2/9/2016. The Evolving Armamentarium for Type 2 Diabetes: Incorporating New Classes in the Treatment of Our Patients. Objectives: Pharmacists

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1 WAYNE STATE UNIVERSITY COLLEGE OF PHARMACY & HEALTH SCIENCES FEBRUARY 28, 2016 The Evolving Armamentarium for Type 2 Diabetes: Clinical Assistant Professor, Department of Pharmacy Practice Ambulatory Care Specialist, Health Centers Detroit Medical Group Incorporating New Classes in the Treatment of Our Patients METFORMIN INSULIN ALPHA GLUCOSIDASE INHIBITORS THIAZOLIDINEDIONES MEGLITINIDES SULPHONYLUREAS GLP-1 RAs SYNTHETIC AMYLIN ANALOG DPP-4 INHIBITORS s 1950 s 1980 S 1990 S FUTURE? INSULIN 1 st BIOSYNTHETIC INSULIN 1 st BASAL INSULIN SGLT-2 INHIBITORS THE DECADES OF DIABETES AFREZZA TOUJEO TRESIBA Objectives: Pharmacists Describe novel physiologic targets for the treatment of diabetes Compare and Contrast the pharmacology, safety & efficacy of 3 new classes: Glucagon-Like Peptide 1 Receptor Agonists (GLP-1 RAs) Dipeptidyl Peptidase-4 Inhibitors (DPP-4 Inhibitors) Sodium-Glucose Cotransporter-2 Inhibitors (SGLT-2 Inhibitors) Construct a diabetes treatment regimen that incorporates these new classes in a given patient scenario 1

2 Objectives: Pharmacy Technicians Describe the 3 new classes of medications for diabetes and how they work to lower blood glucose Glucagon-Like Peptide 1 Receptor Agonists (GLP-1 RAs) Dipeptidyl Peptidase-4 Inhibitors (DPP-4 Inhibitors) Sodium-Glucose Cotransporter-2 Inhibitors (SGLT-2 Inhibitors) Identify the benefits of using each class Explain the most common side effects associated with each class Pathogenesis of T2DM: The Ominous Octet Kruger DF, et al. Diabetes Educ2010; 36: 44S. Case: Part I HP is a 67 yo female who presents to the pharmacist-run diabetes clinic for a follow-up. She is currently taking Metformin ER 1g 2 tablets once daily, and Glipizide XL 10mg 1 tablet once daily for her diabetes. She reports being rather discouraged today as she has been trying to lose weight and has not been successful. Current weight = 190 lbs, Height = 5 3, BMI = 33 PMH: Diabetes x 1 year, HTN, Dyslipidemia, Osteoporosis Point of Care A1c today = 8.6% Which of the following new classes is NOT associated with weight loss: a. Glucagon-Like Peptide 1 Receptor Agonists (GLP-1 RA) b. Dipeptydil Peptidase-4 (DPP-4) Inhibitors c. Sodium Glucose Co-Transporter 2 (SGLT-2) Inhibitors 2

3 Place in Therapy: ADA Position Statement Inzucchi et al. New Classes: Physiologic Targets GLP-1 Receptor Agonists... What is the role of Glucagon-Like Peptide 1? DPP-4 Inhibitors... What is the role of the DPP-4 Enzyme? SGLT-2 Inhibitors... What is the role of SGLT-2? 3

4 What is the role of Glucagon-Like Peptide-1? Incretin Effect Control Subjects T2DM - Oral Glucose - IV Glucose a- p 0.05 Nauck et al. Diabetologia 1986; 29:46-52 Decreased GLP-1 Levels in T2DM Toft-Nielsen et al. J Clin Endocrinol Metab. 2001, 86:

5 Endogenous GLP-1? Neuroprotection Brain Appetite Stomach Heart Gastric emptying *? Cardioprotection? Cardiac output GLP-1 GI tract Insulin secretion Pancreas Glucagon secretion Liver Glucose production * Muscle? β-cell proliferation? β-cell apoptosis? Insulin sensitivity Drucker DJ. Cell Metab. 2006;3: Limitations of Human GLP-1 DPP-IV His Ala Glu Gly Thr Phe Thr Ser Asp Val Ser Lys Ala Ala Gln Gly Glu Leu Tyr Ser Glu Phe Ile Ala Trp Leu Val Lys Gly Arg Gly Mentlein R. Eur J Biochem. 1993;214: BYETTA VICTOZA GLP-1 RECEPTOR AGONISTS - EXENATIDE - LIRAGLUTIDE BYDUREON - EXENATIDE EXTENDED RELEASE TANZEUM - ALBIGLUTIDE TRULICITY - DULAGLUTIDE 5

