Insulin degludec - Sezioni Regionali

Quali insuline in arrivo
Roberto Trevisan
USC Malattie Endocrine – Diabetologia
AO Papa Giovanni XXIII, Bergamo
Cosa ci serve
Problemi tecnici della terapia
• Devices che riducano gli errori
• Devices che aumentino la
compliance
• Devices intelligenti che aiutino il
paziente a calcolare la dose
Caratteristiche della insulina
•
•
•
•
•
•
•
Migliore assorbimento
Stabili in vitro e in vivo
Cinetica adeguata
Ridotto rischio di ipoglicemia
Non aumento di peso
Ripetitività
Sicurezza
• Rapide: maggiore velocità e
minor durata
Insuline rapide
• L’ insulina viene iniettata sottocute e non nel sistema portale
• La secrezione di insulina al pasto inizia solo dopo la ingestione
del cibo e dopo che il glucosio interstiziale inizia ad aumentrare
• Il bolo del pasto viene «spalmato» su 2-3 ore invece che
comparire in pochi minuti. Non copre adeguatamente il picco
iperglicemico post-prandiale e espone al rischio di ipoglicemie
tardive
Linjeta: Insulina ultraveloce
EDTA chela lo Zn e l’acido citrico previene la formazione degli esameri
Linjeta: una farmacocinetica molto
rapida
Heinemann L, Muchmore DB. Ultrafast-acting insulins: state of the art. J
Diabetes Sci Technol. 2012 Jul 1;6(4):728-42.
Lispro-PH20: cospicua capacità di
diffusione tissutale
Nessun
infiltrato
infiammatorio
*Hyaluronidase acts on hyaluronic acid
La Tecnosfera di insulina – una possibile soluzione per la inalazione
(Afresa MannKind Corporation)
Concentrazione di insulina ((µU/ml)
200
180
160
10 U SC Ins umana r
25 U TI
140
120
50 U TI
100 U TI
100
80
60
40
20
0
0
Technosphere® Insulin:
Robert Angelo
Defining the Role of
Technosphere Particles
at the Cellular Level. Journal of Diabetes Science and
Technology
Volume 3, Issue 3, May 2009
1
2
3
4
5
Tempo (ore)
Profilo di assorbimento farmacocinetico
in un clamp euglicemico( Pfutzner et
Al,Diab Technol Ther)
6
Unmet patient need
Caratteristiche dell’insulina basale ideale
• Lunga durata d’azione (>24h in tutti i pazienti)
• Variabilità minima nell’azione insulinica
• Sicurezza ed efficacia
• Possibilità di essere mescolata con insuline rapide
Nuovi analoghi in arrivo
• Degludec
• LY2605541
LY2605541: Engineered to be large in size
Pharmacokinetics & Pharmacodynamics of LY2605541
in Healthy Subjects and Patients with Type 2 Diabetes
Insulin degludec:
the ultra-long-acting basal insulin
Structure and MOA
Insulin degludec structure
Des(B30) LysB29(γ-Glu Nε-hexadecandioyl) human insulin
A1
s
s
G I V E Q C C T S
B1
DesB30
A21
I C S L Y Q L E N Y C N
s
s
T
s
s
F V N Q H L C G S H L V E A L Y L V C G E R G F F Y T P K
desB30 Insulin
NH
O
Glutamic acid
‘spacer’
O
HO
O
N
H
Hexadecandioyl
Fatty diacid
side chain
Jonassen I et al. Pharm Res 2012
L-γ-Glu
OH
O
Insulin degludec from injection to depot
[ Phenol;
Insulin degludec injected
Phenol from the vehicle
diffuses quickly, and degludec
links up via single side-chain
contacts
Long multi-hexamers assemble
Jonassen I et al. Pharm Res 2012
Zn2+]
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
Jonassen I et al. Pharm Res 2012
Summary
• Insulin degludec has a unique protraction mechanism:
– In the pharmaceutical formulation: stable dihexamers
– Once injected, the hexamers link up to form a depot of
soluble multihexamer chains
– As zinc diffuses, multihexamers slowly disassemble
releasing monomers
• These properties are dependent on the fatty acid side
chain and spacer acylated to the B29 position.
