les noves insulines rÀpides i el control de … › files › 425-14696-document › perez...les...
TRANSCRIPT
LES NOVES INSULINES RÀPIDES I EL CONTROL DE LA GLICÈMIA POSTPRANDIAL
Dr Manuel Pérez Maraver Servei d´Endocrinologia i Nutrició Hospital Universitari de Bellvitge
Conflicto de intereses: -Ensayos clínicos: Sanofi, Novo Nordisk -Advisory boards: Sanofi, Novo Nordisk, AZ, Lilly, Boehringer, Abbott -Formación continuada: Novo Nordisk, Lilly, Sanofi, AZ, Boehringer, MSD, Novartis, Menarini -Empleado por: Institut Català de la Salut -Profesor asociado de Medicina en la Universitat de Barcelona
1- Importància de la glicèmia postprandial
2- La HbA1c com a factor de risc CV: dades actuals (breu)
3- Insulina Faster Aspart
4- Conclusions
Fast-acting insulin aspart is approved in Europe and it has not been launched in Spain
Postprandial hyperglycaemia results from loss of early insulin release
Mitrakou et al. Diabetes 1990;39:1381–90.
Estudio Comienzo
Localización
No. de pacient
es
Duración
(años)
Chicago Peoples Gas Company Study
1992 EE.UU 873 19
Oslo Study 1995 EE.UU 873 19
Diabetes Intervention Study
1996 Alemania 1139 11
Chicago Heart Association Detection Project
1997 EE.UU 12220 22
Paris Prospective and Helsinki Policemen Studies
1998 – 7260 20
Rancho Bernardo Study 1998 EE.UU 1858 7
Funagata Diabetes Study 1999 Japón 2534 6
Honolulu Heart Program 1999 Hawaii 8006 23
Hoorn Study 1999 Países Bajos 2363 8
Mauritius-Fiji-Nauru Study 1999 – 9179 8–12
Estudio Comien
zo Localizació
n
No. de pacient
es
Duración (años)
DECODE 1999 EU 22514 8.8
Saydah, Diabetes Care 2001 EE.UU 3092 16
Framingham Offspring Study 2002 EE.UU 3370 4
Cardiovascular Health Study 2002 EE.UU 4014 8.5
Qiao, Eur Heart J 2002 Finlandia 6766 7–10
DECODA 2004 Asia 6817 5
San Luigi Gonzaga Study 2006 Italia 529 5
Whitehall Study 2006 Reino Unido
17869 33
AusDiab Study 2009 Australia 10026 7
Israel Study of Glucose Intolerance, Obesity and Hypertension
2016 Israel 2138 33
Observación consistente Correlación significativa entre la hiperglucemia postprandial y la mortalidad CV o eventos CV
Datos epidemiológicos que correlacionan GPP con enfermedades CV
CV: cardiovascular; CVD: enfermedad cardiovascular; GPP: glucosa plasmática postprandial. Standl et al. Diabetes Care 2011;34 (Suppl. 2):120–7; Bergman et al. Diabet Med 2016;33:1060–6
Raz I et al. Diabetes Care 2009; 32: 381-85
Raz I et al. Diabetes Care 2009; 32: 381-85
Raz I et al. Diabetes Care 2009; 32: 381-85
Faste
r Aspart
Core
Scie
nce 0
8032017 V
6 0
Relationship between fasting and postprandial glucose with HbA1c
HbA1c
PPG FPG PPG has a stronger correlation with
HbA1c than FPG3
PPG is the predominant contributor in patients with satisfactory to good control of diabetes, whereas the
contribution of FPG increases with worsening diabetes2
A recent meta-analysis found that:
Increased PPG and FPG drive increase in HbA1c
1
1. Monnier et al. Diabetes Care 2007;30:263–9; 2. Monnier et al. Endocr Pract 2006;12:S1:42–6; 3. Ketema et al. Arch Public Health 2015;73:43
FPG, fasting plasma glucose; PPG, postprandial plasma glucose
Woerle et al. /Diabetes Research and Clinical Practice 77 (2007) 280–285
Only 64% of patients achieving FPG targets of <100 mg/dl achieved an HbA1c target of <7% whereas 94% of patients achieving the postprandial target of <140 mg/dl did.
