1. 1 Successful Transition to Insulin Therapy in T2DM Merri Pendergrass, M.D., Ph.D. Endocrinology, University of Arizona All Faculty, CME Planning Committee Members, and the CME Office Reviewer have disclosed that they have no financial relationships with commercial interests that would constitute a conflict of interest concerning this CME activity.

2. Learning Objectives Participants should be better able to Select a strategy for insulin initiation Intensify an insulin regimen Understand available modalities (e.g. vials, pens) for insulin administration 2

3. 54 year old patient with T2DM a.Pioglitazone (Actos ® ) b.Exenatide (Byetta ® ) c.Sitagliptin (Januvia ® ) d.Canaglifozin (Invokana ® ) e.Insulin 3 On metformin 1000 bid, glipizide 10 qd A1C 9.1 What would you add now?

4. 54 year old patient with T2DM a.Pioglitazone (Actos ® ) b.Exenatide (Byetta ® ) c.Sitagliptin (Januvia ® ) d.Canaglifozin (Invokana ® ) e.Insulin 4 On metformin 1000 bid, glipizide 10 qd A1C 9.1 What would you add now?

5. 5 Approximate A1C Lowering Metformin ~ A1C Reduction (%) 1.0-2.0 Byetta, Bydureon, Victoza Januvia,Onglyza,Tradjenta, Nesina Sulfonylurea Avandia, Actos 0.5-1.5 0.5-0.8 Invokana 0.8-1.0

6. 6 Insulin for Type 2 Diabetes Safe and effective option Not a last resort Can decrease any level of A1C to goal Indicated if not controlled on non-insulins

7. 7 Improving Insulin Acceptance Don’t threaten as a punishment Address patient concerns/pre- conceptions, e.g. –Not a personal failure –Complications are not inevitable –Can potentially stop insulin later Consider insulin pens

8. 8 Profiles of Available Insulins Insulin Effect NPH Glargine (Lantus) Regular 06121824 Time (hours) Detemir (Levemir) Lispro (Humalog) Aspart (Novolog) Glulisine (Apidra) Basal Bolus Nutritional Correction

9. Which regimen will you start? a.NPH at bedtime b.Lantus ® at bedtime c.NPH/regular bid ac d.NPH at bedtime + regular tid ac 9

10. Which regimen will you start? a.NPH at bedtime b.Lantus ® at bedtime c.NPH/regular bid ac d.NPH at bedtime + regular tid ac 10

11. 11 Same Effects in T2DM with Insulin Given QD, BID, or QID Control AM NPH QID N/R HS NPH BID NPH Yki-Jarvinen H, et al. N Engl J Med. 1992;327:1426-1433. * ** * Least weight gain

12. 12 Evidence Supports Initiating Insulin… TypeRegimen NPH QD, BID Glargine Detemir Lispro, aspart, glulisine TID Pre-mix QD, BID, TID Other combinations QD, BID, TID, QID

13. Sequential Insulin Strategies in T2DM diabetes. Inzucchi S E et al. Dia Care 2012;35:1364-1379 Copyright © 2011 American Diabetes Association, Inc.

14. Initiating Basal Insulin ~50% patients achieve A1C< 7% with basal insulin given at bedtime For T2DM, effects are similar for qHS –NPH –Glargine (Lantus ® ) –Detemir (Levemir ® ) 14 $ $$

15. Insulin Cost* Item Cost ($) / Item $/1000 units (~33 units/day) NPH10 ml vial24.88 NPHBox of 5 (3 ml pens)294.28196.18 Lantus10 ml vial226.68 LantusBox of 5 (3 ml pens)351.62234.41 U50020 ml vial1130.00113.00 15 *Walmart 2/8/14

16. 16 The Treat-to-Target Trial NPH vs. Glargine (Lantus ® ) Mean FBG on Preceding 2 Days Increase in Insulin Dosage > 1808 140-1806 120-1404 100-1202 Start With 10 IU Insulin qHS & Adjust Weekly Riddle et al, Diabetes Care 26, 3080-3086, 2003

