Vito BorzìU.O. I Medicina

Az. Osp. Univ. Vittorio Emanuele – Ferrarotto – S.Bambino

Catania

Nuove frontiere della terapia insulinica

Milestones in Diabetes Treatment

Insulin glargine

Insulin Insulin discovereddiscovered First First

sulphonylureassulphonylureas

NPHNPHinsulininsulin

LenteLenteinsulinsinsulins

MetforminMetformin

Insulin Insulin pumppump

RapidRapid--acting acting insulininsulin

UKPDSUKPDS

19201920 19401940 19601960 19801980 20002000

A1CA1C DCCTDCCT

DCCT, Diabetes Control and Complications Trial; UKPDS, United KiDCCT, Diabetes Control and Complications Trial; UKPDS, United Kingdom Prospective Diabetes Study.ngdom Prospective Diabetes Study.1. 1. TattersallTattersall RB. In: Pickup JC, Williams G, eds. RB. In: Pickup JC, Williams G, eds. Textbook of DiabetesTextbook of Diabetes. 3rd ed. Boston, Mass: Blackwell Science; . 3rd ed. Boston, Mass: Blackwell Science;

2003.2003.2. US FDA Center for Drug Evaluation and Research. Available at:2. US FDA Center for Drug Evaluation and Research. Available at: http://www.fda.gov/cder/da/ddpab96.htm. http://www.fda.gov/cder/da/ddpab96.htm.

Accessed March 18, 2003.Accessed March 18, 2003.3. Lantus Consumer Information. Available at: http://3. Lantus Consumer Information. Available at: http://www.fda.gov/cder/consumerinfo/druginfo/lantus.htmwww.fda.gov/cder/consumerinfo/druginfo/lantus.htm. .

Accessed March 18, 2003.Accessed March 18, 2003.

Complications DCCT1,2 Ohkubo3 UKPDS4

of diabetes mellitus (9% 7%) (9% 7%) (8% 7%)

Retinopathy -63% -69% -21%

Nephropathy -54% -70% -34%

Neuropathy -60% – –

Macrovascular disease -41%* – -16%*

Risk reduction by decrease in A1C (%)

Good Glycaemic Control Reduces Incidence of Complications

*Not statistically significant. *Not statistically significant. DCCT, Diabetes Control and Complications Trial; UKPDS, United KiDCCT, Diabetes Control and Complications Trial; UKPDS, United Kingdom Prospective Diabetes Study.ngdom Prospective Diabetes Study.1. DCCT Research Group. 1. DCCT Research Group. N Engl J MedN Engl J Med. 1993;329:977. 1993;329:977--986. 986. 2. DCCT Research Group. 2. DCCT Research Group. DiabetesDiabetes. 1995;44:968. 1995;44:968--983.983.3. Ohkubo Y et al. 3. Ohkubo Y et al. Diabetes Res Clin PractDiabetes Res Clin Pract. 1995;28:103. 1995;28:103--117. 117. 4. UKPDS Group. 4. UKPDS Group. LancetLancet. 1998;352:837. 1998;352:837--853.853.

ADA- and AACE/ACE-Recommended Goals for Glycaemic Control: A1C, FPG, and PPG

NormalNormal11 GoalGoal11Biochemical ControlBiochemical Control11

A1CA1C** (%)(%) <6.0<6.0 <7.0<7.0††

FPG (mg/dL)FPG (mg/dL)Average preprandialAverage preprandial <110<110 9090--130130‡‡

PPG (mg/dL)PPG (mg/dL) <140<140 <180<180§§

*Referenced to the *Referenced to the nondiabeticnondiabetic range using a DCCT assay.range using a DCCT assay.11

††AACE/ACE recommendation: AACE/ACE recommendation: ≤≤6.5%.6.5%.22

‡‡AACE/ACE recommendation: <110 mg/dL.AACE/ACE recommendation: <110 mg/dL.22

§§AACE/ACE recommendation: <140 mg/dL.AACE/ACE recommendation: <140 mg/dL.22

ADA, American Diabetes Association; AACE/ACE, American AssociatiADA, American Diabetes Association; AACE/ACE, American Association of Clinical Endocrinologists/American on of Clinical Endocrinologists/American College of Endocrinology; FPG, fasting plasma glucose; PPG, postCollege of Endocrinology; FPG, fasting plasma glucose; PPG, postprandial glucose; DCCT, Diabetes Control and prandial glucose; DCCT, Diabetes Control and Complications Trial.Complications Trial.1.1. ADA. ADA. Diabetes CareDiabetes Care. 2003;26(suppl 1):S33. 2003;26(suppl 1):S33--S50.S50.2.2. AACE/ACE. AACE/ACE. EndocrEndocr PractPract. 2002;8(suppl 1):40. 2002;8(suppl 1):40--82.82.

