of Family and Community Medicine, University of Toronto Founding Member, Master Clinician Alliance Inc. Toronto (ON) 2

Disclosure SPEAKER S NAME and Credentials Shaun Goodman, MD RELATIONSHIPS WITH COMMERCIAL INTERESTS Grants/Research Support: Speakers Bureau/Honoraria: Consulting Fees: Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol- Myers Squibb, Ferring Pharmaceuticals, GlaxoSmithKline, Lilly, Luitpold Pharmaceuticals, Matrizyme, Merck, Novartis, Pfizer, Sanofi, Tenax Therapeutics Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol- Myers Squibb, Ferring Pharmaceuticals, Lilly, Merck, Novartis, Pfizer, Sanofi Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol- Myers Squibb, Fenix Group International, Ferring Pharmaceuticals, Lilly, Merck, Pfizer, Sanofi 3

Case Vignette 1: Sarah 4

Case Vignette 1: Sarah 56-year-old woman with type 2 diabetes who is new to your practice She has come in to have her diabetes medications renewed She is worried about her heart as her brother just had a heart attack, and wonders if better control of her blood sugars will reduce her chance of having another heart attack History: Medical: Diabetes for 13 years Hypertension, obesity MI 3 years ago Lifestyle: non-smoker;; sedentary job but walks her dog for 30 min per day Physical exam: BMI 32 kg/m 2 BP 132/78 mm/hg Laboratory: A1C 8.1 % egfr 80 ml/min LDL-C 1.8 mmol/l ACR 5.0 mg/mmol Medications: ASA Beta-blocker ACEi at cardio-protective dose Statin Metformin/DPP-4i combination full dose Gliclazide full dose MI: myocardial infarction;; ACEi: angiotensin-converting-enzyme inhibitor;; BMI: body mass index;; BP: blood pressure;; A1C: glycated hemoglobin;; egfr: estimated glomerular filtration rate;; LDL-C: low-density lipoprotein cholesterol;; ACR: albumin to creatinine ratio;; ASA: acetylsalicylic acid;; DPP4i: dipeptidyl peptidase 4 inhibitor 5

Questions 1. Because she has diabetes, Sarah is at increased risk of another CV event. True or False? 2. Reducing Sarah s A1C to <7% will reduce her risk of death from CVD. True or False? 3. Reducing Sarah s A1C to <7% will reduce her risk of MI. True or False? 4. What A1C target would you choose for Sarah? 6

Absolute Risk of MI is Higher in Patients with Diabetes Database 1994-2000 No. events per 100 person- years 3.0 2.5 2.0 1.5 1.0 0.5 Diabetes (n=379,003) Men Women No diabetes (n=9,018,082) Men Women 0 20-30 31-40 41-45 46-50 51-55 56-60 61-65 66-70 71-75 76-80 81-85 Age group MI = myocardial infarction Booth GL, et al. Lancet 2006;;368:29-36. guidelines.diabetes.ca 1-800-BANTING (226-8464) diabetes.ca Copyright 2013 Canadian Diabetes Association 7

Effects of Intensive Glucose Lowering in T2DM on CV Outcomes: A Meta-analysis of Data from 58,160 Patients in 13 RCTs Event Risk Ratio (95% CI) P Value Total mortality 0.98 (0.91 1.20) 0.69 CV mortality 1.00 (0.87 1.14) 0.99 MACE 0.92 (0.85 1.00) 0.04 MI 0.90 (0.82 0.98) 0.02 Stroke 0.94 (0.84 1.06) 0.33 CHF 1.19 (0.96 1.48) 0.11 ACCORD, ADDITION-Europe, ADVANCE, Steno-2, TECOS, PROACTIVE, RECORD, UGDP, VACSDM, VADT T2DM: type 2 diabetes mellitus;; CV: cardiovascular;; RCTs: randomized controlled trials;; MACE: major adverse cardiovascular events;; MI: myocardial infarction;; CHF: congestive heart failure;; ACCORD: Action to Control Cardiovascular Risk in Diabetes;; ADDITION: Anglo-Danish-Dutch Study in General Practice of Intensive Treatment and Complication Prevention in Type 2 Diabetic Patients Identified by Screening;; ADVANCE: Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation;; TECOS: Trial Evaluating Cardiovascular Outcomes with Sitagliptin;; PROACTIVE: Prospective Pioglitazone Clinical Trial in Macrovascular Events;; RECORD: Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes;; UGDP: University Group Diabetes Program;; VADT: Veterans Affairs Diabetes Trial;; VASCDM: Veterans Affairs Cooperative Study in Type 2 Diabetes Mellitus Fang HJ, et al. Int J Cardiol. 2016;;218:50-58. 8