17. 17 qHS NPH and qHS Lantus ® have Similar Effects on A1C, FPG (T2DM) Riddle et al, Diabetes Care 26, 3080-3086, 2003 041216 20 248 150 200 041216 20 248 7 8 6 9 A1C (%) FPG (mg/dl) NPH Glargine (Lantus)

18. Slightly Less Hypoglycemia: with Glargine (Lantus) vs. NPH Riddle et al, Diabetes Care 26, 3080-3086, 2003 * * *

19. 19 Key Factor Contributing to the Success of the Regimen Not what type of insulin is used Not how many doses are used Not what is the initial starting dose Success depends on –Adherence –How regularly and rapidly insulin is adjusted to achieve targets!

20. 20 Start NPH 20 units at bedtime and increase by 10 units every week if average fasting glucose is above 100 and no hypoglycemia (BG <72)

21. 21 Start NPH 10 units at bedtime and increase by 2 units every night if fasting glucose is above 100 and no hypoglycemia (BG < 72)

22. 22 Insulin Titration: MD Vs. Patients Titrated by MD (N=2315) Titrated by Patient (N=2273) ≥ 100 to < 1200-2* ≥ 120 to < 14022 ≥ 140 to < 18042 ≥ 1806-82 Start with 10 units glargine qHS *Only increase if no values < 72 Diabetes Care 28:1282-1288, 2005

23. 23 Patient and MD Insulin Titration Yield Similar Results Diabetes Care 28:1282-1288, 2005

24. 24 Question: Patient on metformin, NPH 60 hs A1C 8.0 SMBG –Ac breakfast80-100 –Ac lunch80-100 –Ac dinner80-120 –HS 200-250 What would you do? a.Change from NPH to glargine (Lantus) b.Increase NPH to 70 c.Add NPH in AM d.Add lispro (Humalog) ac dinner

25. 25 Question: Patient on metformin, NPH 60 hs A1C 8.0 SMBG –Ac breakfast80-100 –Ac lunch80-100 –Ac dinner80-120 –HS 200-250 What would you do? a.Change from NPH to glargine (Lantus) b.Increase NPH to 70 c.Add NPH in AM d.Add lispro (Humalog) ac dinner

26. 26 Patient now on metformin, insulin Meds: metformin 1 g bid, NPH 60 hs A1C 8.0 SMBG –Before breakfast80-100 –Before lunch80-100 –Before dinner80-120 –Before bedtime200-250 Best to add rapid-acting insulin ac dinner Would NOT increase NPH HS (risk for AM hypoglycemia) Would NOT Add NPH AM (risk for daytime hypoglycemia) Would NOT change NPH  glargine: (glargine = NPH for A1C changes)

27. 27 8 12 6 10 Matching Insulin to Basal and Nutritional Needs

28. 50 year old patient with T2DM, BMI 40.1, A1C 12, FPG 250, Metformin 1 g bid, 70/30 100 bid What is your next step? a)Increase to 70/30, 150 bid b)Increase to 70/30, 100 tid c)Split each dose into 2 injections d)Stop 70/30, start U-500 regular insulin

29. 50 year old patient with T2DM, BMI 40.1, A1C 12, FPG 250, Metformin 1 g bid, 70/30 100 bid What is your next step? a)Increase to 70/30, 150 bid b)Increase to 70/30, 100 tid c)Split each dose into 2 injections d)Stop 70/30, start U-500 regular insulin

30. Strategies to Get “More Insulin Into” Insulin Resistant Patients Add additional injections, e.g. 70/30 three time a day Split large doses into 2 injections (smaller depot = better absorption) Use more concentrated insulins, e.g. U-500 30

31. 31 U-500 is Five Times as Concentrated as U-100 Insulin U-100 = 100 units/ml U-500 = 500 units/ml 1 ml U-100 = 100 units = 0.2 ml U-500 U-500 should be considered when total daily dose (TDD) insulin is > 200 units Initial dosing ~ BID ENDOCRINE PRACTICE Vol 15 No. 1 January/February 2009

