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Impact des nouvelles insulines dans la prise en charge du DT2
@PrAvignon
Antoine Avignon
Pr. A Avignon
CHU Montpellier, Nutrition – Diabète
Université Montpellier 1, UFR Médecine
INSERM U1046, CNRS UMR9214
Disclosures:
Novo Nordisk, MSD, Eli lilly, Sanofi, AstraZeneca,
The consequences of hyperglycaemia
DCCT N Engl J Med 1993;329:977-86; Stratton et al. BMJ 2000;321:405–12
Brain
Eyes
Nervous system
Heart
Kidneys
Circulation
Pregnancy and birth
Intensive vs. conventional treatment in T1D and T2D DCCT/EDIC and UKPDS follow-up data
†p<0.05; intensive vs. conventional treatment; DCCT, Diabetes Control and Complications Trial; EDIC, European Diploma in Intensive Care Medicine; T1D, type 1 diabetes; T2D, type 2 diabetes; UKPDS, UK Prospective Diabetes Study. 1. DCCT/EDIC Group. JAMA 2002;287:2563–9; 2. Martin et al. Diabetes Care 2006;29:340–4; 3. UKPDS Study Group. Lancet 1998;352:837–53; 4. Holman et al. N Engl J Med 2008;359:1577–89
0
5
10
15
20
25
30
Conventional Intensive
Retinopathy Neuropathy Renal
*66%
***76%
**53%
***86% ****62%
****36%
% o
f patients
who p
rogre
ssed
*p=0.006 **p=0.002 ***p<0.001 ****p<0.0001
T1D DCCT/EDIC – microvascular complications1,2
(4-years post-EDIC trial)
Any diabetes-related endpoint
Myocardial infarction
Microvascular disease
1977–1991 Randomisation
2007 (30 years)
10-years post-trial follow-up period (non-interventional)
UKPDS original results: Intensive vs. conventional treatment
12%†
25%†
16%
1997 (20 years)
9%†
24%†
15%†
Improvements in glycaemic control reduce the risk of
complications
T2D UKPDS – macrovascular complications3,4
Glycaemic control recommendations ADA/EASD, AACE and IDF guidelines
*No comorbidities, long life expectancy †Depending on disease duration, life expectancy, important comorbidities, patient attitudes and resource or support targets can be set more or less stringent AACE, American Association of Clinical Endocrinologists; ADA, American Diabetes Association; EASD, European Association for the Study of Diabetes; FPG, fasting plasma glucose; IDF, International Diabetes Federation; T1D, type 1 diabetes; T2D, type 2 diabetes. 1. Chiang et al. Diabetes Care 2014;37:2034–54; 2. Inzucchi et al. Diabetologia 2015;58:429–42; 3. ADA Guidelines Diabetes Care 2015;38:33–40; 4. Garber et al. Endocr Pract 2016;22;84–113; 5. IDF 2012 Global Guideline for Type 2 Diabetes. http://www.idf.org/sites/default/files/IDF-Guideline-for-Type-2-Diabetes.pdf
Age group T1D1 T2D2
Young (<18 years) <7.5% 7.0%
Adult <7.0% 7.0%
Older adults Healthy* Complex/intermediate Very complex/poor health
<7.5% <8.0% <8.5%
7.0%†
Association FPG target
ADA/EASD2,3 <7.2 mmol/L <130 mg/dL
AACE4 <6.1 mmol/L <110 mg/dL
IDF5 <6.5 mmol/L <115 mg/dL
HbA1c recommendations (ADA/EASD)
FPG recommendations
The worldwide challenge of glycaemic control HbA1c in T1D and T2D
*Data are median and in adults (25+ years) T1D, type 1 diabetes; T2D, type 2 diabetes 1. McKnight et al. Diabet Med 2015;32:1036–50; 2. Oguz et al. Curr Med Res Opin 2013;29:911–20; 3. Polinski et al. BMC Endocr Disord 2015;15:46; 4. Mendivil et al. Curr Med Res Opin 2014;30:1769–76
T1D1* T2D2–4
France: 8.0%
Norway: 7.9%
Sweden: 8.0%
