1. Diabetes Update 2016: New Drugs and New Methods of Care Kelly Murray, PharmD, BCACP Clinical Assistant Professor of Clinical Pharmacy OSU College of Osteopathic Medicine Emergency Department Clinical Pharmacist OSU Medical Center

2. Overview  Standards of Care 2016 Updates  New Diabetes Therapies  Oral medications  Injectable medications  Insulin therapies  Innovative Care Solutions and Ideas 2

3. Objectives  Describe the mechanisms of action of the newest type 2 diabetes medications – DPP4-inhibitors, incretin mimetics, and SGLT-2 inhibitors.  Recall advantages of insulin degludec over insulin glargine.  List 3 resources to assist patients with the costs of their medications. 3

4. Standards of Care 2016 Updates

5. General Changes  “Person with diabetes” vs. “diabetic”  Support technology to assist diabetes management  Obesity management/treatment recommendations Cefalu WT. Diabetes Care 2016;29(1):S1-S112. 5

6. Testing  All adults ≥45 years old regardless of weight  Any person who is overweight/obese with ≥1 risk factor Cefalu WT. Diabetes Care 2016;29(1):S1-S112. 6

7. Diabetes Management in Pregnancy  A1c target 6-6.5% instead of 6%  Insulin or metformin > glyburide Cefalu WT. Diabetes Care 2016;29(1):S1-S112. 7

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9. New Diabetes Therapies DPP-4 Inhibitors GLP-1 Agonists SGLT2 Inhibitors New Basal Insulins New Bolus Insulins

10. Where do diabetes meds work? Liver Intestines Brain Pancreas Muscle and Adipose ↓ glucose production ↑ insulin secretion ↑ satiety ↑ peripheral glucose uptake ↓ digestion and absorption of carbs Delay gastric emptying Kidneys ↓ glucose reabsorption SGLT2 inh Insulin Metformin TZDs Pramlintide DPP-4 inh. Incretin mimetics Insulin Sulfonylureas Meglitinides DPP-4 inh. Incretin mimetics Pramlintide Incretin mimetics Insulin Metformin TZDs Metformin a-glucosidase inh. Pramlintide Incretin mimetics 10

11. What level do they fix? FASTINGMIXEDPOSTPRANDIAL Interm. insulin Long insulin Regular insulin Rapid insulins Metformin SU Meglitinides TZDs a-glucosidase (-) DPP-4 (-) SGLT2 (-) Incretin mimetics (Exen.) Incretin mimetics Pramlintide 11

12. Incretin Effect  Eat food  nutrients and glucose in the gut  Intestinal mucosal cells sense this and release hormones called incretins  GLP1 = glucagon like peptide 1  GIP = glucose-dependent insulinotropic polypeptide  The “incretin effect” is decreased in type 2 diabetes, so we need to replace levels. Idris I. Diabetes Obes Metab 2007;9:153-65. 12

13. Need for Drug Therapy That:  Inhibits degradation of DPP-4 so there is more circulating incretin;  DPP-4 inhibitors OR  Replaces incretin altogether by giving an analog exogenously  Incretin mimetic, or GLP-1 receptor agonist 13

14. Dipeptidyl Peptidase - 4 (DPP-4) Inhibitors Sitagliptin (Januvia)Saxagliptin (Onglyza) + Metformin (Janumet, XR) + Simvastatin (Juvisync) + Metformin (Kombiglyze XR) Linagliptin (Tradjenta)Alogliptin (Nesina) + Metformin (Jentadueto) + Empagliflozin (Glyxambi) + Metformin (Kazano) + Pioglitazone (Oseni) Lexi-complete Online. Accessed 4/7/16. 14

15. DPP-4 Inhibitors  Mechanism:  Inhibits DPP-4 (enzyme that breaks down incretin)  Increased circulating incretin, helping control glucose absorbed in the diet  Glucose-dependent increase in insulin secretion  Glucose-dependent inhibition of glucagon secretion Idris I. Diabetes Obes Metab 2007;9:153-65. Drucker DJ. Lancet 2006;368:1696-705. 15

16. DPP-4 Inhibitors - Safety  AE:  Placebo-like: HA, URI, nasopharyngitis, UTI  Rare: pancreatitis, skin reactions, urticaria/angioedema  CI: Hx of pancreatitis, DKA, type 1 diabetes  Counseling:  With or without food Lexi-complete Online. Accessed 4/7/16. 16