A1c >7%, TA >140/80 mm Hg, fumador, LDL >97 mg/dl, EUA +. N Engl J Med 2018; 379: 633-44
N Engl J Med 2018; 379: 633-44
Faste
r Aspart
Core
Scie
nce 0
3/0
8/2
017 V
7 0
Ultra-fast insulin: approaching a physiological insulin profile even further
Rapid-acting insulin
Time (h)
Insulin a
ction (
at
mealtim
e)*
From the normal pancreas
‘Ultra-fast’ insulin
Regular human insulin
Ultra-fast insulin should:
• Better approach physiological insulin secretion in T1D
• Replace early insulin secretion in T2D
• Have a better profile for pump therapy
*Schematic representation T1D, type 1 diabetes; T2D, type 2 diabetes Adapted from Home. Diabetes Obes Metab 2015;17:1011–20
Faste
r Aspart
Core
Scie
nce 0
8032017 V
6 0
Designing an ultra-fast-acting insulin
• Sprinkler needle • Pulmonary
Administration
• Additives e.g.: • EDTA/citric acid • Magnesium • Bio-chaperone • Niacinamide
Formulation
• Application of heat • Hyaluronidase
Injection site
EDTA, ethylenediaminetetra-acetic acid
Faste
r Aspart
Core
Scie
nce 0
3/0
8/2
017 V
7 0
2015 Insulin glargine U300
Glucose-sensitive insulin
BioChaperone lispro
Liver-selective prandial insulin
Oral insulin
Lo
ng
-acti
ng
Goal of insulin development: approach endogenous insulin secretion by healthy pancreatic beta-cells
Future
First clinical use of insulin 1922
Biosynthetic human insulin
1982
Rapid-acting insulin analogue
1996
Exubera inhaled insulin (withdrawn 2007) 2006
Afrezza inhaled insulin
2015
Sh
ort-
acti
ng
1950 NPH insulin
1953 Lente insulin
2000 Insulin glargine
U100
2013 Insulin degludec
1920 1940 1960 1980 2000
Ult
ra-f
ast-
acti
ng
2005 Insulin detemir
Faster aspart 2017
2017
Adapted from Cahn et al. Lancet Diabetes Endocrinol 2015;3:638–52; Eli Lilly. Patent application, 12 November 2015; Eli Lilly. Press release, 4 December 2015; Novo Nordisk. Capital Markets Day R&D update, 19 November 2015
Faster aspart, fast-acting insulin aspart; NPH, neutral protamine Hagedorn
Trepostinil lispro (LY900014)
Faste
r Aspart
Core
Scie
nce 0
8032017 V
6 0
Niacinamide: absorption modifier
Vitamin B3
L-Arginine: added for stability
Naturally occurring amino acid
FDA. Inactive Ingredient Search for Approved Drug Products database. www.accessdata.fda.gov/scripts/cder/iig/index.cfm. Accessed June 2016.
Insulin aspart
Changing the formulation: faster aspart is insulin aspart in a new formulation
Faster aspart, fast-acting insulin aspart
Faste
r Aspart
Core
Scie
nce 0
3/0
8/2
017 V
7 0
Niacinamide increases monomer fraction and permeation rate of insulin aspart Rate of increase similar as leap from human insulin to insulin aspart
Monomer fraction
+35%
Permeation rate across HDMEC cell monolayers
0.00
0.01
0.02
0.03
0.04
0.05
Human insulin
Insulin aspart
Faster aspart†
0
2x10-06
4x10-06
6x10-06
Papp (
cm
/s)
+27%
Volu
me fra
ction o
f m
onom
ers
in b
uff
er
Human insulin
Insulin aspart
Faster aspart†
Buckley et al. ATTD 2016 (ATTD-0083); Novo Nordisk. Data on file
†Concentration of niacinamide simulating subcutaneous environment after injection HDMEC, human dermal microvascular endothelial cells
Dissociation of insulin hexamers Increasing early monomer fraction after injection
Schematic representation
Faste
r Aspart
Core
Scie
nce 0
3/0
8/2
017 V
7 0
Faster aspart vs. insulin aspart via sc injection
Twice as fast onset of appearance in the bloodstream
Two-fold higher insulin exposure within the first 30 min
74% greater insulin action within the first 30 min
Compared with insulin aspart, faster aspart has:
Pooled analysis of NN1218 trials 3887, 3888, 3889, 3891, 3921, 3978. Faster aspart, fast-acting insulin aspart; GIR, glucose infusion rate; IAsp, insulin aspart; sc, subcutaneous
Faster aspart Insulin aspart
0 30 60 Time (min)
0
50
100
150
200
250
300
IAsp s
eru
m c
onc. (p
mol/
L)
9 4
0 30 60
GIR
(m
g/k
g/m
in)
0
2
4
6
8
Time (min) Heise et al. Clin Pharmacokinet 2017;56:551–9
Fast-acting insulin aspart is approved in Europe and it has not been launched in Spain
PD: Early glucose-lowering effect Cross-trial indirect comparison: Comparable improvement with fast-acting insulin aspart over insulin aspart as insulin aspart over human insulin
aIn healthy volunteers; bIn patients with type 1 diabetes. AUC, area under the curve; GIR, glucose infusion rate. Modified from: Heinemann L et al. Exp Clin Endocrinol Diabetes 1997;105:140–4; Heise et al. Clin Pharmacokinet 2017; 56:551–9.