Ukraine: 7.4%
Italy: 7.5%
New Zealand: 8.3%
USA: 7.5%
Greece: 7.6%
Denmark: 7.9%
UK: 8.3–8.5%
Netherlands: 7.5%
Russia: 7.7%3
India: 8.6%3
Sweden: 8.7%2
Poland: 9.0%2
Portugal: 9.7%2
UK: 8.4%3
USA: 8.0%3
Canada: 7.9%3
China: 7.6%3
South Korea: 8.0%3
Romania: 9.9%2
Turkey: 8.9–10.6%2,3
Greece: 9.0%2
Latin America: 8.5%4
Challenges of maintaining glycaemic control Surveys identifying challenges with rigid regimens and the fear of hypoglycaemia
HFS, Hypoglycaemia Fear Survey; 2. Total patient sample, n=1984 1. Peyrot et al. Diabet Med 2012;29:682–9; 2. Marrett et al. Diabetes 2008;57(Suppl. 1):A174
Complex and inflexible regimens1 Fear of hypoglycaemia2
54,4%
81,4%
23,1% 27,6% 0%
20%
40%
60%
80%
100%
Hard to live
normal life
while
managing
diabetes
Wish insulin
regimen would
fit daily life
changes
Number of
daily injections
Taking insulin
at prescribed
time/meals
everyday
Increasing severity of hypoglycaemia
All comparisons significant
Pro
port
ion o
f patients
(%
)
27,5
20,1
12,3
6,2 0
5
10
15
20
25
30
Mean H
FS I
I w
orr
y s
core
Fear of hypoglycaemia conflicts with treatment success for both patients and clinicians
Total patient sample, n=335 (T1D, n=202; T2D, n=133) GAPP™ (A global internet survey of patient and physician beliefs T1D, type 1 diabetes; T2D, type 2 diabetes regarding insulin therapy): n=1250 physicians Leiter et al. Can J Diabetes 2005;29:186–92 Peyrot et al. Diabet Med 2012;29:682–9
74% 79%
43%
58%
0%
20%
40%
60%
80%
100%
Non-severe episodes Severe episodes
Patients
modifyin
g insulin d
ose
T1D T2D
72%
79%
0 50 100
Percentage
I would treat my patients more aggressively if there was no concern about hypoglycaemia
Percentage of patients decreasing their insulin dose following a hypoglycaemic event
Primary care physicians Diabetes specialists
Hypoglycaemia rates are higher than expected Results from the HAT study
HAT, Hypoglycaemia Assessment Tool; T1D, type 1 diabetes; T2D, type 2 diabetes Khunti et al. Diabetes Obes Metab 2016: 2016;18:907–15; Khunti et al. Poster presented at the 10th International Diabetes Federation-Western Pacific Region Congress, 21–24 November 2014, Singapore
HAT study
• Non-interventional, global, 6-month retrospective and 1-month prospective study of patient self-reported hypoglycaemic events
• n=27,585 (T1D: 8,022; T2D: 19,563)
2,1
4,9
0,9
2,5
0
1
2
3
4
5
6
Severe hypoglycaemia
Hypogly
caem
ia
incid
ence,
events
per
patient-
year
Prospective data suggests higher than previously observed rates of hypoglycaemia in both T1D and T2D, in particular severe events
T1D, retrospective (n=8,022)
T1D, prospective (n=7,108)
T2D, retrospective (n=19,563)
T2D, prospective (n=18,518)
Need for innovation
Objectives of developing a new basal insulin
Glycaemic control
Low risk of hypoglycaemia
Once-daily administration
Possibility of flexible dosing
Effectiveness (glucose-lowering effect)
Flat time-action profile
Low variability
Long duration of action
Target profiles for new insulin analogues Mimicking physiological responses
For illustrative purposes only
Action profile of today’s modern insulins
Targeted action profiles of future insulins
Insulin degludec Rationally designed, beyond sequence modification
Jonassen et al. Pharm Res 2012;29:2104–14
