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

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

Limitations and opportunities of insulin therapy

Luigi MeneghiniJune 8th, 2012

Page 2: 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• Adding an incretin to basal insulin

replacement

Page 3: Limitations and opportunities of insulin therapy Luigi Meneghini June 8 th, 2012.

Metabolic Status at Diagnosis of Type 2 Diabetes

Adapted from Lebovitz HE. Diabetes Reviews. 1999;7(3):139–153.

2-12 -2-10 -6 0 6 10 14

Beta Cell Function

(%)

0

50

100

75

25IGT

Years From Diagnosis

PostprandialHyperglycemia Diabetes

Insulin resistance40%

Beta-cell function50%

Page 4: Limitations and opportunities of insulin therapy Luigi Meneghini June 8 th, 2012.

Glycemic Control with Monotherapy in the UKPDS Over 9 Years

Turner RC et al. JAMA 1999; 281: 2005-2012

24U

53U

Short-acting insulin added in 44% by 9 yearsShort-acting insulin added in 44% by 9 years

Page 5: Limitations and opportunities of insulin therapy Luigi Meneghini June 8 th, 2012.

N=2319 N=3394 N=513 N=982

Insulin

A1C>8% (mos) 4 17 12 26

A1C>7% (mos) 16 37 26 51Brown et al. Diabetes Care 2004; 27: 1535

Physicians delay intensifying therapy for months, especially initiating insulin

9.5%9.5%

Page 6: Limitations and opportunities of insulin therapy Luigi Meneghini June 8 th, 2012.

Options for Initiating & Intensifying Insulin Therapy in Type 2 Diabetes

Page 7: Limitations and opportunities of insulin therapy Luigi Meneghini June 8 th, 2012.

Insulin Initiation & Intensification Outcomes in T2DM at Baseline, 1 & 3 Years

Holman, et al. NEJM 2009;361:1736-47. Holman, et al. NEJM 2007;357: 1716-30

235 222 201 239 222 188 234 224 189

-1.3%* -1.4%*-1.2%*

3.03.05.55.5

1.71.7

Less hypoglycemia with basal initiation (events/pt/yr)

*

*

*

* P<0.05

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

Yki-Jarvinen et al. Ann Int Med 1999

Hypoglycaemia limits further reduction of FPG with basal insulin

Mea

n H

bA1c

[%]

Mean annual fasting blood glucose [mmol/l]

12

Fre

quen

cy o

f Hyp

ogly

caem

ic

Epis

odes

[%]

10

8

6

4

40

30

20

10

0

3 4 5 6 7 8 9 10 11

3 4 5 6 7 8 9 10 11

n = 13,072

Page 9: Limitations and opportunities of insulin therapy Luigi Meneghini June 8 th, 2012.

How do Pharmacodynamics of Basal Insulin Preparations Affect Outcomes

Page 10: Limitations and opportunities of insulin therapy Luigi Meneghini June 8 th, 2012.

Pharmacodynamics of NPH versus

Glargine Insulin

Lepore, et al. Diabetes 1999; 48 (suppl 1): A97Bolli et al. The Lancet • Vol 356 • August 5 2000

Plasma glucose

Glucose infusion rate

Page 11: Limitations and opportunities of insulin therapy Luigi Meneghini June 8 th, 2012.

Biologic activity over 24-hours more consistent for basal insulin analogs

GIR = Glucose Infusion RateHeise et al. Diabetes 2004; 53 (6): 1614-1620

Insulin detemir

Page 12: Limitations and opportunities of insulin therapy Luigi Meneghini June 8 th, 2012.

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

*

*

*

*

Page 13: Limitations and opportunities of insulin therapy Luigi Meneghini June 8 th, 2012.

Modeled risk of hypoglycemia based on achieved A1C levels

Little S, et al. Diab Tech Ther 2011; 13 (S1)

Page 14: Limitations and opportunities of insulin therapy Luigi Meneghini June 8 th, 2012.

