Treatment Beyond Lifestyle for the Metabolic Syndrome ... to Implement Prevention Programs for Type 2 Diabetes and the Metabolic Syndrome • up -stream strategies directed to the

Francesco Giorgino, Francesco Giorgino, M.DM.D, , Ph.D.Ph.D.

InternalInternal Medicine, Medicine, EndocrinologyEndocrinology and and MetabolicMetabolic DiseasesDiseases

DepartmentDepartment of of EmergencyEmergency and and OrganOrgan TransplantationTransplantation

University of Bari University of Bari SchoolSchool of Medicineof Medicine

Treatment Beyond Lifestyle for the Metabolic SyndromeTreatment Beyond Lifestyle for the Metabolic Syndrome

Prefer Existing Therapies (Prefer Existing Therapies (MetforminMetformin, , OrlistatOrlistat, , PPARPPARγγ Agonists)Agonists)

BerlinBerlin

OctoberOctober 27, 200627, 2006

1st World Congress on1st World Congress on

Controversies in Obesity, Diabetes and HypertensionControversies in Obesity, Diabetes and Hypertension

Issues in Pharmacological Prevention/Treatment of Issues in Pharmacological Prevention/Treatment of

the Metabolic Syndromethe Metabolic Syndrome

•• LimitedLimited informationinformation fromfrom studiesstudies on on patientspatients fullfillingfullfilling

diagnosticdiagnostic criteriacriteria forfor the MS the MS ((e.ge.g., 53% of MS in DPP)., 53% of MS in DPP)

•• EffectsEffects on on preventionprevention of of typetype 2 2 diabetesdiabetes vs. vs. otherother

componentscomponents of the MSof the MS

•• DurabilityDurability of of effectseffects

•• Impact on CV Impact on CV riskrisk factorsfactors and and outcomesoutcomes

•• EffectsEffects of of drugsdrugs independentindependent of of lifestylelifestyle changeschanges

StrategiesStrategies toto ImplementImplement PreventionPrevention ProgramsPrograms forfor

TypeType 2 2 DiabetesDiabetes and the and the MetabolicMetabolic SyndromeSyndrome

•• upup--streamstream strategiesstrategies

directeddirected toto the the generalgeneral populationpopulation –– healthhealth policiespolicies aimingaiming at at

promotingpromoting healthierhealthier lifestyleslifestyles;;

•• midmid--streamstream strategiesstrategies

directeddirected toto specificspecific populationpopulation groupsgroups or or communitiescommunities at at riskrisk ––

aimingaiming at at influencinginfluencing the the diseasedisease riskrisk;;

•• downdown--streamstream strategiesstrategies

directeddirected toto individualsindividuals at high at high riskrisk –– aimingaiming at at reducingreducing the the

diseasedisease convertionconvertion rate through rate through lifestylelifestyle changeschanges ((dietdiet and/or and/or

physicalphysical exerciseexercise) or ) or useuse of of drugsdrugs..

Therapies Potentially Useful to Prevent Type 2 Diabetes (and the Metabolic Syndrome)

•• LifestyleLifestyle changeschanges dietdiet,, physicalphysical activityactivity

•• InsulinInsulin sensitizerssensitizers metforminmetformin, , TZDsTZDs

•• OtherOther OHAsOHAs acarboseacarbose, , SUSU, , glinidesglinides, , insulininsulin, GLP, GLP--11

•• AntiAnti--obesityobesity drugsdrugs orlistatorlistat, , sibutraminesibutramine, , rimonabantrimonabant

•• LipidLipid--loweringlowering drugsdrugs statinsstatins, , fibratesfibrates, , ωω--33

•• AntiAnti--hypertensivehypertensive drugsdrugs ACEACE--inhibitorsinhibitors, ARB, ARB

•• OtherOther drugsdrugs ERTERT

StudiesStudies of of LifestyleLifestyle InterventionIntervention toto Reduce T2 DM Reduce T2 DM IncidenceIncidence