Overview of the onset programme for fast-acting insulin aspart
MDI, multiple daily injections; T1D, type 1 diabetes; T2D, type 2 diabetes
Faste
r Aspart
Core
Scie
nce 0
3/0
8/2
017 V
7 0
onset 1: trial design A randomised, treat-to-target trial in T1D
Russell-Jones et al. Diabetes Care 2017;doi:10.2337/dc16-1771; Mathieu et al. ADA 2017. Poster 992-P
Key endpoints from baseline to week 26
• Change in HbA1c
• Change in PPG increment (meal test)
• Number of treatment-emergent hypoglycaemic episodes
• Number of treatment-emergent AEs
Faster aspart (mealtime) + detemir
Faster aspart (post-meal) + detemir
Insulin aspart (mealtime) + detemir
26 weeks
Randomisation (1:1:1) Primary endpoint for 26-week trial
8 weeks
Run-in
26 weeks
EOT
Insulin aspart + insulin detemir
FUa
Double-blind
This trial is registered at ClinicalTrials.gov: NCT01831765. aFU (7–30 days) AE, adverse event; BMI, body mass index; DBL, database lock; faster aspart, fast-acting insulin aspart; FU, follow-up; PPG, postprandial plasma glucose; T1D, type 1 diabetes
n=381
n=380
n=382
Key endpoints from baseline to week 52
• Number of hypoglycaemic episodes
• Number of treatment-emergent AEs
• Change in HbA1c from baseline at 52 weeks
• PPG regulation (based on meal test)
• Change in body weight from baseline at 52 weeks
FUa
•
Faste
r Aspart
Core
Scie
nce 0
3/0
8/2
017 V
7 0
Faster aspart (mealtime)
n=381
Insulin aspart (mealtime)
n=380
Faster aspart (post-meal)*
n=382
Age, years 46.1 (13.8) 43.7 (14.0) 43.5 (13.7)
Male, n (%) 215 (56) 238 (63) 219 (57)
BMI, kg/m2 26.4 (3.8) 26.7 (3.7) 26.9 (4.1)
Body weight, kg lb
78.6 (14.9) 173.2 (32.8)
80.2 (15.2) 176.7 (33.5)
80.5 (15.9) 177.5 (35.1)
Duration of diabetes, years 20.9 (12.9) 19.3 (11.8) 19.5 (12.1)
HbA1c, % mmol/mol
7.6 (0.7) 59.7 (7.7)
7.6 (0.7) 59.3 (7.5)
7.6 (0.7) 59.9 (7.9)
FPG, mmol/L mg/dL
8.4 (3.1) 151.4 (55.8)
7.9 (2.8) 141.8 (50.2)
8.1 (3.2) 145.6 (56.9)
onset 1: baseline characteristics at randomisation
*Faster aspart (post-meal) arm was not continued in the additional treatment period. Data are presented as mean (SD) unless stated otherwise BMI, body mass index; faster aspart, fast-acting insulin aspart; FPG, fasting plasma glucose; SD, standard deviation
Russell-Jones et al. Diabetes Care 2017;doi:10.2337/dc16-1771; Russell-Jones et al. Diabetes 2016;65(Suppl. 1):A77
Faste
r Aspart
Core
Scie
nce 0
3/0
8/2
017 V
7 0
onset 1: mean HbA1c over time
HbA
1c (m
mol/m
ol)
8.0
8.2
7.6
7.8
7.2
7.4
64
66
60
62
56
58
HbA
1c (
%)
Faster aspart (mealtime)
Insulin aspart (mealtime)
Faster aspart (post-meal)
0 8 4 12 16 20 24 26 -5 -10 -1 34 40 46 52
Basal optimisation
Bolus intensification
Error bars: ± standard error (mean) EOT, end of treatment; faster aspart, fast-acting insulin aspart
Russell-Jones et al. Diabetes Care 2017;doi:10.2337/dc16-1771; Mathieu et al. ADA 2017. Poster 992-P
HbA1c 7.5%
HbA1c 7.4%
HbA1c 7.3%
EOT HbA1c 7.6%
EOT HbA1c 7.5%
Time since randomisation (weeks)
Faste
r Aspart
Core
Scie
nce 0
3/0
8/2
017 V
7 0
onset 1: PPG increment at week 26 Standardised meal test: mealtime comparison
Faster aspart (mealtime) Insulin aspart (mealtime)
*p<0.0001; P-values are 2-sided. ETD represents PPG changes from baseline estimates. Changes from baseline in PPG increments were analysed based on an ANOVA model.
