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Insulin Therapy of Type 2 Diabetes Jack L. Leahy University of Vermont College of Medicine Division of Endocrinology, Diabetes and Metabolism Burlington,

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Presentation on theme: "Insulin Therapy of Type 2 Diabetes Jack L. Leahy University of Vermont College of Medicine Division of Endocrinology, Diabetes and Metabolism Burlington,"— Presentation transcript:

1 Insulin Therapy of Type 2 Diabetes Jack L. Leahy University of Vermont College of Medicine Division of Endocrinology, Diabetes and Metabolism Burlington, Vermont

2 Global Projections for the Diabetes Epidemic: M 36.2 M 57.0% 14.2 M 26.2 M 85% 48.4 M 58.6 M 21% 43.0 M 75.8 M 79% 7.1M 15.0 M 111% 39.3 M 81.6 M 108% M = million, AFR = Africa, NA = North America, EUR = Europe, SACA = South and Central America, EMME = Eastern Mediterranean and Middle East, SEA = South-East Asia, WP = Western Pacific Diabetes Atlas Committee. Diabetes Atlas 2 nd Edition: IDF World 2003 = 194 M 2025 = 333 M 72% AFR NA SACA EUR SEA WP 19.2 M 39.4 M 105% EMME

3 Standards of Care - American Diabetes Association Glycemia: HbA 1c <7.0%, FPG mg/dL, PP <180 mg/dL. Blood Pressure: <130/80. Lipids: LDL <100 mg/dL; TG <150 mg/dL. Yearly: –Dilated eye exam; urinary protein; foot exam; flu shot. Other: –Aspirin usage; pneumococcal vaccine. AACE goals - HbA 1c 6.5%, FPG 110 mg/dL, PP 140 mg/dL NCEP - LDL 70 mg/dL ADA. Diabetes Care 2005;29:S4-S42

4 Nathan DM et al. Diabetes Care 2009;32: Consensus Algorithm Update 2009 Check A1C every 3 months until <7%. Change treatment if A1C is 7% Step 3 Tier 1: Well-validated core therapies At diagnosis: Lifestyle + Metformin plus Basal Insulin Lifestyle + Metformin plus Sulfonylurea a Lifestyle + Metformin plus Intensive Insulin Step 1 Step 2 Lifestyle + Metformin plus Pioglitazone No hypoglyceamia Oedema / CHF Bone Loss Lifestyle + Metformin plus GLP-1 agonist No hypoglyceamia Weight loss Nausea / vomiting Tier 2: Less well-validated therapies Lifestyle + Metformin plus Pioglitazone plus Sulfonylurea Lifestyle + Metformin plus Basal Insulin

5 Brown JB et al. Diabetes Care 2004;27: % of Subjects Percentage of subjects advancing when A1C < 8% Clinical Inertia: Failure to Advance Therapy When Required Diet 66.6% SulfonylureaMetformin 35.3% 44.6% Combination 18.6% At insulin initiation, the average patient had: 5 years with A1C > 8% 10 years with A1C > 7%

6 Learning Objectives To discuss the nuts and bolts of successful insulin therapy strategies in type 2 diabetes: –Highlight and discuss timely and controversial topics. Use clinical trial data to: –Compare available long-acting (basal) insulins. –Identify expected dosages of basal insulins. –Discuss the importance of patient-driven algorithms for adjustment of basal insulin dosages. Introduce the concept of incomplete basal-bolus insulin therapy - so called Basal Plus.

7 B = breakfast; L = lunch; D = dinner. Polonsky KS et al. N Engl J Med 1988;318: GlucoseInsulin 6:0010:0018:0014:002:0022:006:00 Time 6:0010:0018:0014:002:0022:006:00 Time BLDBLD Nondiabetic Type 2 diabetes mg/dL U/mL Basal insulin Basal Insulin Therapy

8 Lepore M et al. Diabetes 2000;49: Time (hours) Basal Insulin Profiles Glucose Infusion Rates N=20 T1DM Mean SEM 15% with some peak

