GLI ANALOGHI DELL`INSULINA

GLI ANALOGHI DELL’INSULINA
EFFICACIA E SICUREZZA
Involuzione del metabolismo glucidico e
correlazione con la terapia
Holman RR. Diabetes Res Clin Pract 40 (Suppl): S21–S25,1998.
Strategia terapeutica di tipo intensivo
Dieta
OAD in
monoterapia
10
OADs massima
titolazione
HbA1c (%)
OAD in
combinazione
OAD +
insulina basale
9
8
7
6
Durata del diabete
Del Prato S et al. Int J Clin Pract 2005; 59: 1345–1355.
OAD +
insulina basal/bolus
Strategia terapeutica di tipo intensivo
INSULINA
Dieta
OAD in mono
terapia
10
OADs massima
titolazione
HbA1c (%)
OAD in combi
nazione
OAD + insulin
a basale
9
8
7
6
Durata del diabete
Del Prato S et al. Int J Clin Pract 2005; 59: 1345–1355.
OAD +
insulin
a basal/bolus
IDF 2005 Clinical Guidelines Task Force
Standard di cura SID - AMD 2010
5. Quando si avvia la terapia insulinica:
5.1. Utilizzare un’insulina basale come detemir, glargine umana NPH o lispro
protamina (con umana NPH il rischio di ipoglicemia è tuttavia maggiore, non
vi sono evidenze che lispro protamina sia diversa da umana NPH), tenendo
comunque in considerazione le diverse farmacocinetiche
oppure
5.2. Utilizzare un analogo rapido ai pasti
oppure
5.3. Utilizzare direttamente uno schema basal-bolus
oppure
5.4. In presenza di gravi ed evidenti problemi di compliance, utilizzare una
doppia somministrazione di insulina premiscelata (bifasica), tentando
comunque di educare il paziente verso uno schema basal-bolus.
Standard di cura SID - AMD 2010
Nei diabetici anziani gli obiettivi glicemici dovrebbero
essere individualizzati. Se le condizioni generali sono
relativamente buone, il valore di HbA1c potrà essere
compreso tra 6,5% e 7,5%.
(Livello della prova VI, Forza della raccomandazione B)
Negli anziani fragili (con complicanze, affetti da
demenza, con pluripatologie, nei quali il rischio di
ipoglicemia è alto e nei quali i rischi di un controllo
glicemico intensivo superino i benefici attesi) è
appropriato un obiettivo meno restrittivo, con valori di
HbA1c compresi tra 7,5% e 8,5%.
(Livello della prova VI, Forza della raccomandazione B)
Standard di cura SID - AMD 2010
Gli obiettivi glicemici
Gli obiettivi glicemici durante un ricovero ospedaliero possono essere
differenziati in funzione delle diverse situazioni cliniche:
• Pazienti in situazione critica, ricoverati in Terapia Intensiva, medica o
chirurgica: valori glicemici 140-180 mg/dl, in funzione del rischio stimato
di ipoglicemia.
(Livello della prova II, Forza della raccomandazione B)
• Pazienti in situazione non critica: valori glicemici preprandiali
140 mg/dl, post-prandiali 180 mg/dl, se ottenibili senza rischi elevati
di ipoglicemia.
(Livello della prova VI, Forza della raccomandazione B)
• In alcune situazioni cliniche a elevato rischio di ipoglicemia è opportuno
un innalzamento degli obiettivi glicemici.
(Livello della prova VI, Forza della raccomandazione B)
Standard di cura SID - AMD 2010
Il trattamento
L’utilizzo dei principali farmaci ipoglicemizzanti orali
(secretagoghi, biguanidi, tiazolidinedioni) presenta notevoli
limitazioni in ambito ospedaliero. La somministrazione di
insulina è pertanto la terapia di scelta nel paziente diabetico
ospedalizzato non stabilizzato.
(Livello della prova VI, Forza della raccomandazione B)
La terapia insulinica per via sottocutanea deve seguire uno
schema programmato. Questo schema può essere integrato
da un algoritmo di correzione basato sulla glicemia al momento
dell’iniezione.
