vecchi e nuovi farmaci nel trattamento del diabete tipo 2 · vecchi e nuovi farmaci nel trattamento...

Prof. Francesco Giorgino

Bari, 2 febbraio 2008

Vecchi e Nuovi Farmaci

nel Trattamento del Diabete Tipo 2

Dipartimento dell’Emergenza e dei Trapianti di Organi

Sezione di Medicina Interna, Endocrinologia e Malattie Metaboliche

Università degli Studi di Bari

1° Congresso Regionale SIMG Puglia

Il Farmaco come Risorsa per la Salute

Nathan DM et al, Diabetes Care, 2006

Diagnosis

Lifestyle Intervention + Metformin

No Yes*A1C≥7%

Add Basal Insulin#

(most effective)

Add Sulfonylurea

(least expensive)

Add Glitazone

(no hypoglycemia)

No Yes*A1C≥7% No Yes*A1C≥7% No Yes*A1C≥7%

Intensify Insulin# Add Glitazone Add Basal Insulin# Add Sulfonylurea

Add Basal or Intensify Insulin#

Intensive Insulin + Metformin ± Glitazone

No Yes* No Yes*A1C≥7%A1C≥7%

Step 1

Step 2

Step 3

Management of Hyperglycemia in Type 2 Diabetes:

ADA/EASD Consensus Algorithm for the Initiation and Adjustment of Therapy

• Efficacia nel ridurre la glicemia

• Effetti extra-glicemici (riduzione complicanze croniche)

• Fenotipo del paziente (antropometrico, clinico, glicemico)

• Genotipo del paziente

• Sicurezza

• Tollerabilità

• Costo

Hypoglycemic Efficacy of Available Oral Agents for T2DM

Inzucchi SE. JAMA 2002;287:360

Oral Agent HbA1c Change

Sulfonylureas 1.65 (0.9-2.5)

Metformin 1.62 (0.8-3.0)

Glinides 1.30 (0.6-1.9)

Thiazolidinediones 1.3 (1.1-1.6)

Acarbose 0.8 (0.4-1.3)

Lifestyle modifications 1.0 – 2.0

Outcome: HbA1c level

Level of Evidence: Moderate to high

Conclusion:

Most oral diabetes medications (TDZs, second-generation sulfonylureas, and

metformin) produced similar absolute reductions in HbA1c level (approximately 1%)

compared with one another as monotherapy.

Repaglinide produced similar reductions in HbA1c level when compared

directly with sulfonylureas.

Studio ADOPT:

Andamento Temporale della Glicemia a DigiunoRosiglitazone vs Metformina

9.8 (12.7 to 7.0), P<0.001

Rosiglitazone vs Glibenclamide

17.4 (20.4 to 14.5), P<0.001

Glic

em

ia (

mg

/dl)

0

120

160

140

130

150

Glibenclamide

Metformina

Rosiglitazone

0 1 2 3 4 5

Tempo (anni)

Kahn SE et al. N Engl J Med, 2006

1078

1076

958

1207

1205

1114

1393

1397

1337

957

950

781

844

818

617

324

311

218

Pazienti a rischio

Rosiglitazone

Metformina

Glibenclamide

Tempo (anni)0 1 2 3 4 5

Pe

rce

ntu

ale

0

10

20

30

40

Glibenclamide

Metformina

Rosiglitazone

Rosiglitazone vs Metformina

32% riduzione rischio, P<0.001

Rosiglitazone vs Glibenclamide

63% riduzione rischio, P<0.001


Incidenza Cumulativa di Fallimento alla Monoterapia(Glicemia a Digiuno >180 mg/dl)

Rosiglitazone

0 20 40 60

Metformina

Glibenclamide

Mesi

57

45

33


Glibenclamide

Insulina

5

6

7

8

9

0 1 2

Anni

HbA1c (%)