NH
O
OH
O NH
O
OH
O
DesB30 insulin
DesB30
T
Des(B30) LysB29(γ-Glu Nε-hexadecandioyl) human insulin
s s
s s
A1
B1
A21 s s
T Y G E E C Y C C N L Q L S I S Q V I N C
P T Y Y F F F G G G R E E C C V L L A V L H S L H Q N V K
L-γ-Glu Glutamic acid
‘spacer’
NH
O
OH
O NH
O
Hexadecandioyl Fatty diacid side
chain
Insulin degludec Mode of protraction
Jonassen et al. Pharm Res 2012;29:2104–14
[ Phenol; Zn2+]
Insulin degludec is administered with a pen device into the
subcutaneous tissue
Insulin degludec Mode of protraction
Jonassen et al. Pharm Res 2012;29:2104–14
[ Phenol; Zn2+]
The stable dihexamers formed in solution in the pen are injected into the subcutaneous space
fatty acid side-chains
monomers
Insulin degludec Mode of protraction
Jonassen et al. Pharm Res 2012;29:2104–14
[ Phenol; Zn2+]
Insulin degludec Mode of protraction
Jonassen et al. Pharm Res 2012;29:2104–14
[ Phenol; Zn2+]
After injection, the insulin degludec dihexamers adapt to an open conformation after phenol has
rapidly diffused from the vehicle
Insulin degludec Mode of protraction
Jonassen et al. Pharm Res 2012;29:2104–14
[ Zn2+]
After the diffusion of phenol and conformation change, the dihexamers link
together via single side-chain contacts. Long multihexamer chains assemble
Insulin degludec Mode of protraction
Jonassen et al. Pharm Res 2012;29:2104–14
Monomers are absorbed from the depot into the circulation
Zinc diffuses slowly causing individual hexamers to
disassemble, releasing monomers [ Zn2+]
The pharmacokinetics and pharmacodynamics
of insulin degludec
Half-life of IDeg is twice as long as that of IGlar U100
*IGlar U100 was undectable after 48 hours. Results from 66 patients with T1D IDeg, insulin degludec; IGlar U100, insulin glargine U100; T1D, type 1 diabetes Heise et al. Diabetes 2011;60(Suppl. 1):LB11; Heise et al. Diabetologia 2011;54(Suppl. 1):S425; Heise et al. Expert Opin Drug Metab Toxicol 2015;11:1193–201
1
10
100
0 24 48 72 96 120Insulin c
oncentr
ation
(% o
f m
axim
um
)
Time since injection (hours)
*
IDeg 0.8 U/kg
IGlar U100 0.8 U/kg
IDeg IGlar U100
0.4 U/kg 0.6 U/kg 0.8 U/kg 0.4 U/kg 0.6 U/kg 0.8 U/kg
Half-life (hours) 25.9 27.0 23.6 11.5 12.9 11.9
Mean half-life 25.4 12.1
IDeg concentration reaches clinical steady state in 2–3 days
T1D trial, n=66, 0.4, 0.6 or 0.8 U/kg; T2D trial, n=49, 0.4, 0.6 or 0.8 U/kg Estimated ratios and 95% CI CI, confidence interval; IDeg, insulin degludec; T1D, type 1 diabetes; T2D, type 2 diabetes Heise et al. Diabetes 2012;61(Suppl. 1):A259
5 4 3 2 0 1 6
Days since first dose
Seru
m I
Deg c
oncentr
ation
Pro
port
ion o
f D
ay 6
level (%
)
120
110
100
90
80
70
60
50
40
30
20
10
0
T1D T2D
0 1 2 3 4
Seru
m I
Deg c
oncentr
ation
Pro
port
ion o
f D
ay 4
level (%
)
120
110
100
90
80
70
60
50
40
30
20
10
0
Days since first dose
Reaching steady state with IDeg without stacking
IDeg, insulin degludec; s.c., subcutaneous Figure adapted from Heise and Meneghini Endocr Pract 2014;20:75–83
Units added each day
Units remaining from prior injections
(t1/2~24 h) Units absorbed into circulation
Insulin in s.c. depot Insulin in circulation Injected insulin Maximum units present in 24 h
interval
Elimination of any insulin follows
first order kinetics.