9 NPHGlargine

10 Insulin Detemir: Structure Lys Thr Tyr Thr Phe Gly Arg Glu Gly Val Leu Tyr Leu Ala Glu Val Leu His Ser Gly Leu His Gln Val Phe B1 B3 A21 B29 Pro Cys Tyr Asn Glu Cys Gln Leu Gln Tyr Leu Ser Cys Thr Ser lle Gly lle Glu Gln Cys Asp A1 C14 fatty acid chain (Myristic acid)

11 Plank J et al. Diabetes Care 2005;28: DETEMIR DOSE (U/kg) DURATION OF ACTION (h) Time since insulin injection (h) Glucose infusion rate (mg/kg/min) Detemir 0.1 U/kg Detemir 0.2 U/kg Detemir 0.4 U/kg Detemir 0.8 U/kg Detemir 1.6 U/kg Dose Dependency of Action Profiles of Insulin Detemir

12 Insulin Glargine Trials Showing Effective Reduction in HbA 1c HbA 1c (%) APOLLOLAPTOPTriple Therapy LANMET Treat-To- Target INITIATE Baseline Study endpoint

13 Mullins P et al. Clin Ther 2007;29: Less Hypoglycemia with Insulin Glargine vs NPH HbA 1c Hypoglycemia events per 100 patient-years NPHInsulin glargine HbA 1c Hypoglycemia events per 100 patient-years T1DM T2DM p=0.004 between treatments p=0.021 between treatments

14 Key Questions Is there a difference between Glargine and Detemir?

15 Rosenstock J et al. Diabetologia 2008;51: Head to Head Comparison of Glargine Versus Detemir in Type 2 Diabetes 52-weeks. Once daily Glargine or Detemir - could be titrated to BID Detemir (55%). Baseline A1c 8.6% n = 582 Hemoglobin A1c (%) P = NS Glargine Detemir

16 Summary of Results 55% of patients on insulin Detemir were titrated to twice daily injections All patients on insulin Glargine received only 1 injection per day Average daily doses: –Detemir once daily 0.78 U/kg. –Detemir twice daily 1.0 U/kg. –Glargine once daily 0.44 U/kg 3.9 kg weight gain with Glargine versus 3.0 kg with Detemir - no difference between Glargine and twice daily Detemir. Rosenstock J et al. Diabetologia 2008;51:

17 Key Questions Is there a difference between Glargine and Detemir? When to start basal insulin versus adding another agent?

18 Nathan DM et al. Diabetes Care 2009;32: Consensus Algorithm Update 2009 Check A1C every 3 months until <7%. Change treatment if A1C is 7% Step 3 Tier 1: Well-validated core therapies At diagnosis: Lifestyle + Metformin plus Basal Insulin Lifestyle + Metformin plus Sulfonylurea a Lifestyle + Metformin plus Intensive Insulin Step 1 Step 2 Lifestyle + Metformin plus Pioglitazone No hypoglyceamia Oedema / CHF Bone Loss Lifestyle + Metformin plus GLP-1 agonist No hypoglyceamia Weight loss Nausea / vomiting Tier 2: Less well-validated therapies Lifestyle + Metformin plus Pioglitazone plus Sulfonylurea Lifestyle + Metformin plus Basal Insulin

19 Heine RJ et al. Ann Intern Med 2005;143: Prebreakfast Both medications lowered A1C from 8.2% to 7.1% from baseline Weight change: exenatide –2.3 kg, glargine +1.8 kg Nausea: exenatide 57.1%, glargine 8.6% Exenatide vs Once-Daily Insulin Glargine: Self- Monitoring Blood Glucose Profiles (n=549)

20 Key Questions Is there a difference between Glargine and Detemir? When to start basal insulin versus adding another agent? Do what with oral agents?

21 Combined Effects of Metformin with Insulin Therapy in Type 2 Diabetes Sasali A and Leahy JL. Curr Diab Rep 2003;3:

22 Key Questions Is there a difference between Glargine and Detemir? When to start basal insulin versus adding another agent? Do what with oral agents? –Continue OHA - add on therapy, not substitution therapy.

23 Key Questions Is there a difference between Glargine and Detemir? When to start basal insulin versus adding another agent? Do what with oral agents? –Continue OHA - add on therapy, not substitution therapy. What are expected doses of basal insulin (Glargine or NPH)?

