1. Oral Agents in Diabetes MC MacSween MD FRCPC

2. Faculty/Presenter Disclosure Faculty: Mary Catherine MacSween Relationships with commercial interests: Grants/Research Support: NB Health Research Foundation Speakers Bureau/Honoraria:Astra Zeneca, Lilly, Merck, Novo Nordisk, Sanofi Consulting Fees:Astra Zeneca, Janssen, Sanofi Other: -

3. Comprehensive Care Plan Disease management from a multidisciplinary team Antihyperglycemic pharmacotherapy Comprehensive diabetes self-education for the patient Therapeutic lifestyle change Comprehensive Care Plan Handelsman YH, et al. Endocr Pract. 2015;21(suppl 1):1-87. 3

4. UKPDS: Lowering A1C Reduces Risk Of Complications IN T2DM Adapted from Stratton IM, et al. BMJ. 2000;321:405–412. 1% decrease of A1C correlates with the following risk reduction: Prospective observational analysis of UKPDS35 patients (n = 4585, incidence analysis; n = 3642, relative risk analysis).; Median 10.0 years of follow up. * P<0.0001 Lower-extremity amputation or fatal peripheral vascular disease* Microvascular disease* Cataract extraction* Heart failure* Myocardial infarction* Stroke* Cardiovascular complications 43%37%19%16%14%12% The incidence of clinical complications was significantly associated with glycemia

5. Physiologic Insulin Secretion

6. T2D: Most Common Rx of A1C Above Target Reinforce Lifestyle

7. The Burden of Treatment Failure in Type 2 Diabetes 7% 8% Patients spend on average of 59 months on dual oral agents with A1C > 7.0% before insulin is initiated 9% Brown JB. Diabetes Care July 2004.

8. TRIAD Study of A1C Targets That Were Not Met Aim to get A1C at goal within 3 -6 months. 35% due to lack of treatment intensification 23% due to poor adherence (%days covered by pills).

9. Progression of type 2 diabetes – Beta cell apoptosis

10. Insulin Secretagogues Thiazolidinediones Liver Adipose Tissues MusclesIntestine Alpha-glucosidase Inhibitors Delay the absorption of glucose from starch and sucrose Biguanides Reduce hepatic gluconeogenesis Sulfonylureas and meglitinides stimulate insulin secretion Improve insulin resistance MECHANISM OF ACTION 10 Adapted from Krentz AJ, Bailey CJ. Drugs 2005; 65:385-411. SGLT2 Inhibitors Kidneys Reduce the reabsorption of glucose by the kidneys: glucosuria DPP-4 Inhibitors and GLP-1 Agonists Pancreas Increase insulin secretion, inhibit glucagon secretion

12. Individualizing therapy based on patient and agent characteristics 12 Adapted from: Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Can J Diabetes 2013;37(suppl 1):S1-S212.. Start metformin immediately Consider initial combination with another antihyperglycemic agent Start lifestyle intervention (nutrition therapy and physical activity) +/- Metformin A1C < 8.5% Symptomatic hyperglycemia with metabolic decompensation A1C  8.5% If not at glycemic target (2-3 mos) Start / Increase metformin LIFESTYLELIFESTYLE Add an agent best suited to the individual: Patient Characteristics Degree of hyperglycemia Risk of hypoglycemia Overweight or obesity Comorbidities (renal, cardiac, hepatic) Preferences & access to treatment Other AT DIAGNOSIS OF TYPE 2 DIABETES Agent Characteristics BG lowering efficacy and durability Risk of inducing hypoglycemia Effect on weight Contraindications & side-effects Cost and coverage Other If not at glycemic targets A1C < 8.5% A1C  8.5% If not at glycemic targets Patient Characteristics Degree of hyperglycemia Risk of hypoglycemia Overweight or obesity Comorbidities (renal, cardiac, hepatic) Preferences & access to treatment Other Agent Characteristics BG lowering efficacy and durability Risk of inducing hypoglycemia Effect on weight Contraindications & side-effects Cost and coverage Other Start lifestyle intervention (nutrition therapy and physical activity) +/- Metformin Patient Characteristics Degree of hyperglycemia Risk of hypoglycemia Overweight or obesity Comorbidities (renal, cardiac, hepatic) Preferences & access to treatment Other Agent Characteristics BG lowering efficacy and durability Risk of inducing hypoglycemia Effect on weight Contraindications & side- effects Cost and coverage Other Start metformin immediately Consider initial combination with another antihyperglycemic agent Initiate insulin +/- metformin

13. What to Choose after Metformin: Oral Agents -The Big 3 SUDPP- 4 SGLT- 2

14. What to Choose after Metformin: Oral Agents -The Big 3 SU Gliclazide 60- 90 mg (Diamicron) DPP-4 Linagliptin 5mg (Tragenta) Saxagliptin 5 mg (Onglyza) Sitagliptin 100mg (Januvia) SGLT-2 Canagliflozin 300 mg (Invokana) Dapagliflozin 10 mg (Forxiga) Empagliflozin 25 mg (Jardiance)