Question Using selected antihyperglycemic agents (AHA) can reduce Sarah s risk of death from CVD. True or False? 10

AT DIAGNOSIS OF TYPE 2 DIABETES L I F E S T Y L E Start lifestyle intervention (nutrition therapy and physical activity) +/- Metformin Symptomatic hyperglycemia with A1C <8.5% A1C ³ 8.5% metabolic decompensation If not at glycemic target (2-3 mos) Start / Increase metformin Start metformin immediately Consider initial combination with another antihyperglycemic agent If not at glycemic targets Initiate insulin +/- metformin Add another agent best suited to the individual by prioritizing patient characteristics: PATIENT CHARACTERISTIC PRIORITY: Clinical Cardiovascular Disease Degree of hyperglycemia Risk of hypoglycemia Overweight or obesity Cardiovascular disease or multiple risk factors Comorbidities (renal, CHF, hepatic) Preferences & access to treatment CHOICE OF AGENT Antihyperglycemic agent with demonstrated CV outcome benefit (empagliflozin, liraglutide) Consider relative A1C lowering Rare hypoglycemia Weight loss or weight neutral Effect on cardiovascular outcome See therapeutic considerations, consider egfr See cost column;; consider access CDA Clinical Practice Guidelines Expert Committee. Can J Diabetes. 2016;;40:484 486. See next page 11/2016

Recommendation 4 11/2016 4. In adults with type 2 diabetes with clinical cardiovascular disease in whom glycemic targets are not met, an antihyperglycemic agent with demonstrated cardiovascular outcome benefit should be added to reduce the risk of major cardiovascular events (Grade 1, Level 1A for empagliflozin ;; Grade 1, Level 1A for liraglutide if age 50 years;; Grade D, Consensus for liraglutide if age <50 years). CDA Clinical Practice Guidelines Expert Committee. Can J Diabetes. 2016;;40:484 486. guidelines.diabetes.ca 1-800-BANTING (226-8464) diabetes.ca Copyright 2016 Canadian Diabetes Association 12

EMPA-REG OUTCOME Primary Outcome: CV Death, Non-fatal MI or Non-fatal Stroke EMPA-REG OUTCOME included adult patients (>18 years) with type 2 diabetes and established CVD who were receiving standard of care therapy for diabetes Patients with event (%) 20 15 10 5 Empagliflozin (pooled) HR 0.86 (95.02% CI 0.74, 0.99) p=0.04* for superiority p<0.001 for noninferiority Placebo Empagliflozin Empagliflozin 10 mg HR 0.85 (95% CI 0.72, 1.01), p=0.07 Empagliflozin 25 mg HR 0.86 (95% CI 0.73, 1.02), p=0.09 No. of patients Empagliflozin Placebo 0 0 6 12 18 24 30 36 42 48 Months 4687 2333 4580 2256 4455 2194 4328 2112 3851 1875 2821 1380 2359 1161 1534 741 370 166 Cumulative incidence function. MACE: major adverse cardiovascular event;; HR: hazard ratio;; MI: myocardial infarction;; SGLT2: sodium glucose cotransporter 2 *Two-sided tests for superiority were conducted (statistical significance was indicated if p 0.0498) Note: Empagliflozin is an SGLT2 inhibitor. Data from: Zinman B, et al. N Engl J Med. 2015;; 373:2117-2128. 13