Therefore there is no stacking
5 U Day
1 10 U 10 U
50%
7.5 U
5 U 15 U
10 U
Day 2 + 50%
~9 U
7.5 U
17.5 U
10 U
Day 3 + 50%
~9 U
19 U
~10 U
10 U
Day 4 + 50%
~10 U
20 U
10 U
10 U
Day 5 + 50%
10 U
0 2 4 6 8 10 12 14 16 18 20 22 24
Time (hours)
0
1
2
3
4
5
6
GIR
(m
g/k
g/m
in)
Flat time-action profile in T1D and T2D at steady state
1. IDeg, n=66, 0.4 U/kg; 2. Randomised, 2-period, 12-day trial; n=49; Variability was assessed at steady state by clamps on days 6 and 12 AUC, area under the curve; GIR, glucose infusion rate; IDeg, insulin degludec; T1D, type 1 diabetes; T2D, type 2 diabetes 1. Heise et al. Expert Opin Drug Metab Toxicol 2015;11:1193–201; 2. Heise et al. Diabetes Obes Metab 2012;14:944–50
IDeg
Dose level AUCGIR,0–12h AUCGIR,12-24h
0.4 U/kg 51% 49%
T1D at steady state1
0.8 U/kg 0.6 U/kg 0.4 U/kg
0
1
2
3
4
5
0 4 8 12 16 20 24
GIR
(m
g/k
g/m
in)
Time since injection (hours)
T2D at steady state2
0
25
50
75
100
125
150
175
200
225
250
275
Day-t
o-d
ay v
ariability in
AU
CG
IR (
CV%
)
Lower day-to-day variability in glucose-lowering effect for IDeg versus IGlar U100/U300
FAS AUC, area under the curve; CV, coefficient of variation; GIR, glucose infusion rate; IDeg, insulin degludec; IGlar U100, insulin glargine U100; IGlar U300, insulin glargine U300 *NN1250-4227: Heise et al. Presented at Diabetes Technology Meeting, 16th Annual Scientific Sessions, 10–12 November 2016, Bethesda, MD, USA **NN1250-1991: Heise et al. Diabetes Obes Metab 2012;14:859-64
Time interval (hour) Time interval (hour)
IDeg vs. IGlar U300* IDeg vs. IGlar U100**
IDeg
IGlar U300
IGlar U100
Glucose-lowering effect is more consistent with IDeg than IGlar U100
Proportion of effect in 6-hour time intervals across one dosing interval (%) Patients with T1D (n=66) AUC, area under the curve; GIR, glucose infusion rate; IDeg, insulin degludec; IGlar U100, insulin glargine U100; T1D, type 1 diabetes Heise et al. Expert Opin Drug Metab Toxicol 2015;11:1193–201
23
28 26
23
0
5
10
15
20
25
30
35
0-6 6-12 12-18 18-24
Pro
port
ion o
f AU
C G
IR (
%)
Time intervals (hours)
31 29
23
17
0
5
10
15
20
25
30
35
0-6 6-12 12-18 18-24
Pro
port
ion o
f AU
C G
IR (
%)
Time intervals (hours)
IDeg 0.4 U/kg
IGlar U100 0.4 U/kg
Flexible administration of IDeg was tested in both T1D and T2D Two phase 3a clinical trials (6 and 12 months)
IDeg, insulin degludec; T1D, type 1 diabetes; T2D, type 2 diabetes Meneghini et al. Diabetes Care 2013;36:858–64; Mathieu et al. J Clin Endocrinol Metab 2013;98:1154–62
MON TUE WED THUR FRI SAT SUN
12am
2am
12pm
4am
6am
8am
10am
2pm
4pm
6pm
8pm
10pm
Morning Morning Morning
Evening Evening Evening Evening
40h 8h 40h 40h 8h 24h
Flexibility can benefit patients who find it challenging to inject at the same time each day1,2
IDeg, insulin degludec; IGlar U100, insulin glargine U100; NS, not significant; OD, once daily 1. Aye & Atkin. Drug, Healthcare and Patient Safety 2014;6:55–67; 2. Meneghini et al. Expert Rev Endocrinol Metab 2012;7:9–14; 3. Meneghini et al. Diabetes Care 2013;36:858–64
“…In particular, this could include
individuals who travel regularly ... Shift
workers may also greatly benefit from the
freedom to change their dosing schedule…”1
“Flexibility in the timing of insulin
administration can benefit patients who
find it challenging to always inject
insulin at the same time each day.”2
