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

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Presentation on theme: "Limitations and opportunities of insulin therapy Luigi Meneghini June 8 th, 2012."— Presentation transcript:

1 Limitations and opportunities of insulin therapy Luigi Meneghini June 8 th, 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 Adapted from Lebovitz HE. Diabetes Reviews. 1999;7(3):139– Beta Cell Function (%) IGT Years From Diagnosis Postprandial Hyperglycemia Diabetes Insulin resistance 40% Beta-cell function 50%

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

5 N=2319N=3394N=513N=982 Insulin A1C>8% (mos) A1C>7% (mos) Brown et al. Diabetes Care 2004; 27: 1535 Physicians delay intensifying therapy for months, especially initiating insulin 9.5%

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

7 Insulin Initiation & Intensification Outcomes in T2DM at Baseline, 1 & 3 Years Holman, et al. NEJM 2009;361: Holman, et al. NEJM 2007;357: %* -1.4%* -1.2%* Less hypoglycemia with basal initiation (events/pt/yr) * * * * P<0.05

8 Yki-Jarvinen et al. Ann Int Med 1999 Hypoglycaemia limits further reduction of FPG with basal insulin Mean HbA 1c [%] Mean annual fasting blood glucose [mmol/l] 12 Frequency of Hypoglycaemic Episodes [%] n = 13,072

9 How do Pharmacodynamics of Basal Insulin Preparations Affect Outcomes

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

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

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

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 Insulin association state Molecular size determines rate of subcutaneous absorption Rapid absorptionSlow absorption Insulin Molecular size Absorption Zn 2+ Capillary membrane Subcutaneous tissue 36 kDa6 kDa Zn kDa>5000 kDa Absorption rate Brange et al. Diabetes Care 1990;13:923–54 High molecular weight forms

16 Insulin degludec injected Long multi-hexamers assemble Phenol Zn 2+ Insulin degludec from solution to subcutaneous depot As phenol from the vehicle diffuses degludec hexamers link up via single side-chain contacts

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

18 Insulin degludec: slow release following injection Insulin degludec multi-hexamers Zinc diffuses slowly causing individual hexamers to disassemble, releasing monomers Subcutaneous depot Zn 2+ Monomers are absorbed from the depot into the circulation

19 Insulin degludec PD profile at steady state in T1D PD, pharmacodynamic Heise et al. Diabetologia 2011;54(Suppl. 1):S Time (hours) GIR (mg/kg/min) Mean profile, n=66 IDeg = 0.4 U/kg

20 Harmonic mean (h) CV (%) Terminal half-life (steady state) Degludec Glargine Terminal half-life & coefficient of variation at steady state

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

22 Weekly titration algorithm for insulin degludec and insulin glargine in T2DM Pre-breakfast plasma glucose a Adjustment mmol/Lmg/dLU <3.1 b <56 b –4 3.1–3.9 b 56–70 b –2 4.0–4.971– –6.990– –7.9126– –8.9144– 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 Relative serum IDeg trough concentrations during initiation of once-daily (0.4 U/kg) dosing in patients with T1DM Days since first dose Serum IDeg concentration Proportion of Day 10 level (%) Values are estimated ratios and 95% CI relative to day 10 Heise T et al. IDF st World Congress Abstract Book. IDF: Dubai, 2011; Poster 1453

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

25 No difference in HbA 1c decrease over time between degludec & glargine 0.0 Mean±SEM; FAS; LOCF Comparisons: Estimates adjusted for multiple covariates Data on file: NN ; Accepted for presentation at ADA 2012 Time (weeks) Degludec (n=773) Glargine (n=257)

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

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

28 Patients with type 2 diabetes (n=687) 0 26 weeks Inclusion criteria Type 2 diabetes 6 months Previously treated with OADs and/or basal insulin HbA 1c : OADs only 7–11% Basal insulin ± OADs 7–10% BMI 40 kg/m 2 Age 18 years Open label Forced flexible insulin degludec study design Glargine OD ±OADs (n=230) (metformin/SU/pioglitazone) Degludec OD Fixed ±OADs (n=228) (metformin/SU/pioglitazone) Degludec OD Flexible ±OADs (n=229) (metformin/SU/pioglitazone) 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 (NN )

29 Timing of flexible insulin degludec administration morning MonTueWedThuFriSatSun morning evening 40h 8h 24h

30 Degludec Flexible OD Degludec OD Glargine OD No difference in A1C between flexible degludec and fixed dosing 0.0 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 (NN ) Time (weeks)

31 No difference in hypoglycemia between flexible degludec and fixed dosing cumulative events/patient/yr 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 (NN ) Time (weeks) cumulative events/patient/yr Degludec Flexible OD Degludec OD Glargine OD 23%(ns) 18%(ns) Overall hypoglycemia Nocturnal hypoglycemia

32 Insulin Lispro Pegylation = kDa PEG

33 Pegylated Lispro Insulin PD

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

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

36 Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print] 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 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


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