TrialTrial

DPPDPP

DPSDPS

Da Da QingQing

NN

21612161

522522

577577

FollowFollow--upup

YearsYears

2.82.8

3.23.2

66

ReductionReduction

--58%58%

--58%58%

--3131--46%46%

WeightWeight

LossLoss

--55.6.6 kgkg

--44.2.2 kgkg

--00.9.9 kg/mkg/m22

PopulationPopulation

≥≥ 25 25 yearsyears

BMI ≥BMI ≥ 24 kg/m24 kg/m22

IGTIGT

4040--65 65 yearsyears

BMI BMI ≥≥ 25 kg/m25 kg/m22

IGTIGT

> 25 > 25 yearsyears

IGTIGT

AbsoluteAbsolute RiskRisk

Placebo / Placebo / InterventionIntervention

11.0% per 11.0% per yearyear



3.2% per3.2% per yearyear



Effects of Various Therapeutic Interventions on Effects of Various Therapeutic Interventions on

Components of the Metabolic SyndromeComponents of the Metabolic Syndrome

+

B.P.B.P.

+++±++Weight ControlWeight Control

Physical ExercisePhysical Exercise

CV SystemCV System

InflammationInflammationWeightWeight

LossLoss

LipidsLipidsT2DM T2DM

PreventionPrevention

StudiesStudies of of OralOral DrugsDrugs toto Reduce T2 DM Reduce T2 DM IncidenceIncidence

TrialTrial

DPPDPP

STOPSTOP--NIDDMNIDDM

SartorSartor GG

NN

21552155

14291429

9797

AgentAgent

MetforminMetformin

1700 mg1700 mg

AcarboseAcarbose

300 mg300 mg

TolbutamideTolbutamide

1500 mg1500 mg

FollowFollow--upup

YearsYears

2.82.8

3.33.3

99--1010

ReductionReduction

--31%31%

--25%25%

--18%18%


≥≥ 25 25 yearsyears

BMI BMI ≥≥ 24, IGT24, IGT

4040--70 years70 years

BMI 25BMI 25--40, IGT40, IGT

43 43 yearsyears

IGTIGT

00

44

88

1212

2525--44 (n=1000)44 (n=1000) 4545--59 (n=1586)59 (n=1586) ≥≥ 60 (n=648)60 (n=648)

Cases

Cases/100

/100 person

person-- yryr

LifestyleLifestyleMetforminMetformin

Diabetes Incidence Rates by AgeDiabetes Incidence Rates by Age

Age (years)Age (years)The DPP Research Group, The DPP Research Group, NEJMNEJM, 2002, 2002

PlaceboPlacebo

Diabetes Incidence Rates by BMIDiabetes Incidence Rates by BMI

The DPP Research Group, The DPP Research Group, NEJMNEJM, 2002, 2002 BMI (kg/mBMI (kg/m22))

00

44

88

1212

1616

24 24 –– 29.929.9 30 30 –– 34.934.9 ≥≥ 3535

Cases

Cases/100

/100 person

person-- yryr

LifestyleLifestyleMetforminMetformin

(n=1194)(n=1194)(n=1045)(n=1045) (n=995)(n=995)

PlaceboPlacebo

EffectsEffects of of MetforminMetformin and and LyfestyleLyfestyle InterventionsInterventions on on FastingFasting

and and PostPost--LoadLoad GlucoseGlucose LevelsLevels

00

2020

4040

6060

8080

11

100100

00

2020

4040

6060

8080

PlaceboPlacebo MetforminMetformin LifestyleLifestyle

100100

DPP DPP ResearchResearch GroupGroup, , N N EnglEngl J J MedMed , , 20022002

Participants

ParticipantswithwithNormal

NormalPlasma

Plasma Glucose

Glucose(%)

(%) FastingFasting GlucoseGlucose

PostPost--LoadLoad GlucoseGlucose

22 33 44YearYear

11 22 33 44

P<0.001P<0.001

EffectEffect of of WithdrawalWithdrawal fromfrom MetforminMetformin on the on the