Improving on current basal insulin analogs

• Extend duration of action• Flat pharmacodynamic profile• Reduced day-to-day variability

Page 15: Limitations and opportunities of insulin therapy Luigi Meneghini June 8 th, 2012.

Insulin association state

Molecular size determines rate of subcutaneous absorption

Rapid absorption Slow absorption

Insulin

Molecular size

Absorption

Zn2+

Capillary membrane

Subcutaneous tissue

36 kDa6 kDa

Zn2+

Zn2+

72 kDa >5000 kDa

Absorption rate

Brange et al. Diabetes Care 1990;13:923–54

High molecular weight forms

Page 16: Limitations and opportunities of insulin therapy Luigi Meneghini June 8 th, 2012.

Insulin degludec injected

Long multi-hexamers assemble

Phenol Zn2+

Insulin degludec from solution to subcutaneous depot

As phenol from the vehicle diffuses degludec hexamers link up via single

side-chain contacts

Page 17: Limitations and opportunities of insulin therapy Luigi Meneghini June 8 th, 2012.

Kurtzhals et al. Diabetes 2011;60(Suppl . 1):LB12 (Abstract 42-LB) (NN1250-1993 + 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 DEPOTSOLUTION

Page 18: Limitations and opportunities of insulin therapy Luigi Meneghini June 8 th, 2012.

Insulin degludec: slow release following injection

Insulin degludec multi-hexamers

Zinc diffuses slowly causing individual hexamers to disassemble, releasing

monomers

Subcutaneous depot Zn2+

Monomers are absorbed from the depot into the circulation

Page 19: Limitations and opportunities of insulin therapy Luigi Meneghini June 8 th, 2012.

Insulin degludec PD profile at steady state in T1D

PD, pharmacodynamicHeise et al. Diabetologia 2011;54(Suppl. 1):S425

0 2 4 6 8 10 12 14 16 18 20 22 24Time (hours)

0

1

2

3

4

5

6

Mean profile, n=66IDeg = 0.4 U/kg

Page 20: Limitations and opportunities of insulin therapy Luigi Meneghini June 8 th, 2012.

Harmonic mean

(h)

CV(%)

Terminal half-life (steady state)

Degludec 24.5 23

Glargine 12.2 56

Terminal half-life & coefficient of variation at steady state

Page 21: Limitations and opportunities of insulin therapy Luigi Meneghini June 8 th, 2012.

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 weeksInclusion 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

Basal insulin initiation in T2DM

Randomised 3:1 (IDeg OD:IGlar OD)Open label

DPP-4, dipeptidyl peptidase-4 inhibitorSU, sulphonylureaOD, once dailyData on file: NN1250-3579; Accepted for presentation at ADA 2012

Page 22: Limitations and opportunities of insulin therapy Luigi Meneghini June 8 th, 2012.

Weekly titration algorithm for insulin degludec and insulin glargine in T2DM

Pre-breakfast plasma glucosea Adjustment

mmol/L mg/dL U

<3.1b <56b –4

3.1–3.9b 56–70b –2

4.0–4.9 71–89 0

5.0–6.9 90–125 +2

7.0–7.9 126–143 +4

8.0–8.9 144–161 +6

≥9.0 ≥162 +8

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

Page 23: Limitations and opportunities of insulin therapy Luigi Meneghini June 8 th, 2012.

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

0 1 2 3 4 5 6 7 8 9 100

102030405060708090

100110120

Days since first dose

Seru

m ID

eg c

once

ntr

ati

on

Pro

port

ion o

f D

ay 1

0 level (%

)

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

Page 24: Limitations and opportunities of insulin therapy Luigi Meneghini June 8 th, 2012.

Pharmacokinetics of insulin steady state

Absorption from the SC depotReceptor activation &

insulin clearance

Page 25: Limitations and opportunities of insulin therapy Luigi Meneghini June 8 th, 2012.