Optimising Insulin Therapy

Glu

cose

(G

luco

se ( m

mol

/lm

mol

/l )) 9.09.0

5.05.0

160160

00

7.07.0

320320

480480

Insu

lin (

Insu

lin ( p

mol

/lpm

ol/l ))

Glucose HomeostasisGlucose Homeostasis

Mean Mean ±± 2SD 2SD

07000700 12001200 18001800 24002400 0600 hrs0600 hrs

Normal SubjectsNormal Subjects

CiofettaCiofetta M. et al., M. et al., DIabetesDIabetes CareCare 22:79522:795--800, 1999800, 1999

MealsMeals

Glucose

Post-challenge insulin secretion

Time

Phasic insulin release: basal vs. post-challenge

Insu

lin

Glucose

Post-challenge insulin secretion

Time

Insu

lin

Basal insulin secretion

Phasic insulin release: basal vs. post-challenge

Mimicking Nature for Effective Therapy

• Meal-related medication to mimickprandial insulin secretion1

– Short-acting insulin and insulin analogues2

• Medication that mimicks basal insulin secretion2,3

– Long-acting insulin

1.1. McCall AL. In: Leahy JL, McCall AL. In: Leahy JL, CefaluCefalu WT, eds. WT, eds. Insulin TherapyInsulin Therapy. New York, NY: Marcel Dekker, Inc.; 2002.. New York, NY: Marcel Dekker, Inc.; 2002.2.2. Leahy JL. In: Leahy JL, Leahy JL. In: Leahy JL, CefaluCefalu WT, eds. WT, eds. Insulin TherapyInsulin Therapy. New York, NY: Marcel Dekker, Inc.; 2002.. New York, NY: Marcel Dekker, Inc.; 2002.3.3. WittlinWittlin SD et al. In: SD et al. In: Leahy JL, Leahy JL, CefaluCefalu WT, eds. WT, eds. Insulin TherapyInsulin Therapy. New York, NY: Marcel Dekker, Inc.; 2002.. New York, NY: Marcel Dekker, Inc.; 2002.

BB DDLL HSHS

Insu

lin E

ffect

Insu

lin E

ffect

Bolus InsulinBolus Insulin

Basal InsulinBasal Insulin

Endogenous InsulinEndogenous Insulin

B, breakfast; L, lunch; D, dinner; HS, bedtime.B, breakfast; L, lunch; D, dinner; HS, bedtime.

Adapted from:Adapted from:1.1. Leahy JL. In: Leahy JL, Leahy JL. In: Leahy JL, CefaluCefalu WT, eds. WT, eds. Insulin Therapy. Insulin Therapy. New York, NY: Marcel Dekker, Inc.; 2002.New York, NY: Marcel Dekker, Inc.; 2002.2.2. BolliBolli GB et al. GB et al. DiabetologiaDiabetologia. . 1999;42:11511999;42:1151--1167.1167.

Normal Insulin Secretion: The Basal-Bolus Insulin Concept

Time of AdministrationTime of Administration

Insulin Onset of Peak of Duration ofPreparations Action Action (h) Action (h)

Short-actingRegular human 30-60 min 2-4 6-8Lispro/Aspart 5-15 min 1-2 3-4

Intermediate-actingNPH 1-3 h 5-7 13-16Lente 1-3 h 4-8 13-20

Long-actingGlargine 1-2 h Peakless >24 Ultralente 2-4 h 8-14 <20

Time course of action of any insulin can vary in different people or at different times in the same person; thus, time periods indicated here should only be considered general guidelines.

Comparison of Human Insulins and Analogues

Leahy JL. In: Leahy JL, Leahy JL. In: Leahy JL, CefaluCefalu WT, eds. WT, eds. Insulin TherapInsulin Therapy. New York, NY: Marcel Dekker, Inc.; 2002.y. New York, NY: Marcel Dekker, Inc.; 2002.

