Development Committee CHAIR Lawrence A Leiter Endocrinology Metabolism

Development Committee CHAIR • Lawrence A. Leiter, Endocrinology & Metabolism, University of Toronto, Toronto STEERING COMMITTEE • Harpreet S. Bajaj, Endocrinology & Metabolism, LMC Diabetes & Endocrinology, Brampton • C. Keith Bowering, Internal Medicine, University of Alberta, Edmonton • Alice Y. Y. Cheng, Endocrinology & Metabolism, University of Toronto, Toronto • Jean-Marie Ekoé, Endocrinology & Metabolism, Université de Montréal, Montreal • Pierre Filteau, General Practice, Saint-Marc-Des-Carrières • Stewart B. Harris, Family Medicine, Epidemiology & Biostatistics, Western University, London • Ronald M. Goldenberg, Endocrinology & Metabolism, LMC Diabetes & Endocrinology, Thornhill • Vincent C. Woo, Endocrinology & Metabolism, University of Manitoba, Winnipeg • Jean-François Yale, Endocrinology & Metabolism, Mc. Gill University, Montreal EDUCATIONAL COMMITTEE • Carl Fournier, Family Physician, Montreal • Theodore J. Jablonski, Family Physician, Calgary • Kevin K. Saunders, Family Physician, Winnipeg • Richard Ward, Family Physician, Calgary

Faculty/Presenter Disclosure • Faculty: [Speaker’s name] • Relationships with commercial interests: – – Grants / research support: Speakers Bureau / honoraria: Consulting fees: Other:

Disclosure of Commercial Support • This program has received financial support from Merck Canada Inc. in the form of an educational grant. • This program has received in-kind support from Merck Canada Inc. in the form of logistical support. • Potential for conflict(s) of interest: – [Speaker name] has received [payment/funding, etc. ] from Merck Canada Inc. – Merck Canada Inc. benefits from the sale of the products that will be discussed in this program: Sitagliptin (Januvia®), Combination Sitagliptin/Metformin (Janumet®).

Mitigating Potential Bias • The information presented in this CME program is based on recent information that is explicitly “evidence-based. ” • This CME Program and its material is peer-reviewed and all the recommendations involving clinical medicine are based on evidence that is accepted within the profession. All scientific research referred to, reported or used in the CME/CPD activity in support or justification of patient care recommendations conforms to the generally accepted standards.

Objectives Following this program, participants will be able to: 1. Identify glycemic targets for patients with T 2 DM 2. Appropriately select a third antihyperglycemic agent (AHA) for patients with inadequate glycemic control on metformin + sulfonylurea (SU) 3. Identify strategies to improve adherence in patients on polypharmacy 4. Recognize and manage side effects associated with the different AHAs

Case 1 • • 55 -year-old male full-time teacher T 2 DM duration: 8 years with no known complications BMI: 32 kg/m 2 (gained 4 kg over last year) BP: 135/85 mm. Hg HR: 84 bpm Sedentary lifestyle Is unhappy “taking all these pills” Medications Labs • • • Metformin 1, 000 mg BID SU prescribed as BID Statin ACEi ASA PPI Antidepressant A 1 C 7. 9% FPG 8. 4 mmol/L e. GFR 75 m. L/min/1. 73 m 2 ACR normal Lipids at target

Case 1 1. What would the target A 1 C be for this patient?

Individualizing A 1 C Targets ≤ 7% >7% 7% A target ≤ 6. 5% may be considered in some patients with type 2 diabetes to further lower the risk of nephropathy and retinopathy which must be balanced against the risk of hypoglycemia Consider 7. 1 -8. 5% if: Most patients with type 1 and type 2 diabetes • Limited life expectancy • High level of functional dependency • Extensive coronary artery disease at high risk of ischemic events • Multiple co-morbidities • History of recurrent severe hypoglycemia • Hypoglycemia unawareness • Longstanding diabetes patient for whom it is difficult to achieve an A 1 C ≤ 7%, despite effective doses of multiple antihyperglycemic agents, including intensified basal-bolus insulin therapy Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Can J Diabetes. 2013; 37: S 31 -34.

Case 1 2. Before adding another antihyperglycemic agent, what other interventions could you consider?