15. Effects of Agents Commonly Used for T2D MetGLP1RASGLT2IDPP4ITZDSU/ Glinide FBG lowering Mod Mild to mod* Mod Mild Mod SU: mod Glinide: mild PPG lowering Mild Mod to marked Mild Mod Mild Mod DPP4I = dipeptidyl peptidase 4 inhibitors; FPG = fasting plasma glucose; GLP1RA = glucagon-like peptide 1 receptor agonists; Met = metformin; Mod = moderate; PPG = postprandial glucose; SGLT2I = sodium-glucose cotransporter 2 inhibitors; SU = sulfonylureas; TZD = thiazolidinediones. *Mild: albiglutide and exenatide; moderate: dulaglutide, exenatide extended release, and liraglutide. Handelsman YH, et al. Endocr Pract. 2015;21(suppl 1):1-87.

16. Effects of Commonly Used Agents for T2D DPP4I SGLT2I SU Hypoglycemia neutral moderate to severe Weight neutral loss gain CHF neutral* neutral (benefit empagliflozin) neutral CVD neutral ? Renal Impairment/GU dose adjustment (except linagliptin) GU infection riskIncreased hypoglycemia risk * possibly increased CHF hospitalization risk in CV safety trial

17. Patient Values and Preferences SU DPP 4 Inhibitors Empagliflozin +/- SU SGLT 2 inhibitors GLP 1 antagonists

18. Cost Cheap but not Durable

19. Approximate Cost Reference List for Antihyperglycemic Agents Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Can J Diabetes 2013;37(suppl 1):S1-S212. Appendix 5. Approximate cost reference list of antihyperglycemic agents. Available at http://guidelines.diabetes.ca/Browse/Appendices/Appendix5 Accessed August 2014.http://guidelines.diabetes.ca/Browse/Appendices/Appendix5 Antihyperglycemic AgentsAvailable strengths Usual maintenance dose or usual dosage range Approximate wholesale cost* / unit Insulin secretagogues - Sulfonylureas Gliclazide (Diamicron ®, generic) 80 mg 80-320 mg per day (doses >160 mg should be twice a day) $ 0.17/Tab Gliclazide (Diamicron MR ® ) 30 mg30-120 mg once daily $ 0.15/Tab 60 mg60-120 mg once daily $ 0.28/Tab Glimepiride (Amaryl ®, generic) 1 mg 1-4 mg once daily (may increase to a max dose of 8 mg/day) $ 0.47/Tab 2 mg 1-4 mg once daily (may increase to a max dose of 8 mg/day) $ 0.47/Tab 4 mg 1-4 mg once daily (may increase to a max dose of 8 mg/day) $ 0.47/Tab Glyburide2.5 mg1.25-20 mg once daily$ 0.04/Tab (Diabeta ®, generic)5 mg1.25-20 mg once daily$ 0.06/Tab Thiazolidinediones Pioglitazone (Actos) generic 15 mg15-30 mg once daily$ 1.28/Tab 30 mg15-30 mg once daily$ 1.94/Tab 45 mgMaximum daily dose$ 2.71/Tab Rosiglitazone (Avandia ® ) 2 mg 4-8 mg daily as a single or as a divided dose $ 1.43/Tab 4 mg 4-8 mg daily as a single or as a divided dose $ 2.25/Tab Weight loss agent Orlistat (Xenical ® )120 mg tab$ 1.78/Tab SGLT2 inhibitors Canagliflozin100 mg, 300 mg100 mg or 300 mg daily$ 2.62/Tab

20. SU Durability & Efficacy Data ADOPT Study: Fasting glucose over time Analysis includes only patients continuing on monotherapy Adapted from Kahn SE, et al. N Engl J Med 2006;355:2427–2443. FPG (mmol/l) 01 234 5 Time (years) 4-year prespecified time point for analysis Glyburide Metformin Rosiglitazone 0 6.5 8.5 7.5 7.0 8.0 Rosiglitazone vs. metformin  0.5 (  0.7 to  0.4) mmol/l, P < 0.001 Rosiglitazone vs. glyburide  1.0 (  1.1 to  0.8)mmol/l, P < 0.001 From years 1 to 5, SU was shown to have the poorest durability

21. SU’s: Limited DURABILITY of Glycemic Control Adapted from Defronzo RA.. Diabetes 2009;58(4):773-95. Time (years) -2 0 1 Change in A1C (%) 012345610 Hanefeld (n=250) Tan (n=297) Chicago (n=230) ADOPT (n=1,441) UKPDS (n=1,573) PERISCOPE (n=181) Glimepiride Glyburide Gliclazide Glyburide