0
18
36
54
72
90
108
126
0
1
2
3
4
5
6
7
0
Week 26
PPG
incre
ment
(mg/d
L)
Time (min) Bolus dose 0.1 U/kg
PPG
incre
ment
(mm
ol/
L)
0 60 120 180 240
108
126
72
90
36
54
18
0
6
7
4
5
2
3
1
0
PPG
incre
ment (m
g/d
L)
2-h ETD**: –0.67 mmol/L [95% CI: –1.29; –0.04] –12.0 mg/dL [95% CI: –23.3; –0.7]
**
1-h ETD*: –1.18 mmol/L [95% CI: –1.65; –0.71] –21.2 mg/dL [95% CI –29.7; –12.8]
*
**p=0.0375.
aCompared with mealtime insulin aspart. ANOVA, analysis of variance; CI, confidence interval; ETD, estimated treatment difference (faster aspart–insulin aspart); PPG, postprandial plasma glucose
Error bars: ± standard error (mean). *p<0.0001; **p=0.0375.
Russell-Jones et al. Diabetes Care 2017;doi:10.2337/dc16-1771
Faste
r Aspart
Core
Scie
nce 0
3/0
8/2
017 V
7 0
Week 52
Error bars: ± standard error (mean). P-values are 2-sided. ETD represents PPG changes from baseline estimates. Changes from baseline in PPG increments were analysed based on an ANOVA model
onset 1: PPG increment at week 52 Standardised meal test: mealtime comparison
ANOVA, analysis of variance; CI, confidence interval; ETD, estimated treatment difference (faster aspart–insulin aspart); faster aspart, fast-acting insulin aspart; PPG, postprandial plasma glucose
Mathieu et al. ADA 2017. Poster 992-P
0
1-h ETD*: −0.91 mmol/L (95% CI: −1.40;−0.43) −16.5 mg/dL (95% CI: −25.2;−7.8)
*
*p=0.0002
Bolus dose 0.1 U/kg
2-h ETD: −0.42 mmol/L (95% CI: −1.11;0.27)
−7.6 mg/dL (95% CI: −20.0;4.8)
Faster aspart (mealtime) Insulin aspart (mealtime)
0
6
7
4
5
2
3
1
0 0 60 120 180 240
PPG
incre
ment
(mm
ol/
L)
PPG
incre
ment
(mg/d
L)
108
126
72
90
36
54
18
0
PPG
incre
ment (m
g/d
L)
Time (min)
Faste
r Aspart
Core
Scie
nce 0
3/0
8/2
017 V
7 0
0
10
20
30
40
50
60
70
80
Week 26 Week 52
Severe
or
BG
-confirm
ed h
ypogly
caem
ic e
pis
odes p
er
patient-
year
of exposure
NS
NS
Week 261 Week 522
Estimated ratio
95% CI Estimated
ratio 95% CI
Faster aspart (mealtime)/ insulin aspart (mealtime)
1.01 0.88;1.15 1.01 0.88;1.15
Faster aspart (post-meal)/ insulin aspart (mealtime)
0.92 0.81;1.06 n/a n/a
The analysis was based on a negative binomial regression model. Treatment-emergent was defined as an event that has onset up to 1 day after last day of randomised treatment and excluding the events occurring in the run-in period. Estimated treatment ratios (faster aspart/insulin aspart) are presented with 95% CIs BG-confirmed: PG value <3.1 mmol/L (56 mg/dL) BG, blood glucose; CI, confidence interval; faster aspart, fast-acting insulin aspart; PG, plasma glucose; NS, non-significant
onset 1: treatment-emergent hypoglycaemia
Faster aspart (mealtime)
Insulin aspart (mealtime)
Faster aspart (post-meal)
1. Russell-Jones et al. Diabetes Care 2017;doi:10.2337/dc16-1771; 2. Mathieu et al. ADA 2017. Poster 992-P
NS
No difference in the overall rates of severe or BG-confirmed hypoglycaemia between treatment arms
Faste
r Aspart
Core
Scie
nce 0
3/0
8/2
017 V
7 0
onset 1: conclusions
Faster aspart, fast-acting insulin aspart; PPG, postprandial plasma glucose; T1D, type 1 diabetes
Faster aspart effectively improved glycaemic control in subjects with T1D
• Non-inferiority in HbA1c reduction (mealtime and post-meal) to insulin aspart was confirmed after 26 weeks
• The reduction in HbA1c with faster aspart (mealtime) was statistically significantly larger than with insulin aspart.