EMPA-REG OUTCOME: CV Death, Non-fatal MI and Non-fatal Stroke Patients with event/analyzed Hazard ratio (HR) (95% CI) Empagliflozin Placebo HR (95% CI) p-value 3-point MACE 490/4687 282/2333 0.86 (0.74, 0.99)* 0.04 CV death 172/4687 137/2333 0.62 (0.49, 0.77) <0.001 Non-fatal MI 213/4687 121/2333 0.87 (0.70, 1.09) 0.22 Non-fatal stroke 150/4687 60/2333 1.24 (0.92, 1.67) 0.16 0.25 0.50 1.00 2.00 Note: Empagliflozin is an SGLT2 inhibitor Cox regression analysis. * 95.02% CI;; for superiority Data from: Zinman B, et al. N Engl J Med. 2015;; 373:2117-2128. Favours empagliflozin MACE: major adverse cardiovascular event;; HR: hazard ratio;; CV: cardiovascular;; MI: myocardial infarction;; SGLT2: sodium glucose cotransporter 2 Favours placebo 14

LEADER: Primary Endpoint: CV Death, Non-fatal MI, or Non-fatal Stroke LEADER included adults with type 2 diabetes aged 50 years with established CVD or CKD, or aged 60 years with an additional CV risk factor, who were receiving standard of care therapy for diabetes Patients with an event (%) 20 15 10 5 0 Patients at risk Liraglutide Placebo Placebo Liraglutide HR 0.87 95% CI (0.78 0.97) p=0.01 for superiority p<0.001 for non-inferiority 0 6 12 18 24 30 36 42 48 54 Time from randomization (months) 4668 4593 4496 4400 4280 4172 4072 3982 1562 424 4672 4588 4473 4352 4237 4123 4010 3914 1543 407 The primary composite outcome in the time-to-event analysis was the first occurrence of death from CV causes, non-fatal MI, or non-fatal stroke. The cumulative incidences were estimated with the use of the Kaplan Meier method, and the HRs with the use of the Cox proportional-hazard regression model. The data analyses are truncated at 54 months, because less than 10% of the patients had an observation time beyond 54 months. CI: confidence interval;; CV: cardiovascular;; CKD: chronic kidney disease;; HR: hazard ratio;; MI: myocardial infarction;; GLP-1RA: glucagon-like peptide-1 receptor agonist 15 Data from: Marso S, et al. N Engl J Med. 2016;; 375:311-322.

LEADER: CV Death, Non-fatal MI and Non-fatal Stroke Patients with event/analysed Hazard ratio (HR) (95% CI) Liraglutide Placebo HR (95% CI) p-value 3-point MACE 608/4668 694/4672 0.87 (0.78 0.97) 0.01 CV death 219/4668 278/4672 0.78 (0.66 0.93) 0.007 Non-fatal MI 281/4668 317/4672 0.88 (0.75 1.03) 0.11 Non-fatal stroke 159/4668 177/4672 0.89 (0.72 1.11) 0.30 0.50 1.00 1.50 Favours Liraglutide Favours Placebo CV: cardiovascular;; MACE: major adverse cardiovascular event;; MI: myocardial infarction;; GLP-1RA: glucagon-like peptide-1 receptor agonist Data from: Marso S, et al. N Engl J Med. 2016;;375:311-322. 16

CANVAS Program: Primary Outcome: CV Death, Non-fatal MI or Non-fatal Stroke CANVAS included patients with type 2 diabetes aged >30 years with a history of symptomatic atherosclerotic CVD, or >50 years with >2 risk factors for CVD, who were receiving standard of care therapy for diabetes Patients with an event (%) No. of patients Placebo Canagliflozin 20 18 16 14 12 10 8 6 4 2 0 HR 0.86 (95% CI 0.75 0.97) p=0.0158 for superiority p<0.0001 for non-inferiority Placebo Canagliflozin 0 1 2 3 4 5 6 Years since randomization 4347 4153 2942 1240 1187 1120 789 5795 5566 4343 2555 2460 2363 1661 Intent-to-treat analysis Note: Canagliflozin is an SGLT2 inhibitor;; it is not currently indicated for cardiovascular protection in Canada Data from: Neal B, et al. N Engl J Med. 2017;;377:644-57. 17