Case 1 (continued) Upon questioning, the patient reveals that he works late and sometimes forgets his evening dose of metformin and SU. A pharmacist, who is also a diabetes educator, reviews his diet and provides compliance packaging of his medications. A kinesiologist working in your team suggests an “exercise prescription. ” He returns in 3 months and his A 1 C has improved to 7. 4%.

Case 1 3. Would you add a third antihyperglycemic agent? If so, what would you add?

AT DIAGNOSIS OF TYPE 2 DIABETES Start lifestyle intervention (nutrition therapy and physical activity) +/- metformin L I F E S T Y L E A 1 C < 8. 5% If not at glycemic target (2 -3 mos) Start / increase metformin Symptomatic hyperglycemia with metabolic decompensation A 1 C 8. 5% Start metformin immediately Consider initial combination with another antihyperglycemic agent Initiate insulin +/metformin If not at glycemic targets Add another agent best suited to the individual by prioritizing patient characteristics: PATIENT CHARACTERISTICS CHOICE OF AGENT SGLT 2 inhibitor with demonstrated CV outcome benefit 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 • Consider relative A 1 C lowering • Rare hypoglycemia • Weight loss or weight neutral • Effect on cardiovascular outcome • See therapeutic considerations, consider e. GFR • See cost column; consider access See next page Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Can J Diabetes. 2016; 40: 193 -195.

Add another class of agent best suited to the individual (classes listed in alphabetical order): L I F E S T Y L E Class Relative A 1 C Hypo. Weight Lowering glycemia Alpha-glucosidase inhibitor (acarbose) Rare Incretin agents: DPP-4 Inhibitors GLP-1 R agonists Rare Insulin Yes Insulin secretagogue: Meglitinide Yes Sulfonylurea Yes SGLT 2 inhibitors to Rare Superiority Genital infections, UTI, $$$ (empa in T 2 DM patients hypotension, dose-related changes in with clinical CVD) LDL-C, caution with renal dysfunction and loop diuretics, dapagliflozin not to be used if bladder cancer, rare diabetic ketoacidosis (may occur with no hyperglycemia) Thiazolidinediones Rare Neutral None to Rare Weight loss agent (orlistat) Effect in Cardiovascular Outcome Trial Other Therapeutic considerations Cost Neutral to Improved postprandial control, GI side-effects $$ Neutral to Neutral (alo, saxa, sita) Neutral (lixi) Caution with saxagliptin in heart failure GI side effects $$$ No dose ceiling, flexible regimens $-$$$$ Neutral (glar) $$$$ Less hypoglycemia in context of $$ missed meals but usually requires TID to QID dosing Gliclazide and glimepiride associated $ with less hypoglycemia than glyburide CHF, edema, fractures, rare bladder $$ cancer (pioglitazone), cardiovascular controversy (rosiglitazone), 6 -12 weeks required for maximal effect GI side effects alo=alogliptin; empa-empagiflozin; glar-glargine; lixi-lixisenatide; saxa-saxagliptin; sita-sitagliptin If not at glycemic target • Add another agent from a different class • Add/intensify insulin regimen Make timely adjustments to attain target A 1 C within 3 -6 months Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Can J Diabetes. 2016; 40: 193 -195. $$$

Case 1 4. Discuss the advantages and disadvantages of the various options for adjusting antihyperglycemic agents in this case.

Fixed-dose Combination Therapy is Associated with Improved Glycemic Control Study Mean difference of A 1 C (95% CI) Weight (%) Baseline A 1 C Blonde L et al, 2003 -0. 53% (-0. 80, -0. 26) 28. 0% 9. 1– 9. 2% Thayer S et al, 2010 -0. 31% (-0. 66, -0. 04) 22. 7% 8. 0– 8. 1% Thayer S et al, 2010 -0. 45% (-0. 77, -0. 13) 24. 7% 7. 3– 7. 8% Duckworth W et al, 2003 -0. 60% (-0. 97, -0. 23) 21. 4% 8. 3% Raptis AE et al, 1990 -2. 30% (-3. 65, -1. 00) 3. 2% 10. 6% Overall -0. 53% (-0. 78, -0. 28) 100% -4 -3. 5 -3 -2. 5 -2 -1. 5 -1 -0. 5 Mean difference in Hb. A 1 C (FDC – CDT) Favours FDC CDT = coadministered dual therapy; FDC = fixed-dosed combination Adapted from Han S et al. Curr Med Res Opin. 2012; 28(6): 969 -77. 0 0. 5