• Statistically significantly greater reduction in HbA1c was maintained at week 52 with faster aspart (mealtime) vs. insulin aspart
At week 26, superior PPG control with mealtime faster aspart vs. insulin aspart (2-h PPG increment at meal test) was observed • At week 52, a statistically significant difference was observed only for 1-h PPG increment
No statistically significant difference in the overall rate of hypoglycaemia
Similar overall safety profiles, and as expected for insulin aspart
Russell-Jones et al. Diabetes Care 2017;doi:10.2337/dc16-1771; Mathieu et al. ADA 2017. Poster 992-P
Faste
r Aspart
Core
Scie
nce 0
3/0
8/2
017 V
7 0
8 weeks 1 week/30 days Follow-up
onset 2: trial design A double-blind, treat-to-target trial in T2D
Faster aspart + insulin glargine U100 + metformin
Insulin aspart + insulin glargine U100 + metformin
26 weeks
Patients with T2D on basal insulin and metformin ± other OADs
Randomisation (1:1)
End of treatment
Insulin glargine U100 + metformin
Run-in
This trial is registered at ClinicalTrials.gov: NCT01819129 AE, adverse event; BMI, body mass index; faster aspart, fast-acting insulin aspart; OAD, oral antidiabetic drug; PPG, postprandial plasma glucose; T2D, type 2 diabetes
n=345
n=344
Key inclusion criteria
• T2D for ≥6 months and age ≥18 years
• Basal insulin for ≥3 months
• Metformin ± OADs for ≥3 months
• HbA1c
• Metformin/basal insulin only: 7.0–9.5% (53–80 mmol/mol) or
• Metformin/basal insulin + OAD: 7.0–9.0% (53–75 mmol/mol)
• BMI <40 kg/m2
Key endpoints
• Change in HbA1c
• Change in PPG increment (meal test)
• Change in body weight
• Number of treatment-emergent hypoglycaemic episodes
• Number of treatment-emergent AEs
Basal insulin dose optimisation
Bolus intensification
Bowering et al. Diabetes Care 2017;doi:10.2337/dc16-1770
Faste
r Aspart
Core
Scie
nce 0
3/0
8/2
017 V
7 0
Faster aspart n=345
Insulin aspart n=344
Age, years 59.6 (9.3) 59.4 (9.6)
Male, n (%) 163 (47) 173 (50)
BMI, kg/m2 31.5 (4.7) 31.0 (4.5)
Body weight, kg lb
89.0 (16.9) 196.3 (37.3)
88.3 (16.7) 194.7 (36.9)
Duration of diabetes, years 13.2 (6.7) 12.3 (6.3)
HbA1c, % mmol/mol
8.0 (0.7) 63.5 (7.5)
7.9 (0.7) 62.7 (7.7)
FPG, mmol/L mg/dL
6.8 (1.8) 121.7 (32.7)
6.8 (2.0) 122.7 (35.1)
onset 2: baseline characteristics at randomisation
Data are presented as mean (SD) unless stated otherwise BMI, body mass index; faster aspart, fast-acting insulin aspart; FPG, fasting plasma glucose; SD, standard deviation
Bowering et al. Diabetes Care 2017;doi:10.2337/dc16-1770
Faste
r Aspart
Core
Scie
nce 0
3/0
8/2
017 V
7 0
onset 2: mean HbA1c over time1
Faster aspart
Insulin aspart
8.5
7.5
8.0
6.5
7.0
6.0
5.5
26 -1 -5 -10
0 0.0
HbA
1c (
%)
Time since randomisation (weeks)
HbA
1c (m
mol/m
ol)
64
69
53
58
42
48
8 4 12 16 20 0
37
8.2%
8.1%
8.0%
7.9% EOT 6.6%
EOT 6.6% ETD: –0.02%
(95% CI: –0.15;0.10)
Non-inferiority was confirmed
Error bars: ± standard error (mean) BMI, body mass index; CI, confidence interval; EOT, end of trial; ETD, estimated treatment difference (faster aspart–insulin aspart); faster aspart, fast-acting insulin aspart
Change from baseline in HbA1c was analysed using a mixed-effect model for repeated measurements
Baseline
Basal optimisation Bolus intensification
1. Bowering et al. Diabetes Care 2017;doi:10.2337/dc16-1770
Faste
r Aspart
Core
Scie
nce 0
3/0
8/2
017 V
7 0
2-h ETD:† −0.36 mmol/L (95% CI: −0.81;0.08)
−6.6 mg/dL (95% CI: −14.5;1.4)
