1. A Tale of New Drugs Rebecca Nick-Dart, PharmD, BCPS Clinical Pharmacy Specialist rnick@svhs.org

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3. Page 3 DPP-4 INHIBITORS

4. Page 4 Overview Mechanism – Slows inactivation of endogenous incretins (prolongs action of GLP-1 and GIP) – Increases release of insulin in glucose-dependent manner – Decreases glucagon levels Indicated for adults as adjunct therapy to diet and exercise in type 2 diabetes mellitus Available DPP-4 inhibitors: – Alogliptin (Nesina ® ), Takeda – Linagliptin (Tradjenta ® ), Boehringer-Ingelheim – Saxagliptin (Onglyza ® ), AstraZeneca – Sitagliptin (Januvia ® ), Merck

5. Dosing and Administration GenericUsual Dose Dose Adjustment in Renal Insufficiency CrCl ≥ 60 mL/min Moderate: CrCl ≥ 30 to < 60mL/min Severe: CrCl ≥ 15 to < 30 mL/min (or HD) Alogliptin25mg once dailyNo adjustment 12.mg once daily 6.25mg once daily Linagliptin5mg once dailyNo adjustment CrCl > 50mL/min Moderate to Severe: CrCl ≤ 50mL/min (or HD) Saxagliptin2.5-5mg once dailyNo adjustment2.5mg once daily

6. Page 6 Dosing and Administration All four agents may be taken with or without regard to meals Dose-adjustments may be necessary when used concomitantly with oral secretagogues and/or insulin Dose adjustments are required when saxagliptin (2.5mg daily) is used concomitantly with a strong CYP3A4/5 inhibitor GenericUsual Dose Dose Adjustment in Renal Insufficiency CrCl ≥50mL/min (SCr ≤1.7mg/dL in men and≤1.5mg/dL in women) CrCl ≥30 to <50mL/min (SCr 1.7- 3mg/dL in men, and SCr 1.5-2.5mg/dL in women) CrCl 3mg/dL in men and SCr >2.5mg/dL in women) or HD/PD Sitagliptin 100mg once daily No adjustment50mg once daily25mg once daily

7. Page 7 Efficacy ↓ HbA1c (%)↓ FPG (mg/dL)↓ PPG (mg/dL) % of Patients Achieving HbA1c <7% Alogliptin0.14 – 0.592 – 16N/A20 – 49 Linagliptin0.69 – 2.0223 – 30N/A25 – 40 Saxagliptin0.35 – 0.549 - 17N/A35 - 41 Sitagliptin 0.43 – 0.766 - 2047 – 5629 - 69

8. Page 8 Efficacy ↓ HbA1c (%)↓ FPG (mg/dL)↓ PPG (mg/dL) % of Patients Achieving HbA1c <7% Alogliptin + metformin 0.6 – 1.552 - 4511 – 1346 – 60 Linagliptin + metformin 0.16 – 2.812– 1128 – 4926 - 30 Saxagliptin + metformin 0.52 – 0.8911 – 2518 – 4231 - 36 Sitagliptin + metformin 0.62 – 0.6516 – 35N/A

9. Page 9 Safety Contraindications – Hypersensitivity Warnings/Precautions – Pancreatitis, hypersensitivity reactions, severe and disabling arthralgia (8/2015), renal impairment Adverse effects – Nasopharyngitis, headache, upper respiratory tract infections 4/5/2016 labeling changes for alogliptin and saxagliptin for heart failure

10. Page 10 Safety Cardiovascular Data: – RCTs Sitaglipin: TECOS Saxagliptin: SAVOR-TIMI53 Alogliptin: EXAMINE – Pooled population analysis Sitagliptin Linagliptin

11. Page 11 Insurance Coverage DrugHighmark Highmark Medicare UPMC Medical Assistance Alogliptin (Nesina) Tier 3Tier 4Tier 3/NFNF Linagliptin (Tradjenta) Tier 2Tier 3Tier 2Tier 1 Saxagliptin (Onglyza) Tier 3Tier 4Tier 3/NFNF Sitagliptin (Januvia) Tier 2Tier 3Tier 2Tier 1

12. Page 12 Summary: DPP-4 Inhibitors Modest decreases in HbA1c Well tolerated with a low incidence of adverse effects Agents in class similar in terms of efficacy and safety – Warning for heart failure for alogliptin and saxagliptin Patient considerations – Renal function – Cardiac history – Formulary