Jonassen I et al. Pharm Res 2012
Degludec: farmacocinetica
Insulin degludec
pharmacokinetic profile
Single dose and steady state
People with type 1 diabetes (n=12)
0.4 U/kg once daily for 6 days
Insulin degludec (pmol/l)
10000
1000
Day 6 (steady state)
Day 1
100
0
4
8
12
16
Time since last injection (h)
Jonassen I et al. Diabetes 2010; 59 (Suppl. 1): 0039-OR
20
24
Mean glucose infusion rate profiles over
24 h at steady state
Nosek L, Diabetes July 2011; vol 60 (Supplement 1): 49-LB
Mean glucose infusion rate profiles over
24 h at steady state
Nosek L, Diabetes July 2011; vol 60 (Supplement 1): 49-LB
Insulin Degludec Has a Two-fold
Longer Half-life than Insulin Glargine
Heise T, Diabetes July 2011; vol 60 (Supplement 1): 37-LB
Insulin Degludec Has a Two-fold
Longer Half-life than Insulin Glargine
Heise T, Diabetes July 2011; vol 60 (Supplement 1): 37-LB
Variability in glucose-lowering effect over 24
hours at steady state
Day-to-day
day variability (CV%)
IDeg
IGlar
Area under the GIR curve (time interval, hours)
Heise et al. Diabetes Obes Metab 2012. DOI: 10.1111/j.1463-1326.2012.01627.x
Insulin degludec
Summary
• Insulin degludec is a new generation ultra-long acting basal
insulin
– Unique protraction mechanism (multi-hexamer
formation in subcutaneous depot)
– Ultra-long action >24 hours
• Flat and stable PK/PD profile, very low intra-subject
variability (four times lower within-subject variability in
pharmacodynamic response compared to insulin glargine at
steady state)
• Can be combined with insulin aspart such that the individual
action profiles are maintained
Heise et al. Diabetologia 2010 53:[Suppl1]:S387 (Poster 971)
E Nishimura, Diabetologia 2010;53(Suppl.1):S388-9 974-P
Efficacia Clinica
Nuove prospettive per la terapia
del diabete di tipo 1 e di tipo 2?
Studi Clinici principali
disegno degli studi: TREAT TO TARGET
BEGIN: BB T1 Long1
629 T1DM, 52 weeks
BEGIN: BB2
1006 T2DM, 52 weeks
BEGIN: ONCE Long3
1030 T2DM insulin-naive, 52 weeks
BEGIN: Flex4
687 T2DM, 26 weeks
1)
2)
3)
4)
Heller et al. Lancet 2012;379:1489-97.
Garber et al. Lancet 2012;379:1498-507.
Zinman et al. Diabetes Care 2012; 35: 2464-71.
Meneghini et al. Diabetes Care 2013; 36: 858-64.
Titration algorithm: insulin degludec
and insulin glargine
Meneghini et al. Diabetes Care 2013; DOI: 10.2337/dc12-1668
Primary Endpoint: A1c
• Insulin degludec effectively improved
HbA1c and was non-inferior to insulin
glargine in basal–bolus therapy in
type 1 diabetes
• Insulin degludec effectively improved
HbA1c in patients with type 2
diabetes similarly to insulin glargine
Ipoglicemia
Hypoglycaemia classification in the BEGIN®
Phase 3a Trials
Suspected hypoglycaemia or
routine PG measurement
Patient able
to treat self?