CANVAS Program: CV Death, Non-fatal MI and Non-fatal Stroke Hazard ratio (95% CI) Primary CV outcome 0.86 (0.75 0.97) CV death 0.87 (0.72 1.06) Non-fatal MI 0.85 (0.69 1.05) Non-fatal stroke 0.90 (0.71 1.15) 0.5 1.0 2.0 Favours Canagliflozin Favours Placebo Intent-to-treat analysis Note: Canagliflozin is an SGLT2 inhibitor;; it is not currently indicated for cardiovascular protection in Canada Data from: Neal B, et al. N Engl J Med. 2017;;377:644-57. 18

Choosing Between Empagliflozin and Liraglutide (as per Diabetes Canada s Recommendation)* Depends on Patient/Agent Characteristics Discuss with Sarah: Empagliflozin Liraglutide Relative A1C lowering to to Remember to adjust gliclazide as needed for hypoglycemia Weight loss Hypoglycemia Rare Rare Side effects Genital infections, UTI, hypotension, dose-related changes in LDL-C, caution with renal dysfunction and loop diuretics Gastrointestinal side effects Route of administration Oral Injectable Dosing Start at 10 mg OD;; increase to 25 mg OD if needed for glycemic control Start at 0.6 mg OD and then titrate up to 1.8 mg OD (as per LEADER trial) Cost $$$ $$$$ Reduction in MACE 14% 13% Reduction in CV death 38% 22% NNT 3y (CV mortality) 46 to prevent 1 CV death 104 to prevent 1 CV death A1C: glycated hemoglobin;; UTI: urinary tract infection;; LDL-C: low-density lipoprotein cholesterol;; NNT: number needed to treat;; OD: once daily;; MACE: major adverse cardiac event *The Diabetes Canada recommendation to add empagliflozin or liraglutide in patients with diabetes and clinical CVD was released before the results of the CANVAS Program with canagliflozin became available. 19 CDA Clinical Practice Guidelines Expert Committee. Can J Diabetes. 2016;;40:484 486. Zinman B, et al. N Engl J Med. 2015;; 373:2117-2128. Marso S, et al. N Engl J Med. 2016;;375:311-322.

Question What if Sarah s A1C is close to target (i.e., 7.2%) with her current antihyperglycemic regimen (i.e., metformin/dpp-4i combination and gliclazide), but she is experiencing episodes of hypoglycemia What, if any, changes would you make to her antihyperglycemic regimen? 20

ADVANCE: Severe Hypoglycemia Associated with Adverse Clinical Endpoints and Death Patients with 1 hypoglycemic events (%) 25 20 15 10 5 3.53 (2.41 5.17) a 15.9 10.2 2.19 (1.40 3.45) a 11.5 10.1 3.27 (2.29 4.65) a 19.5 9.0 Severe hypoglycemia (n=231) No severe hypoglycemia (n=10,909) 3.79 (2.36 6.08) a 9.5 4.8 2.80 (1.64 4.79) a 10.0 4.3 0 Major macrovascular event b Major microvascular event b Death from any cause CV disease Non-CV disease Numbers above sets of bars are HR (95% CI). a Adjusted for multiple baseline covariates. b Primary endpoints: major macrovascular event = CV death, non-fatal myocardial infarction, or non-fatal stroke;; major microvascular event = new or worsening nephropathy or retinopathy;; ADVANCE: Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation;; HR: hazard ratio;; CV: cardiovascular Data from: Zoungas S, et al. N Engl J Med. 2010;;363:1410 8. 21

