FRANCESCO GIORGINO

Transcription

FRANCESCO GIORGINO

FRANCESCO GIORGINO
DIPARTIMENTO DELL’EMERGENZA
E DEI TRAPIANTI DI ORGANI
SEZIONE DI MEDICINA INTERNA, ENDOCRINOLOGIA,
ANDROLOGIA E MALATTIE METABOLICHE
Intensive
Glucose Control
Wrong
patient
«Imperfect»
glucoselowering drugs
Limited benefit on
CVD prevention
↑ Weight gain
↑ Hypoglycemia
Potential
↑ CV risk
Drug-drug
interactions
Excess
(CV) mortality
Giorgino F. et al., Ann N Y Acad Sci, in press
Baseline (t=0)
End of clamp (t=150 min)
P=0.0003
Mean QT interval, ms
450
440
430
420
P=NS
Significant prolongation of QT
interval after hypoglycemic clamps
410
400
390
380
Increased risk of arrhythmias
370
360
0
Euglycemic clamp
(n=8)
Hypoglycemic* clamp
2 weeks after
glibenclamide withdrawal
(n=13)
NS=not significant.
*2.5 and 3.0 mmol/L (45 and 54 mg/dL) during the last 60 minutes of the clamp.
Landstedt-Hallin L et al. J Intern Med. 1999;246:299–307.
Intensive Tx
Standard Tx
No previous
hypoglycemia
At least one HR (adj.)
hypoglycemia
1.3%
2.8%
220/17031
34/1208
1.0%
4.9%*
180/17516
17/345
Hypoglycemic events requiring medical assistance
Annualized mortality rates
*p=0.009
1.28 (0.88-1.85)
2.87 (1.73-4.76)
Bond DE et al., BMJ, 2010
Tight Glycemic
Control
↑ Incidence of
Hypoglycemia
↓ Long-Term
Complications
↓ Medication Adherence
(↓ QoL, Fear of Hypos,
Lost Productivity)
↑ QoL
Compromized Glycemic
Control
Positive
↑ Long-Term
Complications
Impact on Healthcare
Budget & QoC
Negative
Adapted from Fidler C et al, J Med Econ, 2011
Missing 2 basal insulin
injections per week
=
Randløv et al. J Diabetes Sci Technol 2008;2:229–35
0.2–0.3%
increase
in HbA1c
 Basal insulin usually the
optimal initial regimen,
with 1-2 noninsulin agents.
 Insulin secretagogues
(SU/glinides) typically
stopped with more
complex insulin regimens.
 Comprehensive education
regarding SMBG, diet,
exercise, and the
avoidance of, and
response to,
hypoglycemia.
Holman R et al. N Engl J Med 2007
 Currently available long-acting insulin analogues do not always
last 24 hours1
 Variability of glucose lowering effect of current insulins (interpatient and intra-patient)1
 Basal insulins must be administered at the same time every
day2
 Variability and suboptimal duration of action limit titration and
favor the incidence of hypoglycaemia1
1. Evans et al. Diabetes, Obesity and Metabolism 2011;13: 677–684; 2. Joshi et al. SA Fam Pract 2009;51:97–102;
Tolerable insulin range
Mean profile
B
Plasma insulin
A
Plasma insulin
Plasma insulin
Individual data
C
Time
Time
Time
Peaked mean profile,
Smooth, flat mean profile,
Smooth, flat mean profile,
with high variability
but high variability
with low variability
Figures show theoretical data
Patients with NOCT
Patients without NOCT
Type 2 diabetes
CV FPG (%)
CV FPG (%)
Type 1 diabetes
3 months
3 months
FBG, fasting blood glucose; FPG, fasting plasma glucose; NOCT, Nocturnal
Nocturnal hypoglycaemia; CV FPG,
coefficient of variance for fasting plasma glucose
Adapted from Niskanen et al. Diabetes Res Clin Pract 2009;86:e15–18.