0,00,20,40,60,81,01,21,41,61,82,0
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Confirm
ed h
ypogly
caem
ia
(cum
ula
tive e
vents
per
patient)
0
45
60
50
75
70
55
40
HbA
1c (m
mol/m
ol)
65
35
5,0
5,5
6,0
6,5
7,0
7,5
8,0
8,5
9,0
0 2 4 6 8 10 12 14 16 18 20 22 24 26
HbA
1c (
%)
HbA1c3
0.0
IDeg Flexible vs IGlar U100 Treatment difference:
non-inferior
NS
Time (weeks)
IDeg Flexible vs IDeg Fixed Treatment difference:
NS
Confirmed hypoglycaemia3
Time (weeks)
IDeg Flexible OD IDeg Fixed OD IGlar U100 OD
Insuline Degludec delivers
significant reductions in severe hypoglycaemia vs IGlar U1001-4
Reference: 1. Ratner et al. Diabetes Obes Metab. 2013;15:175-184. 2. Lane et al. 87-LB. Presented at ADA 10-14 June 2016, New Orleans. 3. Wysham et al. 90-LB. Presented at the ADA 76th Annual Scientific Sessions, 10-14 June 2016, New Orleans. 4. Marso et al. June 12, 2017. NEJM. DOI: 10.1056/NEJMoa1615692.
Reduction in severe hypoglycaemic events Estimated rate ratio [95% CI]
Meta-analysis of patients with T2DM BOT (insulin naïve)1
86%*
0.14 [0.03-0.70]
Insuline Degludec significantly reduces severe hypoglycaemia when compared with IGlar U100:†1-4
DEVOTE – patients with T2DM and high CV risk [all
severe]4
40%*
0.60 [0.48; 0.76]
SWITCH 1 – patients with T1DM with ≥1 risk factor
for hypoglycaemia2‡
FULL TREATMENT PERIOD§
26%*
0.74 [0.61; 0.91]
MAINTENANCE PERIOD§
35%*
0.65 [0.48; 0.89]
SWITCH 2 – patients with T2DM with ≥1 risk factor
for hypoglycaemia3‡
FULL TREATMENT PERIOD§
51%*
0.49 [0.26; 0.94
MAINTENANCE PERIOD§
46%#
0.54 [0.21; 1.42]
*p < 0.05; #p= NS
†A significant reduction in severe hypoglycaemia not observed in T2DM B/B; §Maintenance was the
predefined period of analysis; ‡Combined treatment period 1 and 2; B/B, basal bolus therapy; BOT, basal
oral therapy; CI, confidence interval; CV, cardiovascular; NS, non-significant
Stable IDeg dihexamers can be co-formulated with insulin aspart
IDeg, insulin degludec
IDeg with insulin aspart (IDegAsp)
IDeg and IAsp exist separately in solution
Size-exclusion chromatography of IDegAsp in conditions simulating the pharmaceutical formulation IAsp, insulin aspart; IDeg, insulin degludec Havelund et al. Pharm Res 2015;32:2250–8
1.00
0.90
0.80
0.70
0.60
0.50
0.40
0.30
0.20
0.10
0.00
4 5 6 7 8 9 10 11 12 13 14
IDeg
dihexamer
IAsp
hexamer
Absorb
ance u
nits
Minutes
IDeg:IAsp
Challenges with co-formulating IDet or IGlar U100 with rapid-acting analogues
IAsp, insulin aspart; IDet, insulin detemir; IGlar U100, insulin glargine U100; PD, pharmacodynamic; PK, pharmacokinetic 1. Lantus® US Prescribing Information. Sanofi April 2010; 2. Jonassen et al. Pharm Res 2012;29:2104–14
IDet IAsp Mixed hexamers
pH 7.0 0.0 14.0
IGlar U100 is soluble at pH 4
Rapid-acting analogue soluble at pH 7.4
IGlar U100 is soluble at pH 4 and designed to microprecipitate at neutral pH (7.4) in subcutaneous tissue, whereas commercially available rapid-acting analogues are
soluble at pH 7.41
Insulin glargine
Insulin detemir
When IDet is co-formulated with commercially available rapid-acting analogues under standard conditions, mixed hexamers form with unsuitable PK/PD profiles2
1. Heller S, et al. Diabetes Metab Res Rev. 2012;28(1):50-61. 2. Heise T, et al. Diabetes Care. 2011;34(3):669-674. 3. Jonassen I, et al. Pharm Res. 2012;29(8):2104–2114.