6 Benefits of GLP-1 RAs Weight loss Low risk of hypoglycemia A1c Efficacy Weekly Dosing β-cell preservation? Adverse Effects Nausea Vomiting Diarrhea Headache Injection site reactions Chemical Structures of GLP-1 RAs BYETTA (Exenatide) 53% Homology Gila monster saliva VICTOZA (Liraglutide) 97% Homology C-16 Fatty Acid Chain TANZEUM (Albiglutide) 97% Homology Dimer fused to Albumin BYDUREON (Exenatide ER) 53% Homology Microsphere technology TRULICITY (Dulaglutide) 90% Homology Linked to modified IgG 6

7 Pharmacology Dosing Frequency BYETTA Exenatide VICTOZA Liraglutide BYDUREON Exenatide ER TANZEUM Albiglutide TRULICITY Dulaglutide BID QD QW QW QW Dosage 5 & 10 mcg 0.6, 1.2 & 1.8 mg 2 mg 30 & 50 mg 0.75 & 1.5 mg Half-life 2.4 hours ~ 13 hours ~ 2 weeks ~ 5 days Renal Excretion Renal Dosing CrCL Renal Dosing CrCl < CAUTION - CAUTION - - Not recommended CAUTION Not recommended CAUTION Administration BYETTA Exenatide VICTOZA Liraglutide BYDUREON Exenatide ER TANZEUM Albiglutide TRULICITY Dulaglutide Dosing Frequency BID QD QW QW QW RoomTemp. 30 days 30 days 4 weeks 4 weeks 4 weeks Food 60 mins Needle Gauge 32 G 32 G 23 G 29 G 29 G Reconstitution Pre-Injection Waiting Time minutes AUTOINJECTOR Patient Education Nausea & Vomiting Transient Eat slow and stop when full Smaller meals Avoid overeating Byetta: take closer to meal time Severe, sudden onset with abdominal pain Don t expect rapid BG lowering Changes in urination urine color/frequency/amount, unexplained extremity swelling 7

8 Head-to-Head Comparisons ARE THERE DIFFERENCES? Exenatide BID vs. QW: DURATION 1 & 5 Liraglutide vs. Exenatide BID: LEAD-6 Exenatide QW: DURATION-6 Albiglutide: HARMONY-7 Dulaglutide: AWARD-6 A1c QW PPBG BID Weight DURATION-1 & DURATION-5 FBG QW N/V BID Injection Reactions QW Head-to-Head Studies vs. Liraglutide: A1c EXENATIDE EXENATIDE ER ALBIGLUTIDE DULAGLUTIDE LEAD-6 (n=464) DURATION-6 (n=911) HARMONY-7 (n=841) AWARD-6 (n=599) BYETTA: VICTOZA: BYDUREON: VICTOZA: TANZEUM: VICTOZA: TRULICITY: VICTOZA: % [p<0.0001] % [p=0.02] % [p=0.0846, Non-Inferiority] % [p<0.0001, Non-Inferiority] 8

9 Head-to-Head Studies vs. Liraglutide: Weight EXENATIDE EXENATIDE ER ALBIGLUTIDE DULAGLUTIDE LEAD-6 (n=464) DURATION-6 (n=911) HARMONY-7 (n=841) AWARD-6 (n=599) BYETTA: VICTOZA: BYDUREON: VICTOZA: TANZEUM: VICTOZA: TRULICITY: VICTOZA: kg [p=0.2235] kg [p=0.0005] kg [p<0.0001] kg [p=0.011] Additional Results FBG vs PPBG GI AEs Injection Site Reactions CV Risk Factors: BP, Cholesterol, HR Hypoglycemia Glucose-Dependent Mechanism Caution: Sulfonylureas & Insulin 9