40

80

120

0

insu

linem

ia (mU/l)

colazionepranzo cena

08 13 20 08

Insu

lin E

ffect

MEALBOLUS

Afternoon

MEALBOLUS

Evening

BASALINFUSION

Night

MEALBOLUS

Morning

Continuous Subcutaneous Insulin InfusionContinuous Subcutaneous Insulin Infusion

DISSOCIATION

Short-acting(soluble) insulin

Hexamer

Monomer

CapillaryLong-actinginsulins

Insulin crystalor particle

DISSOLUTION

Dimer

Tissue-boundinsulin

Monomer

DIFFUSION

Injection Site

80

60

40

20

00 2 4 6 8 10 12

Plas

ma

Free

Insu

lin (µ

U/m

l)

Time After Insulin Injection or Meal Ingestion (Hrs)

Normal postprandial values(Mean±SD, n=23)

S.c. injection of soluble insulinin diabetic subjects(Mean ± SEM, n=20)

Bolli G.B., N.Engl.J.Med. 310:1706-11, 1984

PLASMAPLASMAINSULININSULIN

S.c. injection of lisproin diabetic subjects(Mean ± SEM, n=10)

Time-Action Curves of Regular and Lispro/Aspart Insulin

MealMealSC injectionSC injection

Time (min)Time (min) Time (min)Time (min)

AspartAspart

Glu

cose

Infu

sion

Rat

e G

luco

se In

fusi

on R

ate

(mg/

min

)(m

g/m

in)11

Plas

ma

Insu

lin (p

mol

/L)

Plas

ma

Insu

lin (p

mol

/L)22

MealMealSC injectionSC injection

SC, subcutaneous.SC, subcutaneous.

1. Campbell RK et al. 1. Campbell RK et al. Ann Pharmacother.Ann Pharmacother. 1996;30:12631996;30:1263--1271.1271.2. 2. MudaliarMudaliar SR et al. SR et al. Diabetes CareDiabetes Care. 1999;22:1501. 1999;22:1501--1506.1506.

00 5050 100100 150150 200200 300300250250

400400350350300300250250200200150150100100505000

450450500500LisproLispro

RegularRegularhumanhumaninsulininsulin

00 6060 120120 180180 240240

400400

300300

200200

100100

00

500500

600600

700700

300300

RegularRegularhumanhumaninsulininsulin

Formulazione Humalog® Mix25™ e Mix50™

Humalog Mix25

Humalog Mix50

NPL

75%

50%

25%

50%

Humalog

Farmacocinetica: Humalog®, Miscele di Humalog e NPL

Dati adattati da Heise T et al. Diabetes Care 1998;21(5):800-803.

Tempo (ore dopo la somministrazione)0 2 4 6 8 10 12 14 16 18 20 22 24

Con

cent

razi

oni s

eric

he d

’insu

lina

(ng/

ml)

0

1

2

3

4

5

6

7

Le proprietà farmacocinetiche di Humalog, inclusa la rapidità d’azione,

sono mantenute nelle miscele stabili di Humalog e NPL

Humalog

Humalog Mix25™Humalog Mix50™

Humalog NPL

N=30 Soggetti non-diabeticidosaggio 0.3 U/kg

BB DDLL HSHS

Insu

lin E

ffect

Insu

lin E

ffect

Bolus InsulinBolus Insulin

Basal InsulinBasal Insulin

Endogenous InsulinEndogenous Insulin

B, breakfast; L, lunch; D, dinner; HS, bedtime.B, breakfast; L, lunch; D, dinner; HS, bedtime.

Adapted from:Adapted from:1.1. Leahy JL. In: Leahy JL, Leahy JL. In: Leahy JL, CefaluCefalu WT, eds. WT, eds. Insulin Therapy. Insulin Therapy. New York, NY: Marcel Dekker, Inc.; 2002.New York, NY: Marcel Dekker, Inc.; 2002.2.2. BolliBolli GB et al. GB et al. DiabetologiaDiabetologia. . 1999;42:11511999;42:1151--1167.1167.

Normal Insulin Secretion: The Basal-Bolus Insulin Concept

Time of AdministrationTime of Administration

Physiologic Basal Insulin Secretion

• Characteristics of normal pancreatic basal insulin

– Endogenous secretion over 24 h

– Relatively constant insulin release without peaks

– Predictable secretion pattern in healthy individuals without diabetes

BolliBolli GB et al. GB et al. DiabetologiaDiabetologia. 1999;42:1151. 1999;42:1151--1167.1167.

