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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.

7

6

9

8

Hb

A1

c (

%)

10

Strategia terapeutica di tipo intensivo

Durata del diabete

Del Prato S et al. Int J Clin Pract 2005; 59: 1345–1355.

Dieta

OAD in

monoterapia

OAD in

combinazione

OADs massima

titolazione

OAD +

insulina basale

OAD +

insulina basal/bolus

Strategia terapeutica di tipo intensivo

7

6

9

8

Hb

A1

c (

%)

10

Durata del diabete

Dieta

OAD in mono

terapia

OAD in combi

nazione

OADs massima

titolazione

OAD + insulin

a basale

OAD + insulin

a basal/bolus

INSULINA

Del Prato S et al. Int J Clin Pract 2005; 59: 1345–1355.

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.


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)


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.



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.


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)


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.


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

NPH 1 - 4 6 - 10 16 - 20 Humulin I

Bifasica 0.5 - 1 2 - 4 10 - 12 Humulin 30/70

RCP Humalog; Hirsch IB. NEJM 2005; RCP Humulin; RCP Humalog NPL

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 - 4 h 6 15 Humalog Basal

Detemir 1 – 3 h 6 - 8 in base alla dose Levemir

Glargine 1 h Nessuno ~ 24 Lantus

Analoghi dell’insulina


Insulin Analogues: Chemical Properties

Human Insulin Dimers and hexamers

in solution

Lispro Limited self-aggregation

Monomers in solution

Aspart Limited self-aggregation


Glargine Soluble at low pH

Precipitates at

neutral (subcutaneous) pH

Glulisine Limited self-aggregation


Asp

Lys Glu

Lys Pro

Gly

Arg Arg

Insulina

Azione

Nome commerciale Inizio Picco (h) Durata (h)

25% lispro

75% ILPS < 15’ 0,5 – 1 ~ 14 Humalog Mix 25

30% aspart

70% asp+prot < 15’ 0,5 – 1 ~ 14 Novomix 30

50% lispro

50% ILPS < 15’ 0,5 – 1 ~12 Humalog Mix 50

50% aspart

50% asp+prot < 15’ 0,5 – 1 ~12 Novomix 50

70% aspart

30% asp+prot < 15’ 0,5 – 1 ~10 Novomix 70

Miscele di analoghi dell’insulina


Profili farmacocinetici di Lispro, Lispro miscele,

e Lispro-Protamina

Data derived from Heise T et al. Diabetes Care 1998;21(5):800-803.

Time (hours after dosing)

0 2 4 6 8 10 12 14 16 18 20 22 24

0

1

2

3

4

5

6

7

The PK properties of Lispro, including

rapid onset, are preserved in stable

mixtures of Lispro and NPL

Lispro

Lispro 25:75

Lispro 50:50

NPL

N=30 Nondiabetic subjects

0.3 U/kg dose

Data derived from Heise T et al. Diabetes Care 1998;21(5):800-803.

Time (hours after dosing)

0 2 4 6 8 10 12 14 16 18 20 22 24

0

2

4

6

8

10

12

14

lispro

Lispro 25:75

Lispro 50:50

NPL

107 ± 21*

121 ± 22*

141 ± 36

252 ± 64

tmax (min)

* p<0.001 vs Mix25™ and NPL

The mean glucose infusion rate

increased in proportion to the

amount of Lispro

N=30 Nondiabetic subjects

0.3 U/kg dose

Profili farmacodinamici di Lispro, Lispro miscele,

e Lispro-Protamina

Hompesch M et al. Curr Med Res Opin 25 (11): 2679–2687, 2009

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,


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


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

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

• People with acromegaly have increased rates of cancer

Insulin Insulin Receptor a

ffinity (%)

IGF-1 Receptor a

ffinity (%)

Mitogenic pote

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§ ?

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 Malignancy Follow u

p

Findings

Hemkens,

2009

127,031 (G

ermany)

Glargine vs

human insul

in

“Any malignan

t neoplasm”

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)

Jonasson,

2009

114,841

(Sweden)

Glargine vs

all other ins

ulins

Breast

GI

Prostate

“Any type of m

alignancy”

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

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

Diabetologia (2010) 53:1743–1753

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.

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

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.

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.


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.


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

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

GLI ANALOGHI DELL’INSULINA - medeacom.org - Settembre/18-09 Lilly... · I pazienti non critici,...

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