DevelopmentDevelopment of of DiabetesDiabetes in the DPPin the DPP

DPP DPP ResearchResearch GroupGroup, , DiabetesDiabetes Care,Care, 20032003

prewashoutprewashout washoutwashout

00

FastingFasting FastingFasting 22--HourHour

Plasma

Plasma Glucose

Glucose(mg/dl)

(mg/dl)

4040

8080

120120

160160

2020

6060

100100

140140

180180

22--HourHour

PlaceboPlaceboMetforminMetformin

DiabetesDiabetes OddsOdds 95% CI95% CI

DiagnosisDiagnosis RatioRatio

PriorPrior toto washoutwashout 0.66*0.66* 0.540.54--0.820.82

At At washoutwashout 1.491.49 0.930.93--2.382.38

OverallOverall 0.75*0.75* 0.620.62--0.920.92

“… a “… a significantsignificant proportionproportion of the of the abilityability ofof

meforminmeformin toto preventprevent diabetesdiabetes can can bebe

accountedaccounted forfor byby a a pharmacologicalpharmacological effecteffect

of the of the drugdrug thatthat diddid notnot persistpersist whenwhen itit

waswas stoppedstopped.”.”

MetforminMetformin

↓↓ ACCACC

↑↑ FA OxidationFA Oxidation

↓↓ FA & VLDL SynthesisFA & VLDL Synthesis

LiverLiver

↑↑ LiverLiver

Insulin SensitivityInsulin Sensitivity

↓↓ Plasma GlucosePlasma Glucose

((↓↓ Triglycerides)Triglycerides)ShawShaw RJ RJ etet al, al, ScienceScience, 2005, 2005

AMPKAMPK

LKB1LKB1

↓↓ GlucoseGlucose

ProductionProduction

↓↓ PGCPGC--11αα

The DPP Research Group, The DPP Research Group, NEJMNEJM, 2002, 2002

WeightWeight ChangesChanges in the DPPin the DPP

%

% Hypertension

Hypertension

PlaceboPlacebo MetforminMetformin LifestyleLifestyleBaselineBaseline 11

1.21.2

1.41.4

1.61.6

1.81.8

2.02.0

Triglycerides

Triglycerides(mM)

(mM)

11

1.11.1

1.21.2

1.31.3



HDL (

HDL ( mMl

mMl ))

% LDL

% LDL phenotype

phenotypeBB


p < 0.001p < 0.001

3 3 yearsyears

p < 0.001p < 0.001

p = p = nsns p < 0.001p < 0.001

00

1010

2020

3030

4040

5050

00

1010

2020

3030

4040

5050

DPP DPP ResearchResearch GroupGroup, , DiabetesDiabetes Care,Care, 20052005

Impact of Intensive Impact of Intensive LifestyleLifestyle and Metformin and Metformin TherapyTherapy on on

CardiovascularCardiovascular DiseaseDisease RiskRisk FactorsFactors

p p representsrepresents the the pairwisepairwise comparisoncomparison fromfrom generalizedgeneralized estimatingestimating equationequation modelsmodels

Intensive Intensive LifestyleLifestyle InterventionIntervention or or MetforminMetformin

on CRP on CRP LevelsLevels in the DPPin the DPP

00

2020

4040

6060

--2020

--4040

--6060

00

2020

4040

6060

--2020

--4040

--6060

MalesMales

FemalesFemales


0.50.5 11 0.50.5 11 0.50.5 11

Perc

ent

Perc

entchange

change

in C

RP

in

CR

P fro

mfr

om

base

line

base

line

YearYear fromfrom randomizationrandomization

DPP DPP ResearchResearch GroupGroup, , DiabetesDiabetes,, 20052005

IncidenceIncidence of of TypeType 2 2 DiabetesDiabetes and of the and of the MetabolicMetabolic

SyndromeSyndrome in the DPPin the DPP

Cumulative

Cumulative Incidence

Incidence

of

of Diabetes

Diabetes(%)

