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Limitations and opportunities of insulin therapy

Limitations and opportunities of insulin therapy. Luigi Meneghini June 8 th , 2012. Outline. Insulin need versus implementation Options for initiating insulin in T2DM Limitations & opportunities for more stable basal insulins Degludec pharmacodynamics and clinical studies

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Limitations and opportunities of insulin therapy

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  1. Limitations and opportunities of insulin therapy Luigi Meneghini June 8th, 2012

  2. Outline • Insulin need versus implementation • Options for initiating insulin in T2DM • Limitations & opportunities for more stable basal insulins • Degludec pharmacodynamics and clinical studies • Adding an incretin to basal insulin replacement

  3. Metabolic Status at Diagnosis of Type 2 Diabetes 100 Beta-cell function Insulin resistance 40% 50% 75 Beta Cell Function (%) 50 IGT 25 PostprandialHyperglycemia Diabetes 0 -12 -10 -6 -2 0 2 6 10 14 Years From Diagnosis Adapted from Lebovitz HE. Diabetes Reviews. 1999;7(3):139–153.

  4. Glycemic Control with Monotherapy in the UKPDS Over 9 Years 24U Short-acting insulin added in 44% by 9 years 53U Turner RC et al. JAMA 1999; 281: 2005-2012

  5. Physicians delay intensifying therapy for months, especially initiating insulin Insulin 9.5% N=2319 N=3394 N=513 N=982 Brown et al. Diabetes Care 2004; 27: 1535

  6. Options for Initiating & Intensifying Insulin Therapy in Type 2 Diabetes

  7. Insulin Initiation & Intensification Outcomes in T2DM at Baseline, 1 & 3 Years -1.3%* -1.4%* -1.2%* Less hypoglycemia with basal initiation (events/pt/yr) 5.5 * 3.0 235 222 201 239 222 188 234 224 189 1.7 * * * P<0.05 Holman, et al. NEJM 2009;361:1736-47. Holman, et al. NEJM 2007;357: 1716-30

  8. Hypoglycaemia limits further reduction of FPG with basal insulin 12 10 8 Mean HbA1c [%] 6 4 3 4 5 6 7 8 9 10 11 40 n = 13,072 30 Frequency of Hypoglycaemic Episodes [%] 20 10 0 3 4 5 6 7 8 9 10 11 Mean annual fasting blood glucose [mmol/l] Yki-Jarvinen et al. Ann Int Med 1999

  9. How do Pharmacodynamics of Basal Insulin Preparations Affect Outcomes

  10. Plasma glucose Pharmacodynamics of NPH versus Glargine Insulin Glucose infusion rate Lepore, et al. Diabetes 1999; 48 (suppl 1): A97 Bolli et al. The Lancet • Vol 356 • August 5 2000

  11. Biologic activity over 24-hours more consistent for basal insulin analogs Insulin detemir GIR = Glucose Infusion Rate Heise et al. Diabetes 2004; 53 (6): 1614-1620

  12. Less hypoglycemiawith basal analogues vs. NPH * * * * *P<0.05 Riddle et al. Diabetes Care 2003; 26: 3080–3086. Philis-Tsimikas et al. Clin Ther 2006; 28 (10).

  13. Modeled risk of hypoglycemia based on achieved A1C levels Little S, et al. Diab Tech Ther 2011; 13 (S1)

  14. Improving on current basal insulin analogs • Extend duration of action • Flat pharmacodynamic profile • Reduced day-to-day variability

  15. Molecular size determines rate of subcutaneous absorption Subcutaneous tissue Molecular size 6 kDa 36 kDa 72 kDa >5000 kDa Insulin association state Insulin High molecular weight forms Zn2+ Zn2+ Zn2+ Absorption Absorption rate Capillary membrane Rapid absorption Slow absorption Brange et al. DiabetesCare 1990;13:923–54

  16. Insulin degludec from solution to subcutaneous depot PhenolZn2+ Insulin degludec injected As phenol from the vehicle diffuses degludec hexamers link up via single side-chain contacts Long multi-hexamers assemble

  17. Insulin degludec multi-hexamers visible with transmission electron microscopy SOLUTION SC DEPOT Main picture shows elongated insulin degludec structures in absence of phenol; inset shows absence of elongated insulin degludec structures in presence of phenol Kurtzhals et al. Diabetes 2011;60(Suppl . 1):LB12 (Abstract 42-LB) (NN1250-1993 + MOA)

  18. Insulin degludec: slow release following injection Zn2+ Subcutaneous depot Insulin degludec multi-hexamers Zinc diffuses slowly causing individual hexamers to disassemble, releasing monomers Monomers are absorbed from the depot into the circulation

  19. Insulin degludec PD profile at steady state in T1D 6 5 GIR (mg/kg/min) Mean profile, n=66 IDeg = 0.4 U/kg 4 3 2 1 0 0 2 4 6 8 10 12 14 16 18 20 22 24 Time (hours) PD, pharmacodynamic Heise et al. Diabetologia 2011;54(Suppl. 1):S425

  20. Terminal half-life & coefficient of variation at steady state

  21. Basal insulin initiation in T2DM IDeg OD + metformin ± DPP-4 (n=773) Insulin-naïve patients with type 2 diabetes (n=1030) IGlar OD + metformin ± DPP-4 (n=257) • Inclusion criteria • Type 2 diabetes ≥6 months • Insulin naïve treated with metformin ± SU, DPP-4 or acarbose for ≥3 months • HbA1c 7.0–10.0% • BMI ≤40 kg/m2 • Age ≥18 years 52 weeks 0 Randomised 3:1 (IDeg OD:IGlar OD) Open label DPP-4, dipeptidyl peptidase-4 inhibitorSU, sulphonylurea OD, once dailyData on file: NN1250-3579; Accepted for presentation at ADA 2012