Question Reminder: Sara is currently prescribed ASA, a beta-blocker, an ACEi, a statin, a metformin/dpp-4i combination and gliclazide. What if Sarah was also started on empagliflozin or liraglutide and then calls your office to tell you that she has a really bad stomach flu with vomiting and diarrhea What does Sarah need to know? ACEi: angiotensin-converting-enzyme inhibitor;; ASA: acetylsalicylic acid;; DPP4i: dipeptidyl peptidase 4 inhibitor 22

Counsel all Patients About Sick Day Medication List 2015

Application to our Case Vignette: Treatment Plan(s)* 1. Ensure ABCDEs of CV protection: A: A1C not at target B: BP at target C: LDL-cholesterol at target D: Cardioprotective drugs (statin/acei) E: Exercise/diet S: Non-smoker 2. Twin goals for selection of antihyperglycemic agent (AHA) Glycemic improvement Reduce CV outcomes in a patient with clinical CVD Pathway: Based on patient preference for oral AHA à Empagliflozin 10 mg OD Counselling: Possible weight loss Possible hypoglycemia and need to titrate gliclazide Possible genital mycotic infections No need to adjust any of the other medications proactively Pathway: Based on preference for AHA that leads to possibility of increased satiety, no contraindications (pancreatitis) and acceptance of injectable: à Liraglutide 0.6 mg SC daily for 1 week then titrated to 1.2 mg SC daily, as tolerated, and then 1.8 mg SC daily as tolerated Counselling: Possible weight loss Possible hypoglycemia and need to titrate gliclazide Possible GI side effects How to inject therapy *Note that pathway options are based on Diabetes Canada s most recent interim guideline update (CDA Clinical Practice Guidelines Expert Committee. Can J Diabetes 2016;;40:484 486) A1C: glycated hemoglobin;; BP: blood pressure;; CVD: cardiovascular disease;; LDL: low-density lipoprotein;; ACEi: angiotensin-converting enzyme inhibitor;; OD: once daily;; SC: subcutaneously;; GI: gastrointestinal 24

Case Vignette 2: Jake 25

Case Vignette 2: Jake 63-year-old metal recycling business owner with type 2 diabetes and peripheral arterial disease (PAD) Jake is in to see you for a routine diabetes follow-up visit He apologizes for not seeing you in 8 months as he and his wife spent the winter in Hawaii He does recall that you discussed changing meds before Hawaii (A1C was high), but he declined He feels well with no angina, dyspnea or symptoms of intermittent claudication 26

Case Vignette 2: Jake (continued) History: Type 2 diabetes x 5 years PAD with percutaneous transluminal angioplasty (PTA) and stent of superficial femoral artery 3 years ago Hypertension 45 pack year smoking history: quit after the PTA Minimal exercise, but trying to walk more Physical Exam: BP 128/78 mm Hg BMI 28 kg/m 2 Rest of exam unremarkable Labs: A1C 7.8% (was 7.5% 8 months ago) LDL-C 1.79 mmol/l ACR 4.8 mg/mmol egfr 64 ml/min/1.73 m 2 Current Medications: Metformin 1 g bid Linagliptin 5 mg daily Perindopril 8 mg daily Rosuvastatin 20 mg daily ASA 81 mg daily PAD: peripheral arterial disease;; ACEi: angiotensin-converting-enzyme inhibitor;; BMI: body mass index;; BP: blood pressure;; A1C: glycated hemoglobin;; egfr: estimated glomerular filtration rate;; LDL-C: low-density lipoprotein cholesterol;; ACR: albumin to creatinine ratio;; ASA: acetylsalicylic acid 27

Question Jake has worked hard all his life and now wants to enjoy his retirement, so he wants to know what he can do to help himself. What will you tell Jake about his diabetes and CV disease? 28