Alvarsson M et al, Diabetes Care, 2003

HbA1c in Diabetici di Tipo 2 di Nuova Diagnosi

Trattati con Insulina vs. Glibenclamide

*

§

* P <0,01 anno 0 vs 1§ P <0,005 anno 0 vs 2

# P <0,01 anno 1 vs 2

*

#

Intensive Insulin Therapy in Newly Diagnosed

Type 2 Diabetes

Induction of Long-Term Glycemic Control in Newly Diagnosed Type 2 Diabetic Patients by Transient Intensive Insulin Treatment.Ilkova H, Glaser B, Tunckale A, Bagriacik N, Cerasi E.Diabetes Care 20:1353, 1997

Short-Term Intensive Insulin Therapy in Newly Diagnosed Type 2 Diabetes.Ryan E, Imes S, Wallace C.Diabetes Care 27:1028, 2004

Induction of Long-Term Glycemic Control in Newly Diagnosed Type 2 Diabetic Patients Is Associated with Improvement of Beta-Cell Function Li Y, Xu W, Liao Z, Yao B, Chen X, Huang Z, Hu G, Weng J.Diabetes Care 27:2597, 2004





• Sicurezza

• Tollerabilità

• Costo

Improvement of Cardiovascular Risk Markers by Pioglitazone

Is Independent from Glycemic Control

Pfutzner A et al, J Am Coll Cardiol, 2005

-30

-25

-20

-15

-10

-5

0

5

10

hsCRP MCP-1 MMP-9 IMT

p<0.05 p<0.05 p<0.05 p<0.001

Glimepiride 1-6 mg/die (n=84)

Pioglitazone 45 mg/die (n=89)

Patients treated for 6 months

% c

ha

ng

e fro

m b

ase

line

Effetti di Rosiglitazone e Metformina su Adipochine e Marker Infiammatori

120 soggetti con DMT2 – rosiglitazone vs metformina per 12 settimane

Adiponectina (g/ml)

0

20

40

60

80

100P=0.077

P<0.001

P<0.599

% C

hang

e fr

om b

asel

ine

Resistina (ng/ml)

-60

-40

-20

0

20

40

CRP (mg/dl)

-60

-40

-20

0

20

IL-18 (pg/ml)

-30

-10

10

IL-6 (pg/ml)

-60

-40

-20

0

20

TNF- (pg/ml)

-60

-50

-40

-30

-20

-10

0

10

20

P=0.001 P=0.088

P=0.033P=0.089P=0.038

P<0.001

P=0.002

P<0.001

P=0.960

P<0.001

P=0.957 P=0.730

P=0.008

P=0.004

P=0.981

Kim HJ et al, Clinical Endocrinology, 2007

% C

hang

e fr

om b

asel

ine

% C

hang

e fr

om b

asel

ine

% C

hang

e fr

om b

asel

ine

% C

hang

e fr

om b

asel

ine

% C

hang

e fr

om b

asel

ine

Rosiglitazone + Glimepiride

Metformina + Glimepiride

The Lancet, 2005

Studio PROACTIVEProspective Pioglitazone Clinical Trial in Macrovascular Events

• 5238 pazienti diabetici di tipo 2 con evidenza di malattia CV

• 2605 con pioglitazone aggiunto a pre-esistente terapia, 2633 con

placebo

• 3 anni di follow-up

HbA1C - 0,5% Pressione sistolica - 3 mmHg

Trigliceridi - 13,2% HDL-C + 8,9%

16% RR IMA non fatale, stroke, morte

NUMBER OF FIRST EVENTS CONTRIBUTING TO

THE PRIMARY COMPOSITE ENDPOINT

Any endpoint 514 572

Death 110 122

Non-fatal MI (excluding silent) 85 95

Silent MI 20 23

Stroke 76 96

Leg amputation 9 15

ACS 42 63

CABG/PCI 101 101

Leg revascularization 71 57

Pioglitazone

n=2605

Placebo

2633

CARDIOVASCULAR OUTCOMES FROM PIO META-ANALYSIS OF CLINICAL TRIALS (excludes PROactive)

Kaplan-Meier Estimate of Event

Rate for Death, MI, Stroke

0

0.02

0.04

0.06

40 80 120 160

Comp 5203 2978 1297 488 34Pio 5949 2859 1247 459 40

Comparator

Pioglitazone

0

Pro

bab

ility

of

Even

ts

TIME (weeks)