IDegAsp is a unique combination of two soluble insulin analogues in one pen: 70% IDeg and 30% IAsp
Comparators
SIMPLE vs STEP-WISE Prior BOT, n=272
Simple vs. step-wise
IDegAsp phase 3 clinical trial programme overview
*Simple vs. step-wise titration algorithm; BB, basal–bolus; BIAsp 30, biphasic insulin aspart 30; BID, twice daily; BOT, basal-oral therapy; IAsp, insulin aspart; IDegAsp, insulin degludec/insulin aspart; IDeg, insulin degludec; IGlar U100, insulin glargine U100
Phase 3a Phase 3b
T1 Basal-bolus, n=548
INTENSIFY PREMIX I Intensify from premix, n=447
TWICE-DAILY vs BB
Prior BOT, n=274
START I Insulin-naïve, n=530
T1 paediatric Basal–bolus,
n=362
SIMPLE USE Basal start, n=276
Simple vs. step-wise
JAPAN Insulin-naïve, n=296
INTENSIFY BASAL BOT, n=465
INTENSIFY ALL Intensify any
insulin, n=424
INTENSIFY BID Intensify from
IDegAsp, n=40
START TWICE DAILY Insulin start, n=394
Type 1 diabetes
Insulin-naïve type 2 diabetes
Insulin-experienced type 2 diabetes
vs. insulin detemir vs. IGlar U100 vs. IDeg + IAsp with meals vs. BIAsp 30
OD
B
ID
vs. IDegAsp*
RAMADAN Insulin experienced,
fasting, n=263
Standards of Medical Care in Diabetes 2017
*Si la glycémie > 3g/l ou si l’HbA1c > 10%. ADA. Diabetes Care 2017;40:S1–135
Considérer d’emblée un schéma multi-injections si le patient est franchement
déséquilibré*
Insulin-experienced T2D BID: study design BOOST TWICE-DAILY vs BASAL-BOLUS
Pre-trial OADs included metformin, DPP-4 inhibitor, sulphonylurea/glinides or α-glucosidase inhibitor. Basal insulin and sulphonylurea/glinides (if administered) were discontinued at randomisation. 64% of patients had been previously treated with IGlar U100 BID, twice daily; BMI, body mass index; IAsp, insulin aspart; IDeg, insulin degludec; IDegAsp, insulin degludec/insulin aspart; IDet, insulin detemir; IGlar U100, insulin glargine U100; NPH, neutral protamine Hagedorn; OAD, oral antidiabetic drug; OD, once daily; T2D, type 2 diabetes Rodbard et al. Diab Obes Metab 2016;18:274-80
IDegAsp BID ± OADs (n=138)
IDeg OD + IAsp (2–4 injections/day) ± OADs (n=136)
Patients with type 2 diabetes (n=274)
0 26 weeks
Open-label
Inclusion criteria
• Type 2 diabetes ≥26 weeks
• Currently treated with basal insulin (IDet, IGlar U100, NPH) ± OADs for ≥12 weeks
• HbA1c 7.0–10.0%
• BMI ≤40 kg/m2
• Age ≥18 years
Primary endpoint • Change from baseline in HbA1c after 26 weeks of treatment.