(%)

00

1010

2020

3030

4040LifestyleLifestyle

MetforminMetformin

PlaceboPlacebo

Cumulative


Incidence

of

of Metabolic

MetabolicSyndrome

Syndrome(%)

(%)

00

1515

3030

4545

6060

7575

OrchardOrchard TJ TJ etet al., al., AnnAnn InternIntern MedMed,, 20052005DPP DPP ReserchReserch GroupGroup, , N N EnglEngl J J MedMed,, 20022002

LifestyleLifestyle

MetforminMetformin

PlaceboPlacebo

New New CasesCases of of TypeType 2 2 DiabetesDiabetes New New CasesCases of of MetabolicMetabolic SyndromeSyndrome

260/490 236/503 201/530260/490 236/503 201/530333/1082 234/1073 145/1079333/1082 234/1073 145/1079



-

+

B.P.B.P.

±±±±+±±±±+MetforminMetformin

++++++Weight ControlWeight Control


CV SystemCV System


LossLoss



TrialTrial

XENDOSXENDOS

HeymsfieldHeymsfield etet al.al.

AgentAgent

OrlistatOrlistat

360 mg360 mg

OrlistatOrlistat

360 mg360 mg

FollowFollow--upup

YearsYears

4.04.0

2.02.0

ReductionReduction

--37%37%

--75%75%


3030--60 60 yearsyears

obeseobese

44 44 yearsyears

obeseobese

NN

33053305

642642

StudiesStudies of of AntiAnti--ObesityObesity AgentsAgents toto Reduce T2 DM Reduce T2 DM IncidenceIncidence

Change

Changein body

in body weight

weight (kg)

(kg)

--1212

00

--33

--66

--99

00 5252 104104 156156 208208

p<0.001p<0.001

Placebo + Placebo + lifestylelifestyle -- IGTIGT

OrlistatOrlistat + + lifestylelifestyle -- IGTIGT

OrlistatOrlistat + + lifestylelifestyle -- AllAll

Cumulative

Cumulative incidence

incidence

of

of diabetes

diabetes(%)

(%)

00

55

1010

1515

2020

2525

3030

52522626 7878 104104 130130 156156 182182 208208

--45%45%

--37.3%37.3%

p=0.0024p=0.0024

p=0.0032p=0.0032

Placebo + Placebo + lifestylelifestyle

OrlistatOrlistat + + lifestylelifestyle

WeekWeek

WeekWeek00

EffectsEffects of of OrlistatOrlistat on on DiabetesDiabetes IncidenceIncidence

TorgersonTorgerson JS JS etet al, al, DiabetesDiabetes CareCare, 2004, 2004

Placebo + Placebo + lifestylelifestyle -- AllAll



±±±±+-±±±±+MetforminMetformin

±±±±

+

B.P.B.P.

?++++OrlistatOrlistat



CV SystemCV System


LossLoss



StudiesStudies of of TZDsTZDs toto Reduce T2 DM Reduce T2 DM IncidenceIncidence

TrialTrial

TRIPODTRIPOD

DPPDPP

DREAMDREAM

AgentAgent

TroglitazoneTroglitazone

400 mg 400 mg �� PioPio


400 mg400 mg

RosiglitazoneRosiglitazone8 mg8 mg

FollowFollow--upupYearsYears

2.52.5

33

33

ReductionReduction

--65%65%

--89%89%

--60%60%


HispanicHispanic ♀♀♀♀♀♀♀♀GDM GDM historyhistory

≥ 25 ≥ 25 yearsyears

BMI > 24, IGTBMI > 24, IGT

≥≥ 30 30 yearsyearsIGT/IFGIGT/IFG

AbsoluteAbsolute riskriskPlacebo / Placebo / InterventionIntervention



26.8% over 3 26.8% over 3 yearsyears

2.9% over 3 2.9% over 3 yearsyears

26.0% over 3 26.0% over 3 yearsyears11.6% over 3 11.6% over 3 yearsyears

DREAM StudyDREAM Study

Baseline CharacteristicsBaseline Characteristics

57.957.957.157.157.357.357.757.757.5%57.5%IIGT (%)IIGT (%)