1-h ETD:* −0.59 mmol/L (95% CI: −1.09;−0.09) −10.6 mg/dL (95% CI: −19.6;−1.7)
PPG
incre
ment (m
g/d
L)
90
72
54
36
18
0
PPG
incre
ment
(mm
ol/
L)
5
4
3
2
1
0
Time (min) Median bolus dose: 0.16 U/kg
Week 26
**
*
0 60 120 180 240
onset 2: PPG increment at week 26 Significantly greater reduction at 1 h with faster aspart vs. insulin aspart
Faster aspart
Insulin aspart
Error bars: ± standard error (mean). ANOVA, analysis of variance; CI, confidence interval; ETD, estimated treatment difference (faster aspart–insulin aspart); faster aspart, fast-acting insulin aspart; PPG, postprandial plasma glucose
*p=0.0198.
ETD represents PPG change from baseline estimates. The analysis was based on an ANOVA model
†Confirmatory secondary endpoint, not statistically significant
Bowering et al. Diabetes Care 2017;doi:10.2337/dc16-1770
Faste
r Aspart
Core
Scie
nce 0
3/0
8/2
017 V
7 0
onset 2: mean body weight over time
Faster aspart
Insulin aspart
Body w
eig
ht (lb
)
Time since randomisation (weeks)
87
89
91
93
95
Body w
eig
ht
(kg)
192
196
201
205
209
0 12 26
Error bars: ± standard error (mean) CI, confidence interval; ETD, estimated treatment difference (faster aspart–insulin aspart); faster aspart, fast-acting insulin aspart
ETD: 0.00 kg (95% CI: −0.60;0.61)
2.7 kg weight gain for both groups
*p=0.0198.
ETD represents PPG change from baseline estimates. The analysis was based on an ANOVA model
Bowering et al. Diabetes Care 2017;doi:10.2337/dc16-1770
Faste
r Aspart
Core
Scie
nce 0
3/0
8/2
017 V
7 0
onset 2: treatment-emergent hypoglycaemia No difference in rates of severe or BG-confirmed hypoglycaemia
0
5
10
15
20
25
Severe
or
BG
-confirm
ed h
ypogly
caem
ic e
pis
odes p
er
patient-
year
of
exposure
NS
Estimated ratio
95% CI
Faster aspart/ insulin aspart
1.09 0.88;1.36
The analysis was based on a negative binomial regression model. Treatment-emergent was defined as an event that has onset up to 1 day after last day of randomised treatment and excluding the events occurring in the run-in period. Estimated treatment ratios (faster aspart/insulin aspart) are presented with 95% confidence intervals. BG-confirmed: PG value <3.1 mmol/L (56 mg/dL) BG, blood glucose; CI, confidence interval; faster aspart, fast-acting insulin aspart; PG, plasma glucose; NS, non-significant
Faster aspart (mealtime)
Insulin aspart (mealtime)
Bowering et al. Diabetes Care 2017;doi:10.2337/dc16-1770
Faste
r Aspart
Core
Scie
nce 0
3/0
8/2
017 V
7 0
onset 2: conclusions
†Confirmatory secondary endpoint BG, blood glucose; CI, confidence interval; EOT, end of trial; ETD, estimated treatment difference (faster aspart–insulin aspart); faster aspart, fast-acting insulin aspart; PPG, postprandial plasma glucose; T2D, type 2 diabetes
PPG regulation (meal test): • 1-h PPG increment significantly improved vs. insulin aspart
(ETD [95% CI]:−0.59 mmol/L [−1.09;−0.09]; −10.6 mg/dL [−19.6;−1.7]) • 2-h PPG increment† not significantly improved vs. insulin aspart
(ETD [95% CI]: −0.36 mmol/L [−0.81;0.08]; −6.6 mg/dL [−14.5;1.4])
Faster aspart effectively improved glycaemic control (EOT HbA1c = 6.6%) in subjects with T2D previously on basal insulin only • HbA1c reduction: non-inferior to insulin aspart
No statistically significant difference was seen in overall rate of severe or BG-confirmed hypoglycaemic episodes
Similar overall safety profile with faster aspart and insulin aspart