10 GLP-1 RAs & Insulin Benefits of Combination: Weight loss / Minimize weight gain Minimize hypoglycemia Dosing Recommendations: Reduce insulin dose by 20% Pipeline: Xultophy (Liraglutide and Degludec) Approved in Europe LixiLan (Lixisenatide and Glargine) - Phase III Additional Precautions Altered/Worsening Kidney Function Pancreatitis Thyroid C-Cell / Medullary Thyroid Carcinoma (MTC) Black Box Warning CI: Multiple endocrine neoplasia syndrome type 2 CI: Personal or FHx of medullary thyroid carcinoma REMS Pancreatitis & MTC Case: Part II Last month HP was started on Byetta 5 mcg BID and is at the pharmacy for today for a refill. She is unhappy that the numbers on her meter are still high, however, she admits that she doesn t always take her medications during the week. She takes care of her 3 grandchildren from Monday to Friday and misses 2-3 doses per week, as these days are very hectic. HP injects her Byetta immediately prior to a meal. She reports nausea which is bothersome, however, she is happy to have seen some weight loss. In addition to counseling her on compliance, which of the following is the most appropriate recommendation at this time? a. Increase the dose of Byetta (Exenatide) b. Inject Byetta (Exenatide) 60 minutes prior to meals c. Change to Victoza (Liraglutide) d. Change to Trulicity (Dulaglutide) 10

11 GLP-1 RAs: Clinical Pearls Benefits Efficacy: A1c ~1-1.5% PPBG > FBG: Exenatide FBG > PPBB: Longer acting agents Weight Loss Low risk of hypoglycemia Insulin dose reduction Long Acting: Compliance, less N/V/D, Use in CKD Delayed disease progression? Additional benefits? Concerns FDA Warnings: Kidney failure, pancreatitis, thyroid c-cell cancer Prescriber unfamiliarity GI Adverse Effects Nodules Interactions Gastroparesis Injectable Cost What is the role of DDP-4? Limitations of Human GLP-1 DPP-IV His Ala Glu Gly Thr Phe Thr Ser Asp Val Ser Lys Ala Ala Gln Gly Glu Leu Tyr Ser Glu Phe Ile Ala Trp Leu Val Lys Gly Arg Gly Mentlein R. Eur J Biochem. 1993;214:

12 DPP-4 INHIBITORS JANUVIA ONGLYZA TRADJENTA NESINA - SITAGLIPTIN - SAXAGLIPTIN - LINAGLIPTIN - ALOGLIPTIN MOA: DPP-4 Inhibitor vs. GLP-1 RA DPP-4 GLP-1 RA Inhibitor Glucose-dependent insulin secretion Glucagon secretion Plasma glucose levels Rate of gastric emptying - Satiety - Food intake - DPP-IV Degredation - - Duration of action Long Intermediate Benefits of DPP-4 Inhibitors Low risk of hypoglycemia Weight neutral Once daily ORAL Well tolerated 12

13 Adverse Effects URI Nasal pharyngitis Headache Hypersensitivity Pancreatitis Pharmacology Dosing Frequency JANUVIA (SITAGLIPTIN) ONGLYZA (SAXAGLIPTIN) TRADJENTA (LINAGLIPTIN) NESINA (ALOGLIPTIN) Dosage 25, 50, 100 mg 2.5 & 5 mg 5 mg 6.25, 12.5, 25 mg Half-life (hours) (active metabolite= 3.1) Metabolism Not extensively metabolized CYP3A4/5 > (active metabolite) Not extensively metabolized CYP2D6/3A4 Majority of Elimination Dose Adjustment in CKD/ESRD Combination Products Renal Renal Bile Renal -- Severe Arthralgia Substantial reduction in prior level of activity 33 cases ( ) 10 Hospitalizations 8 cases re-challenged Symptom onset: 1 month 1 year Does the pain go away? 13

14 HEART FAILURE? CARDIOPROTECTIVE? EXAMINE (Alogliptin) Neutral effect on All-Cause and CV mortality TECOS (Sitagliptin) Heart Failure Hospitalizations SAVOR-TIMI 53 (Saxagliptin) Further Evaluation Cardiovascular Effects? Case: Part III HP is now on Metformin, Glipizide and Trulicity (Dulaglutide) for her diabetes. One year later, her A1c is 7.6%. Her PCP wants to add a DPP-4 inhibitor and asks you for your recommendation. Which of the following is most the most appropriate recommendation? a. Add Januvia (Sitagliptin) b. Add Onglyza (Saxagliptin) c. Add Nesina (Alogliptin) d. A DPP-4 Inhibitor will not be beneficial for this patient DPP-4 Inhibitors: Clinical Pearls Benefits Oral agents: QD dosing A1c reduction ~ 1% PPBG > FBG control Low risk of hypoglycemia Well tolerated Weight neutral Clinical benefits: CKD/ESRD Elderly Additional benefits? Concerns FDA Warnings: Severe arthralgia, pancreatitis Upper respiratory infections Hypersensitivity reactions 14