FDA and Center for Drug Evaluation &

Research; July 30,2007

CI = 0.55-1.02

HR=

0.75

SUMMARY OF PIOGLITAZONE

CLINICAL TRAILS

Hazard Ratio

0.5 0.75

PIO Meta-analysis

- without PROactive

PROactive

PIO Meta-Analysis

plus PROactive

0.83

0.84

0.75

Center for Drug Evaluation & Research, July 30, 2007

375 450

8554 7836

1.0

PIO COMP

#CV Events

# of Subjects

Erdmann E et al. JACC 2007;49:1772-80.

0,4 0,6 0,8 1,0 1,2

Primary

Secondary

Fatal/non-fatal MIa

CV death or

non-fatal Mia

CV death, non-fatal MI or strokea

p=0.135

p=0.059

p=0.045

p=0.201

p=0.149

Main PROACTIVEendpoints

Pre-specified forpatients with prior MI

Hazard ratio (95% CI)aExcluding silent MI





• Sicurezza

• Tollerabilità

• Costo

A Typical Patient with T2 Diabetes & Abdominal Obesity

Metabolic

Syndrome

Increased

Mortality from CHD

Waist

112 cm

TG

168

mg/dLHDL-C

36 mg/dL

FPG

146 mg/dL

Vis

cera

l fat

are

a (c

m2 )

Wai

st c

ircum

fere

nce

(cm

)

100

120

140

160

180

200

220

1

1

1,31,3

90

94

98

102

106

110

11

1,21,2,3

PCR Quintiles

(1) (2) (3) (4) (5)(1) (2) (3) (4) (5)

Lemieux I et al., ATVB, 2001

PCR Quintiles

Inflamed Fat: What Starts the Fire?

Neels JP et al, JCI, 2006

STUDY Mean Change (95% CI)

Ebeling 2001 1.3 (-1.24, 3.83)

Haffner (4 mg) 2002 -3.70 (-5.90, -1.50)

Haffner (8 mg) 2002 -3.90 (-4.46, -3.34)

Kernan 2003 -0.14 (-1.31, 1.03)

Satoh 2003 -0.40 (-0.57, -0.23)

Sidhu 2003 -0.19 (-0.23, -0.15)

Choi 2004 -2.08 (-2.21, -1.95)

Hallsten 2004 0.5 (0.03, 1.03)

Natali 2004 0.15 (-0.03, 0.33)

Sidhu 2004 -0.07 (-0.11, -0.03)

Sutinen 2004 -0.50 (-0.83, -0.17)

Wang 2004 -1.09 (-1.41, -0.77)

Mattoo 2005 -1.47 (-3.05, 0.11)

Wang 2005 -0.94 (-1.60, -0.28)

Total (95% CI) -0.82 (-1.15, -0.49)

Test for overall effect: Z= 4.89 (P<0.00001) Test for heterogeneity: Chi2=1120.60, df=13 (p<0.00001)

Meta-Analysis of Thiazolidinediones Effects

on Serum C-Reactive Protein (CRP) Levels

-4 -2 0 2 4

Qayyum R. et al, Am J Cardiol 2006; 97, 655-658

Meglio

Glib

Studio ADOPT - Fallimento alla Monoterapia:

Eterogeneità per Sottogruppi di Pazienti

Valutazione totale

Analisi per sottogruppi

Età (anni) 50

5060

>60

Sesso Femmine

Maschi

Meglio

Rosi

Meglio

Met

Hazard ratio (95% CI)

0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4

Meglio

Rosi

Hazard ratio (95% CI)

0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4

Waist (cm) 99

99110

>110

BMI (kg/m2) 30

3035

>35

P<0.05 per eterogeneità

0.2 0.4 0.6 0.8 1.0 1.2

Weight<75kg

75-91

91+

BMI<28

28-32

33+

WHR<0.87

0.87-0.94

0.94+

Waist<91.5

91.5-103

103+

Hip<103

103-112

112+

Weight <75 kg

Weight 75-91 kg

Weight 92+ Kg

BMI < 28 kg/m2

BMI 28-32kg/m2

BMI 33+kg/m2

WHR <0.81

WHR 0.81-.94

WHR 0.95+

Waist < 91.5 cm

Waist 91.5-103

Waist 104+ cm

Hip < 103 cm

Hip 103-112 cm

Hip 113+ cm

Placebo Rosiglitazone

(%/yr) (%/yr)