No difference in HbA1c decrease over time between degludec & glargine

0.0

Mean±SEM; FAS; LOCFComparisons: Estimates adjusted for multiple covariatesData on file: NN1250-3579; Accepted for presentation at ADA 2012

Time (weeks)

Degludec (n=773)Glargine (n=257)

Page 26: Limitations and opportunities of insulin therapy Luigi Meneghini June 8 th, 2012.

No difference in overall confirmed hypoglycaemia

18% (ns)

SASComparisons: Estimates adjusted for multiple covariatesData on file: NN1250-3579; Accepted for presentation at ADA 2012

Time (weeks)

Degludec (n=773)Glargine (n=257)

HYPOGLYCEMIABG < 56 mg/dl or severe

HYPOGLYCEMIABG < 56 mg/dl or severe

Page 27: Limitations and opportunities of insulin therapy Luigi Meneghini June 8 th, 2012.

Lower nocturnal confirmed hypoglycaemia with insulin degludec

36% p<0.05

SASComparisons: Estimates adjusted for multiple covariatesData on file: NN1250-3579; Accepted for presentation at ADA 2012

Time (weeks)

Degludec (n=773)Glargine (n=257)

Page 28: Limitations and opportunities of insulin therapy Luigi Meneghini June 8 th, 2012.

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

•HbA1c:OADs only 7–11%Basal insulin ± OADs 7–10%

•BMI ≤40 kg/m2

•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 (NN1250-3668)

Page 29: Limitations and opportunities of insulin therapy Luigi Meneghini June 8 th, 2012.

Timing of flexible insulin degludec administration

morning

Mon Tue Wed Thu Fri Sat Sun

morning morning

evening evening evening evening

40h 40h 40h

8h 8h

24h

Page 30: Limitations and opportunities of insulin therapy Luigi Meneghini June 8 th, 2012.

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 (NN1250-3668)

Time (weeks)

Page 31: Limitations and opportunities of insulin therapy Luigi Meneghini June 8 th, 2012.

No difference in hypoglycemia between flexible degludec and fixed dosing

cum

ula

tive e

vents

/pati

ent/

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 (NN1250-3668)

Time (weeks)

cum

ula

tive e

vents

/pati

ent/

yr

Degludec Flexible OD Degludec OD Glargine OD

23%(ns)

18%(ns)

Overall hypoglycemiaOverall hypoglycemia Nocturnal hypoglycemiaNocturnal hypoglycemia

Page 32: Limitations and opportunities of insulin therapy Luigi Meneghini June 8 th, 2012.

Insulin Lispro Pegylation

= 20-40 kDaPEG PEG

PEG PEG

PEG PEG

PEG

PE

G

Page 33: Limitations and opportunities of insulin therapy Luigi Meneghini June 8 th, 2012.

Pegylated Lispro Insulin PD

Page 34: Limitations and opportunities of insulin therapy Luigi Meneghini June 8 th, 2012.

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): 2508-2514

Page 35: Limitations and opportunities of insulin therapy Luigi Meneghini June 8 th, 2012.

Exenatide added to basal insulin glargine improves control in T2DM

Buse, et al. Ann Intern Med. 2011;154:103-112. Rosenstock, et al. Diabetes Care 2012; 35(5):955-8. Epub 2012 Mar 19.

A1C8.3-8.5%

A1C8.3-8.5%

Insulin0.5 u/kgInsulin

0.5 u/kgBMI

33-34BMI

33-34

-1.0%-1.0% +20u+20u +1.0kg+1.0kg

-1.7%-1.7% +13u+13u -1.8kg-1.8kg

Minor hypoglycemia25% (EXE) vs 29% (PLB)

Minor hypoglycemia25% (EXE) vs 29% (PLB)

Longer diabetes duration and lower BMI had greater A1C reductions. Longer diabetes

duration also lost the most weight.

Longer diabetes duration and lower BMI had greater A1C reductions. Longer diabetes

duration also lost the most weight.

Page 36: Limitations and opportunities of insulin therapy Luigi Meneghini June 8 th, 2012.

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