Il metodo di praticare insulina solamente “al bisogno” (sliding
scale) deve essere abbandonato.
(Livello della prova IV, Forza della raccomandazione B)
Standard di cura SID - AMD 2010
In pazienti critici e/o che non si alimentano per os, nel periodo
perioperatorio e in situazioni di grave instabilità metabolica, la terapia
insulinica deve essere effettuata in infusione venosa continua,
applicando algoritmi basati su frequenti controlli dei valori glicemici e
validati nel contesto di applicazione.
(Livello della prova VI, Forza della raccomandazione B)
I pazienti non critici, esperti nell’autosomministrazione di insulina e
nell’autocontrollo glicemico, possono essere autorizzati a proseguire
l’autogestione anche durante il ricovero, concordandone le modalità
con l’équipe curante. (Livello della prova VI, Forza della
raccomandazione B)
Nei pazienti già in trattamento con microinfusore (CSII) può essere
utile proseguire tale modalità di somministrazione della terapia anche
durante il ricovero ospedaliero, purché ne sia possibile la corretta
gestione nella specifica situazione clinica.
(Livello della prova VI, Forza della raccomandazione B
Insuline umane
Azione
Insulina
Inizio (h)
Picco (h)
Durata (h)
Nome commerciale
Regolare
0.5 - 1
2-3
6-8
Humulin R
1-4
6 - 10
16 - 20
Humulin I
0.5 - 1
2-4
10 - 12
Humulin 30/70
NPH
Bifasica
RCP Humalog; Hirsch IB. NEJM 2005; RCP Humulin; RCP Humalog NPL
Analoghi dell’insulina
Insulina
Azione
Nome
commerciale
Inizio
Picco (h)
Durata (h)
Lispro
< 15’
0,5 – 1
2-5
Humalog
Aspart
< 15’
0,5 – 1
2-5
Novorapid
Glulisine
< 15’
0,5 – 1
2-5
Apidra
Lispro
Protamina
1-4h
6
15
Detemir
1–3h
6-8
in base alla dose
Glargine
1h
Nessuno
~ 24
RCP Humalog; Hirsch IB. NEJM 2005; RCP Humulin; RCP Humalog NPL
Humalog Basal
Levemir
Lantus
Insulin Analogues: Chemical Properties
Human Insulin
Dimers and hexamers
in solution
Aspart
Asp
Limited self-aggregation
Monomers in solution
Glulisine
Lys
Glu
Limited self-aggregation
Monomers in solution
Lispro
Lys Pro
Limited self-aggregation
Monomers in solution
Glargine
Gly
Arg Arg
Soluble at low pH
Precipitates at
neutral (subcutaneous) pH
Miscele di analoghi dell’insulina
Azione
Insulina
25% lispro
75% ILPS
30% aspart
70% asp+prot
50% lispro
50% ILPS
50% aspart
50% asp+prot
70% aspart
30% asp+prot
Nome commerciale
Inizio
Picco (h)
Durata (h)
< 15’
0,5 – 1
~ 14
Humalog Mix 25
< 15’
0,5 – 1
~ 14
Novomix 30
< 15’
0,5 – 1
~12
Humalog Mix 50
< 15’
0,5 – 1
~12
Novomix 50
< 15’
0,5 – 1
~10
Novomix 70
RCP Humalog; Hirsch IB. NEJM 2005; RCP Humulin; RCP Humalog NPL
Profili farmacocinetici di Lispro, Lispro miscele,
e Lispro-Protamina
7
The PK properties of Lispro, including
rapid onset, are preserved in stable
mixtures of Lispro and NPL
6
5
Lispro
Lispro 50:50
Lispro 25:75
NPL
4
3
2
N=30 Nondiabetic subjects
0.3 U/kg dose
1
0
0
2
4
6
8
10
12
14
16
18
Time (hours after dosing)
Data derived from Heise T et al. Diabetes Care 1998;21(5):800-803.