Network Meta-analysis Comparing Antihyperglycemic Drugs as Add-ons to Metformin Plus SU Change in A 1 C vs. PBO (%) Change in Risk of wt vs. PBO SBP vs. PBO hypoglycemia vs. (kg) (mm Hg) PBO (OR) DPP-4 inhibitors -0. 68* NS NS 2. 99* GLP-1 R agonists -1. 07* -1. 14* NS 3. 26* SGLT 2 inhibitors -0. 86* -1. 71* -3. 73* 3. 12* TZDs -0. 93* +3. 62* NS 2. 64* Insulin: basal -1. 08* +2. 63* NS 5. 61* Insulin: premixed -1. 30* +3. 98* NS 11. 62* Insulin: bolus -1. 54* +5. 69* NS 38. 90* * Significant vs. PBO; NS= not significant vs placebo Lozano-Ortega G, et al. Network Meta-analysis of Treatments for Type 2 Diabetes Mellitus following Failure with Metformin + Sulfonylurea. Abstract 1266 -P. Presented at the 75 th Scientific Sessions of the American Diabetes Association, June 5 - 9, 2015, Boston, Massachusetts.

Placebo-controlled Clinical Trials of SGLT 2 inhibitor as an Add-on to Metformin + SU Canagliflozin (CANA) Change in A 1 C from baseline (%) MET + SU combination 26 weeks BL A 1 C ~8. 1% Dapagliflozin (DAPA) MET + SU combination 24 weeks BL A 1 C ~8. 2% Empagliflozin (EMPA) MET + SU combination 24 weeks BL A 1 C~8. 1% 0. 4 0. 2 0. 0 CANA 100 OD 300 OD PBO -0. 2 DAPA 10 OD -0. 13 PBO EMPA 10 OD 25 OD -0. 17 PBO -0. 17 -0. 4 -0. 6 -0. 8 -1. 0 -0. 85* -0. 86* -0. 77* -1. 06* -1. 2 * Significant vs. comparator -1. 4 Δ wt (kg): Hypos (%): -0. 82* -2. 1* 25. 8 -2. 6* -0. 7 30. 1 15. 4 -2. 7* 12. 8* -0. 6 3. 7 -2. 2* 16. 1 -2. 4* 11. 5 -0. 4 8. 4 SGLT 2: sodium-glucose cotransporter 2; MET: metformin; SU: sulfonylurea; BL: baseline; A 1 C: glycated hemoglobin; PBO: placebo Wilding J, et al. Int J Clin Pract 2013; 67: 1267– 82. Wilding J, et al. ADA 2012. Abstract 1022 -P. Matthaei S, et al. Diabetes Care 2015; 38: 365– 72. Haring HU, et al. Diabetes Care 2013; 36: 3396– 404.

Case 1 5. What side effects could the patient experience with the new therapy/therapies and how would you and the patient co-manage them?

ACARBOSE DPP-4 INHIBITORS GASTROINTESTINAL SIDE EFFECTS MAJOR ADVERSE CV EVENTS & HEART FAILURE (HF) • Titrate slowly • Reassure - Alogliptin (EXAMINE), Saxagliptin (SAVOR) and Sitagliptin (TECOS) neutral on major adverse CV events - Alogliptin and sitagliptin neutral on HF - Saxagliptin increased HF (SAVOR), so use with caution in patients with HF PANCREATIC ISSUES • Reassure - EMA release and ADA/EASD/IDF position statement: Cases of pancreatitis were uncommon and pancreatic cancers rare in the SAVOR, EXAMINE and TECOS populations - Avoid if the patient has a history of pancreatitis