17. DPP-4 Inhibitors - Efficacy  Average A1c reduction: 0.6-0.8%  Primarily acts on postprandial glucose  Remember they are glucose-dependent 17

18. DPP-4 Inhibitors  Advantages:  No hypoglycemia as monotherapy  Weight neutral  Placebo-like AE  Beta cell preservation  Linagliptin – no renal adjustments needed  Disadvantages:  Modest A1c lowering  Cost  Long term safety unknown 18

19. DPP-4 Inhibitors Dosing Guide  Sitagliptin 100mg po daily  CrCl 30-49= 50mg po daily  CrCl ≤ 30= 25mg po daily  ESRD= 25mg po daily without regard to HD  Reduce dose of concomitant insulin/secretagogues  Saxagliptin 2.5 – 5mg po daily  CrCl ≤ 50 = 2.5mg po daily  ESRD = 2.5mg po daily, post-HD  With strong CYP 3A4/5 inhibitors (“conazoles” and protease inhibitors) = 2.5mg po daily  Reduce dose of concomitant insulin/secretagogues Lexi-complete Online. Accessed 4/7/16. 19

20. DPP-4 Inhibitors Dosing Guide  Linagliptin 5mg po daily  Reduce dose of concomitant insulin/secretagogues  No renal dose adjustment needed  Alogliptin 25mg po daily  CrCl 30-59= 12.5mg po daily  CrCl 15-29= 6.25mg po daily  ESRD= 6.25mg po daily, without regard to HD  Reduce dose of concomitant insulin/secretagogues Lexi-complete Online. Accessed 4/7/16. 20

21. GLP 1 Receptor Agonists (a.k.a. incretin mimetics)  Exenatide (Byetta, Bydureon)  Liraglutide (Victoza, Saxenda)  Albiglutide (Tanzeum)  Dulaglutide (Trulicity)  Lixisenatide (Lyxumia)  App. for new drug approval submitted 9/2015 Lexi-complete Online. Accessed 4/7/16. FDA Drugs. Accessed 4/11/16. 21

22.  Mechanism: GLP1 analog  Increases incretin levels  Glucose-dependent increase in insulin secretion  Glucose-dependent inhibition of glucagon  Reduces gastric emptying  Increases satiety GLP 1 Receptor Agonists (a.k.a. incretin mimetics) Lexi-complete Online. Accessed 4/7/16. 22

23.  Adverse Effects:  Nausea – 8-40% more vs. placebo/comparator  Exen BID>Lira>Exen Q7D>Alb/Dula  Diarrhea – 3-118% more vs. placebo/comparator  Rare – pancreatitis, renal dysfunction, thyroid tumors  CI:  Gastroparesis  Pancreatitis  Exen: CrCl <30 (maybe others?)  Lira, Alb, Dula, Exen: PMH or FH of thyroid cancer, multiple endocrine neoplasia GLP 1 Receptor Agonists (a.k.a. incretin mimetics) Shyangdan DS. Cochrane Database Syst Rev 2011. Lexi-complete Online. Accessed 4/7/16. 23

24. GLP 1 Receptor Agonists (a.k.a. incretin mimetics)  Efficacy:  A1c reduction 1-2%  Adjunct for type 2 diabetes  BID = More postprandial reduction  Daily, Q7D Dosing = More fasting reduction Drucker DJ. Lancet 2006;368:1696-705. Lexi-complete Online. Accessed 4/7/16. 24

25. GLP 1 Receptor Agonists (a.k.a. incretin mimetics)  Dosing considerations  Inject into thigh, abdomen, upper arm  Exenatide BID 60 minutes prior to 2 main meals  Reduce incidence of nausea with proper dose titration (start low, go slow)  Once-weekly injections < twice daily injections Lexi-complete Online. Accessed 4/7/16. 25

26.  Start weekly dose the day after D/C IR  D/C IR Monday, start ER Tuesday  Pt may have increased BG levels for 2 weeks  Pretreatment for this temporary rise is unnecessary Exenatide IR to ER Lexi-complete Online. Accessed 4/7/16. 26

27. GLP 1 Receptor Agonists (a.k.a. incretin mimetics)  Advantages:  Weight loss – 1-5kg  No priming after initial dose  Extended release option available  Preservation of beta cell function  Decrease insulin resistance Shyangdan DS. Cochrane Database Syst Rev 2011. 27