14.014.014.014.014.114.114.014.014.0%14.0%IIFG (%)IIFG (%)

28.128.128.928.928.628.628.428.428.5%28.5%IGT + IFG (%)IGT + IFG (%)

54.854.854.654.654.754.754.754.754.754.7AgeAge

26.8%26.8%

44.6%44.6%

43.5%43.5%

52695269

OverallOverall

45.345.343.943.945.145.144.244.2SmokingSmoking

27.227.226.426.426.526.527.127.1SedentarySedentary

26342634263526352646264626232623NN

43.743.7

PlacPlac

43.343.3

RamiRami

Hypertension Hypertension 44.044.0

RosiRosi

43.043.0

PlacPlac

30.930.9 30.930.930.930.9BMI (kg/mBMI (kg/m22)) 30.830.8 31.031.0

DREAMDREAM

Primary Outcome: Primary Outcome: RosiglitazoneRosiglitazone

HR = 0.40 (0.35HR = 0.40 (0.35--0.46); P<0.00010.46); P<0.0001

YearYear

PlaceboPlacebo

13101310

11481148

217217241424142538253826352635RosiglitaRosiglita

177177215021502470247026342634PlaceboPlacebo

Cu

mu

lative

C

um

ula

tive

Ha

za

rdH

aza

rd

0.0

0.0

0.1

0.1

0.2

0.2

0.3

0.3

0.4

0.4

0.5

0.5

0.6

0.6

00 11 22 33 44

RosiglitazoneRosiglitazone


PlaceboPlacebo

Weight (Kg)Weight (Kg)

RosiglitazoneRosiglitazone & Weight, Waist, Hip& Weight, Waist, Hip

0.170.17

--0.090.09

PlaceboPlacebo

<0.0001<0.0001

<0.0001<0.0001

pp

0.840.84Hip (cm)Hip (cm)

0.670.67Weight (kg)Weight (kg)

Rosiglitazone Rosiglitazone Change/yr (Slope)Change/yr (Slope)

P < 0.0001P < 0.00018282

8484

8686

8888

9090

00 11 22 33 44 55YearYear

95

99

103

107

111

115

0 1 2 3 4 5Year

P<0.0001P<0.0001

P=NSP=NS

HipHip (cm)(cm)

WaistWaist (cm)(cm)

I. Blot: antiI. Blot: anti--AktAkt

AktAkt

66 303000Time (Time (minmin)) 66 303000

Akt Protein Content and ActivationAkt Protein Content and Activation

in Human Adipose Tissuein Human Adipose Tissue

Arbitrary

ArbitraryUnits

Units

00

5050

100100

150150

200200

250250

SCSC OO

Total AktTotal Akt

SCSCOO

I. Blot: antiI. Blot: anti--PhPh--Akt (Ser473)Akt (Ser473)

SCSC OO

66 303000Time (Time (minmin)) 66 303000

PhPh--AktAkt

66 303000 66 303000Time (Time (minmin))00

40004000* #* #

Arbitrary

ArbitraryUnits

Units

10001000

20002000

30003000

**

**

** p p < 0.05 < 0.05 vsvs 0 0 minmin ((11--way ANOVAway ANOVA))

## pp < 0.05 < 0.05 vsvs SCSC ((t testt test))

PhosphoPhospho--Akt (Ser473)Akt (Ser473)