Why NPH and LENTE Why NPH and LENTE

((SemilenteSemilente, , UltralenteUltralente) are not ) are not

idealideal

•• peak effectpeak effect

nocturnal nocturnal hypoglycaemiahypoglycaemia

•• relatively short durationrelatively short duration

fasting fasting hyperglycaemiahyperglycaemia

High variability in s.c. absorptionHigh variability in s.c. absorption

wide blood glucose fluctuations fromwide blood glucose fluctuations from

dayday--toto--dayday

Inappropriate PharmacokineticsInappropriate Pharmacokinetics

Glucose Infusion Raten=20 T1DMMean ± SEM

sc insulin

4.0

3.0

2.0

1.0

0

24

20

16

12

8

4

0

0 4 8 12 16 20 24

Time (hours)

mg/

Kg/

min

mol

/Kg/

min

µ

LeporeLepore M. et al., M. et al., Diabetes Diabetes 49: 2142-8, 2000

NPH

Glargine

Basal-Bolus Insulin Therapy: Insulin Glargine at HS and Mealtime Lispro or Aspart

BB DDLL HSHS

Insulin GlargineInsulin Glargine

Insulin Insulin LisproLispro or or AspartAspart

Time of AdministrationTime of AdministrationB, breakfast; L, lunch; D, dinner; HS, bedtime.B, breakfast; L, lunch; D, dinner; HS, bedtime.

Adapted from:Adapted from:1.1. Leahy JL. In: Leahy JL, Leahy JL. In: Leahy JL, CefaluCefalu WT, eds. WT, eds. Insulin Therapy. Insulin Therapy. New York, NY: Marcel Dekker, Inc.; 2002.New York, NY: Marcel Dekker, Inc.; 2002.2.2. BolliBolli GB et al. GB et al. DiabetologiaDiabetologia. . 1999;42:11511999;42:1151--1167.1167.

Type 1 DMType 1 DM

Design of study

RunRun--inin

00 12 months12 months

GlargineGlargine dinnertime (N=61)dinnertime (N=61)

NPH 4 times/day (N=60)NPH 4 times/day (N=60)

Both groups continued Both groups continued lisprolispro at mealsat mealsPorcellati F. et al. Diabetes 51 (Suppl.2):A53, 2002

100

120

140

160

180

mm

ol/

l

5 .0

6 .0

7 .0

8 .0

9 .0

10 .0

mg

/dl

BR E AKF AS T LU N C H DINNER BE D T IM Ebefore afterbeforeafter before after 03:00 h

N P H

G la rg inebe f o re d inne r

Blood Glucose Monitoring

Porcellati F. et al. Diabetes 51 (Suppl.2):A53, 2002

% HbA1c

5.5

6.0

6.5

7.0

7.5

0 2 4 6 8 10 12 months

GlargineNPH

%

**

* **

*

*p<0.05Porcellati F. et al. Diabetes 51 (Suppl.2):A53, 2002

Frequency of hypoglycaemia(BG < 4.0 mmol/L, 72 mg/dl)

0

2

4

6

8

10

12

14

NPH glargine

dinnertime

Epis

odes

/pat

ien

t-m

onth

TOTAL EPISODES

*

*p<0.05

Porcellati F. et al. Diabetes 51 (Suppl.2):A53, 2002

Frequency of hypoglycaemia(BG < 4.0 mmol/L, 72 mg/dl)

0

2

4

6

8

10

12

14

NPH glargine

dinnertime

Epis

odes

/pat

ien

t-m

onth Night-time (24:00-07:00 h)

*

*p<0.05

Porcellati F. et al. Diabetes 51 (Suppl.2):A53, 2002

Insulin Dose

dose

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

Total Basalinsulin

Lisprodose

GlargineNPH

U/K

g/di

e

* *

*p<0.05

Porcellati F. et al. Diabetes 51 (Suppl.2):A53, 2002

INTRANASAL

• Nasal administration of certain proteins (e.g., oxytocin, desmopressin, and calcitonin) is now well established

• Permeability enhancers are generally required to augment insulinbioavailability; insulin bioavailability is typically in the range of 8-15% with enhancers

• Nasal irritation is common (e.g., with lecithin, bile salts, or laureth-9 as enhancers)

• Nasal tolerance and high rates of treatment failure are major limitations

• Recent clinical studies have shown more promising results (e.g., with gelified nasal insulin)

SISTEMI ALTERNATIVI PER LA SOMMINISTRAZIONE DI INSULINA

CefaluCefalu WT. WT. DiabetesDiabetes Care 27: 239Care 27: 239--46, 200446, 2004

INSULINA INTRANASALE

• Il trattamento intranasale non rappresenta un’alternativa realistica alla via sottocutanea per la bassa biodisponibilità e l’alto tasso di fallimento

(Pontiroli AE et Al. Br Med J 284:303-306, 1982)

• Alcuni studi più recenti effettuati in pazienti con diabete, sia tipo 1 sia tipo 2, hanno dato risultati incoraggianti sul controllo dell’iperglicemia postprandiale

(Coates PA et al. Diabet Med 12:235-239,1995)(Lalej-Bennis D et al Diabetes Metab 27:372 377,2001)(Lalej-Bennis D et al Diabet Med 18:614-618,2001)