Bowering et al. Diabetes Care 2017;doi:10.2337/dc16-1770
Faste
r Aspart
Core
Scie
nce 0
3/0
8/2
017 V
7 0
Randomised, double-blind, crossover trial evaluating the PK/PD properties of faster aspart, under glucose clamp conditions, during CSII in 48 patients with T1D receiving faster aspart or insulin aspart as a CSII bolus dose on top of basal CSII
Inclusion criteria
• T1D for ≥12 months
• Treatment with MDI or CSII for ≥12 months
• BMI 18.5–28.0 kg/m2
• HbA1c ≤8.5%
PK/PD study in CSII Comparing faster aspart with insulin aspart
3–12 days washout period
Dosing 1 day
Follow-up 7–21 days
Screening 3–21 days
Dosing 1 day
Faster aspart basal 0.02 U/kg/h bolus 0.15 U/kg
Insulin aspart basal 0.02 U/kg/h bolus 0.15 U/kg
Insulin aspart basal 0.02 U/kg/h bolus 0.15 U/kg
Faster aspart basal 0.02 U/kg/h bolus 0.15 U/kg
N=48 Primary endpoint
• AUCIAsp, 0–30 min (pmol*h/L)
Heise et al. Diabetes Obes Metab 2017;19(2):208–215
This trial is registered at ClinicalTrials.gov: NCT01992588. AUC, area under the curve; BMI, body mass index; CSII, continuous subcutaneous insulin infusion; faster aspart, fast-acting insulin aspart; IAsp, insulin asaprt; MDI, multiple daily injections; PK/PD, pharmacokinetic/pharmacodynamic; T1D, type 1 diabetes
Fast-acting insulin aspart is approved in Europe and it has not been launched in Spain
PK: Early insulin exposure ~3-fold higher insulin exposure within the first 30 min with fast-acting insulin aspart vs. IAsp
*p<0.001. Treatment ratios (fast-acting insulin aspart / insulin aspart) and 95% CI. AUC, area under the curve; CI, confidence interval; CSII, continuous subcutaneous insulin infusion; IAsp, insulin aspart; LLoQ, lower limit of quantification; PK, pharmacokinetic. Heise T et al. Diabetes Obes Metab 2017;19:208–15.
3890
Fast-acting insulin aspart is approved in Europe and it has not been launched in Spain
Trial design A randomised exploratory crossover pump trial with meal test
CSII, continuous subcutaneous insulin infusion; BMI, body mass index; CGM, continuous glucose monitoring; PG, plasma glucose. Bode B et al. Diabetes Technol Ther 2017;19:25–33.
3930
Faste
r Aspart
Core
Scie
nce 0
8032017 V
6 0
PPG in CSII with faster aspart Improved PPG after a meal test in CSII with faster aspart vs. insulin aspart
Time (min)
0 120 180 240 60
0
8
2
4
6
Baseline-a
dju
ste
d p
lasm
a g
lucose
(mm
ol/
L)
Insulin aspart
Faster aspart
∆PG0–1 ha
–0.50 (–1.07;0.07) mmol/Lb
∆PG0–2 ha
–0.99 (–1.95;–0.03) mmol/Lb*
Bode et al. Diabetes Technol Ther 2017;19:25–33
*p<0.05 aPGav,0–1 (2)h was calculated as AUCPG,0-2 h/2 h – PGPre-dose where AUCPG,0-2h was the area under the plasma glucose concentration time profile based on observed
values and actual measurement times in relation to time of injection between 0 and 2 h; btreatment difference, 95% CI AUC, area under the curve; CI, confidence interval; CSII, continuous subcutaneous insulin infusion; faster aspart, fast-acting insulin aspart; PG, plasma glucose; PPG, postprandial plasma glucose
Fast-acting insulin aspart is approved in Europe and it has not been launched in Spain
Trial design
*Follow-up (7 and 30 days). 1,5-AG, 1,5-anhydroglucitol; AE, adverse event; BMI, body mass index; CGM, continuous glucose monitoring; CSII, continuous subcutaneous insulin infusion; FU, follow-up; IG, interstitial glucose; PPG, postprandial glucose. 1. NN1218-3854. Klonoff D et al. Diabetes Technol Ther 2018; 20(Suppl 1): A32–3.