LaviolaLaviola L L etet al, al, DiabetesDiabetes, 2006, 2006

ResistinResistin7575

5050

4545

3030

1515

00

##

PAIPAI--111212

99

66

33

00

AdiponectinAdiponectin

00

22

44

66

88

1010

SCSC VV

##

DifferentialDifferential ResponsesResponses of of VisceralVisceral andand

SubcutaneousSubcutaneous FatFat DepotsDepots toto NutrientsNutrients

SCSC VV SCSC VV

ILIL--66

00

11

22

33

44

55

SCSC VV

LeptinLeptin

##

00

11

22

33

44

55

66

SCSC VV00

22

44

66

88

TNFTNF--αα

****

**

*#*#

**

*#*#

**

**

*#*#

**

**

*#*#

**

SCSC VV

SalineSaline GlucoseGlucose InsulinInsulin

Einstein et al, Einstein et al, DiabetesDiabetes, , 20052005

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+Hip 113+ cm

Hip 103-112 cm

Hip < 103 cm

Waist 104+ cm

Waist 91.5-103

Waist < 91.5 cm

WHR 0.95+

WHR 0.81-.94

WHR <0.81

BMI 33+kg/m2

BMI 28-32kg/m2

BMI < 28 kg/m2

Weight 92+ Kg

Weight 75-91 kg

Weight <75 kg

RosiglitazonePlacebo(%/yr)(%/yr)

9.7

8.7

7.2

10.8

8.7

6.1

10.4

9.1

6.2

10.2

8.6

6.5

10.8

8.2

6.4

3.9

3.4

4.1

3.6

3.9

3.9

4.0

3.7

3.7

3.7

3.3

4.2

3.8

3.8

3.8

0.03

0.0002

0.009

0.0004

0.002

RosiglitazoneRosiglitazone Subgroups: PrimarySubgroups: PrimaryP (Heterogeneity)P (Heterogeneity)Overall Overall

FavoursFavours RosiglitazoneRosiglitazone FavoursFavours PlaceboPlacebo

TZDsTZDs

PPARPPARγγ

FatFat

LehrkeLehrke M & M & LazarLazar MA, MA, CellCell, 2005, 2005

↑↑ LPL, FATP, CD36LPL, FATP, CD36

Glycerol Kinase, Aq7Glycerol Kinase, Aq7

↑↑ FFA uptake, FFA uptake,

clearance & recyclingclearance & recyclingPGCPGC--11α,α,mitochondrial mitochondrial

biogenesisbiogenesis

↑↑ FA OxidationFA Oxidation

↑↑ AdiponectinAdiponectin

↓↓ TNFTNF--αα, IL, IL--66

↓↓ Plasma GlucosePlasma Glucose

((↓↓ Triglycerides)Triglycerides)

↑↑ Systemic Systemic

Insulin SensitivityInsulin Sensitivity

12

612

612

812

813

013

013

213

213

413

413

613

613

813

8

SystolicSystolic BPBP

DiastolicDiastolic BPBP

RosiRosi

PlaceboPlacebo

<0.0001<0.000179.8 (10.5)79.8 (10.5)78.4 (10.7)78.4 (10.7)DiastolicDiastolic BP (mm)BP (mm)

0.00010.0001131.1 (17.5)131.1 (17.5)129.4 (17.0)129.4 (17.0)SystolicSystolic BP (mm)BP (mm)

PPPlaceboPlaceboRosiglitazoneRosiglitazoneMeanMean FinalFinal

<0.0001<0.000179.8 (10.5)79.8 (10.5)78.4 (10.7)78.4 (10.7)DiastolicDiastolic BP (mm)BP (mm)

0.00010.0001131.1 (17.5)131.1 (17.5)129.4 (17.0)129.4 (17.0)SystolicSystolic BP (mm)BP (mm)

PPPlaceboPlaceboRosiglitazoneRosiglitazoneMeanMean FinalFinal

76

76

78

78

80

80

82

82

84

84

86

86

BaseBase 22 66 1212 2424 36,36, 4848 EUFEUFBaseBase 2 6 2 6 1212 2424 3636 4848 FinalFinal

P=0P=0.0001.0001

P<0.0001P<0.0001

RosiglitazoneRosiglitazone EffectsEffects on on BloodBlood PressurePressure

Effects of Effects of PioglitazonePioglitazone and and RosiglitazoneRosiglitazone

on Lipids in Type 2 Diabeteson Lipids in Type 2 Diabetes

ChiquetteChiquette E. et al, E. et al, Arch Intern Med, Arch Intern Med, 20042004