6.4 3.8

8.2 3.8

10.8 3.8

6.5 4.2

8.6 3.3

10.2 3.7

6.2 3.7

9.1 3.7

10.4 4.0

6.1 3.9

8.7 3.9

10.8 3.6

7.2 4.1

8.7 3.4

9.7 3.90.03

0.0002

0.009

0.0004

0.002

DREAM – Rosiglitazone SubgroupsP (Heterogeneity)Overall

Favors Rosiglitazone Favors Placebo

0

5

10

15

20

25

Insulin Tx

C-P

eptide p

ost-

OG

TT

(ng/m

l)

At registration 4 years

Follow-up period

0

5

10

15

20

25

30

35

40

Insulin Tx SU Tx

P=0.0879/30

2/24Fre

quency (

%)

Muruyama T et al, Ann. N. Y. Acad. Sci., 2003

Effects of Insulin vs SU Treatment

in Patients with LADA (The Tokio Study)

SU Tx

Progression to IDDM





• Sicurezza

• Tollerabilità

• Costo

• PPARg activators and PPARg2 geneBluher M, Diabetes Care 26: 825, 2003

Snitker S, Diabetes Care 27: 1365, 2004

Kang ES, Clin Pharmacol Ther 78: 202, 2005

Wolford JK, Diabetes 54: 3319, 2005

Hansen L, J Clin Endocrinol Metab 91: 3446, 2006

• PPARg activators and Adiponectin geneKang ES et al, Diabetes Care 28: 1139, 2005

0

20

40

60

80

100%

di R

espo

nder

s

Pro12Pro

N=110

Totale

N=131

Pro12Ala

N=16

Riduzione >20% di glicemia a digiuno

Riduzione >15% di HbA1c Blüher M et al, Diabetes Care 2003

Relazione tra Polimorfismo Pro12Ala di PPARg

e Risposta al Pioglitazone (45 mg/die, 6 mesi)

in Diabetici Tipo 2

0

20

40

60

80

100%

of P

atie

nts

Pro12Pro

N=183

Total

N=198

Pro12Ala

N=15

Responders

Non-respondersKang ES et al, Clin Pharmacol Ther 2005

Relationship between PPARg Pro12Ala Polymorphism and

Response to Rosiglitazone (4 mg/day) in T2DM

*





• Sicurezza

• Tollerabilità

• Costo

Bolen S et al, Arch Int Med, 2007

Home PD et al. N Engl J Med 2007

Hazard ratio (95% CI) for rosiglitazone + metformin or SUversus metformin +SU

CV hospitalisation or CV death (primary endpoint): p=0.43

CV death: p=0.46

All-cause death: p=0.63

Acute MI: p=0.50

CHF: p=0.006

CV death, MI or stroke: p=0.83

Based on adjudicated outcomes

0 1 2 3 4

Pro/Pro Females

X/Ala Females

X/Ala Males

Pro/Pro Males

The Pro12Ala Variant of the PPARg Gene is a Risk Factor for

PPARg/ Agonist-induced Edema in Type 2 Diabetic Patients

Hansen L et al, J Clin Endocrinol Metab, 2006

http://www.fda.gov/Medwatch/SAFETY/2007/safety07.htm#actosHampton T. , JAMA, 2007;297:1645.