32. 32 U500 Lets Patient Inject Less u 1 00 u 5 00 100 units

33. Convert Insulin Units  U-500 cc: Divide Units by 500 125 units insulin = ?? cc u500 33 150 units insulin = 1 cc 125 units insulin 500 units insulin.25 cc 150 / 500 =.30 cc 175 units insulin = 175 / 500 =.35 cc

34. Convert U-500 cc  Units Insulin: Multiply cc by 500.30 cc u500 = ?? units insulin 34.35 cc u500 = 500 units insulin.30 cc u500 1 cc u500 150 units insulin.35 X 500 = 175 units.15 cc u500 =.15 X 500 = 75 units

35. Include Two Identifiers of Correct Dose on Prescriptions 35 U500 insulin: Sig: Pull to the 25 unit mark (125 units) before breakfast and pull to the 20 unit mark (100 units) before dinner

36. Better Control with u500 N = 53, 6-52 months f/uBaseline (u-100) End (u-500) A1C (%)9.18.1* Insulin dose (units)391415* Weight (kg)134136 Cholesterol (mg/dL)176156* TG (mg/dL)349252* Severe hypoglycemia (total events in first 12 months f/u) 33 36 Endocr Pract. 2011 Jul 8:1-15. * P < 0.05

37. Additional Insulin Concentrations May Become Available Soon Insulin degludec (Tresiba TM ) –Approved in the EU and Japan –Under regulatory review in the US –Developed both as a 100-unit/ml formulation and a 200-unit/ml formulation 37

38. 70/30 Effective When Given Once, Twice, or Thrice a Day 38 Diabetes, Obesity and Metabolism, 8, 2006, 58–66

39. Splitting Large Volume into Two Injection Sites May Improve Effect 39 100 units (1.0 ml) 50 units (o.5 ml) 50 units (0.5 ml) Depots more than ~.6 ml not well absorbed Better Absorption

40. High Dose Insulin More Effective Injected in Two vs. One Site 40 Saryusz-Wolska M. Abstract #109. EASD; Sept. 12-16, 2011; Lisbon.

41. Ordering Insulin and Supplies Examples for 90-Day Supply Vial/syringe = 2 scripts 1.NPH 50 units SC qHS, Disp: 5 vials 2.Syringes, 1 ML 6 MM (15/64”) X 31 G, 100- count box 41 90 daysX 50 units/day= 4.5 vialsX 1 vial/1000 units Shorter, thinner needles hurt less!

42. Ordering Insulin and Supplies Examples for 90-Day Supply Pen/needles = 2 scripts 1.NPH 50 units SC qHS, Disp: 3 boxes (5 X 3 mL) 2.Pen needles, 4mm x 32G, 100-count box 42 300 units

43. Recommendations - 1 Start with a single injection of basal insulin at bedtime –NPH has lowest cost and similar clinical effects as Lantus ® and Levemir ® –Insulin pens easier but more expensive Titrate insulin often to normalize FBG 43

44. Recommendations - 2 If FBG at goal (~100) and A1C above goal, add an injection of a short-acting insulin before the largest meal –Regular is cheapest but adherence may be better with Humalog ®, Novolog ® or Apidra ® Consider adding additional pre-meal injections, based on BG monitoring 44

45. Recommendations - 3 Continue metformin Stop sulfonylureas if insulin dose is more than ~20-40 units Consider potential risks and benefits of continuing other non-insulin agents, e.g. –Multiple agents can get expensive –Not much incremental A1C benefit –Invokana ®, Byetta ®, Victoza ® associated with weight loss 45

46. Recommendations - 4 If A1C is above goal with > 200 units of insulin per day, consider switching to U-500 bid 46

47. 47 Comments or Questions? mpendergrass@deptofmed.arizona.edu