terapia con insuline: levoluzione della specie limiti e rischi

Terapia con insuline: “l’evoluzione della specie”

Limiti e rischi

Terapia insulinica: limiti

Insulin treatment and special populations

• Insulin analogues are currently used for treating diabetic patients

• PK/PD profiles for specific insulin analogues may be altered in special patients populations such as elderly patients or children but also in special conditions such as pregnancy

• Specific efficacy and safety data about the use of insulin analogues across the spectrum of special populations, although limited, should be considered when designing treatment regimens for special patient group

Cura del diabete in popolazioni specifiche

Standard Italiani per la cura del diabete mellito SID/AMD 2010.

Steatment sugli analoghi rapidi SID, AMD, SIEDP Giugno 2012

Terapia insulinica: indicazioni terapeutiche in sottogruppi di pazienti o condizioni patologiche specifiche

Aspart Glulisine Lispro

Uso in gravidanza(dati prospettici) (dati retrospettivi)

Pediatria(>2 anni) (>6 anni)

Anziani (>65 anni) (studi di PK) (dati limitati)

Insufficienza renale(studi di PK) (studi di PK)

Insufficienza epatica(studi di PK)

Somministrazione dopo il pasto

Uso in microinfusori

Somministrazione per via endovenosa

( con limitazioni)


Riassunto della caratteristiche di prodotto Insulina Aspart, Insulina Glulisine, Insulina Lispro

Detemir Glargine

Uso in gravidanza (dati prospettici) (dati

retrospettivi)

Pediatria(>2 anni) (>2 anni)

Anziani (>65 anni)(studi di PK )

Insufficienza renale(studi di PK)

Insufficienza epatica(studi di PK)


Riassunto della caratteristiche di prodotto Insulina Detemir, Insulina Glargine

Aspart Glulisine Lispro Detemir Glargine

Uso in gravidanza

(dati prospettici) (dati retrospettivi)

(dati prospettici)

(dati retrospettivi)

Pediatria

(>2 anni) (>6 anni) (Nessun limite

specificato)

(>2 anni) (> 2 anni)

Anziani (>65 anni)

(studi di PK) (dati limitati) (Nessun limite

specificato)

(studi di PK )

Insufficienza renale

(studi di PK) (studi di PK) (studi di PK)

Insufficienza epatica

(studi di PK) (studi di PK)


Riassunto della caratteristiche di prodotto Insulina Aspart, Insulina Glulisine, Insulina Lispro, Insulina Detemir, Insulina Glargine

Diabetes in pregnancy and risk of complications

Dunne et al. Diabetes Care 2009;32:1205–6

Blood glucose control is linked with outcomes in diabetic pregnancy

Diabetes Control and Complications Trial. Am J Obstet Gynecol 1996;174(4):1343–53

Major Hypoglycemia in type 1 diabetic pregnancy

Fetal and perinatal outcomes in type 1 diabetes pregnancy

Major hypoglycaemia during pregnancy was similar with insulin detemir and NPH insulin

Mathiesen et al. Diabetes Care 2012 NPH, neutral protamine Hagedorn

14

Composite fetal endpoint

CI, confidence interval; GW, gestational week; IDet, insulin detemir; NPH, neutral protamine Hagedorn

Hod et al. Diabetes 2011:Abstract 62-LB and and ADA 2011 poster presentation

Farmaci in gravidanza: classificazione FDA

Aspart Detemir Lispro Insulina umana

Glargine Glulisine


Uso in gravidanza


(dati prospettici)


Pediatria(>2 anni) (>6 anni) (Nessun limite

specificato)(>2 anni) (>2 anni)

Anziani (>65 anni)

(studi di PK) (dati limitati) (Nessun limite specificato)

(studi di PK )







Aspart in children aged 2–6 years

Danne et al, Diabetes Care. 2003 Aug;26(8):2359-64


Uso in gravidanza

(dati prospettici) (dati retrospettivi

)

(dati prospettici)


Pediatria


specificato)

(>2 anni) (>2 anni)

Anziani (>65 anni)


specificato)

(studi di PK )







Nominal time (min)0 60 120 180 240 300 360 420 480 540

800

700

600

500

400

300

200

100

Exogen

ou

s se

rum

insu

lin (

pm

ol/l)

*

NS

*= AUCINS(0-300 min) was greater with IAsp than RHI (p<0.0001)

IAsp RHI

Krones et al. Diabetes Obes Metab 2009;11(1):41-4.

Preserved pharmacokinetic profile of insulin aspart vs. human insulin in the elderly

Insulina detemir nei soggetti anziani con diabete tipo 2


Uso in gravidanza

(dati prospettici) (dati retrospettivi

)

(dati prospettici)


Pediatria


specificato)

(>2 anni) (>2 anni)

Anziani (>65 anni)


specificato)

(studi di PK )







Mean plasma concentration vs. time for insulin aspart by degree of renal impairment

Mean insu

lin a

spart

conce

ntr

ati

on (

mU

/L)

60

30

50

20

40

0

10

0 200 400 600 800 1000 1200 14001600Time (mins)

Regression analyses showed no significant difference in PK endpoints between normal and variable degrees of renal impairment

Ln(Cmax), ln(AUC0-360) and t1/2(mins): p=0.92, p=0.78 and p=0.65, respectively.