Patients with Diabetes are More Likely to be Hospitalized for Many Conditions Prevalence rate ratios of complications among hospitalized individuals aged >20 years, by diabetes status, Canada, 2008/09 22 Rate ratios (with diabetes: without diabetes) 20 18 16 14 12 10 8 6 4 2 0 COMPLICATION Cerebrovascular disease (stroke) Acute myocardial infarction (heart attack) Ischemic heart disease Heart failure Chronic kidney disease End-stage renal disease Lower limb amputations Rate ratios based on rates age-standardized to the 1991 Canadian population. A person with diabetes hospitalized with more than one complication was counted once in each category, except for cases of acute myocardial infarction, where regardless of multiple counts in the acute myocardial infarction category, the individual was counted only once under the broader ischemic heart disease category. Source: Public Health Agency of Canada (August 2011);; using 2008/09 data from the Canadian Chronic Disease Surveillance System (Public Health Agency of Canada). 29

Clinical Approach to Jake Jake has CVD and diabetes and is at high risk of other CV events (e.g., stroke, MI) Review the ABCDs for vascular protection: A: A1C his A1C is above target B: BP his BP is well controlled C: Cholesterol his cholesterol is at target D: Drugs to protect the heart he is on an ACEi, statin and ASA Priorities will be getting Jake to target A1C to reduce risk of microvascular events, particularly given that he has evidence of early kidney disease, and using an antihyperglycemic agent with demonstrated CV benefits CVD: cardiovascular disease;; ACEi: angiotensin-converting-enzyme inhibitor;; BP: blood pressure;; A1C: glycated hemoglobin;; ASA: acetylsalicylic acid 30

Question What would you do about Jake s diabetes treatment? 1. Add canagliflozin 100 mg daily 2. Add dapagliflozin 5 mg daily 3. Add empagliflozin 10 mg 4. Add gliclazide MR 30-60 mg daily 5. Add dulaglutide 0.75 mg sc weekly 6. Add liraglutide 0.6 mg daily (titrating up to 1.8 mg) 31

guidelines.diabetes.ca 1-800-BANTING (226-8464) diabetes.ca Copyright 2016 Canadian Diabetes Association 11/2016 Add another agent best suited to the individual by prioritizing patient characteristics: PATIENT CHARACTERISTIC PRIORITY: Clinical Cardiovascular cardiovascular disease Disease Degree of hyperglycemia Risk of hypoglycemia Overweight or obesity CV disease or multiple risk factors Comorbidities (renal, CHF, hepatic) Preferences & access to treatment CHOICE OF AGENT Antihyperglycemic agent with demonstrated CV outcome benefit (empagliflozin, liraglutide) Consider relative A1C lowering Rare hypoglycemia Weight loss or weight neutral Effect on cardiovascular outcome See therapeutic considerations;; consider egfr See cost column;; consider access

Question Jake has PAD with prior angioplasty/stenting of a superficial femoral artery 3 years ago. Would this PAD history influence your choice of which antihyperglycemic/vascular protective agent he should receive next? 33

Amputations in CANVAS Event rate per 1000 patient-years Hazard ratio Canagliflozin Placebo (95% CI) All amputations (n=187) 6.3 3.4 1.97 (1.41 2.75) Minor amputation (71%) 4.5 2.4 1.94 (1.31 2.88) Toe 3.4 2.2 Transmetatarsal 1.0 0.3 Major amputation (29%) 1.8 0.9 2.03 (1.08 3.82) Ankle 0.04 0.07 Below-knee 1.2 0.6 Above-knee 0.6 0.2 Data from: Neal B, et al. N Engl J Med. 2017;;377:644-57. 0.25 0.5 1.0 2.0 4.0 8.0 Favours Canagliflozin Favours Placebo 34

