A Tale of New Drugs Rebecca Nick-Dart, PharmD, BCPS Clinical Pharmacy Specialist

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Page 3 DPP-4 INHIBITORS

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

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

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 mg/dL in men, and SCr mg/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

Page 7 Efficacy ↓ HbA1c (%)↓ FPG (mg/dL)↓ PPG (mg/dL) % of Patients Achieving HbA1c <7% Alogliptin0.14 – – 16N/A20 – 49 Linagliptin0.69 – – 30N/A25 – 40 Saxagliptin0.35 – N/A Sitagliptin 0.43 – –

Page 8 Efficacy ↓ HbA1c (%)↓ FPG (mg/dL)↓ PPG (mg/dL) % of Patients Achieving HbA1c <7% Alogliptin + metformin 0.6 – – 1346 – 60 Linagliptin + metformin 0.16 – 2.812– 1128 – Saxagliptin + metformin 0.52 – – 2518 – Sitagliptin + metformin 0.62 – – 35N/A

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

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

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

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

Page 13 SGLT-2 INHIBITORS

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

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

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

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

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:

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

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

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

Page 22 GLP-1 AGONISTS

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

Page 24 Dosing and Administration GenericUsual Dose Albiglutide30-50mg once weekly Dulaglutide mg once weekly Exenatide5-10mcg twice daily Exenatide ER2mg once weekly Liraglutide mg 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

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

Page 26 Efficacy ↓ HbA1c (%)↓ FPG (mg/dL)↓ Weight (kg) Exenatide IR + metformin 0.5 – 0.95 – – 2.9 Exenatide ER + metformin Albiglutide + metformin Dulaglutide + metformin 0.9 – – – 3.1 Liraglutide + metformin 1.2 – – – 2.8 Lixisenatide + metformin – – 2.7

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

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

Page 29 Liraglutide and Cardiovascular Outcomes OutcomeLiraglutide (%)Placebo (%)HR (95% CI) Primary outcome (0.78 – 0.97) Primary expanded (0.81 – 0.96) Death any cause (0.74 – 0.97) Death CV cause (0.66 – 0.93) Death non-CV cause (0.77 – 1.18) MI (0.73 – 1.00) Stroke (0.71 – 1.06) Revascularization (0.80 – 1.04) Hospital for USA (0.76 – 1.26) Hospital for HF (0.73 – 1.05) Microvascular event (0.73 – 0.97 ) NEJM 2016;375:311-22

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) ????

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

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

A Tale of New Drugs Rebecca Nick-Dart, PharmD, BCPS Clinical Pharmacy Specialist