  22. Weekly titration algorithm for insulin degludec and insulin glargine in T2DM a Mean of 3 consecutive days’ measurements for up titration. b Unless there is obvious explanation for the low value, such as a missed meal

  23. Insulin degludec steady state is reached within 2–3 days of once-daily dosing 120 110 100 90 80 70 Serum IDeg concentrationProportion of Day 10 level (%) 60 50 40 30 20 10 0 0 1 2 3 4 5 6 7 8 9 10 Days since first dose Relative serum IDeg trough concentrations during initiation of once-daily (0.4 U/kg) dosing in patients with T1DM Values are estimated ratios and 95% CI relative to day 10 Heise T et al. IDF 2011 21st World Congress Abstract Book. IDF: Dubai, 2011; Poster 1453

  24. Pharmacokinetics of insulin steady state Receptor activation & insulin clearance Absorption from the SC depot

  25. No difference in HbA1c decrease over time between degludec & glargine Degludec (n=773) Glargine (n=257) 0.0 Time (weeks) Mean±SEM; FAS; LOCF Comparisons: Estimates adjusted for multiple covariatesData on file: NN1250-3579; Accepted for presentation at ADA 2012

  26. No difference in overall confirmed hypoglycaemia Degludec (n=773) Glargine (n=257) HYPOGLYCEMIA BG < 56 mg/dl or severe 18% (ns) Time (weeks) SAS Comparisons: Estimates adjusted for multiple covariatesData on file: NN1250-3579; Accepted for presentation at ADA 2012

  27. Lower nocturnal confirmed hypoglycaemia with insulin degludec Degludec (n=773) Glargine (n=257) 36% p<0.05 Time (weeks) SAS Comparisons: Estimates adjusted for multiple covariatesData on file: NN1250-3579; Accepted for presentation at ADA 2012

  28. Forcedflexibleinsulindegludecstudy design Degludec OD Flexible ±OADs (n=229) (metformin/SU/pioglitazone) Patients with type 2 diabetes (n=687) Degludec OD Fixed ±OADs (n=228) (metformin/SU/pioglitazone) Glargine OD ±OADs (n=230) (metformin/SU/pioglitazone) • Inclusion criteria • Type 2 diabetes ≥6 months • Previously treated with OADs and/or basal insulin • HbA1c:OADs only 7–11%Basal insulin ± OADs 7–10% • BMI ≤40 kg/m2 • Age ≥18 years 26 weeks 0 Open label Birkeland et al. IDF 2011:P-1443;Bain et al. IDF 2011:O-0508; Birkeland et al. Diabetologia 2011;54(suppl. 1):S423; Atkin et al. Diabetologia 2011;54(suppl. 1):S53; Meneghini et al. Diabetes 2011;60(suppl. 1A):LB10 (NN1250-3668)

  29. Timing of flexibleinsulindegludecadministration Mon Tue Wed Thu Fri Sat Sun 8h 8h morning morning morning 8-12 AND 36-40 hours between insulin administration 40h 40h 40h 24h evening evening evening evening

  30. No difference in A1C between flexible degludec and fixed dosing Degludec Flexible OD Degludec OD Glargine OD 0.0 Time (weeks) Birkeland et al. IDF 2011:P-1443;Bain et al. IDF 2011:O-0508; Birkeland et al. Diabetologia 2011;54(suppl. 1):S423; Atkin et al. Diabetologia 2011;54(suppl. 1):S53; Meneghini et al. Diabetes 2011;60(suppl. 1A):LB10 (NN1250-3668)

  31. No difference in hypoglycemia between flexible degludec and fixed dosing Degludec Flexible OD Degludec OD Glargine OD Overall hypoglycemia Nocturnal hypoglycemia 23%(ns) 18%(ns) cumulative events/patient/yr cumulative events/patient/yr Time (weeks) Birkeland et al. IDF 2011:P-1443;Bain et al. IDF 2011:O-0508; Birkeland et al. Diabetologia 2011;54(suppl. 1):S423; Atkin et al. Diabetologia 2011;54(suppl. 1):S53; Meneghini et al. Diabetes 2011;60(suppl. 1A):LB10 (NN1250-3668)

  32. Insulin Lispro Pegylation PEG PEG PEG PEG = 20-40 kDa

  33. Pegylated Lispro Insulin PD

  34. Fasting vs. post-prandial contribution to A1C: baseline & after basal insulin Baseline Fasting hyperglycemia Post-prandial hyperglycemia Basal insulin Riddle, et al. Diabetes Care 2011; 34 (12): 2508-2514

  35. Exenatide added to basal insulin glargine improves control in T2DM A1C 8.3-8.5% Insulin 0.5 u/kg BMI 33-34 Longer diabetes duration and lower BMI had greater A1C reductions. Longer diabetes duration also lost the most weight. -1.0% +20u +1.0kg -1.7% +13u -1.8kg Minor hypoglycemia 25% (EXE) vs 29% (PLB) Buse, et al. Ann Intern Med. 2011;154:103-112. Rosenstock, et al. Diabetes Care 2012; 35(5):955-8. Epub 2012 Mar 19.

  36. Conclusions • Ultra-long acting basal insulin with improved consistency & less hypoglycemia • Effective combinations of basal replacement and GLP-1 Ras • Smarter & simpler approaches to treatment Diabetes Care,Diabetologia. 19April 2012 [Epub ahead of print]

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