CANVAS: Relationship to PAD History and Amputations Effects of canagliflozin vs. placebo on atraumatic lower limb amputation in key subgroups in the CANVAS program History of amputation Canagliflozin per 1000 patient-years Placebo per 1000 patient-years Hazard ratio (95% confidence interval) Yes 96.30 59.16 2.15 (1.11 4.19) No 4.68 2.48 1.88 (1.27 2.78) History of peripheral vascular disease Yes 12.09 8.16 1.39 (0.80 2.40) No 5.20 2.41 2.34 (1.53 3.58) 136 of 5795 subjects in the canagliflozin group and 102 of 4347 in the placebo group had a history of amputation 1176 of 5795 subjects in the canagliflozin group and 937 of 4347 in the placebo group had a history of PAD Data from: Neal B, et al. N Engl J Med. 2017;;377:644-57. 35

CANVAS Program: Summary Canagliflozin in addition to standard of care reduced CV risk in adults with T2D and age 30 years with established CVD (66%) or age 50 yrs with 2 CV risk factors (34%) 14% CV death, non-fatal MI, non-fatal stroke (P=0.02;; NNT 5y = 44) 33% HF hospitalization (NNT 5y = 63) 40% egfr, dialysis, renal death (NNT 5y = 58) 97% Lower extremity amputations (P<0.001;; NNH 5y = 69) 26% No increased risk of amputations was observed in EMPA-REG OUTCOME or LEADER Fractures (P=0.02;; NNH 5y = 58) The primary prevention cohort accounted for fewer primary MACE events and while subgroup analysis did not show heterogeneity, no conclusion can be made regarding the CV benefit in this group (HR 0.98;; 95% CI 0.74-1.30) Canagliflozin is not currently indicated for cardiovascular or renal protection in Canada CVD: cardiovascular disease;; HF: heart failure;; MI: myocardial infarction;; NNT: number needed to treat;; NNH: number needed to harm;;t2d: type 2 diabetes Neal B, et al. N Engl J Med. 2017;;377:644-57 ;; ADA Annual Meeting 2017. Slide courtesy of Dr. R. Goldenberg. 36

EMPA-REG OUTCOME: Summary Empagliflozin in addition to standard of care reduced CV risk and improved overall survival in adults with T2D with established CVD 14% 38% 32% 35% 39% CV death, non-fatal MI, non-fatal stroke (NNT 3y = 63) CV death (NNT 3y = 46) All-cause mortality (NNT 3y = 39) HF hospitalizations NNT 3y = 72 New or worsening nephropathy (NNT 3y = 17) The overall safety profile of empagliflozin was consistent with previous clinical trials and current label information Empagliflozin is not currently indicated for renal protection in Canada CVD: cardiovascular disease;; MI: myocardial infarction;; NNT: number needed to treat;; T2D: type 2 diabetes;; HF: heart failure Zinman B, et al. N Engl J Med. 2015;;373:2117-28. Wanner C, et al. N Engl J Med. 2016;;375:323-334. Slide courtesy of Dr. R. Goldenberg. 37

LEADER: Summary Liraglutide in addition to standard of care reduced CV risk and improved overall survival in adults with T2D and age 50 yrs with established CVD or CKD or age 60 yrs with an additional risk factor 13% 22% 15% 14% 22% CV death, non-fatal MI, non-fatal stroke (NNT 3y = 66) CV death (NNT 3y = 104) All-cause mortality (NNT 3y = 98) Fatal and non-fatal MI (NNT 3y = 127) New or worsening nephropathy (NNT 3y = 85) The overall safety profile of liraglutide was consistent with previous clinical trials and current label information LEADER: Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results A Long Term Evaluation;; CVD: cardiovascular disease;; CKD: chronic kidney disease;; T2D: type 2 diabetes;; MI: myocardial infarction;; NNT: number needed to treat Liraglutide is not currently indicated for renal protection in Canada Marso S, et al. N Engl J Med. 2016;;375:311-322. Slide courtesy of Dr. R. Goldenberg. 38

Questions What if Jake s egfr was 54 rather than 64 ml/min/1.73 m 2 What would you do about Jake s diabetes treatment? Add canagliflozin Add dapagliflozin SGLT2 inhibitors Add empagliflozin Add gliclazide sulfonylurea Add dulaglutide Add liraglutide GLP-1R agonists Add another antihyperglycemic agent not listed above What renal outcomes have been noted in LEADER, EMPA-REG and CANVAS? 39