Normal Mild

Moderate

Severe

Holmes et al. Br J Clin Pharmacol 2005;60(5):469-76

Pharmacokinetics of Insulin Detemir in Subjects with Renal Impairment

L.V. Jacobsen1, G. Popescu2, A. Plum3

1Copenhagen, Denmark; 2Munich, Germany; and 3Copenhagen, Denmark


Uso in gravidanza


(dati prospettici)


Pediatria(>2 anni) (>6 anni) (Nessun limite

specificato)(>2 anni) (>2 anni)

Anziani (>65 anni)

(studi di PK) (dati limitati) (Nessun limite specificato)

(studi di PK )







Terapia insulinica: rischi

27

Pedersen-Bjergaard U. et al, Diabetes Metab Res Rev (2004) 20: 479-86Akram K. et al, Diabet Med (2006) 23: 750-6

0,44 eventi / anno / paziente 16,5% con almeno un episodio

1,3 eventi / anno / paziente Il 36,7% con almeno un

episodio, il 21,3% con due o più episodi

Il 5% giustifica il 54% degli episodi, il 10% il 69%

Epidemiology of hypoglycaemia in UK

UK Hypoglycaemia Study Group. Diabetologia 2007;50:1140–7

SU, sulphonylurea

Incidence of severe hypoglycaemia in individuals with impaired awareness of hypoglycaemia

Impaired awareness of hypoglycaemia is associated with higher rate of severe hypoglycaemia (type 1 or type 2)

Graveling & Frier. Diabetes Metab 2010;36(Suppl. 3):S64–74

Patient fear of hypoglycaemia increases with increased severity of hypoglycaemia

Marrett et al. Diabetes 2008;57(suppl. 1):A174

HFS: Hypoglycaemia Fear Survey

Patients rank fear of severe hypoglycaemia as high as fear of developing chronic

complications

Pramming et al. Diabetes Med 1991;8:217–22

*Based on patient (n=411, type 1 diabetes) attitudes to hypoglycaemia using a visual analogue scale

Hypoglycaemia represents a psychological barrier to effective glycaemic control

• Physicians and patients express fear of hypoglycaemia, which may impede effective diabetes management1

• To avoid hypoglycaemia, some patients intentionally maintain a state of hyperglycaemia2

• Fear of hypoglycaemia extends to family members2

• Hypoglycaemia are associated with significantly lower treatment satisfaction and barriers to adherence3

1. Nakar et al. J Diabetes Complications 2007;21:220–6; 2. Frier. Diabetes Metab Res Rev 2008;24:87–92; 3. Alvarez Guisasola et al. Diabetes Obes Metab 2008;10(Suppl. 1):25–32

Higher rate of severe hypoglycaemia with intensive glycaemic control*

1. UKPDS Group. Lancet 1998;352:837–53; 2. Patel et al; ADVANCE Collaborative Group. N Engl J Med 2008;358:2560–72; 3. Gerstein et al; ACCORD Group. N Engl J Med 2008;358:2545–59; 4. Duckworth et al. N Engl J Med 2009;360:129–39

*Intensive glycaemic control was defined differently in these trials

†Hypoglycaemia requiring any assistance in glucose-lowering trials

Conv, conventional therapy; gly, glibenclamide; HR, hazard ratio; ins, insulin; int, intensive therapy; std, standard therapy

Int. Diab. Monitor, 2009;21(6):210-218

Adverse outcomes among patients with type 2 diabetes experiencing severe hypoglycaemia

Zoungas. N Engl J Med 2010;363:1410–8, for the ADVANCE Collaborative Group

Link between hypoglycaemia and acute cardiovascular events in type 2 diabetes

• Retrospective, observational study (n=860,845) assessing association between hypoglycaemic events and acute cardiovascular events

• 3.1% patients had a hypoglycaemic event during the evaluation period (1 year)

• Patients with hypoglycaemic events had 79% higher odds of acute cardiovascular events than patients without hypoglycaemic events

Johnston et al. Diabetes Care 2011;34:1164–70

Pathophysiological cardiovascular consequences of hypoglycaemia

Desouza et al. Diabetes Care 2010;33:1389–94CRP, C-reactive protein;IL-6, interleukin 6 VEGF, vascular endothelial growth factor

• Abnormalities in:• atrioventricular conduction • ventricular depolarisation• ventricular repolarisation

• R-wave amplification associated with norepinephrine counter-regulatory response

• T-wave flattening associated with epinephrine counter-regulatory response

Laitinen et al. Ann Noninvasive Electrocardiol 2008;13:97–105

Int. Diab. Monitor, 2009;21(6):210-218

Card

iova

scul

ar m

orta

lity

In trials in which the reduction of HbA1c was obtained with a higher incidence of hypoglycaemia, CV MORTALITY is increased

Multiple logistic regression of acute CV events as a function of hypoglycaemic events

Johnston et al. Diabetes Care 2011;34:1164–70

Hypoglycemia Rates with Basal Insulin Analogs

Little et al., Diab Tech & Ther 2011, Volume 13, Supplement 1, S53

Relationship of hypoglycaemia rate and HbA1c target

Adapted from Kolendorf et al. Diabetes 2005; 54 (Suppl 2): P489

Basal Insulin AnaloguesBasal Insulin Analogues

NPH

Basal Insulin Analogues

Target Profile

Conclusion

Hypoglycaemia is:

• a common side effect of diabetes treatment in both type 1 and type 2 diabetes

• feared by both physicians and patients

• linked with cardiovascular and neurological pathophysiology

• a barrier to effective glycaemic management

terapia con insuline: levoluzione della specie limiti e rischi

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