28. GLP 1 Receptor Agonists (a.k.a. incretin mimetics)  Disadvantages:  May reduce absorption rate and extent of drugs requiring rapid absorption (i.e. pain relievers, antibiotics, BCPs). Separate by 1 hour.  Requires subcutaneous injection  Cost  GI side effects Lexi-complete Online. Accessed 4/7/16. 28

29. GLP-1 Agonists Dosing Guide  Byetta (exenatide) 5mcg subq BID ac, increase to 10mcg subq BID after 1 month  CrCl <30= use is not recommended  Bydureon (exenatide) 2mg subq once weekly  CrCl <30= use is not recommended  Victoza (liraglutide) 0.6 mg subq once daily x 1 week, then increase to 1.2mg subq once daily. May go to 1.8mg if optimal glycemic response not achieved.  If missed doses, resume with next scheduled dose.  If >3 days of missed doses, resume with 0.6mg dose and retitrate.  No CrCl limitations on use Lexi-complete Online. Accessed 4/7/16. 29

30. GLP-1 Agonists Dosing Guide  Tanzeum (albiglutide) 30mg subq once weekly, may increase to 50mg once weekly if inadequate response at week 12.  Missed dose = administer ASAP within 3 days. If >3 days have passed, omit dose and resume with next scheduled dose.  No renal adjustment necessary.  Trulicity (dulaglutide ) 0.75mg subq once weekly; may increase to 1.5mg weekly if inadequate response.  Same missed dose regimen as albiglutide  No renal adjustment necessary.  Lyxumia (lixisenatide) – once daily prandial subq injection, dose TBA Lexi-complete Online. Accessed 4/7/16. 30

31. Incretin Mimetic vs. DPP-4 Inhibitors Incretin MimeticDPP-4 Inhibitor Delay gastric emptyingNo effect on gastric emptying Increase satietyNo increase in satiety Lots of N/VPlacebo-like AE Weight lossNo change in weight SC administrationPO administration Drucker DJ. Lancet 2006;368:1696-705. 31

32. SGLT2 Inhibitors Canagliflozin (Invokana)Dapagliflozin (Farxiga) Approved 3/13 + Metformin (Invokamet) Approved 1/14 + Metformin (Xigduo) Empagliflozin (Jardiance) Approved 8/14 + Metformin (Synjardy) + Linagliptin (Glyxambi) Lexi-complete Online. Accessed 4/7/16. 32

33. SGLT2 Inhibitors Mechanism of Action  Blocks renal absorption of ~90% of excess glucose  Causes renal wasting of glucose, lowering serum BG and A1c over time  Minimizes chance of hypoglycemia Jurczak MJ. Diabetes 2011;60:890-8. Lexi-complete Online. Accessed 4/7/16. 33

34. SGLT2 Inhibitors  Adverse Effects:  Urinary/genital infections  Hypotension  Bone fractures  DKA  Hyperkalemia  Renal insufficiency  Contraindications:  Hypersensitivity  ESRD/Dialysis Lexi-complete Online. Accessed 4/7/16. 34

35. SGLT2 Inhibitors  Counseling Points:  With or without food  Before the first meal of the day  Efficacy  0.5-0.9% A1c lowering  Mostly post-prandial glucose lowering Lexi-complete Online. Accessed 4/7/16. 35

36. SGLT2 Inhibitors  Advantages:  New mechanism, another option  Less hypoglycemia  Weight loss  Potential BP- lowering  Disadvantages:  DKA  Price / insurance coverage  May encourage diet indiscretions?  Cancer risk? 36

37. Dosing Recommendations  Canagliflozin (Invokana)  100mg po once daily before first meal of the day  eGFR 45-59 = 100mg po daily max  eGFR <45 = use is not recommended/CI  Dapagliflozin (Farxiga)  10 mg po once daily without regard to meals  eGFR <60 = use is not recommended/CI  Empagliflozin (Jardiance)  10mg po once daily without regard to meals  eGFR <45 = use is not recommended/CI Lexi-complete Online. Accessed 4/7/16. 37

38. Type 2 Therapies (Fig 7.1) Cefalu WT. Diabetes Care 2016;29(1):S1-S112. 38

39. New Insulin Therapies

40.  Ideal basal insulin  Peakless  Consistent rate of absorption  No weight gain  True 24-hour coverage  Bolus insulin  Lots of injections  Titratable dose  Minimize side effects 1. Insulin degludec (Tresiba) 2. Insulin glargine (Toujeo) 3. Insulin glargine (Basaglar) 4. Humalog U-200 KwikPen 5. Inhaled insulin (Afrezza) Hess R. ACSAP 2016;1:35-64. 40

