Limitations and opportunities of insulin therapy Luigi Meneghini June 8 th , 2012
Mar 26, 2015
Limitations and opportunities of insulin therapy
Luigi MeneghiniJune 8th, 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
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%
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
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%
Options for Initiating & Intensifying Insulin Therapy in Type 2 Diabetes
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
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
How do Pharmacodynamics of Basal Insulin Preparations Affect Outcomes
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
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
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
*
*
*
*
Modeled risk of hypoglycemia based on achieved A1C levels
Little S, et al. Diab Tech Ther 2011; 13 (S1)
Improving on current basal insulin analogs
• Extend duration of action• Flat pharmacodynamic profile• Reduced day-to-day variability
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
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
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
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
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
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
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
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
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
Pharmacokinetics of insulin steady state
Absorption from the SC depotReceptor activation &
insulin clearance
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)
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
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)
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)
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
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)
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
Insulin Lispro Pegylation
= 20-40 kDaPEG PEG
PEG PEG
PEG PEG
PEG
PE
G
Pegylated Lispro Insulin PD
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
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.
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