Yes
No
PG <3.1 mmol/La
56 mg/dL
No
Not classified as confirmed
hypoglycaemia in this trial
Yes
Minor
hypoglycaemia
Severe
hypoglycaemia
Confirmed hypoglycaemia
aWith
or without symptoms
A nocturnal episode is any confirmed episode with time of onset between midnight and 05.59am
Ratner et al., DOM 2012 – doi: 10.1111/dom12032
BEGIN Basal Bolus Type 1 Diabetes
Heller et al. Lancet 2012;379:1489-97
BEGIN Basal Blous Type 2 diabetes
Garber et al. Lancet 2012;379:1498-507
BEGIN Once Long
Insulin Degludec vs Insulin Glargine in Insulin-Naive patients with T2DM
Zinman et al. Diabetes Care October 5, 2012 Published online before print, doi: 10.2337/dc12-1205
Confirmed nocturnal hypoglycaemia events in
maintenance period
Type 1 and type 2 diabetes
Reduction in nocturnal
hypoglycaemia with
Degludec
(all IDeg vs. IGlar studies,
maintenance period)
Nocturnal
T2 DM
T2 Ins. naïve
T1 DM
T1 and T2
-38%*
-49%*
-25%*
-32%*
*statistically significant improvement
The reduction in hypoglycaemia rate with Ideg vs Iglar
was more pronounced during the maintenance period
in all populations
Ratner et al., DOM 2013; 15: 175-84
Summary
•T2DM insulin-naïve:
• Lower rates of overall confirmed (-17%), nocturnal
confirmed (-36%) and severe episodes (-86%) with Ideg
vs Iglar
•T2DM overall:
• Lower rates of overall confirmed (-17%), nocturnal
confirmed episodes (-32%) with Ideg vs Iglar
•T1DM overall:
• Lower rates of nocturnal confirmed episodes (-25%) with
Ideg vs Iglar in the maintenance period
•The reduction in hypoglycaemia rate with Ideg vs Iglar was
more pronounced during the maintenance period in all
popolations
Ratner et al., DOM 2013; 15: 175-84
A 26-week treat-to-target trial
comparing the efficacy and safety
of a flexible insulin degludec
dosing regimen with fixed insulin
degludec and insulin glargine
dosing, each given once daily in
patients with type 2 diabetes
(BEGIN®: FLEX)
Clinical trial.gov identifier: NCT01006291
Meneghini et al. Diabetes Care 2013; DOI: 10.2337/dc12-1668
Insulin degludec flexible dosing arm
Forcing flexible dosing in extremes
Meneghini et al. Diabetes Care 2013; DOI: 10.2337/dc12-1668
HbA1c and FBG over time
Meneghini et al. Diabetes Care 2013; DOI: 10.2337/dc12-1668
Confirmed hypoglycaemia
SAS
Comparisons: estimates adjusted for multiple covariates
Meneghini et al. Diabetes Care 2013; DOI: 10.2337/dc12-1668
Nocturnal confirmed hypoglycaemia
SAS
Comparisons: estimates adjusted for multiple covariates
Meneghini et al. Diabetes Care 2013; DOI: 10.2337/dc12-1668
Conclusion
In a treat-to-target trial:
• Insulin degludec administered flexibly effectively
improved HbA1c in patients with type 2 diabetes
similarly to insulin glargine and insulin degludec
administered once daily
• FPG was reduced more (0.42 mmol/L) with insulin
degludec dosed flexibly than with insulin glargine dosed
once daily
• The rate of overall hypoglycaemia with flexible dosing
was similar to the comparators
• Insulin degludec administered flexibly was generally
well tolerated
Meneghini et al. Diabetes Care 2013; DOI: 10.2337/dc12-1668
Significato clinico
• Questi risultati dimostrano che Degludec può essere
particolarmente utile in particolari sottogruppi di
pazienti:
• Che dimenticano di eseguire la terapia insulinica ad orari
prestabiliti
• Che spesso tornano a casa molto tardi nelle ore notturne
• Che fanno lavoro con turni notturni
Gli errori nella tempistica di somministrazione e la
paura di eseguire la terapia insulinica in orari sbagliati è
molto più diffusa di quanto stimato (almeno il 25% dei
pazienti omette per “paura” le somminstrazioni di
insulina)
Conclusioni
• Degludec presenta al momento attuale la minore
variabilità nell’assorbimento e una durata stabile nelle
24 ore
• Degludec permette la massima flessibilità nella
somministrazione e può essere somministrata in
qualsiasi momento della giornata
• Degludec, a parità di controllo glicemico, si associa al
minor rischio di ipoglicemia soprattutto nelle ore
notturne
• Degludec potrebbe permettere di raggiungere targets
più ambiziosi di controllo glicemico senza aumentare il
rischio ipoglicemico
Grazie per la vostra attenzione!!