Antihyperglycemic Agents and Renal Function Alpha-glucosidase Inh. Biguanide DPP-4 inhibitors GLP-1R agonists Insulin secretagogues SGLT2 inhibitors CKD Stage: 5 4 3 2 1 egfr (ml/min/1.73 m 2 ): <15 15 29 30 59 60 89 90 Acarbose Not recommended 25 Metformin 30 60 Alogliptin Not recommended 6.25 mg 30 12.5 mg 50 Linagliptin 15 Saxagliptin 15 2.5 mg 50 Sitagliptin 25 mg 30 50 mg 50 Lixisenatide Exenatide (BID/QW) Liraglutide 15 30 50 Gliclazide/Glimepiride Glyburide 15 30 30 50 Repaglinide Canagliflozin 25 45 100 mg 60* Dapagliflozin 60 Empagliflozin Thiazolidinediones 30 30 50 Dulaglutide 50 45 60* Contraindicated Not recommended Caution and/or reduce dose Safe No dose adjustment but close monitoring of renal function * = do not initiate if egfr <60 ml/min Approved but not yet available in Canada Adapted from: Product Monographs as of December 2017;; Harper W, et al. Can J Diabetes. 2015;;39:250-52. 40

Differences in Renal Outcomes of Patients Treated in EMPA-REG OUTCOME, LEADER and CANVAS* CAUTION: Cross-trial comparisons cannot be made due to differences in study designs, trial durations and patient populations. 0 EMPA-REG OUTCOME LEADER CANVAS -5-10 -15-20 -25-30 -35-40 -45-50 P<0.001-39% P=0.003-22% New or worsening nephropathy P<0.001-38% P=0.004-26% -27%** (95% CI: -21% to -33%) Progression to macroalbuminura or progression of albuminuria P<0.001 Wanner C, et al. N Engl J Med. 2016;;375:323-334. Marso S, et al. N Engl J Med. 2016;;375:311-322. Neal B, et al. N Engl J Med. 2017;;377:644-57. Mann JFE, et al. N Engl J Med. 2017;;377:839-48. -44% *Empagliflozin, canagliflozin and liraglutide are not currently indicated for renal protection. **Exploratory outcome 41 P=0.43-11% Doubling of serum creatinine P<0.001-46% Doubling of serum creatinine, initiation of replacement therapy or death due to renal disease 40% reduction in egfr, renal replacement therapy, or renal death EMPA-REG -39% -38% -44% -46% Not reported LEADER -22% -26% -11% (NS) Not reported Not reported CANVAS Not reported -27%** Not reported Not reported -40%** -40%** (95% CI: -23% to -53%)

Application to our Case Vignette: Treatment Plan(s)* Reduce CV outcomes Improve glycemic control Consider implications with PAD Consider other factors: Comfort with injectables Coverage Interaction with current meds Patient/physician preference Pathway: Patient has private insurance plan Motivated to prevent further CV risk Add empagliflozin or liraglutide as per Diabetes Canada guidelines Avoid canagliflozin due to history of PAD All other meds adequate for CV protection Pathway: low egfr Consider liraglutide for CV protection to follow Diabetes Canada guidelines as egfr <60 ml/min Empagliflozin and canagliflozin should not be initiated in patients with an egfr <60 ml/min For patients already on empagliflozin, if egfr falls between 45-60 ml/min, no dose adjustment but close monitoring of renal function is required For patients already on canagliflozin, if egfr falls between 45-60 ml/min, the dose should be reduced to 100 mg daily Avoid canagliflozin due to history of PAD NOTE: Jake should be taken off DPP- 4 inhibitor therapy (linagliptin) if adding a GLP- 1RA (liraglutide). *Note that pathway options are based on Diabetes Canada s most recent interim guideline update (CDA Clinical Practice Guidelines Expert Committee. Can J Diabetes. 2016;;40:484 486) 42