22. Safety Cardiovascular Outcome Trials

23. Antihyperglycemic agents and Renal Function Adapted from: Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Can J Diabetes 2013;37(suppl 1):S1-S212. Not recommended / contraindicated Safe Caution and/or dose reduction 30 60 54321 25 Repaglinide Metformin Saxagliptin Linagliptin Glyburide Thiazolidinedion es GFR (mL/min): CKD Stage: Gliclazide/Glimepirid e Liraglutide Exenatide Acarbose Sitagliptin 50 15 2.5 mg 15 30 50 mg 25 mg < 15 15-29 30-5960-89 ≥ 90 50 30 50 15 30 50 30 5 mg 100 mg 10 mcg bid 5 mcg bid Dapagliflozin Canagliflozin 60 45 c

24. Normal human kidneys reabsorb ~162 g of filtered glucose/day SGLT2 Inhibitors: Mechanism of Action GLUT, facilitative glucose transporter; SGLT, sodium-dependent glucose transporter. Adapted from Abdul-Ghani MA, DeFronzo, RA. Endocr Pract. 2008;14(6):782–790; Bays H. Curr Med Res Opin. 2009;25(3):671–681. Wright EM. Am J Physiol Renal Physiol. 2001;280(1):F10-8; Lee YJ et al. Kidney Int Suppl. 2007 ;106:S27-35; Han S, et al. Diabetes. 2008 ;57:1723-9. Proximal tubule S1 Glomerulus Distal tubule Loop of Henle Collecting duct Glucose filtration Glucose reabsorption S3 ~10% ~90% Increased glucose excretion SGLT2 inhibitor Reduced glucose reabsorption SGLT2 Inhibition Reduces Renal Glucose Reabsorption and Increases Glucose Elimination

25. Renal Patients eGFR < 15 eGRF 15-30eGFR 30-45eGFR 46-60 Repaglinide With caution: Linagliptin 5 mg Sitagliptin 25 mg With caution: Saxagliptin 2.5 mg Gliclazide 30 mg With caution: Sitagliptin 50 mgSitagliptin100mg Saxagliptin 5 mg

26. CV Outcomes Trials Sitagliptin Saxagliptin* Alogliptin Glargine Lixisenatide

27. Zinman B et al. N Engl J Med Sept 2015. Cardiovascular Outcomes and Death EMPA-REG: Empagliflozin CV Safety Trial

28. Weight

29. Range of weight change (kg) S M SUSU I DPP-4 inhibitors Sulphonylureas Glinides Thiazolidinediones Insulin Metformin & acarbose GLP-1 receptor agonists SGLT2 inhibitor 10.0 8.0 6.0 4.0 2.0 0.0 -2.0 -4.0 -6.0 Weight neutral/loss Weight gain What if: patient is concerned about weight? Effect of Diabetes Therapies on Body Weight Adapted from Mitri J et al. J Expert Opinion Drug Saf 2009;8:573-84. Ferrannini E, et al. Diabetes Care 2010;33(10):2217-24. Adapted from http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugshttp://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs Rosenstock J et al. ADA Annual Meeting 2013. Abstract 1102-P. /EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM336236.pdf. Accessed January 23, 2013; Wysham C et al. ADA 2013; Abstract 1080-P. Not head-to- head comparisons and cross-study comparisons may be misleading D

30. Sometimes Helpful Pioglitazone Can be helpful in young very insulin resistant patients. New data (IRIS Trial) reduces recurrent stroke and non fatal MI in insulin resistant patients. New data ? helps in MS. BUT weight gain and fractures in post menopausal women. No cancer. Repaglinide Helpful when a very short half life is needed i.e. advanced renal or hepatic failure. Useful if just have hyperglycemia for part of the day i.e. after supper or variable meals. BUT frequent dosing and more expensive than SU.

31. TZD Proactive CV Study PRINCIPLE SECONDARY endpoint: Significant Difference in MACROVASCULAR EVENTs *Death, MI (excluding silent) or stroke Pioglitazone vs.. placebo: HR: 0.84; 95% CI: 0.72–0.98 Dormandy JA et al. Lancet 2005; 366:1279-89. 5,2385,1024,9914,8774,7524,651 785 (256) 0612182430 36 0.0 N at risk: Time from randomization (months) Placebo (n = 358) Pioglitazone (n = 301) Kaplan–Meier event rate (all cause mortality, non-fatal MI, stroke) P = 0.027 0.15 0.10 0.05

32. Ideal Rx of Type 2 Diabetes Early treatment to glycemic goals. Sustained duration of response. Minimal weight gain and hypoglycemia. Long term safety. Fair price.

33. Active Comparator Trials Metformin plus SU vs. DPP 4 Inhibitor vs. GLP 1 agonist vs Glargine Results 2019