13. Page 13 SGLT-2 INHIBITORS

14. Page 14 Overview Mechanism – Reduces glucose reabsorption by kidney (increases glucose excretion) – Lowers blood glucose levels Indicated for adults as adjunct therapy to diet and exercise in type 2 diabetes mellitus Available SGLT2 inhibitors: – Canagliflozin (Invokana ® ), Janssen – Dapagliflozin (Farxiga ® ), AstraZeneca – Empagliflozin (Jardiance ® ), Boehringer-Ingelheim

15. Page 15 Dosing and Administration GenericUsual Dose Dose Adjustment in Renal Insufficiency Mild: eGFR ≥ 60 mL/min/1.73 m 2 Moderate: eGFR <60 to 45 mL/min/1.73 m 2 Severe: eGFR < 45 mL/min/1.73 m 2 Canagliflozin100 – 300mg once dailyNo adjustment100mg once dailyNot recommended Dapagliflozin5 – 10mg once dailyNo adjustmentNot recommended Empagliflozin10 – 25mg once dailyNo adjustment Not recommended All three agents may be taken with or without food before the first meal of the day Dose-adjustments may be necessary when used concomitantly with oral secretagogues and/or insulin Urine Glucose Test: All SGLT2 Inhibitors enhance urinary glucose excretion – thus the test will always be positive

16. Page 16 Efficacy ↓ HbA1c (%)↓ FPG (mg/dL)↓ PPG (mg/dL)↓ Weight (kg) Canagliflozin0.76 – 1.0327 – 3543 – 592.3 – 3.9 Dapagliflozin0.8 – 1.524 – 29N/A1.6 – 2.3 Empagliflozin0.5 – 0.7820 – 26N/A2 – 2.6 Canagliflozin + metformin 0.79 – 0.9516 – 27N/A2 – 2.9 Dapagliflozin + metformin 0.52 – 0.8418 – 23N/A2.2 – 3.2 Empagliflozin + metformin 0.63 – 0.7720 – 2245 – 462.1 – 4

17. Page 17 Safety Contraindications – Hypersensitivity, severe renal impairment Warnings/Precautions – Genital mycotic infections, hypotension, hypoglycemia Adverse effects – Genital mycotic infections, UTI, increased urination FDA warnings and safety communication – 2015 ketoacidosis – 2016 amputations with canagliflozin – 2016 AKI with canagliflozin and dapagliflozin

18. Page 18 Empagliflozin, Cardiovascular Outcomes and Mortality 7028 patients with Type 2 diabetes and high cardiovascular risk randomized to empagliflozin vs. placebo Primary outcome: – Death from cardiovascular causes, nonfatal MI, or nonfatal stroke Secondary outcome: – Composite of primary outcome plus hospitalization for USA Safety outcomes: – Hypoglycemia, UTI, genital infection, volume depletion, AKI, bone fracture, DKA, VTE NEJM 2015;373:2117-28

19. Page 19 NEJM 2015;373:2117-28 10.5% vs. 12.1% 3.7% vs. 5.9% 5.7% vs. 8.3%2.7% vs. 4.1%

20. Page 20 Insurance Coverage DrugHighmark Highmark Medicare UPMC Medical Assistance Canagliflozin (Invokana) Tier 2Tier 3Tier 2Tier 1 Dapagliflozin (Farxiga) Tier 2Tier 3NF Empagliflozin (Jardiance) Tier 3NFTier 2Tier 1

21. Page 21 Summary: SGLT-2 Inhibitors Modest decreases in HbA1c Well tolerated with a low incidence of hypoglycemia Agents in class similar in terms of efficacy and safety – ? positive cardiovascular outcomes with empagliflozin Monitor for genital mycotic and urinary infections Urine glucose screening always positive Patient considerations – Renal function – Cardiac history – Formulary

22. Page 22 GLP-1 AGONISTS

23. Page 23 Overview Mechanism – Increases glucose-dependent insulin release – Decreases inappropriate glucagon release – Slows gastric emptying Indicated for adults as adjunct therapy to diet and exercise in type 2 diabetes mellitus Available GLP-1 agonists: – Albiglutide (Tanzeum®), GSK – Dulaglutide (Trulicity®), Eli Lilly – Exenatide (Byetta®, Bydureon®), AstraZeneca – Liraglutide, (Victoza®), Novo Nordisk – Lixisenatide (Adlyxin™), Sanofi approved July 2016

