1. New Diabetes Therapies: Practical Considerations for Outpatient Use Sarah L. Anderson, PharmD, BCPS CPS 2016 Winter Seminar January 13, 2016

2. Disclosures  No financial conflicts of interest to disclose  Sarah L. Anderson is a Member-At-Large on the CPS Board of Directors 2 NEW DIABETES THERAPIES: PRACTICAL CONSIDERATIONS FOR OUTPATIENT USE01-13-16

3. Learning Objectives 1.Describe new and emerging oral and injectable therapies for the treatment of diabetes. 2.List the potential pros and cons of new oral and injectable therapies for the treatment of diabetes. 3.Given a patient case, make an appropriate recommendation regarding an antihyperglycemic regimen. NEW DIABETES THERAPIES: PRACTICAL CONSIDERATIONS FOR OUTPATIENT USE 3 01-13-16

4. NEW DIABETES THERAPIES: PRACTICAL CONSIDERATIONS FOR OUTPATIENT USE 4 01-13-16

5. Quick audience poll! Raise your hand if you work in a: 1)Community pharmacy 2)Health-system 3)Outpatient clinic 4)Inpatient pharmacy 5)Place other than the above NEW DIABETES THERAPIES: PRACTICAL CONSIDERATIONS FOR OUTPATIENT USE 5 01-13-16

6. A brief history… NEW DIABETES THERAPIES: PRACTICAL CONSIDERATIONS FOR OUTPATIENT USE 6 01-13-16 1936 Protamine insulin 1955 Sulfonylureas 1961 Glucagon 1972 U-100 insulin 1995 Biguanides 1996 α-glucosidase inhibitors 1998 Meglitinides 2005 GLP-1 RAs 2006 DPP-4s 2013 SGLT2s Adapted from: http://www.diabetes.org/research-and-practice/student-resources/history-of-diabetes.html … Inhaled insulin

7. Place in therapy… NEW DIABETES THERAPIES: PRACTICAL CONSIDERATIONS FOR OUTPATIENT USE 7 01-13-16 1 st line = METFORMIN! Metformin + TZD Metformin + Sulfonylurea Metformin + DPP-4 Metformin + SGLT2 Metformin + GLP1-RA Metformin + Basal insulin 3 rd line = metformin + choose your own adventure! Clin Diabetes 2015;33(2):97-111

8. What’s new? NEW DIABETES THERAPIES: PRACTICAL CONSIDERATIONS FOR OUTPATIENT USE 8 01-13-16

9. DPP-4 Inhibitors Inhibit DPP-4 enzyme  prolonging incretin levels (GIP & GLP1) Incretin hormone levels increase in response to a meal and are typically inactivated by DPP-4; inhibiting DPP-4 prolongs their effects. NEW DIABETES THERAPIES: PRACTICAL CONSIDERATIONS FOR OUTPATIENT USE 9 01-13-16

10. DPP-4 Inhibitors  Newest kid on the block: alogliptin  Latest class issue: joint pain (August 2015)  33 cases of arthralgia reported 2006-2013  Timing: 1 day to years  Advice: contact provider immediately if joint pain occurs after DPP-IV initiation  Symptoms typically go away with drug D/C  Symptoms typically persist if switched to alternative DPP-IV NEW DIABETES THERAPIES: PRACTICAL CONSIDERATIONS FOR OUTPATIENT USE 10 01-13-16 http://www.fda.gov/Drugs/DrugSafety/ucm459579.htm

11. DPP-4 Inhibitors: Comparisons NEW DIABETES THERAPIES: PRACTICAL CONSIDERATIONS FOR OUTPATIENT USE 11 01-13-16 DRUGDOSERENALHEPATICOTHER Alogliptin25mg PO dailyCrCl 30-60: 12.5mg CrCl < 30: 6.25mg ESRD: 6.25mg Not studiedNewest agent Linagliptin5mg PO dailyNo adjustment necessary Great in renal impairment! Saxagliptin2.5-5mg PO dailyCrCl ≤ 50: 2.5mgNot studied Sitagliptin100mg PO dailyCrCl 30-50: 50mg CrCl < 30: 25mg Not studiedPatent expires 2017