24 1. Riddle M, et al. Diabetes Care 2003;26: Gerstein HC, et al. Diabet Med 2006;23: Yki-Järvinen H, et al. Diabetologia 2006;49: Yki-Järvinen H, et al. Diabetes Care 2007;30: Treat-to-Target 1 INSIGHT 2 LANMET 3 INITIATE 4 Target FBG<100 mg/dL100 mg/dL<100 mg/dL Algorithm+ 2 to 8 U every week + 1 U every day+2 U or + 4 U every 3 days +2 U every 3 days Final dose Glargine 0.48 U/kg 0.42 U/kg (NPH) 0.41 U/kg 0.69 U/kg 0.66 U/kg (NPH) 0.60 to 0.64 U/kg Published Insulin Glargine Doses and Titration Algorithms

25 Key Questions Is there a difference between Glargine and Detemir? When to start basal insulin versus adding another agent? Do what with oral agents? –Continue OHA - add on therapy, not substitution therapy. What are expected doses of basal insulin (Glargine or NPH)? –Average dosage of Glargine or once daily NPH U/kg. –No maximal dose - consider mealtime when reach 0.7 U/kg.

26 Key Questions Is there a difference between Glargine and Detemir? When to start basal insulin versus adding another agent? Do what with oral agents? –Continue OHA - add on therapy, not substitution therapy. What are expected doses of basal insulin (Glargine or NPH)? –Average dosage of Glargine or once daily NPH U/kg. –No maximal dose - consider mealtime when reach 0.7 U/kg. How to start and titrate?

27 Recommendations for Starting and Adjusting Basal Insulin Bedtime or morning long-acting insulin OR Bedtime intermediate-acting insulin Daily dose: 10 units or 0.2 U/kg Increase dose by 2 units every 3 days until FBG is 70–130 mg/dL. If FBG is >180 mg/L, increase dose by 4 units every 3 days. Check FBG daily Continue regimen and check HbA 1c every 3 months In the event of hypoglycemia or FBG level <70 mg/dL. Reduce bedtime insulin dose by 4 units, or by 10% if >60 units. Nathan DM et al. Diabetes Care 2009;32:

28 1. Riddle M, et al. Diabetes Care 2003;26: Gerstein HC, et al. Diabet Med 2006;23: Yki-Järvinen H, et al. Diabetologia 2006;49: Yki-Järvinen H, et al. Diabetes Care 2007;30: Treat-to-Target 1 INSIGHT 2 LANMET 3 INITIATE 4 Target FBG<100 mg/dL100 mg/dL<100 mg/dL Algorithm+ 2 to 8 U every week + 1 U every day+2 U or + 4 U every 3 days +2 U every 3 days Final dose Glargine 0.48 U/kg 0.42 U/kg (NPH) 0.41 U/kg 0.69 U/kg 0.66 U/kg (NPH) 0.60 to 0.64 U/kg Published Insulin Glargine Doses and Titration Algorithms

29 Optimizing Dose of Glargine Allows Achievement of FPG Target (LANMET study) Study in 110 insulin-naïve subjects with type 2 diabetes receiving insulin glargine plus metformin Adapted from Yki-Järvinen H, et al. Diabetologia 2006;49:442–51 Time (weeks) FPG / weekly means (mg/dL) Insulin dose (IU/day)

30 Key Questions Is there a difference between Glargine and Detemir? When to start basal insulin versus adding another agent? Do what with oral agents? –Continue OHA - add on therapy, not substitution therapy. What are expected doses of basal insulin (Glargine or NPH)? –Average dosage of Glargine or once daily NPH U/kg. –No maximal dose - consider mealtime when reach 0.7 U/kg. How to start and titrate? Why not start with premixed insulins?