L’intolleranza, l’ irritazione nasale e l’alto tasso di trattamenti falliti rimangono un ostacolo per il futuro di questa via alternativa

(Cefalu WT. Diabetes Care 27:239-246, 2004)

PULMONARY

• High permeability and large surface area provide a favorable anatomy for protein/drug uptake

• Very rapid absorption of insulin after inhalation mimicstime-activity profile of fast-acting insulin; appropriate forpremeal delivery

• Appears comparable to subcutaneous insulin on glycemicparameters for both type 1 and type 2 diabetic patients

• Several pulmonary insulin delivery systems are in development and in phase III testing

SISTEMI ALTERNATIVI PER LA SOMMINISTRAZIONE DI INSULINA

CefaluCefalu WT. WT. DiabetesDiabetes Care 27: 239Care 27: 239--46, 200446, 2004

INSULINA INALATORIA

RidottoRidotto spessorespessore delladellapareteparete alveoloalveolo capillarecapillare(2.2 microns) (2.2 microns)

Enorme superficie d’assorbimento ed elevata vascolarizzazionealveolare

L’ASSORBIMENTO è essenzialmente per via ematica.

La quantità di particelle che viene depositata dipende dalle loro dimensioni, ma anche dal loro peso e da altri fattori sconosciuti. La misura ideale è da 2 a 3 microns. Le particelle più grosse vengono fermate nell’orofaringe o nei bronchioli, quelle più fini vengono espirate (30%).

In totale circa il 70% dell’insulina raggiunge gli alveoli e viene assorbita.

VALUTAZIONI PRE-TRATTAMENTO

Test di funzionalità polmonare (SPIROMETRIA, DLCO)

Esclusione di: fumatori, pazienti affetti da BPCO, asma, altre patologiepolmonari

INSULINA INALATORIAINSULINA INALATORIA

EXUBERA (Nektar Therapeutics, Pfizer, Aventis)

• Questa metodica utilizza il principio dell’ aria compressa; l’insulina in polvere liberata da una capsula (1 mg equivale a 2-3 U di insulina rapida) si vaporizza nella camera di nebulizzazione e si mantiene in sospensione (nube di particelle di 3,8 micron).

• La nube di insulina può essere inalata nel momento in cui il paziente lo decide, nel corso di una inspirazione profonda

• Elevata concentrazione di insulina per puff

• Minore rischio di contaminazione• Dose media giornaliera circa 15

mg

EXUBERA: STUDI DI FASE III NEL EXUBERA: STUDI DI FASE III NEL DIABETE DI TIPO 1 E TIPO 2DIABETE DI TIPO 1 E TIPO 2

TipoTipo 11

Controllo glicemicoControllo glicemicoequiparabileequiparabile a un a un trattamentotrattamento insulinicoinsulinicoconvenzionale convenzionale

((QuattrinQuattrin T et Al. Diabetes T et Al. Diabetes Care 27: 2622Care 27: 2622--7, 2004)7, 2004)

TipoTipo 22

Effetto comparabileEffetto comparabile nelnel controllocontrollodelladella glicemiaglicemia postpost--prandiale prandiale e e nellanella riduzioneriduzione di di HbA1c HbA1c tratrainsulina inalatoriainsulina inalatoria e e sottocutanea sottocutanea

(Hollander PA et Al. Diabetes Care (Hollander PA et Al. Diabetes Care 27: 235627: 2356--62, 2004)62, 2004)

• Per molto tempo è prevalso il convincimento che fosse irrealistica qualunque via non invasiva per la somministrazione dell’insulina

• Oggi vi sono evidenze convincenti che la somministrazione dell’insulina attraverso vie alternative è possibile

• Al momento, la via inalatoria per la somministrazione polmonare è quella che ha fornito i migliori risultati ed appare ormai prossima all’ impiego clinico routinario

CONCLUSIONI

Somministrazione inalatoria mediante Exubera

Vantaggi• Efficacia paragonabile alla via s.c.• Maggiore accettabilità e soddisfazione dei

pazienti• Miglior controllo glicemico post-prandiale• Minori ipoglicemie

CONCLUSIONI

Somministrazione inalatoria mediante Exubera

Svantaggi• Effetti polmonari indesiderati a breve

come tosse e minore diffusibilità del CO• Aumento degli anticorpi anti-insulina

Incognite• Effetti polmonari a lungo termine

CONCLUSIONI

1922 – Child with type 1 diabetes before and after several months of insulin therapy

The miracle of insulin

Grazie per

l’attenzione !