onset 5
Fast-acting insulin aspart is approved in Europe and it has not been launched in Spain
Baseline characteristics at randomisation
Data are mean unless otherwise stated. BMI, body mass index; FPG, fasting plasma glucose; n, number of randomised subjects. 1. NN1218-3854. Klonoff D et al. Diabetes Technol Ther 2018; 20(Suppl 1): A32–3.
onset 5
Fast-acting insulin aspart is approved in Europe and it has not been launched in Spain
Mean HbA1c over time
*Non-inferiority confirmed at 0.4% level p-value for non-inferiority p<0.001, **p=0.022. Error bars: ± standard error (mean). Primary estimand. All available information regardless of treatment discontinuation was used. Change from baseline in HbA1c was analysed using a multiple imputation model. ETD represents fast-acting insulin aspart minus insulin aspart values. CI, confidence interval; ETD, estimated treatment difference. 1. NN1218-3854. Klonoff D et al. Diabetes Technol Ther 2018; 20(Suppl 1): A32–3.
onset 5
Fast-acting insulin aspart is approved in Europe and it has not been launched in Spain
PPG increment at baseline and week 16
*p<0.001, **p=0.001, ***p=0.01. Error bars: ± standard error (mean). Primary estimand. All available information regardless of treatment discontinuation was used. The conversion factor between mmol/L and mg/dL is 0.0555 Change from baseline in PPG increment was analysed using a multiple imputation model. CI, confidence interval; ETD, estimated treatment difference [fast-acting insulin aspart – insulin aspart] for PG changes from baseline; PG, plasma glucose; PPG, postprandial glucose. 1. NN1218-3854. Klonoff D et al. Diabetes Technol Ther 2018; 20(Suppl 1): A32–3.
onset 5
Meal test
Fast-acting insulin aspart is approved in Europe and it has not been launched in Spain
Treatment-emergent hypoglycaemia after 16 weeks
Treatment-emergent is defined as an event that has onset up to 1 day after last day of randomised treatment and excluding the events occurring in the run-in period BG-confirmed: PG value <3.1 mmol/L (56 mg/dL). Statistical analysis is based on a negative binomial regression model. BG, blood glucose; N, number of subjects with at least one event; %, percentage of subjects; E, number of events; R, number of events per patient-year of exposure. 1. NN1218-3854. Klonoff D et al. Diabetes Technol Ther 2018; 20(Suppl 1): A32–3.
onset 5
Fast-acting insulin aspart is approved in Europe and it has not been launched in Spain
Why was the HbA1c reduction with fast-acting insulin aspart vs. IAsp lower, despite of improved PPG profile?
IAsp, insulin aspart.
Examination of CGM profiles for fast-acting insulin aspart vs. IAsp, showed:
Fast-acting insulin aspart is approved in Europe and it has not been launched in Spain
Fast-acting insulin aspart vs. IAsp treatment with CSII has benefits for patients:
How can we interpret findings from onset 5?
BG, blood glucose; CSII, continuous subcutaneous insulin infusion; IAsp, insulin aspart; PPG, postprandial glucose.
Fast-acting insulin aspart is approved in Europe and it has not been launched in Spain
1- La glicèmia postprandial és un element molt important del control glicèmic
2- Faster Aspart presenta una PK/PD més fisiològica que els anàlegs actuals
3- Faster Aspart presenta un millor control glicèmic postprandial
4- L´impacte sobre el control glicèmic global és encara limitat: aspecte pràctic
de la flexibilitat d´administració valorable
5- Hem de tenir més dades d´estudis per definir bé l´abast del seu benefici i
disposar d´estratègies per maximitzar-ho.
Fast-acting insulin aspart is approved in Europe and it has not been launched in Spain
Treatment-emergent AEs during 16 weeks
Treatment emergent is defined as an event that has onset up to 7 days after last day of randomised treatment and excluding the events occurring in the run-in period. AE, adverse event; E, number of events; ECG, electrocardiogram; N, number of subjects with at least one event; R, number of events per patient-year of exposure; %, percentage of subjects. 1. NN1218-3854. Klonoff D et al. Diabetes Technol Ther 2018; 20(Suppl 1): A32–3.
onset 5