GLP-1 R AGONIST METFORMIN GASTROINTESTINAL SIDE EFFECTS • Reduce metformin • Slowly titrate the dose • Decrease meal portions and reduce fat content • Provide hand-holding reassurance – inform patients that GI issues are transient ENDOCRINE ISSUES • Thyroid medullary cancer occurred in rodents - Not observed in monkeys and humans - No other related thyroid issues • Avoid if patient has a personal or family history of MTC or if patient has MEN 2 PANCREATIC ISSUES • Reassure and discuss - EMA release and ADA/EASD/IDF position statement - ELIXA reported numerically and percentagewise lower pancreatitis and pancreatic cancer events in test group vs. placebo • Avoid if the patient has a history of pancreatitis MAJOR CV EVENTS & HEART FAILURE (HF) • ELIXA reported neutral results for rates of MACE and HHF • • • Take in the middle of the meal Try different brand/formulation of metformin or switch to a DPP-4 fixed-dose combination Slowly down-titrate and continue to use if the patient is able to tolerate a lower dose Limit dose to 1, 500 or 2, 000 mg a day Add a second agent before up-titrating to the maximum dose

SGLT 2 INHIBITORS GENITAL MYCOTIC INFECTIONS (GMI) • Reassure - GMIs are infrequent, more common in women, usually mild to moderate and easily treated, plus, most with GMI have only 1 event • Consider proactive prescription (cream or fluconazole) • Encourage local hygiene • Avoid if resistant GMIs recur LIPID PROFILE • Small increase in LDL-C of about 0. 1 to 0. 2 mmol/L on average – dose-dependent • Reassure that HDL-C also goes up • Empagliflozin superior for MACE and CV mortality in patients with established CVD in EMPA-REG OUTCOME • Ongoing long-term trials will provide more information POLYURIA/POLLAKIURIA • Occurs in 3 -6% of patients • Provide reassurance as polyuria/pollakiuria may be temporary • Consider reducing diuretic dose or stopping entirely, as it may not be necessary • Avoid alcohol and coffee DIABETIC KETOACIDOSIS (DKA) • Rare (≤ 0. 1%), usually associated with major illness, dietary restriction (low carbohydrate or reduced intake), inappropriate insulin reduction. • May be euglycemic • Most cases are in insulin-treated patients, some of whom have had unrecognized T 1 D or LADA HYPOTENSION • Consider reducing the dose of the antihypertensive agent(s) (start with the diuretic if taking) if blood pressure is low-normal or volume-depleted • Down-titrate, as the occurrence of hypotension may be dose-dependent • If patient has concomitant diseases, stop temporarily (SADMANS) MALIGNANCIES • 10: 1 imbalance in bladder cancer in dapagliflozin trials • Not observed with other SGLT 2 inhibitors • Most of the cases of bladder cancer occurred in patients who had hematuria at baseline • Dapagliflozin should not be used in patients with a history of bladder cancer URINARY TRACT INFECTIONS (UTI) • Reassure - 20 -30% higher rates than placebo in pooled analyses - More common in women, mild to moderate - Most with UTI have 1 event FRACTURES • Rare fractures with canagliflozin • Higher rates of fractures: may be in part related to more falls related to hypotension • Reduction in bone mineral density: may be in part related to weight loss. Increased phosphate levels and PTH levels may also contribute • No increase in EMPA-REG OUTCOME trial

SULFONYLUREAS HYPOGLYCEMIA • If possible, switch to an incretin agent or a SGLT 2 inhibitor • Provide/refer for education on nutrition, physical activity, alcohol • If staying on sulfonylureas - Decrease dose - Use gliclazide or glimepiride in the morning (discuss timing) rather than glyburide - Use repaglinide if skipping meals • Verify e. GFR • Reduce dose or discontinue if patient becomes ill WEIGHT GAIN • Lifestyle changes • If possible, switch to - Acarbose - DPP-4 inhibitor - GLP-1 R agonist - SGLT 2 inhibitor • To avoid hypoglycemia - Use gliclazide rather than glyburide - Use repaglinide if skipping meals