24. Page 24 Dosing and Administration GenericUsual Dose Albiglutide30-50mg once weekly Dulaglutide0.75-1.5mg once weekly Exenatide5-10mcg twice daily Exenatide ER2mg once weekly Liraglutide1.2 -1.8mg once daily Lixisenatide10-20mcg once daily Use caution with renal impairment (exenatide not recommended CrCL<30mL/min Inject subcut in upper arm, thigh or abdomen Administer without regard to meals – Exenatide IR and lixisenatide: 60 min prior to food Do not inject with or adjacent to insulin Albiglutide, exenatide ER require reconstitution Refrigerate until use Consider dose reduction of insulin or sulphonylurea

25. Page 25 Efficacy ↓ HbA1c (%)↓ FPG (mg/dL)↓ Weight (kg) Exenatide IR0.5 – 117 – 191.6 – 2.7 Exenatide ER1.2 – 2412 – 3.7 Albiglutide0.7 – 1.0416 – 250.4 – 1.1 Dulaglutide0.6 – 1.426 – 290.9 – 3.1 Liraglutide0.5 – 1.515 – 262.1 – 3.6 Lixisenatide0.3 – 0.713 – 161.9

26. Page 26 Efficacy ↓ HbA1c (%)↓ FPG (mg/dL)↓ Weight (kg) Exenatide IR + metformin 0.5 – 0.95 – 101.3 – 2.9 Exenatide ER + metformin 1.5322.3 Albiglutide + metformin 0.6181.2 Dulaglutide + metformin 0.9 – 1.130 – 412.7 – 3.1 Liraglutide + metformin 1.2 – 1.530 – 392.6 – 2.8 Lixisenatide + metformin 0.717 – 201.6 – 2.7

27. Page 27 Safety Boxed Warning – Risk of thyroid tumors Contraindications – Hypersensitivity, personal or family history of medullary thyroid carcinoma (MTC), multiple endocrine neoplasia type 2 (MEN2) Warnings/Precautions – Antibody formation, CV effects (dulaglutide, liraglutide), pancreatitis, severe pre-existing GI disease Adverse Effects – GI (N/V/D), hypoglycemia, HA, injection site reactions

28. Page 28 Liraglutide and Cardiovascular Outcomes 9340 patients with Type 2 diabetes and one cardiovascular coexisting condition randomized to liraglutide or placebo Primary outcome – Death from CV causes, nonfatal MI, nonfatal CVA Expanded primary outcome – Also coronary revscularization, hospitalization for USA or HF Adverse events more common with liraglutide – Acute gallstone disease, injection site reaction, N/V/D, decreased appetite, abdominal discomfort NEJM 2016;375:311-22

29. Page 29 Liraglutide and Cardiovascular Outcomes OutcomeLiraglutide (%)Placebo (%)HR (95% CI) Primary outcome1314.90.87 (0.78 – 0.97) Primary expanded20.322.70.88 (0.81 – 0.96) Death any cause8.29.60.85 (0.74 – 0.97) Death CV cause4.760.78 (0.66 – 0.93) Death non-CV cause3.53.60.95 (0.77 – 1.18) MI6.37.30.86 (0.73 – 1.00) Stroke3.74.30.86 (0.71 – 1.06) Revascularization8.79.40.91 (0.80 – 1.04) Hospital for USA2.62.70.98 (0.76 – 1.26) Hospital for HF4.75.30.87 (0.73 – 1.05) Microvascular event7.68.90.84 (0.73 – 0.97 ) NEJM 2016;375:311-22

30. Page 30 Insurance Coverage DrugHighmark Highmark Medicare UPMC Medical Assistance Albiglutide (Tanzeum) Tier 3NFTier 3NF Dulaglutide (Trulicity) Tier 3NFTier 2Tier 1 Exenatide (Byetta) Tier 3NFTier 3NF Exenatide ER (Bydureon) Tier 2Tier 3 NF Liraglutide (Victoza) Tier 2Tier 3Tier 2Tier 1 Lixsenatide (Adlyxin) ????

31. Page 31 Summary: GLP-1 Agonists Potential to lower HbA1c up to 1-2% Most common adverse effects are GI Patient considerations – Dosing frequency – FPG or PPG – Adverse effects – Renal function – Patient adherence – Administration prep – Formulary

32. Page 32 New Insulin Products Be aware there are several new insulin products available – Most not the typical U-100 Generic NameBrand NameConcentration Insulin lisproHumalog200 units/mL Insulin glargineToujeo300 units/mL Insulin degludecTresiba100 units/mL Insulin degludecTresiba200 units/mL Insulin regularHumulin R Kwikpen500 units/mL Insulin (oral inhalation)Afrezza4, 8, 12 units/cartridge

33. A Tale of New Drugs Rebecca Nick-Dart, PharmD, BCPS Clinical Pharmacy Specialist rnick@svhs.org