Key secondary endpoints
• FPG
• 8-point SMPG profiles
• Insulin dose
• Number of daily insulin injections
• Body weight
• AEs
• Rate of severe, confirmed and nocturnal confirmed hypoglycaemia.
TWICE DAILY vs BASAL-BOLUS Pays participants
Rodbard HW et al. Diabetes Obes Metab 2015; doi: 10.1111/dom.12609 [Epub ahead of print]
United States
Austria
France
Algeria
Norway
Baseline
*Calculated, not measured. FAS; Values are mean (SD) unless otherwise stated. BMI, body mass index; FAS, full analysis set; FPG, fasting plasma glucose; HbA1c, glycated haemoglobin; IAsp, insulin aspart; IDeg, insulin degludec; IDegAsp, insulin degludec/insulin aspart; OAD, oral antidiabetic drug; SD, standard deviation Rodbard HW et al. Diabetes Obes Metab 2015; doi: 10.1111/dom.12609 [Epub ahead of print]
Characteristic [IDegAsp] [IDeg+IAsp]
N 138 136
Female/male, % 47.1/52.9 36.8/63.2
Race: White/Black/Asian/Other, % 92.0/6.5/0.0/1.4 92.6/5.1/2.2/0.0
Ethnicity: Hispanic or Latin American, % 13.8 12.5
Age, years 59.6 (8.3) 59.6 (9.2)
Weight, kg 91.2 (17.7) 93.3 (15.2)
BMI, kg/m2 32.2 (4.7) 32.0 (4.5)
Duration of diabetes, years 13.5 (7.2) 11.7 (7.2)
HbA1c, % 8.3 (0.9) 8.3 (0.7)
HbA1c, mmol/mol* 67.2 67.2
FPG, mmol/L FPG, mg/dL
9.0 (3.0) 162.4 (54.0)
8.8 (2.9) 159.2 (52.7)
With OAD at screening, n 130 122
Insulin-experienced T2D BID: results BOOST TWICE-DAILY vs BASAL-BOLUS
aCalculated, not measured. BID, twice daily; ETD, estimated treatment difference; ERR, estimated rate ratio; FPG, fasting plasma glucose; IAsp, insulin aspart; IDeg, insulin degludec; IDegAsp, insulin degludec/insulin aspart; NS, not significant; OD, once daily; T2D, type 2 diabetes Rodbard et al. Diab Obes Metab 2016;18:274-80
IDegAsp BID (n=138)
IDeg OD + IAsp (n=136)
HbA
1c (m
mol/m
ol)
a
63
0
51
60
75
69
57
45
72
66
54
48
6,0
6,5
7,0
7,5
8,0
8,5
9,0
0 2 4 6 8 10 12 14 16 18 20 22 24 26
HbA
1c (%
)
HbA1c
0.0
Time (weeks)
Treatment difference:
non-inferiority not confirmed
ETD: 0.18%-points [-0.04; 0.41]
NS
0
1
2
3
4
5
6
7
8
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Confirm
ed h
ypogly
caem
ia
(cum
ula
tive e
vents
per
patient)
Confirmed hypoglycaemia
Time (weeks)
19% lower rate with IDegAsp ERR: 0.81 [0.61; 1.07]
NS
84
96
108
120
132
144
156
168
FPG
(mg/d
L)
0
180
4,0
5,0
6,0
7,0
8,0
9,0
10,0
0 2 4 6 8 10 12 14 16 18 20 22 24 26
FPG
(m
mol/
L)
FPG
0.0
Time (weeks)
Treatment difference:
ETD: -0.31 mmol/L [-0.97; 0.34]
NS
Nocturnal confirmed hypoglycaemia
Time (weeks)
0,0
0,1
0,2
0,3
0,4
0,5
0,6
0,7
0,8
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Noctu
rnal confirm
ed h
ypogly
caem
ia
(cum
ula
tive e
vents
per
patient)
20% lower rate with IDegAsp ERR: 0.80 [0.50; 1.29]
NS
4
5
6
7
8
9
10
11
12
13
14
Pre BF 90 minsafter BF