20
22
24
Profili farmacodinamici di Lispro, Lispro miscele,
e Lispro-Protamina
tmax (min)
14
The mean glucose infusion rate
increased in proportion to the
amount of Lispro
12
10
lispro
107 ± 21*
Lispro 50:50
121 ± 22*
Lispro 25:75
141 ± 36
NPL
252 ± 64
8
* p<0.001 vs Mix25™ and NPL
6
4
N=30 Nondiabetic subjects
0.3 U/kg dose
2
0
0
2
4
6
8
10
12
14
16
18
Time (hours after dosing)
Data derived from Heise T et al. Diabetes Care 1998;21(5):800-803.
20
22
24
Profili farmacocinetici di
Lispro-Protamina, Glargine e Detemir
Concentrazione insulinica media totale (endogena ed esogena) dopo somministrazione sottocutanea
di insulina glargine, detemir, o lispro protamina (0.8 U/kg) in 34 pazienti con diabete di tipo 2,
Hompesch M et al. Curr Med Res Opin 25 (11): 2679–2687, 2009
Profili farmacodinamici di
Lispro-Protamina, Glargine e Detemir
Tasso di infusione di glucosio (GIR) dopo somministrazione sottocutanea di insulina glargine, detemir e lispro
protamina (0.8 U/kg) in 34 pazienti con Diabete di tipo 2
Hompesch M et al. Curr Med Res Opin 25 (11): 2679–2687, 2009
Profili farmacodinamici di Lispro-Protamina a vari dosaggi
Tasso di infusione di glucosio (GIR) dopo somministrazione sottocutanea di insulina lispro protamina
a 0.4, 0.8, e 1.2 U/kg
Hompesch M et al. Curr Med Res Opin 25 (11): 2679–2687, 2009
Diabetes is associated with cancer risk
• Type 2 DM is associated with three of five leading causes of cancer
mortality in the US
– Colon (30% excess risk)
– Pancreas (50% excess risk)
– Breast (postmenopausal; 20% excess risk)
• Type 1 DM carries an overall excess cancer risk of ~20%
– Stomach
– Cervix
– Endometrium
• Metformin associated with fewer malignancies than insulin or sulfon
ylureas
Smith U et al, 2009; Zendehdel K et al, 2003
Circumstantial evidence
Insulin
Insulin Receptor a
ffinity (%)
IGF-1 Receptor a Mitogenic pote
ffinity (%)
ncy (%)
Human
100%
100%
100%
Aspart
92 ± 6
81 ± 9
58 ± 22
Lispro
84 ± 6†
156 ± 16
66 ± 10
Glargine
86 ± 3
641 ± 51
783 ± 132
Detemir
46 ± 5‡/18 ± 2§
16 ± 1§
?
• People with acromegaly have increased rates of cancer
Kurtzhals et al, 2000
†Slieker et al
‡Markussen et al; §Binding assays for detemir were done in albumin-free buffer
systems, with varying degrees of success
Insulin and cancer risk: four studies
Study
Population
Hemkens,
2009
Jonasson,
2009
Malignancy
Follow u
p
Findings
127,031 (G “Any malignan
ermany)
t neoplasm”
Glargine vs
human insul
in
Mean 1.
63 yrs
Increased, dose-dependent cancer ri
sk with glargine vs human insulin (p<
0.0001);
HR 1.09 (10 U)-1.31 (50 U)
114,841
(Sweden)
Glargine vs
all other ins
ulins
2 yrs
Glargine alone vs. other insulins:
RR 1.97 (95% CI 1.31–3.03) for
breast cancer
RR 1.07 (95% CI 0.91–1.27) for any
malignancy
Breast
GI
Prostate
“Any type of m
alignancy”
www.diabetologiajournal.org/cancer.html
Insulin and cancer risk: four studies
Study
Population
Malignancy
Follow u
p
Findings
Colhoun,
2009
36,254
(Scotland)
Any glargine vs. n
o glargine
Breast
Colon
Pancreatic
Prostate
Lung
“All cancers”
4 years
Any glargine had the same incidence for all cancers as no
glargine (HR 1.02, 95% CI 0.77–1.36, p=0.9)
Glargine alone had higher incidence of all cancer than “ot
her insulins alone” (HR 1.55, 95% CI 1.01–2.37, p=0.045)
No increase in breast CA with glargine (HR 1.49, 95% CI
0.79–2.83)
“Glargine only” users had a higher breast CA
rate than those using non-glargine insulin only (HR 3.39, 9
5% CI 1.46–7.85, p=0.004).
