Limitations and opportunities of
insulin therapy
Luigi Meneghini
June 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
Beta Cell
Function
(%)
100
Insulin resistance
40%
75
Beta-cell function
50%
50
25
IGT
0
-12 -10
Postprandial
Hyperglycemia
-6
-2
Diabetes
0
2
Years From Diagnosis
Adapted from Lebovitz HE. Diabetes Reviews. 1999;7(3):139–153.
6
10
14
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
Physicians delay intensifying therapy for
months, especially initiating insulin
Insulin
9.5%
N=2319
N=3394
N=513
N=982
A1C>8%
(mos)
4
17
12
26
A1C>7%
16
37
26
51
Brown
et al. Diabetes Care 2004; 27: 1535
(mos)
Options for Initiating & Intensifying
Insulin Therapy in Type 2 Diabetes
Insulin Initiation & Intensification
Outcomes in T2DM at Baseline, 1 & 3 Years
9.0%
-1.3%*
-1.4%*
-1.2%*
8.5%
8.0%
Less hypoglycemia with basal initiation
(events/pt/yr)
A1C (%)
7.5%
7.0%
*
6.5%
*
5.5
*
3.0
1.7
6.0%
5.5%
235 222
201
239 222 188
234 224 189
Prandial
Basal
5.0%
Biphasic
Holman, et al. NEJM 2009;361:1736-47. Holman, et al. NEJM 2007;357: 1716-30
* P<0.05
Frequency of Hypoglycaemic
Episodes [%]
Mean HbA1c [%]
Hypoglycaemia limits further
reduction of FPG with basal insulin
12
10
8
6
4
3
4
40
5
6
7
8
9
10
11
n = 13,072
30
20
10
0
3
4
5
6
7
8
9
10
Mean annual fasting blood glucose [mmol/l]
Yki-Jarvinen et al. Ann Int Med 1999
11
How do Pharmacodynamics of Basal
Insulin Preparations Affect Outcomes
Plasma glucose
Pharmacodynamics
of NPH versus
Glargine Insulin
Lepore, et al. Diabetes 1999; 48 (suppl 1): A97
Bolli et al. The Lancet • Vol 356 • August 5 2000
Glucose infusion rate
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
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
Molecular size determines rate of
subcutaneous absorption
Subcutaneous
tissue
Molecular size
6 kDa
Insulin
association
state
36 kDa
Zn2+
72 kDa
Zn2+
Zn2+
>5000 kDa
High molecular
weight forms
Absorption rate
Capillary membrane
Rapid absorption
Brange et al. Diabetes Care 1990;13:923–54
Slow absorption
Insulin degludec from solution to
subcutaneous depot
Phenol
Insulin degludec
injected
As phenol from the vehicle diffuses
degludec hexamers link up via single
side-chain contacts
Long multi-hexamers
assemble
Zn2+
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)
Insulin degludec: slow release
following injection
Subcutaneous depot
Zn2+
Insulin degludec
multi-hexamers
Zinc diffuses slowly causing individual
hexamers to disassemble, releasing
monomers
Monomers are absorbed from
the depot into the circulation
Insulin degludec PD profile at steady
state in T1D
GIR (mg/kg/min)
6
5
Mean profile, n=66
IDeg = 0.4 U/kg
4
3
2
1
0
0
2
4
6
PD, pharmacodynamic
Heise et al. Diabetologia 2011;54(Suppl. 1):S425
8
10 12 14 16 18 20 22 24
Time (hours)
Terminal half-life & coefficient
of variation at steady state
Harmonic
mean
(h)
CV
(%)
Degludec
24.5
23
Glargine
12.2
56
Terminal half-life
(steady state)
Basal insulin initiation in T2DM
IDeg OD + metformin ± DPP-4 (n=773)
Insulin-naïve patients
with type 2 diabetes
(n=1030)
Inclusion criteria
• Type 2 diabetes ≥6 months
• Insulin naïve treated with metformin
± SU, DPP-4 or acarbose for ≥3
months
IGlar OD + metformin ± DPP-4 (n=257)
0
Randomised 3:1 (IDeg OD:IGlar OD)
Open label
• HbA1c 7.0–10.0%
• BMI ≤40 kg/m2
• Age ≥18 years
DPP-4, dipeptidyl peptidase-4 inhibitor
SU, sulphonylurea
OD, once daily
Data on file: NN1250-3579; Accepted for presentation at ADA 2012
52 weeks
Weekly titration algorithm for insulin
degludec and insulin glargine in T2DM
Pre-breakfast plasma glucosea
a
b
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
Mean of 3 consecutive days’ measurements for up titration.