Pre lunch 90 minsafter lunch
Pre dinner 90 minsafter dinner
Bedtime Pre BF
SM
PG
(m
mol/
L)
Insulin-experienced T2D BID: 8-point SMPG profile BOOST TWICE-DAILY vs BASAL-BOLUS
*p<0.05 FAS, full analysis set; LOCF, last observation carried forward. Comparisons: Estimates adjusted for multiple covariates BF, breakfast; BID, twice daily; IAsp, insulin aspart; IDeg, insulin degludec; IDegAsp, insulin degludec/insulin aspart; OD, once daily; SMPG, self-measured plasma glucose; T2D, type 2 diabetes Rodbard et al. Diab Obes Metab 2016;18:274-80
SM
PG
(mg/d
L)
180
0
126
252
216
162
90
234
198
144
108
IDegAsp BID (n=138) IDeg OD + IAsp (n=136)
Week 0
Week 26
*
0
Insulin-experienced T2D BID: insulin dose BOOST TWICE-DAILY vs BASAL-BOLUS
SAS, safety analysis set; LOCF, last observation carried forward. Comparisons: Estimates adjusted for multiple covariates BID, twice daily; ERR, estimated rate ratio; IAsp, insulin aspart; IDeg, insulin degludec; IDegAsp, insulin degludec/insulin aspart; OD, once daily; T2D, type 2 diabetes Rodbard et al. Diab Obes Metab 2016;18:274-80; Cooper et al. Diabetologia 2014;57(Suppl. 1):S69
IDegAsp BID vs IDeg OD + IAsp Mean ratio (U/kg)
Basal insulin dose 1.05
Bolus insulin dose 0.55
Total insulin dose 0.83
0
20
40
60
80
100
120
140
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Tota
l in
sulin d
ose (
U)
ERR: 0.88 [95% CI 0.78; 1.00], p<0.05
1.11 (107)
1.34 (131)
EOT U/kg (U)
Time (weeks)
IDegAsp BID (n=136) IDeg OD + IAsp (n=135)
0
1
2
3
4
5
Change in w
eig
ht
from
baseline (
kg)
IDeg OD + IAsp (2–4) (n=135)
IDegAsp BID (n=136)
Treatment difference: –1.04 kg, p<0.05
SAS; LOCF Comparisons: Estimates adjusted for multiple covariates LOCF, last observation carried forward; SAS, safety analysis set Cooper J et al. EASD 2014. Oral presentation (abstract 147)
TWICE DAILY vs BASAL-BOLUS Poids
2.8 3.8
Conclusion
BID, twice-daily; HbA1c, glycated haemoglobin; IAsp, insulin aspart; IDeg, insulin degludec; IDegAsp, insulin degludec/insulin aspart; T2DM, type 2 diabetes mellitus Rodbard HW et al. Diabetes Obes Metab 2015; doi: 10.1111/dom.12609 [Epub ahead of print]
• les deux stratégies d'intensification à partir d’une insuline basale avec IDegAsp, en co-formulation [IDegAsp] 2 fois/jour , ou sous forme de Basal-bolus [IDeg + IAsp], ont été aussi efficaces que sures de façon similaire et ont amélioré le contrôle glycémique
• Bien que la non-infériorité n'ait pas été confirmée pour l’HbA1C, il n'y avait pas de différence significative entre les groupes qui pourraient affecter l'utilité clinique
• Le schéma d'IDegAsp BID peut apporter une solution au besoin d'intensification de l'insuline chez de nombreux patients atteints de DT2 dont l'adhésion à des schémas plus complexes et exigeants est difficile