THIAZOLIDINEDIONES (TZD) MYOCARDIAL INFARCT CONCERNS FRACTURES • Not an issue with pioglitazone • Pioglitazone may reduce stroke and revascularization • Controversial - Not demonstrated by all meta-analyses - Not demonstrated in RCTs • Evidence that TZDs double the risk of fractures after 3 years of usage (MOA is integral to this class effect) • Switch to a different class of AHA • Note that BMD is not a predictor fractures HEART FAILURE WEIGHT GAIN • Use of rosiglitazone and pioglitazone has been associated with a >2 -fold increased risk of heart failure EDEMA • Switch to another class of AHA • Avoid if patient has a history of CHF • As edema is more evident with insulin, avoid combining TZDs with insulin • Initiate potassium-sparing diuretics MALIGNANCIES (BLADDER CANCER) • Rare • Although a signal has been suggested by some observational studies, an ADA position statement states there is no causal relationship • FDA has indicated that TZDs are safe except in those with a (family) history of bladder cancer • NOT an issue with rosiglitazone • Encourage healthy lifestyle changes • Reduce dose • As weight gain is more evident with insulin, avoid combining TZDs with insulin • If possible, switch to acarbose, a DPP-4 inhibitor, a GLP-1 R agonist, or a SGLT 2 inhibitor

NEWER AGENTS + SU/INSULIN SU, INSULIN & DRIVING HYPOGLYCEMIA • Consider reducing SU/insulin dose when adding DPP-4 inhibitor, GLP-1 R agonist or SGLT 2 inhibitor if the A 1 C is not very high • Recognize and educate on the variability in glucose levels • Consider switching to another class • The patient should be advised to: - Test glucose levels before driving and every 4 hours if s/he is on a long trip - Keep a meter and source of carbohydrate handy - NOT drive if blood glucose is under 5. 0 mmol/L - Pull over if experiencing symptoms of hypoglycemia - NOT drive for an hour even after an occurrence of mild hypoglycemia

Antihyperglycemic Agents and Renal Function CKD Stage e. GFR (m. L/min/1. 73 m 2) Acarbose Biguanide Metformin 4 3 2 1 <15 15 -29 30 -59 60 -89 ≥ 90 25 Alogliptin 6. 25 mg 30 30 Linagliptin Saxagliptin 15 15 2. 5 mg Sitagliptin 25 mg 30 60 12. 5 mg 50 mg Albiglutide Dulaglutide Exenatide (BID/QW) Liraglutide† Gliclazide/glimepiride 15 Glyburide 30 30 50 50 Repaglinide SGLT 2 inhibitors Insulin secretagogues GLP-1 receptor agonists DPP-4 inhibitors ɑ-Glucosidase inhibitor 5 45 60* 60 4510 or 25 mg 60* Canagliflozin Dapagliflozin Empagliflozin 30 Thiazolidinediones • Do not initiate if GFR < 60 m. L/min/1. 73 m 2 100 mg Contraindicated Not recommended Caution and/or dose reduction †Based on Saxenda. TM Product Monograph November 2015 Adapted from: Product Monographs as of Nov. 2015; Harper W et al. Can J Diabetes 2015; 39: 250 -252. No dose adjustment but dose monitoring of renal function Safe

FEAR ABOUT INTENSIVE GLUCOSE CONTROL AND MORTALITY • Intensive control has been proven to reduce microvascular complications, particularly nephropathy • Guidelines suggest intensive therapy to achieve - A 1 C ≤ 6. 5% when there is no risk of hypoglycemia to reduce microvascular complications - ≤ 7. 0% in most patients - 7. 1% to 8. 5% in people with short life expectancy, extensive CAD at high risk of ischemic events or recurrent severe hypoglycemia • One study (ACCORD) showed an increase in CV and total mortality in patients randomized to intensive glycemic control, but this risk was confined to those not achieving A 1 C ≤ 7% and was not demonstrated in a meta-analysis - Reduced myocardial infarctions – also demonstrated in a meta-analysis • Although there is a link between severe hypoglycemia and mortality, a causal relationship has not been proven KEY MESSAGES • Medication side effects can affect adherence, quality of life and, ultimately, glycemic control • Ask about side effects and make therapeutic choices to maximize tolerability

Conclusions • In most patients, strive for an A 1 C target of ≤ 7. 0% • For patients who are not at target, first consider adherence and lifestyle modification prior to altering medical therapy • The choice of a “third agent” should be individualized to the patient’s characteristics, co-morbidities and values