Frac

ture

s/1

00

pat

ien

t-ye

ars

0.8 fractures/100 patient-years

0.0

0.5

1.0

1.5

2.0

Pioglitazone Comparator Drugs





• Sicurezza

• Tollerabilità

• Costo

Nathan DM et al, Diabetes Care, 2006

Diagnosis

Lifestyle Intervention + Metformin

No Yes*A1C≥7%

Add Basal Insulin#

(most effective)

Add Sulfonylurea

(least expensive)

Add Glitazone

(no hypoglycemia)

No Yes*A1C≥7% No Yes*A1C≥7% No Yes*A1C≥7%

Intensify Insulin# Add Glitazone Add Basal Insulin# Add Sulfonylurea

Add Basal or Intensify Insulin#

Intensive Insulin + Metformin ± Glitazone

No Yes* No Yes*A1C≥7%A1C≥7%

Step 1

Step 2

Step 3

Management of Hyperglycemia in Type 2 Diabetes:

ADA/EASD Consensus Algorithm for the Initiation and Adjustment of Therapy

Pleiotropic Actions of GLP-1

CNS

promotes satiety and reduces appetite

Stomach

slows gastric emptying

Liver

reduces HGO by inhibiting

glucagon secretion

Flint A et al. J Clin Invest. 1998;101:515-520

Larsson H et al. Acta Physiol Scand. 1997;160:413-422

Nauck MA et al., Diabetologia 1996, 1546-1553

Drucker DJ. Diabetes. 1998;47:159–169.

Alpha-cell

inhibits glucagon secretion

Beta-cell

stimulates glucose-dependent

insulin secretion

promotes proliferation/survival

inhibits apoptosis

GLP-1 is secreted from the L-cells in the intestine

Structure of GLP-1, GLP-1 R Agonists and DPP-4 Inhibitors

Drucker DJ & Nauck MA, The Lancet, 2006

GLP-1 (amidated form)

Exenatide (Byetta)

Liraglutide

Vildagliptin (Galvus) Sitagliptin (Januvia)

Proteolytic inactivation (DPP-4)

Inactive GLP-1Inactive GIP

DPP-4

t1/2 ~ 1 min

Incretins•Intact GLP-1•Intact GIP

Intact GLP-1

15

10

5

0

Meal

DPP-4 inhibition

ExenatideLiraglutide

Sitagliptin

Vildagliptin

Saxagliptin

Exenatide LARKim et al, 2006 0.8-2.0 mg 15 45 5 8.5 -2.10

LiraglutideMadsbad et al, 2004 0.75 mg 12 193 4 7.4 -0.75

SitagliptinScott et al, 2007 10-100 mg 12 743 5 7.9 -0.77

Raz et al, 2007 100-200 mg 18 521 5 8.1 -0.60

Aschner et al, 2007 100-200 mg 24 741 4 8.0 -0.79

Nonaka et al, 2006 100 mg 12 151 4 7.6 -1.05

Hanefeld et al, 2005 25-100 mg 12 555 4 7.7 -0.56

VildagliptinRistic et al, 2005 25-100 mg 12 279 3 7.7 -0.40

Pratley et al, 2006 50 mg 12 100 4 8,0 -0.60

Pi-Sunyer et al, 2007 50-100 mg 24 354 2 8.4 -0.90

Dejager et al, 2007 50-100 mg 24 632 2 8.4 -0.60

Mimori et al, 2006 20-100 mg 12 219 nd 7.4 -1.20

Study Dose Duration N. Diabetes Duration HbA1c ΔHbA1c

(weeks) (years) (%) (%)

-0.75

-0.74

Inactivity / Fuel surfeit

Insulin resistance

Stressed b-cells

Compensation / NGT

Enhanced secretion & growth

Robust b-cells

Sustained adaptation

NGT

Mechanisms of b-Cell Failure in Type 2 Diabetes Mellitus

Adapted from Prentki M et al., J. Clin. Invest., 2006

Susceptible b-cells

b-cell dysfunction

IGT & early T2DM

b-cell failure

Overt & late T2DM

Genetic & Acquired Defects

Mitochondrial function

Insulin biosynthesis

Coupling mechanisms

IUGR

Initiation Factors

Lipo- / Gluco-toxicity

Oxidative stress / ROS

Changes in adipocytokines

Altered AMPK / MalonylCoA

ER stress

Progression Factors

Lipo- / Gluco-toxicity

Oxidative stress / ROS

AGEs

Reduced incretin action

Apoptosis

Amyloid deposition

Sulphanylureas

TZD

TZD

TZD

TZD

100

InsulinoResistenza

(HOMA)