Unless there is obvious explanation for the low value, such as a missed meal
Serum IDeg concentration
Proportion of Day 10 level (%)
Insulin degludec steady state is reached
within 2–3 days of once-daily dosing
120
110
100
90
80
70
60
50
40
30
20
10
0
0
1
2
3
4
5
6
7
Days since first dose
8
9
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
10
Pharmacokinetics of insulin steady
state
Absorption from the SC depot
Receptor activation &
insulin clearance
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 covariates
Data on file: NN1250-3579; Accepted for presentation at ADA 2012
No difference in overall confirmed
hypoglycaemia
18% (ns)
HYPOGLYCEMIA
BG < 56 mg/dl or severe
Degludec (n=773)
Glargine (n=257)
Time (weeks)
SAS
Comparisons: Estimates adjusted for multiple covariates
Data on file: NN1250-3579; Accepted for presentation at ADA 2012
Lower nocturnal confirmed
hypoglycaemia with insulin degludec
Degludec (n=773)
Glargine (n=257)
Time (weeks)
SAS
Comparisons: Estimates adjusted for multiple covariates
Data on file: NN1250-3579; Accepted for presentation at ADA 2012
36%
p<0.05
Forced flexible insulin degludec study
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
0
Open label
• HbA1c:
OADs only 7–11%
Basal insulin ± OADs 7–10%
• BMI ≤40 kg/m2
• Age ≥18 years
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)
26 weeks
Timing of flexible insulin degludec
administration
Mon
Tue
Wed
Thu
8h
morning
Fri
Sat
Sun
8h
morning
morning
8-12 AND 36-40 hours between insulin administration
40h
40h
evening
40h
evening
24h
evening
evening
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)
No difference in hypoglycemia between
flexible degludec and fixed dosing
Degludec OD
Overall hypoglycemia
Glargine OD
Nocturnal hypoglycemia
cumulative events/patient/yr
cumulative events/patient/yr
Degludec Flexible OD
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)
23%(ns)
18%(ns)
Insulin Lispro Pegylation
PEG
PEG
PEG = 20-40 kDa
Pegylated Lispro Insulin PD
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
Exenatide added to basal insulin
glargine improves control in T2DM
Longer diabetes duration and lower BMI had
greater A1C reductions. Longer diabetes
duration also lost the most weight.
A1C
8.3-8.5%
Insulin
0.5 u/kg
BMI
33-34
-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.
Healthy eating, weight control, increased physical activity
Initial drug
monotherapy
Metformin
high
low risk
neutral/loss
GI / lactic acidosis
low
If needed to reach individualized HbA1c target after ~3 months, proceed to 2-drug combination
(order not meant to denote any specific preference):
Efficacy (! HbA1c)
Hypoglycemia
Weight
Side effects
Costs
Conclusions
+
+
+
Two
drug
• combinations*
Ultra-long acting basal insulin with
improved consistency & less
hypoglycemia
• Effective combinations of basal
+
+
replacement
and GLP-1
Ras+
Three
drug
combinations
+
+
+
• Smarter & simpler
approaches
to
treatment
Metformin
Efficacy (! HbA1c)
Hypoglycemia
Weight
Major side effect(s)
Costs
Metformin
Metformin
Metformin
+
Metformin
+
Sulfonylurea†
Thiazolidinedione
DPP-4
Inhibitor
GLP-1 receptor
agonist
Insulin (usually
basal)
high
moderate risk
gain
hypoglycemia ‡
low
high
low risk
gain
edema, HF, fx’s‡
high
intermediate
low risk
neutral
rare‡
high
high
low risk
loss
GI‡
high
highest
high risk
gain
hypoglycemia ‡
variable
If needed to reach individualized HbA1c target after ~3 months, proceed to 3-drug combination
(order not meant to denote any specific preference):
Metformin
Sulfonylurea†
Metformin
Thiazolidinedione
DPP-4-i
or
GLP-1-RA
or
Insulin§
DPP-4
Inhibitor
or
DPP-4-i
or GLP-1-RA
or
Metformin
+
GLP-1 receptor
agonist
+
SU†
SU†
TZD
or
Metformin
Metformin
+
Insulin (usually
basal)
+
SU†
TZD
or
TZD
or
TZD
or
DPP-4-i
or
Insulin§
or
Insulin §
or
GLP-1-RA
Insulin §
If combination therapy that includes basal insulin has failed to achieve HbA1c target after 3-6 months,
proceed to a more complex insulin strategy, usually in combination with 1-2 non-insulin agents:
More complex
insulin strategies
Diabetes Care, Diabetologia.
19 April 2012 [Epub ahead of print]
Insulin #
(multiple daily doses)