15 What is the role of Sodium Glucose CoTransporter-2? MOA of SGLT-2 Inhibitors SGLT-2 INHIBITORS INVOKANA - CANAGLIFLOZIN FARXIGA - DAPAGLIFLOZIN JARDIANCE - EMPAGLIFLOZIN 15

16 Benefits of SGLT- Inhibitors Weight loss Low risk of hypoglycemia Novel MOA Once daily ORAL Adverse Effects Urinary Tract Infection Yeast infection Dehydration Electrolyte changes Pharmacology Dosing Frequency INVOKANA (CANAGLIFLOZIN) FARXIGA (DAPAGLIFLOZIN) JARDIANCE (EMPAGLIFLOZIN) Dosage 100 & 300 mg 5 & 10 mg 10 & 25 mg Half-life (hours) ~ 12.9 ~ 12.4 Metabolism UGT1A9, UGT2BA UGT1A9 UGT2B7, UGT1A3 UGT1A8, UGT1A9 Elimination Fecal / Renal Renal / Fecal Renal / Fecal Renal Dosing (egfr): Not Recommended < 45 ml/min < 60 ml/min < 45 ml/min 16

17 Additional Precautions KETOACIDOSIS USA: 20 Cases (03/ /2014) 101 Cases worldwide; T2DM Euglycemicdiabetic ketoacidosis Be vigilant Check ketone levels Stop SGLT2 Inhibitors 3 days prior to surgery Caution in T1DM, off-label BONE FRACTURES Canagliflozin Class effect? BLADDER CANCER Dapagliflozin Macrovascular Benefits Composite endpoint: CV death, nonfatal MI & nonfatal stroke Case: Part IV A few years later, HP is diagnosed with CKD and her CrCl = 50 ml/min. Which of the following agents should NOT be used with her current CKD status? a. Trulicity (Dulaglutide) b. Tradjenta (Linagliptin) c. Invokana (Canagliflozin) d. Farxiga (Dapagliflozin) 17

18 Case: Part IV A few years later, HP is diagnosed with CKD and her CrCl = 50 ml/min. Which of the following agents should NOT be used with her current CKD status? a. Trulicity (Dulaglutide) - Caution b. Tradjenta (Linagliptin) - No renal adjustment c. Invokana (Canagliflozin) - Do not use < 45 ml/min d. Farxiga (Dapagliflozin) - Do not use < 60 ml/min SGLT-2 Inhibitors: Clinical Pearls Benefits Novel MOA: Oral QD dosing A1c reduction ~ 1% FBG > PPBG control Weight loss Low risk of hypoglycemia CV mortality Concerns FDA Warnings: Euglycemic ketoacidosis Bone fractures (Canagliflozin) UTIs & genital mycotic infections Do NOT use in CKD/ESRD Caution in elderly Caution interpreting macrovascular outcomes SUMMARY 18

19 Place in Therapy: ADA Position Statement Inzucchi et al. Comparison of the 3 Classes GLP1- RAs DPP-4 Inhibitors SGLT2 Inhibitors Administration BID, QD, QWeek QD QD Route Subcutaneous Oral Oral Weight Effects LOSS NEUTRAL LOSS Hypoglycemia Risk LOW LOW LOW CKD Use Adverse Effects FDA Warnings (Albiglutide & Dulaglutide) N/V/D Injection SiteReactions Pancreatitis Thyroid C-Cell Tumors Kidney Failure URI Nasal pharyngitis Pancreatitis Severe Arthralgia x UTI Yeast Infections DKA Bone Fractures Therapeutic Use Highlights Greatest A1c (long-acting) Compliance (long-acting) Reduced insulin dose Modest A1c CKD Elderly Well Tolerated Modest A1c Novel MOA CV Benefits Caution in elderly Use in T1DM? THANK YOU! 19