Sovrappeso

(BMI >25)

Ipertensione

(>140/90)Dislipidemia Trombofilia

80

60

40

20

0

%

Success of Metformin Monotherapy in Maintaining Goals

UK GPRD Database

Years after achieving goal

Pro

port

ion w

ith A

1C

< 7

%

Cook, Girman, Stein, Alexander et al, Diabetes Care, 2006

<6.5%

<7.0%

Effetti di Vari Interventi Terapeutici sulle Caratteristiche Fenotipiche del DMT2

Iperglicemia Lipidi P.A. Sistema CV

Controllo peso + + + ?

Esercizio fisico + + ?

Metformina + - - +

TZD + + + (+)

SU + - - ?

Acarbosio + - - +

126895-2/04

IDEAL ORAL

HYPOGLYCEMIC AGENT

Corrects hyperglycemia and prevents

microvascular complications

Improves known CVRFs and prevents

macrovascular complications

Effectively reverses known

pathophysiologic disturbances (insulin

resistance; beta cell dysfunction)

126895-2/04

Treatment of T2DM

IncreasedHGP

Impaired Insulin Secretion

Hyperglycemia

Decreased GlucoseUptake

Sulfonylureas

Meglitinides

TZDs

Exenatide

DPPIV Inhibitors Glitazones

Metformin

Metformin

Glitazones

Θ

EFFICACY OF

SULFONYLUREAS

∆FPG = 60 - 70 mg/dl

∆HbA1c = 1.5 - 2%

Monotherapy controls

~25-30%Diab Care 19:1194 and 20:597, 1997

EFFICACY OF

METFORMIN

DFPG = 60 - 70 mg/dl

DHbA1c = 1.5 - 2%

Monotherapy controls

25-30%NEJM 33:541, 1995; AJM 103:491, 1997

0

15

30

45

UKPDS: EFFECT OF METFORMINON DIABETIC COMPLICATIONS

RIS

K R

ED

UC

TIO

N(%

)

Micro-vascular

MI Stroke Death

29%

39% 41% 42%

EFFICACY OF

ROSIGLITAZONE AND

PIOGLITAZONE

∆FPG = 40-50 mg/d

∆ HbA1c = 1.4-1.6%

MONOTHERAPY CONTROLS

~15-20%

Exenatide vs. Insulin GlargineHeine et al, 2005 10 mcg 26 551 10 SU/Met 8.2 0.02

Exenatide vs. Insulin Aspart (± protamine)Nauck et al, 2007 10 mcg 52 505 10 SU/Met 8.6 -0.15

Liraglutide vs. MetforminFeinglos et al, 2005 0,75 mg 12 210 5 - 7.0 0.09

Sitagliptin vs. GlipizideNauck et al, 2007 100 mg 52 1172 6 Met 7.70 0.04

Vildagliptin vs. TZDsRosenstock et al, 2007 (Rosi) 100 mg 24 786 2 - 8.7 0.20

Rosenstock et al, 2007 (Pio) 100 mg 24 315 2 - 8.7 0.30

Vildagliptin vs. MetforminSchweizer et al, 2007 100 mg 52 780 1 - 8.7 0.40

Study Dose Duration N. Diabetes Associated HbA1c ΔHbA1c

(weeks) Duration Diabetes (%) (%)

(years) Therapy

Rad 03/20/00

CHICAGO

• Effect of PIOglitazone versus GLIMeperide on Carotid Intima Media Thickness in T2DM

462 T2DM

at 28 sites

N=186 N=175

18 MONTHS

GLIM

(1-4 mg/d)PIO

(15-45 mg/d)

CHANGE FROM BASELINE TO WEEK 72 IN MEAN

WALL CIMT OF COMMON CARTOID IN 462

TYPE 2 DIABETIC PATIENTSMazzone et al, JAMA, Nov 13, 2006

-0.004

0

0.004

0.008

0.012

0.016

GLIM

PIO

P=0.02

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