Currie, 20
09
62,809
(Wales)
Metformin vs. SFU
vs. metformin+SF
U vs. insulin
Colorectal
Pancreatic
~5 years
Metformin alone: HR 0.54
Insulin therapy: HR 1.42 overall; 1.69 for colorectal, 4.63 f
or pancreatic
www.diabetologiajournal.org/cancer.html
Problems with all four studies
• Retrospective
• Differences in baseline characteristics (insulin patients were older)
• Very short follow-up
– Suggests glargine, if anything, may accelerate progression of pr
e-existing malignancies
• Small absolute numbers of malignancies
• Apparent direct conflicts between studies
Mitogenic properties might be mediated through interaction
with IGF1 receptor
Receptor phosphorylation of serum-starved R−/ IR-A cells which were incubated
with or without 5 nmol/l of insulin, IGF1 or B10Asp for the indicated times.
Diabetologia (2010) 53:1743–1753
Receptor phosphorylation of serum-starved R−/ IR-A cells which were incubated with
or without 5 nmol/l of short-acting analogues for the indicated times.
Diabetologia (2010) 53:1743–1753
Receptor phosphorylation of serum-starved R−/ IR-A cells which were incubated with or
without 5 nmol/l of long-acting analogues for the indicated times.
Diabetologia (2010) 53:1743–1753
Receptor phosphorylation in R−/IR-B cells. Average densitometric values (±SD) of three separate experi
ments are shown as fold increase over basal activity. Insulin (mean ± SD) is indicated with a grey area. S
olid line, B10Asp; dashed line, IGF1
Diabetologia (2010) 53:1743–1753
Receptor phosphorylation in R−/IR-B cells. Average densitometric values (±SD) of three separate experim
ents are shown as fold increase over basal activity.
Insulin (mean ± SD) is indicated with a grey area. Short-acting analogues: solid line, aspart; dashed line, li
spro; dotted line, glulisine;
Diabetologia (2010) 53:1743–1753
Receptor phosphorylation in R−/IR-B cells. Average densitometric values (±SD) of three separate
experiments are shown as fold increase over basal activity.
Insulin (mean ± SD) is indicated with a grey area. Long-acting analogues: solid line, glargine; dashed line,
detemir.
Diabetologia (2010) 53:1743–1753
Receptor phosphorylation was evaluated in IGF1R-expressing cells. Densitometric average values (±SD) o
f three independent experiments of IGF1R phosphorylation are shown.
Data are expressed as fold increase over basal activity. Insulin mean value ± SD is indicated with a grey
area. Solid line, B10Asp; dashed line, IGF1;
Diabetologia (2010) 53:1743–1753
Receptor phosphorylation was evaluated in IGF1R-expressing cells. Densitometric average values (±SD)
of three independent experiments of IGF1R phosphorylation are shown.
Data are expressed as fold increase over basal activity. Insulin mean value ± SD is indicated with a grey
area. Short-acting analogues: solid line, aspart; dashed line, lispro; dotted line, glulisine;
Diabetologia (2010) 53:1743–1753
Receptor phosphorylation was evaluated in IGF1R-expressing cells. Densitometric average values (±SD)
of three independent experiments of IGF1R phosphorylation are shown.
Data are expressed as fold increase over basal activity. Insulin mean value ± SD is indicated with a grey
area. Long-acting analogues: solid line, glargine; dashed line, detemir;
Diabetologia (2010) 53:1743–1753
Intracellular signalling serum-starved R−/IR-A cells which were incubated with or without 5 n
mol/l of either insulin, IGF1 or B10Asp for the indicated times. Densitometric average values
(±SD) of AKT (middle) or ERK (right) phosphorylation are shown. Data are expressed as fold
increase over basal activity. Insulin mean value ± SD is indicated with a grey area.