12. DPP-IV Inhibitors: How do you choose?  Role: intolerance or contraindication to 1 st -line therapies  Similar glycemic efficacy amongst products  Renal dysfunction (CrCl < 30 ml/min): linagliptin  Sitagliptin, saxagliptin, alogliptin all require dose adjustments  Otherwise, choice usually is dictated by payer NEW DIABETES THERAPIES: PRACTICAL CONSIDERATIONS FOR OUTPATIENT USE 12 01-13-16

13. GLP-1 Receptor Agonists ↑ glucose-dependent insulin secretion ↑ satiety ↓ glucagon production ↓ gastric emptying NEW DIABETES THERAPIES: PRACTICAL CONSIDERATIONS FOR OUTPATIENT USE 13 01-13-16

14. GLP-1 Receptor Agonists  Things to consider: »Frequency of dosing  Twice daily: exenatide (Byetta ® )  Once daily: liraglutide (Victoza ® )  Once weekly: albiglutide (Tanzeum ® ), dulaglutide (Trulicity ® ), exenatide (Bydureon ® ) »Complexity of device/use NEW DIABETES THERAPIES: PRACTICAL CONSIDERATIONS FOR OUTPATIENT USE 14 01-13-16

15.  Advantages »Less-frequent dosing »Little to no hypoglycemia »Weight loss  Disadvantages »Injectable »GI side effects »Pancreatitis (?) »Medullary thyroid cancer (?) NEW DIABETES THERAPIES: PRACTICAL CONSIDERATIONS FOR OUTPATIENT USE 15 01-13-16 GLP-1 Receptor Agonists

16. GLP-1 Receptor Agonists – Weight Loss  Saxenda ® (liraglutide)  Dosing: »Start at 0.6mg daily; titrate up in 0.6 increments to 3mg daily »(T2D: 0.6mg daily; titrate up to max of 1.8mg daily)  Re-evaluate in 16 weeks; D/C if > 4% weight loss  If > 3 doses missed, revert back to 0.6mg and re-titrate NEW DIABETES THERAPIES: PRACTICAL CONSIDERATIONS FOR OUTPATIENT USE 16 01-13-16 Novo Nordisk A/S (2014) Saxenda [package insert]. Bagsvaerd, Denmark.

17. GLP1 agonists: Albiglutide example  Must be reconstituted prior to use  “Rock” the pen back-and-forth 5 times  Let the pen sit for 15 minutes, cartridge pointed up  “Rock” the pen back-and-forth 5 more times…  Attach the pen needle & prime  Inject! NEW DIABETES THERAPIES: PRACTICAL CONSIDERATIONS FOR OUTPATIENT USE 17 01-13-16 http://www.tanzeum.com/how-to-use.html

18. GLP1 agonists: How do you choose?  Shorter-acting agents (exenatide, liraglutide): »Improved PPG coverage  Longer-acting agents (albiglutide, dulaglultide, exenatide LAR): »More effect on fasting BG (also improve PPG)  Beneficial effects & adverse effects relatively similar…  Ease of use (patient preference) and payer may dictate NEW DIABETES THERAPIES: PRACTICAL CONSIDERATIONS FOR OUTPATIENT USE 18 01-13-16 Diabetes Educ 2015;41(1 suppl):32S-46S.