41. Insulin degludec (Tresiba) Image: https://www.diabetesdaily.com/blog/2015/09/tresiba-fda-approves-new-basal-insulin-in-the-usa/. Accessed 4/11/16.https://www.diabetesdaily.com/blog/2015/09/tresiba-fda-approves-new-basal-insulin-in-the-usa/ 1 1 41

42. Insulin degludec (Tresiba)  Long-acting insulin  Onset = 1 hour  Time to peak = 9 hours  t ½ = 25 hours  Duration = 42 hours Lexi-complete Online. Accessed 4/7/16. 42

43. Insulin degludec Mechanism  Naturally, insulin dimers form hexameric complexes to maximize storage within beta-cell vesicles  Degludec mimics this natural process  Hexamer  multihexameric chain = depot formation with a slow constant release over time Jonassen I. Pharm Res 2012;29:2104-14. 43

44. Head-to-Head: Insulin degludec vs.  Insulin glargine  Noninferiority criteria met (95% CI -0.14 to 0.11)  Nocturnal hypoglycemia rates 25% lower (p=0.021)  Mean weight gain similar (1.8 kg with degludec and 1.6 kg with glargine) (p=0.62)  Insulin detemir (+ aspart)  Noninferiority criteria met (95% CI -0.23 to 0.05)  Nocturnal hypoglycemia 34% lower (p=0.0049)  Weight gain higher with degludec (est. diff. 1.08 kg; p<0.0001) Heller S. Lancet 2012;379:1489-97. (BEGIN) Mathieu C. J Clin Endocrinol Metab 2013;98:1154-62. (BEGIN:Flex T1) 44

45. HbA1c Comparison Mathieu C. J Clin Endocrinol Metab 2013;98:1154-62. (BEGIN:Flex T1) 45

46. Insulin degludec (Tresiba)  100 units/mL and 200 units/mL available  No conversion calculation necessary; same unit per unit dose  Dosing:  Type 1: 0.2-0.4 units/kg (1/3-1/2 the TDD)  Type 2: 10 units once daily  Missed doses: administer ASAP to ensure at least 8 hours between doses  Stable at room temp for 8 weeks Mathieu C. J Clin Endocrinol Metab 2013;98:1154-62. (BEGIN:Flex T1) Lexi-complete Online. Accessed 4/7/16. 46

47. Insulin glargine (Toujeo) Image: https://www.toujeo.com. Accessed 4/7/16. 2 2 47

48. Insulin glargine (Toujeo)  No change in physiological mechanism  Smaller amount of depot insulin  Smaller surface area  More gradual and prolonged release of hexamers  Smaller amount of liquid per unit  450 units (300 u/mL) vs. 300 units (100 u/mL) in Lantus pen Home PD. Am Diabetes Assoc 2014;2014:abstract 80-LB. 48

49. Head-to-Head: Toujeo vs. Lantus  Noninferiority met at 26 weeks (95% CI 0.1- 0.19)  Nocturnal hypoglycemia  31% lower in first 8 weeks (CI 0.53-0.91)  No difference at 26 weeks  Less weight gain (est. diff. 0.5 kg, p=0.037) Home PD. Am Diabetes Assoc 2014;2014:abstract 80-LB. 49

50. Basaglar (insulin glargine) Eli Lilly/Boerhinger Ingelheim. Introducing: Basaglar. https://www.basaglar.com/# (accessed 4/7/16).https://www.basaglar.com/# 3 3 50

51. Basaglar (insulin glargine)  Lilly/BI’s answer to Sanofi-Aventis’s Lantus  Same PK profile, not interchangeable  Approved for use in type 1 kids and adults, and type 2 adults  Available starting 12/2016 Blevins TC. Diabetes Obes Metab 2015;17:726-33. (ELEMENT 1) Eli Lilly/Boerhinger Ingelheim. Introducing: Basaglar. https://www.basaglar.com/# (accessed 4/7/16).https://www.basaglar.com/# 51

52. Head-to-Head: Basaglar vs. Lantus  Noninferiority met at 24 weeks  95% CI -0.002 to 0.219  Symptomatic and nocturnal hypoglycemia similar  Weight gain similar  0.36 kg Basaglar vs. 0.12 kg Lantus  Insulin antibodies similar Blevins TC. Diabetes Obes Metab 2015;17:726-33. (ELEMENT 1) 52