FPG
(mmol/L)
FPG
(mg/dL)
Target zone
Hypoglycaemia zone
Day
Adapted from Kovatchev et al. Diabetes Care 2006;29:2433–8
Adapted from Kovatchev et al. Diabetes Care 2006;29:2433–8
LysB29(Nε-hexadecandioyl-γ-Glu) des(B30) human insulin
s
s
G
V E
E Q
Q C
C C
C T
T S
S II C
C S
S LL Y
Y Q
Q LL E
E N
N Y
Y C
C N
N
G II V
A chain
s
s
s
s
F
V N
N Q
Q H
H LL C
C G
G S
S H
H LL V
V E
E A
A LL Y
Y LL V
V C
C G
G E
E R
R G
G F
F F
F Y
Y T
T P
P K
F V
K
B chain
desB30 Insulin
NH
O
Glutamic acid
‘spacer’
O
HO
O
N
H
Hexadecandioyl
Fatty diacid
side chain
I Jonassen et al. Diabetes 59 (Suppl. 1): A11, 2010
I Jonassen et al. Diabetologia 2010;53(Suppl.1):S388 972-P
L-γ-Glu
OH
O
Brange et al. Diabetes Care 1990;13:923–54
Insulin degludec association
From injection to absorption
Multi-hexamer formation key to protraction mechanism
Insulin degludec
di-hexamers
Injected
formulation
Loss of Phenol
Insulin degludec
multi-hexamers
S.c. depot formation
Loss of Zn2+
[
Phenol;
Zn2+]
Insulin degludec
monomers
I Jonassen et al. Diabetes 59 (Suppl. 1): A11, 2010
I Jonassen et al. Diabetologia 2010;53(Suppl.1):S388 972-P
Absorption
AUC: area under the curve
AUCGIR,τ
GIR,τ, total area under the GIR curve over a 24-hour dosing interval at steady state
Nosek et al. IDF 2011:P-1452; Diabetologia 2011;54(suppl. 1):S429 (1055-P); Diabetes 2011;60(suppl. 1A):LB14
Half-life of Insulin Degludec and Insulin
Glargine
IDeg 0.8 U/kg
IGlar 0.8 U/kg
Insulin concentration
(% of maximum)
100
10
1
0
24
48
72
Time since injection (hours)
IDeg
Half-life (hours)
Mean half-life
96
120
IGlar
0.4 U/kg
0.6 U/kg
0.8 U/kg
0.4 U/kg
0.6 U/kg
0.8 U/kg
25.9
27.0
23.9
11.8
14.0
11.9
25.4
12.5
Heise et al. IDF 2011:P-1444; Diabetologia 2011;54(suppl. 1):S425; Diabetes 2011;60(suppl. 1A):LB11
Diabetes Obes Metab. 2012 May 17. doi: 10.1111/j.1463-1326.2012.01627.x. [Epub ahead of print]
*
*
*
*
α-gluc, alpha glucose; BB, basal–bolus; BOT, basal–oral therapy; DPP-4, dipeptidyl peptidase-4; met,
metformin; OAD, oral antidiabetic drugs; SU, sulphonylurea; TZD, thiazolidinedione; T1, type 1 diabetes;
T2, type 2 diabetes; * Study with extension
Mean±SEM; FAS; LOCF
Comparisons: Estimates adjusted for multiple covariates
In the following results presentations, p-values are shown for results that show statistically significant
differences, and not for results that are not statistically significant
Heller S et al. Lancet 2012;379:1489-97
IDeg OD (n=773)
IGlar OD (n=257)
Treatment difference:
non-inferior
Time (weeks)
Mean±SEM; FAS, full analysis set; LOCF, last observation carried forward
Comparisons: estimates adjusted for multiple covariates
Zinman et al. Diabetes Care October 5, 2012
In the following results presentations, p-values are shown for results that show statistically significant
differences, and not for results that are not statistically significant
Garber A et al. Lancet 2012;379:1498-507
10.5
IDeg OD (n=744)
IGlar OD (n=248)
10.0