19. SGLT2 Inhibitors ↓ reabsorption of filtered glucose ↓ renal threshold for glucose ↑ urinary glucose excretion NEW DIABETES THERAPIES: PRACTICAL CONSIDERATIONS FOR OUTPATIENT USE 19 01-13-16

20.  Advantages »Oral »Little to no hypoglycemia »Weight loss »BP lowering »CV benefit (?) »Role in T1D (?)  Disadvantages »Genitourinary infections »Orthostasis »Euglycemic DKA »Decreased bone mass »Brand-name only NEW DIABETES THERAPIES: PRACTICAL CONSIDERATIONS FOR OUTPATIENT USE 20 01-13-16 SGLT2 Inhibitors

21. SGLT2 Inhibitors – BP lowering  ↓ SBP : 1-7 mmHg, ↓ DBP: 0-3 mmHg  Effects are seen in ~ 1 week and typically stabilize  Potential mechanism: osmotic diuresis  Concerns »Elderly »Renal impairment »Low SBP NEW DIABETES THERAPIES: PRACTICAL CONSIDERATIONS FOR OUTPATIENT USE 21 01-13-16 J Am Soc Hypertens 2014;8(5):330-9.

22. SGLT2 Inhibitors – CV benefit?  Empagliflozin: EMPA-REG study  7020 patients with T2D & CVD  Primary outcome: CV-related death, non-fatal MI, non- fatal stroke »10.5% empagliflozin group (A1C = 7.8%) »12.1% placebo group (A1C = 8.2%) »HR=0.86; p=0.04 for superiority NEW DIABETES THERAPIES: PRACTICAL CONSIDERATIONS FOR OUTPATIENT USE 22 01-13-16 N Engl J Med 2015; Sept 17 [epub ahead of print].

23. SGLT2 Inhibitors – T1D treatment?  18-week study of canagliflozin 100mg, 300mg, or placebo added to insulin in T1D »Had to ↓ insulin dose 10-20% prior to initiation  Efficacy:  Significant ↓ A1C by ≥ 0.4% in canagliflozin groups  Safety:  ↑ incidence of ketone-related AE’s (5-9% vs. 0%)  ↑ incidence of DKA (4-6% vs. 0%) NEW DIABETES THERAPIES: PRACTICAL CONSIDERATIONS FOR OUTPATIENT USE 23 01-13-16 Diabetes Care 2015; Oct 20 [epub ahead of print].

24. SGLT2 Inhibitors – GU Infections  Females (10%) > males (4%)  Candidiasis (vulvovaginal, balanitis), mycotic infections, cystitis, urosepsis  Questions: »Dose-related? »Does T2D increase risk on its own? NEW DIABETES THERAPIES: PRACTICAL CONSIDERATIONS FOR OUTPATIENT USE 24 01-13-16 Diabetes Res Clin Pract 2014;103(3):373-81.

25. SGLT2 Inhibitors – Euglycemic DKA  Euglycemic DKA = DKA with uncharacteristically mild- moderate glucose ↑  20 clinical cases reported in US 03/2013-06/2014 »101 cases in Europe  Concern: »Could be in DKA and not know it based on BG values  delayed treatment NEW DIABETES THERAPIES: PRACTICAL CONSIDERATIONS FOR OUTPATIENT USE 25 01-13-16 Diabetes Care 2015;38(9):1638-42.

26. SGLT2 Inhibitors – ↓ bone mass  Specific to canagliflozin (Invokana ® )  New information added to safety information in September 2015  Warning: »Greater ↓ in bone mineral density at the hip »Can occur as early as 12 weeks into treatment NEW DIABETES THERAPIES: PRACTICAL CONSIDERATIONS FOR OUTPATIENT USE 26 01-13-16 Janssen Pharmaceuticals, Inc. (2015) Invokana [package insert]. Titusville, NJ.