Diabetologia (2010) 53:1743–1753
Intracellular signalling serum-starved R−/IR-A cells which were incubated with or without 5 nmol/l of either
insulin, IGF1 or B10Asp for the indicated times. Densitometric average values (±SD) of AKT (middle) or ER
K (right) phosphorylation are shown. Data are expressed as fold increase over basal activity. Insulin mean
value ± SD is indicated with a grey area.
Diabetologia (2010) 53:1743–1753
Intracellular signalling serum-starved R−/IR-A cells which were incubated with or without 5 nmol/l of
either insulin, IGF1 or B10Asp for the indicated times.
Densitometric average values (±SD) of AKT (middle) or ERK (right) phosphorylation are shown.
Data are expressed as fold increase over basal activity. Insulin mean value ± SD is indicated with
a grey area
Diabetologia (2010) 53:1743–1753
Intracellular signalling in R−/IR-B cells. Both AKT and ERK phosphorylation were evaluated in R−/IR-B
cells. Average densitometric values (±SD) of three separate experiments are shown as fold increase over
basal activation. Insulin (mean ± SD) is indicated with a grey area
Diabetologia (2010) 53:1743–1753
Intracellular signalling in R−/IR-B cells. Both AKT and ERK phosphorylation were evaluated in
R−/IR-B cells. Average densitometric values (±SD) of three separate experiments are shown as
fold increase over basal activation. Insulin (mean ± SD) is indicated with a grey area.
Diabetologia (2010) 53:1743–1753
Intracellular signalling in R−/IR-B cells. Both AKT and ERK phosphorylation were evaluated in R−/IR-B
cells.
Average densitometric values (±SD) of three separate experiments are shown as fold increase over basal
activation. Insulin (mean ± SD) is indicated with a grey area.
Diabetologia (2010) 53:1743–1753
Intracellular signalling in R+ cells. Average densitometric values (±SD) of three separate
experiments are shown as fold increase overbasal activity. Insulin (mean ± SD) is indicated
with a grey area.
Diabetologia (2010) 53:1743–1753
Intracellular signalling in R+ cells. Average densitometric values (±SD) of three separate
experiments are shown as fold increase over basal activity. Insulin (mean ± SD) is
indicated with a grey area.
Diabetologia (2010) 53:1743–1753
Intracellular signalling in R+ cells. Average densitometric values (±SD) of three separate
experiments are shown as fold increase over basal activity. Insulin (mean ± SD) is
indicated with a grey area.
Diabetologia (2010) 53:1743–1753
Cell DNA was measured in serum-starved R−/IRA cells exposed for 18 h to insulin, IGF1or insulin anal
ogues at 5 nmol/l (except detemir, at 19 nmol/l). Each column indicates the mean value of 11 independ
ent experiments as the percentage increase with respect to unstimulated cells (BSA 0.1%, white bars).
The broken line indicates the level of the insulin effect. Insulin effect vs unstimulated †p<0.001, ††p<0.
0001; IGF1 and analogue effects vs insulin *p<0.05, **p<0.01
Diabetologia (2010) 53:1743–1753
Cell DNA was measured in serum-starved R−/IR-B cells exposed for 18 h to insulin, IGF1 or insulin analo
gues at 5 nmol/l (except detemir, at 19 nmol/l). Each column indicates the mean value of 11 independent
experiments as the percentage increase with respect to unstimulated cells (BSA 0.1%, white bars). The b
roken line indicates the level of the insulin effect. Insulin effect vs unstimulated †p<0.001, ††p<0.0001; IG
F1 and analogue effects vs insulin *p<0.05, **p<0.01
Diabetologia (2010) 53:1743–1753
Cell DNA was measured in serum-starved and R+ cells exposed for 18 h to insulin, IGF1 or insulin analo
gues at 5 nmol/l (except detemir, at 19 nmol/l). Each column indicates the mean value of 11 independent
experiments as the percentage increase with respect to unstimulated cells (BSA 0.1%, white bars). The
broken line indicates the level of the insulin effect. Insulin effect vs unstimulated †p<0.001, ††p<0.0001; I
GF1 and analogue effects vs insulin *p<0.05, **p<0.01
Diabetologia (2010) 53:1743–1753