FPG (mmol/L)
9.5
9.0
8.5
8.0
7.5
7.0
6.5
0.0
0
4
8
12
16
20
24
28
Time (weeks)
32
36
40
44
48
52
IDeg OD (n=773)
IGlar OD (n=257)
Time (weeks)
Mean±
FPG (mg/dL)
–0.43 mmol/L (–7.74 mg/dL), p<0.05
IDeg OD (n=766)
IGlar OD (n=257)
36% lower
rate with
IDeg,
p<0.05
Time (weeks)
Mean±
Mean±SEM; FAS
10.0
9.5
FPG (mmol/L)
9.0
8.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
0.0
0
4
8
12
16
20
24
28
Time (weeks)
32
36
40
44
48
52
BMI: body mass index; IGlar: insulin glargine; OAD: oral antidiabetic
antidiabetic drug; OD: once daily; Flex, flexible
Birkeland et al. IDF 2011:P2011:P-1443; Bain et al. IDF 2011:O2011: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
Mon
Tue
Wed
Thu
8h
morning
Sun
morning
40h
evening
Sat
8h
morning
40h
Fri
40h
evening
24h
evening
evening
IDeg Flexible (n=229)
IDeg Fixed (n=228)
IGlar (n=230)
IDeg Flexible/IDeg Fixed
Non-inferior
IDeg Flexible/IGlar
Non-inferior
Mean±
SAS
n, number of patients with events; %, proportion of patients with
with events; rate, rate of hypoglycaemia in episodes per
100 patientpatient-years; RR, rate ratio for IDeg Flexible/IDeg Fixed or IGlar once daily (FAS)
Glucose
Variability
Fasting
Hyperglycemia
SMBG
(CGM)
Hypoglycemia
Post-prandial
Hyperglycemia
Study design
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 7–10%
• BMI ≤40 kg/m2
• Age ≥18 years
0
52 weeks
Randomised 3:1
Open label
Treat-to-target trial
*With evening meal
Any time of day but same time every day (as per label)
§
BMI, body mass index; DPP-4, dipeptidyl peptidase-4 inhibitor; IDeg, insulin degludec; IGlar, insulin glargine; OD, once daily; SU,
sulphonylurea
Zinman et al. Diabetes Care October 5, 2012 Published online before print, doi: 10.2337/dc12-1205
Endpoints
Primary endpoint: HbA1c
Key secondary endpoints
• Fasting plasma glucose (FPG)
• Insulin dose
• Weight
• Patient-reported outcomes (PRO)
• Hypoglycaemia
• Adverse events
Titration algorithm: insulin degludec
and insulin glargine
Pre-breakfast plasma glucosea
a Mean
Adjustment
mmol/L
mg/dL
U
<3.1b
<56b
–4
(If dose >45 U, reduce by 10%)
3.1–3.9b
56–70b
–2
(If dose >45 U, reduce by of 5%)
4.0–4.9
71–89
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
of 3 consecutive days’ measurements for up titration
there is obvious explanation for the low value, such as a missed meal
b Unless
0
Participating countries
Norway
Canada
Denmark
Finland
Belgium
France
Germany
Czech Republic
United States
Spain
Austria
Serbia &
Montenegro
Subject disposition
Screened 1597
Failed screening criteria 567
Randomised 1030
IDeg OD 773
IGlar OD 257
Withdrawals: 166 (22%)
AE: 20 (3%)
Non-compliance: 46 (6%)
Ineffective therapy: 7 (1%)
Other: 93 (12%)
Completers
607 (79%)
Withdrawals: 60 (23%)
AE: 5 (2%)
Non-compliance: 18 (7%)
Ineffective therapy: 2 (1%)
Other: 35 (14%)
3:1 randomisation
AE, adverse event
Completers
197 (77%)
Baseline characteristics
Characteristic
IDeg OD
IGlar OD
773
257
39.1/60.9
35.0/65.0