27. SGLT2 Inhibitors – How do you choose?  Glycemic efficacy relatively similar (and relatively weak)  Weight loss comparable  Empagliflozin may have beneficial effects in those with established CVD & is ok to use in patients with hepatic impairment  Canagliflozin may increase risk of bone fracture & must be taken with food NEW DIABETES THERAPIES: PRACTICAL CONSIDERATIONS FOR OUTPATIENT USE 27 01-13-16

28. Inhaled insulin NEW DIABETES THERAPIES: PRACTICAL CONSIDERATIONS FOR OUTPATIENT USE 28 01-13-16  Advantages »Not injectable »Much smaller device than previous version  Disadvantages  Cannot use in asthma or COPD, smokers  Must be used with long- acting insulin in T1D  Only for adults (age ≥ 18)  Lung cancer (?)  Brand-name only

29. Inhaled Insulin – Afrezza ® NEW DIABETES THERAPIES: PRACTICAL CONSIDERATIONS FOR OUTPATIENT USE 29 01-13-16 Sanofi-Aventis U.S., LLC. (2015) Afrezza [package insert]. Bridgewater, NJ. https://www.afrezza.com/step-by-step-guide Short-acting insulin! https://www.youtube.com/watch?v=qHUZImm7-2I

30. Inhaled Insulin – Clinical Pearls  Short-acting (meal-time) ONLY!  3 doses available: »4 units »8 units »12 units  Afrezza ® COACH program: https://www.afrezza.com/support- and-savings https://www.afrezza.com/support- and-savings NEW DIABETES THERAPIES: PRACTICAL CONSIDERATIONS FOR OUTPATIENT USE 30 01-13-16

31. Concentrated insulin (U300)  Toujeo ® (insulin glargine U300) »Long-acting basal insulin »Approved in T1D and T2D  Switching to and from once-daily Lantus ® (insulin glargine U100) »Toujeo  Lantus: decrease dose by 80% »Lantus  Toujeo: use 1:1 conversion, but may need larger dose of Toujeo NEW DIABETES THERAPIES: PRACTICAL CONSIDERATIONS FOR OUTPATIENT USE 31 01-13-16 Sanofi-Aventis U.S., LLC. (2015) Toujeo [package insert]. Bridgewater, NJ.

32. Concentrated insulin (U300)  Supplied as a pen (not vial & syringe) NEW DIABETES THERAPIES: PRACTICAL CONSIDERATIONS FOR OUTPATIENT USE 32 01-13-16 Sanofi-Aventis U.S., LLC. (2015) Toujeo [package insert]. Bridgewater, NJ.

33. Concentrated insulin (U200)  Tresiba ® (insulin degludec U200) »Long-acting basal insulin, approved in T1D & T2D »Also available as U100 …  How supplied: »Insulin pen, 600 total units (3 mL) »Max 1-time injection of 160 units »Ok for up to 8 weeks at room temp when opened NEW DIABETES THERAPIES: PRACTICAL CONSIDERATIONS FOR OUTPATIENT USE 33 01-13-16 Novo Nordisk A/S (2015) Tresiba [package insert]. Bagsvaerd, Denmark.

34. Concentrated insulin (U200) NEW DIABETES THERAPIES: PRACTICAL CONSIDERATIONS FOR OUTPATIENT USE 34 01-13-16 Novo Nordisk A/S (2015) Tresiba [package insert]. Bagsvaerd, Denmark.

35. Patient Case #1 TR is a 52 y/o female with HTN and T2D. She currently takes lisinopril/HCTZ 20/12.5 and metformin ER 2000mg/day. Recent vitals: BP 116/72, HR 78; recent labs: A1C 8.6%, SCr 0.8 mg/dl, K + 4.3 mmol/L The patient saw a commercial on TV for Invokana ® and wants to know if this would be a good option for her. How would you respond? NEW DIABETES THERAPIES: PRACTICAL CONSIDERATIONS FOR OUTPATIENT USE 35 01-13-16

36. Patient Case #2 LK is a 60 y/o male with T2D. He is currently on metformin 2000mg/day, glipizide 5mg BID, and insulin glargine 60 units SC QPM. His A1C this month was 7.1%. LK’s insurance will now pay for Toujeo ® and he’s interested in switching products. How would you dose- convert his glargine to Toujeo ® ? NEW DIABETES THERAPIES: PRACTICAL CONSIDERATIONS FOR OUTPATIENT USE 36 01-13-16

37. Questions?