•• MetaMeta--analysisanalysis ofof 2323 randomizedrandomized controlledcontrolled trialstrials of of pioglitazonepioglitazone and and

rosiglitazonerosiglitazone in in patientspatients withwith T2DMT2DM

•• PrimaryPrimary analysisanalysis waswas toto compare compare TZDsTZDs withwith placeboplacebo

•• SecondarySecondary analysisanalysis waswas toto identifyidentify whetherwhether treatment treatment withwith pioglitazonepioglitazone

differeddiffered fromfrom rosiglitazonerosiglitazone in in anyany outcomesoutcomes

PioglitazonePioglitazone


LDLLDL--CC TrygliceridesTryglicerides HDLHDL--CC TotalTotal--CC

--29.7629.76 29.7629.76

--0.370.37

15.2815.28

--123.57123.57 123.57123.57

--39.7139.71

--1.061.06

4.554.55

--10.3910.39 10.3910.39

2.712.71

--39.4639.46 39.4639.46

--0.090.09

21.321.3

mg/mg/dLdL

Thiazolidinediones Effects on CV Risk FactorsThiazolidinediones Effects on CV Risk Factors

•• LipidsLipids ↓↓ triglyceride (pioglitazone), triglyceride (pioglitazone), ↑↑ HDLHDL--C and LDLC and LDL--CC↓↓ LDL oxidation, LDL oxidation, ↑↑ LDL sizeLDL size

•• HemostasisHemostasis ↓↓ PAIPAI--1 and fibrinogen1 and fibrinogen

•• InflammationInflammation ↓↓ PCR, ILPCR, IL--6 and sCD40L6 and sCD40L

•• MicroalbuminuriaMicroalbuminuria ↓↓ AERAER

•• Direct CV effectsDirect CV effects ↓↓ IMT, IMT, ↓↓ BPBPmacrophage modulation, macrophage modulation, ↓↓ VSMC proliferationVSMC proliferation↓↓ CaCa++++ flux flux �� ↑↑ arterial vasodilationarterial vasodilation

PPARPPARγ γ –– Mechanism of ActionMechanism of ActionTranscriptional transrepressionTranscriptional transrepression

NFNF--κκBB--RERE APAP--11--RERE STATSTAT--RERE NFATNFAT--RERE

NF-κB AP-1 STAT NFAT

DNADNA

PPARγγγγ

SUMOSUMO--11

83.883.8

64.864.8

50.150.1

-- ++ -- ++

w.t.w.t. KK107107AA

kDakDa

PPARPPARγγ--SUMOSUMO--11

PPARPPARγγ

Melchiorre M Melchiorre M etet al, al, submittedsubmitted



?++-++OrlistatOrlistat

±±±±+-±±±±+MetforminMetformin

+

+

B.P.B.P.

+Weight gain

& Fat

redistribution

+++TZDsTZDs



CV SystemCV System


LossLoss



Effects of Effects of TZDsTZDs and and MetforminMetformin

on CV Risk Factors/Markerson CV Risk Factors/Markers

11Freed MI, Freed MI, et alet al. . Am J Am J CardiolCardiol 2002; 90:9472002; 90:947––952. 952. 22Chu NV, Chu NV, et al. Diabetes Careet al. Diabetes Care 2002; 25:5422002; 25:542––549.549. 33DeFronzo RA. DeFronzo RA. Ann Ann IntInt MedMed 1999; 131:2811999; 131:281––303. 303. 44Viberti GC. Viberti GC. IntInt J J ClinClin PractPract 2003; 57:1282003; 57:128––134. 134. 55Kirpichnikov D, Kirpichnikov D, et al. Ann et al. Ann IntInt MedMed 2002; 137:252002; 137:25––33.33.