88.0/7.4/2.3/2.3
89.9/6.2/1.2/2.7
16.7
18.7
Age, years
59.3 (±9.7)
58.7 (±9.9)
Weight, kg
[lb]
89.4 (±17.7)
[197.1 (±39.0)]
91.8 (±15.8)
[202.4 (±34.8)]
BMI, kg/m2
30.9 (±4.8)
31.6 (±4.4)
Duration of diabetes, years
9.4 (±6.3)
8.6 (±5.7)
HbA1c, %
8.2 (±0.8)
8.2 (±0.8)
9.6 (±2.6)
[172.8 (±46.8)]
9.7 (±2.6)
[174.6 (±46.8)]
Full analysis set (FAS), n
Female/Male, %
Race: White/Black/Asian/Other, %
Ethnicity: Hispanic or Latin American, %
FPG, mmol/L
[mg/dL]
Values are mean (±SD) unless otherwise stated
Daily insulin dose
Mean insulin dose (±SD)
Number of patients, n
Basal insulin
End of trial, U/kg
Basal insulin
End of trial, U
IDeg OD
IGlar OD
766
257
0.59 (±0.35)
0.60 (±0.32)
56 (±39)
58 (±34)
SAS, safety analysis set; LOCF
Weight change
Change in weight from baseline
(lb)
0.28 kg (0.62 lb) (ns)
Baseline
IDeg OD
(n=766)
IGlar OD
(n=257)
89.4 kg
197.1 lb
91.8 kg
202.4 lb
SAS; LOCF
Hypoglycaemia classification
Suspected hypoglycaemia or
routine PG measurement
Yes
No
Not classified as confirmed
hypoglycaemia in this trial
PG <3.1 mmol/La
(56 mg/dL)
Patient able
to treat self?
No
Yes
Minor hypoglycaemia
Severe
hypoglycaemia
Confirmed hypoglycaemia
With or without symptoms; PG, plasma glucose
A nocturnal episode is any confirmed episode with time of onset from midnight to 05.59 am
a
Confirmed hypoglycaemia
IDeg OD (n=766)
IGlar OD (n=257)
18% lower
rate with
IDeg (ns)
Time (weeks)
SAS
Hypoglycaemia
Randomisation 3:1
(IDeg OD:IGlar OD)
IDeg OD
IGlar OD
(n=766)
(n=257)
Incidence
% patients
(# patients)
Severe
0.3%
Confirmed
46.5%
(2/766)
(356/766)
Rate
episodes/P
YE
0.00
1.52
Incidence
% patients
(# patients)
1.9%
(5/257)
46.3%
(119/257)
Rate
episodes/P
YE
0.02
1.85
SAS; % patients, proportion of patients with events; # patients, number of patients with events; PYE, patient-years of exposure
Hypoglycaemia
Randomisation 3:1
(IDeg OD:IGlar OD)
IDeg OD
IGlar OD
(n=766)
(n=257)
Incidence
% patients
(# patients)
Severe
0.3%
Confirmed
46.5%
Nocturnal
confirmed
(2/766)
(356/766)
13.8%
(106/766)
Rate
episodes/P
YE
0.00
1.52
0.25
Incidence
% patients
(# patients)
1.9%
(5/257)
46.3%
(119/257)
15.2%
(39/257)
Rate
episodes/P
YE
0.02
1.85
0.39
Hypoglycaemia
Randomisation 3:1
(IDeg OD:IGlar OD)
IDeg OD
IGlar OD
(n=766)
(n=257)
Incidence
% patients
(# patients)
Severe
0.3%
Confirmed
46.5%
Nocturnal
confirmed
(2/766)
(356/766)
13.8%
(106/766)
Rate
episodes/P
YE
0.00
1.52
0.25
Incidence
% patients
(# patients)
1.9%
(5/257)
46.3%
(119/257)
15.2%
(39/257)
IDeg vs. IGlar
Rate
episodes/P
YE
Rate
ratio
ΔRisk
0.02
0.14*
-86%
1.85
0.82
-18%
0.39
0.64*
-36%
* p<0.05
Clinical interpretation of the
hypoglycaemia evidence
Type of event
Risk reduction
(significance)
To avoid
1 hypoglycaemic episode
you would need to treat
If you treat
100 patients for 1
year with IDeg
Nocturnal
confirmed
36%,
p<0.05
(in favour of IDeg)
8 patients for 1 year
13 fewer
episodes
Adverse events
Randomisation 3:1 (IDeg OD:IGlar OD)
IDeg OD