31 Split-Mixed/Pre-Mixed Insulin Therapy 4:0016:0020:0024:004:00 BreakfastLunchDinner 12:008:00 Time Plasma Insulin Regular NPH

32 LAPTOP: Insulin Glargine Versus 70/30 Premixed Insulin in OHA Failures Janka H et al. Diabetes Care 2005;28: *Confirmed symptomatic hypoglycaemia (blood glucose <60 mg/dl [<3.3 mmol/l]) N=371 insulin-naïve patients Insulin glargine + OADs vs twice-daily human NPH insulin (70/30) Follow-up: 24 weeks Hypoglycaemia* (events/patient year) p= HbA 1c (%) 7.5% 7.2% 1.3% 1.7% p= Twice-daily premixed insulin Insulin glargine + OADs

33 Analog Pre-Mixed Insulin Therapy 4:0016:0020:0024:004:00 BreakfastLunchDinner 12:008:00 Time Plasma Insulin

34 Raskin P et al. Diabetes Care 2005;28: Change in A1C From Baseline to Study End 9.8% 6.9% 7.4% Insulin Glargine + OADsPreMix Baseline Endpoint P<0.01 A1C (%) - 2.4% - 2.8% %

35 Hypoglycemia Documented Hypoglycemic Episodes (<56 mg/dL) Episodes per patient year P<0.05 Insulin Glargine PreMix Raskin P et al. Diabetes Care 2005;28: Total units = 51.3 ± 26.7 with glargine plus OADs vs 78.5 ± 39.5 with premixed insulin

36 Key Questions Is there a difference between Glargine and Detemir? When to start basal insulin versus adding another agent? Do what with oral agents? –Continue OHA - add on therapy, not substitution therapy. What are expected doses of basal insulin (Glargine or NPH)? –Average dosage of Glargine or once daily NPH U/kg. –No maximal dose - consider mealtime when reach 0.7 U/kg. How to start and titrate? Why not start with premixed insulins? What if basal insulin is not enough?

37 Raskin P et al. Diabetes Care 2005;28: * Plasma Glucose (mg/dL) Week 28 Baseline Glargine Premix Time of Day BBB90BLL90BDD90Bed3AM * * * * Blood Glucose Profiles

38 Lifestyle changes + Metformin Additional Oral agents Basal Add basal insulin and titrate Basal Plus Add prandial insulin at main meal Basal Bolus Insulin Initiation Intensification Further intensification Progressive deterioration of -cell function Stepwise Treatment of Type 2 Diabetes

39 Eleonor Study Aim: To determine if a Telecare program facilitates optimization of basal insulin Glargine followed by addition of one mealtime insulin injection of insulin Glulisine. Protocol: –24-week, open label, multicenter, randomized study in Italy. –200 patients with type 2 diabetes. –Poor glycemic control (A1C 8.9±0.9%) on one or more oral hypoglycemic agents. –Adjust Glargine to FBG <126 mg/dL followed by adding Glulisine to meal with highest PPG value. Del Prato S, et al. Diabetologia 2008;51 Suppl. 1:S452

40 HbA 1c (%) Group 1 Group ADA/EASD target Weeks Glargine + OHAs Glargine + 1 Glulisine + OHAs pts achieving HbA 1c <7.0 (%) 51% 55% 0 p=NS Group 1 Group 2 Eleonor Study Results No clinically significant weight gain. Low rate of severe hypoglycemia Del Prato S, et al. Diabetologia 2008;51 Suppl. 1:S452

41 Basal Plus Mealtime Insulin Use rapid-acting analogs, not regular insulin –Easier timing, less postprandial hypoglycemia –Can be taken up to 20 minutes after start eating Start with 1 shot, at largest meal : –4 units, and titrate, OR –By weight U/kg Titrate to: –<160 mg/dL 2 hours post-prandial OR –<130 mg/dL next meal or bedtime Continue oral secretagogues until full basal-bolus regimen

42 Hours RHI = regular human insulin. Adapted with permission from Howey DC et al. Diabetes 1994;43: Insulin Activity RHI Timing of food absorbed Analog insulin Lispro, Aspart, Glulisine vs Regular Insulin

43 Basal Plus Mealtime Insulin Use rapid-acting analogs, not regular insulin –Easier timing, less postprandial hypoglycemia –Can be taken up to 20 minutes after start eating Start with 1 shot, at largest meal : –4 units, and titrate. –By weight U/kg Titrate to: –<160 mg/dL 2 hours post-prandial OR –<130 mg/dL next meal or bedtime Continue oral secretagogues until full basal-bolus regimen

44 We dont start insulin early enough, or use it aggressively enough Robert Turner MA, MD, FRCP Professor of Medicine University of Oxford


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