53. Humalog U-200 KwikPen Image: http://www.ulticare.com/pen-needles/. Accessed 4/11/16. 4 4 53

54. Humalog U-200 KwikPen  200 units/ml  600 units/pen (versus 300 units/pen)  Good for patients who go through 2 or more mealtime insulin pens each month Lexi-complete Online. Accessed 4/7/16. 54

55. Inhaled insulin (Afrezza) Images: Afrezza. https://www.afrezza.com/hcp 5 5 55

56. Inhaled insulin (Afrezza)  “Technosphere insulin”  Helps reduce injection barriers to therapy  Lungs have a large surface area and high bioavailability  New inhaler device called “Dreamboat”  Replace every 15 days  Insulin cartridges available:  4 units, 8 units, 12 units  Concerns: pulmonary toxicity/malignancy Lexi-complete Online. Accessed 4/7/16. Bode BW. Diabetes Care 2015;38:2266-73. Raskin P. Diabetes Obes Metab 2012;14:163-73. 56

57. Head-to-Head: Inhaled insulin vs. aspart  Mean change in HbA1c noninferior  More aspart patients achieved HbA1c <7.0% (30.7% vs. 18.3%)  Inhaled insulin had less hypoglycemia (9.8 vs 14.0 events/patient-month, p<0.0001)  Inhaled insulin patients experienced weight loss (-0.4 kg) vs. gain (+0.9 kg) for aspart patients (p=0.0102)  Most frequent AE = cough which led to discontinuation in 5.7% of patients Bode BW. Diabetes Care 2015;38:2266-73. 57

58. Dosing Chart Configurations Afrezza. https://www.afrezza.com/AfrezzaConfigurationChart.pdf 58

59. Diabetes Meds in the Pipeline  Novo Nordisk  Xultophy (insulin degludec + liraglutide)  Faster-acting insulin aspart  Semaglutide (oral and injectable)  Eli Lilly  BioChaperone insulin lispro R&D Pipeline. http://www.novonordisk.com/rnd/rd-pipeline.html. Accessed 4/11/16. Anderson G. Diabetes 2014;63(suppl 1). 59

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61. Innovative Care Solutions and Ideas Patient Assistance Programs Coupons Medication Pricing Apps Medication Lists

62. Patient Assistance Programs (PAPs)  Provided by pharmaceutical companies  To provide brand-name medications  For low-income individuals who lack prescription drug coverage  Vs. coupon, sample, 340B, drug card, bulk replacement programs, and Medicare Part D  Advocate “PAPs are a long term solution to a current medication access problem” Am J Health-Syst Pharm. 2006; 63:1254-9. Sagall RJ. Pharmaceutical companies helping patients get their medications. Accessed at http://www.needymeds.org/indices/article.htm on 2/21/13. 62

63. Programs Available  NeedyMeds  http://www.needymeds.org http://www.needymeds.org  Partnership for Prescription Assistance  http://www.pparx.org http://www.pparx.org  RxAssist  http://www.rxassist.org http://www.rxassist.org  TogetherRx Access  http://www.togetherrxaccess.com http://www.togetherrxaccess.com  National Council on Patient Information and Education  http://www.talkaboutrx.org http://www.talkaboutrx.org  Manufacturers’ websites 63

64. Finding an application  Medications covered  Type (brand, generic)  Insurance status  Private insurance  Medicare Part D (coverage gap)  No insurance 64

65. Coupons  Discount the price of medications for a set number of fills  Search patient assistance websites for coupons  Hard copy cards at physician offices from drug company representatives 65

66. Medication Pricing - GoodRx  Losartan 50mg #30  Wal-Mart pricing by phone = $39.41 Price obtained by phone from Wal-Mart Neighborhood Market, 4404 S. Peoria Ave. Tulsa, OK on 4/11/16. 66

67. Medication Pricing - GoodRx Screenshots taken 4/7/16. 67

68. Medication Pricing - GoodRx Screenshots taken 4/7/16. 68

69. Medication Lists  MyMedSchedule.com 69

70. Medication Lists  My Medicine List  http://www.safemedication.com 70

71. Questions?

72. Diabetes Update 2016: New Drugs and New Methods of Care Kelly Murray, PharmD, BCACP Clinical Assistant Professor of Clinical Pharmacy OSU College of Osteopathic Medicine Emergency Department Clinical Pharmacist OSU Medical Center