IGlar OD
All patients
766
257
Patients with events
572
182
74.7%
70.8%
Number of events
2688
837
Adverse event rate per 100 PYE
403
384
Number of patients with serious AEs
62
26
8.1%
10.1%
Number of events
78
33
Serious adverse event rate per 100 PYE
12
15
Number of patients withdrawn due to AEs
20
5
2.6%
1.9%
Percentage of patients
Percentage of patients with serious AEs
Percentage of randomised patients withdrawn
Only treatment-emergent events occurring after first exposure and
no later than 7 days after last exposure
SAS; PYE, patient-years of exposure
Conclusion
In a treat-to-target trial:
• Insulin degludec administered OD effectively improved
HbA1c in patients with type 2 diabetes similarly to
insulin glargine
• Despite a significantly lower FPG with insulin degludec
as compared with insulin glargine:
– a lower risk of both nocturnal confirmed hypoglycaemia
(36%) and severe hypoglycaemia (86%) were observed for
insulin degludec compared with insulin glargine
• Insulin degludec was generally well tolerated
Type 1 diabetes
Coester et al., Diabetologia 2012; 55 (Suppl. 1): S373 (Abstract 909-P)
Type 2 diabetes
Korsatko et al., Diabetologia 2012; 55 (Suppl. 1): S379 (Abstract 924-P)
Disegno dello studio
Simulated IDeg pharmacokinetic profiles at steady state in subjects with
normal renal function and subjects with renal impairment (IDeg 0.4 U/kg).
Total exposure of IDeg vs. creatinine clearance in subjects with
normal renal function and subjects with mild, moderate and severe renal
impairment following a single dose of IDeg (0.4 U/kg)
Haahr et al., Diabetologia 2012; 55 (Suppl. 1): S379 (Abstract 923-P)
Cooper et al., Diabetologia 2012; 55 (Suppl. 1): S374 (Abstract 911-P)
Rodbard et al., Diabetologia 2012; 55 (Suppl. 1): S378 (Abstract 920-P)
Rate (number of episodes per PYE) and incidence (% of patients) of hypoglycaemic episodes in patients with T2D or T1D
Gough et al., Diabetologia 2012; 55 (Suppl. 1): S253 (Abstract 615-P)
Kurtzhals P, Diabetes July 2011; vol 60 (Supplement 1): 4242-LB
aCalculated,
not measured
FPG, fasting plasma glucose
Garber et al. The Lancet 2012;379:1489-97
9.5
IDeg Flexible/IDeg Fixed
–0.05 [–0.45; 0.35]
9.0
FPG (mmol/L)
8.5
8.0
IDeg Flexible/IGlar
–0.42 [–0.82; –0.02]
7.5
7.0
6.5
IDeg Flexible (n=229)
6.0
IDeg Fixed (n=228)
5.5
IGlar (n=230)
5.0
0
2
4
6
8
10
12 14 16
Time (weeks)
FAS; LOCF
Meneghini L, Diabetes July 2011; vol 60 (Supplement 1): 3535-LB
18
20
22
24
26
Duration of action, peak profiles and
intra-patient variability
NPH insulin (0.4 U/kg)
Insulin glargine (0.4 U/kg)
Glucose infusion rate (mg/kg/min)
Insulin detemir (0.4 U/kg)
Time (hours)
Heise et al. Diabetes 2004;53:1614–20
Subcutaneous
Omental
Subcutaneous
Omental
HI (100 nM)
Detemir (100 nM)
Detemir (1000 nM)
No Ins
Cignarelli A et al, manuscript in preparation
Cignarelli A et al, manuscript in preparation

FRANCESCO GIORGINO

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