66Mather KJ, Mather KJ, et al.et al. J Am J Am CollColl CardiolCardiol 2001; 37:13442001; 37:1344––1350. 1350. 77BakrisBakris G, G, et alet al. . J Hum J Hum HypertensHypertens 2003; 17:72003; 17:7––12.12.8 8 UK Prospective Diabetes Study (UKPDS) Group. UK Prospective Diabetes Study (UKPDS) Group. Lancet Lancet 1998; 352:8541998; 352:854––865. 865.

99Lebovitz HE, Lebovitz HE, et al.et al. J J ClinClin EndocrinolEndocrinol MetabMetab 2001; 86:2802001; 86:280––288. 288. 1010GlaxoSmithKline. GlaxoSmithKline. AvandiaAvandia prescribing information, 2003prescribing information, 2003..

TZDsTZDs MetforminMetformin

SmallSmall/dense LDL /dense LDL 1,21,2 ↓↓↓↓↓↓↓↓ ↔↔↔↔↔↔↔↔

LDLLDL--cholesterolcholesterol 33 ↑↑↑↑↑↑↑↑ +/+/-- or or ↓↓↓↓↓↓↓↓

HDLHDL--cholesterolcholesterol 33 ↑↑↑↑↑↑↑↑ ↑↑↑↑↑↑↑↑ +/+/-- or or ↑↑↑↑↑↑↑↑

TriglyceridesTriglycerides 33 ↓↓↓↓↓↓↓↓ or or ↔↔↔↔↔↔↔↔ ↓↓↓↓↓↓↓↓

FreeFree fattyfatty acidsacids 4,54,5 ↓↓↓↓↓↓↓↓ ↓↓↓↓↓↓↓↓ ↓↓↓↓↓↓↓↓ ↓↓↓↓↓↓↓↓ ↓↓↓↓↓↓↓↓

InsulinInsulin resistanceresistance 4,54,5 ↓↓↓↓↓↓↓↓ ↓↓↓↓↓↓↓↓ ↓↓↓↓↓↓↓↓

BloodBlood pressurepressure 4,54,5 ↓↓↓↓↓↓↓↓ ↔↔↔↔↔↔↔↔

EndothelialEndothelial functionfunction 66 ↑↑↑↑↑↑↑↑ ↑↑↑↑↑↑↑↑ ↔↔↔↔↔↔↔↔

Microalbuminuria Microalbuminuria 7,87,8 ↓↓↓↓↓↓↓↓ ↔↔↔↔↔↔↔↔

PAIPAI--1 1 2,42,4 ↓↓↓↓↓↓↓↓ or or ↓↓↓↓↓↓↓↓ ↓↓↓↓↓↓↓↓ ↓↓↓↓↓↓↓↓ or or ↔↔↔↔↔↔↔↔

CRP CRP 2,42,4 ↓↓↓↓↓↓↓↓ ↓↓↓↓↓↓↓↓ ↓↓↓↓↓↓↓↓

PotentialPotential on on ββ--cellcell 9,39,3 ↑↑↑↑↑↑↑↑ ↔↔↔↔↔↔↔↔

AdverseAdverse effectseffects 9,39,3 WtWt gain, gain, fluidfluid GI, GI, lacticlactic acidacid

Males Females

Ris

k f

or

Dia

gn

osis

of

Dia

bete

s,

%

55

100

NarayanNarayan KMV et al, JAMA, 2003 KMV et al, JAMA, 2003

Cumulative Lifetime Risk for Diagnosis of Diabetes

If an individual is diagnosed at age 40 years, men will lose 11.If an individual is diagnosed at age 40 years, men will lose 11.6 life6 life--years and 18.6 qualityyears and 18.6 quality--adjusted lifeadjusted life--

years and women will lose 14.3 lifeyears and women will lose 14.3 life--years and 22.0 qualityyears and 22.0 quality--adjusted lifeadjusted life--yearsyears

50

45

40

35

30

25

20

15

10

5

0

55

50

45

40

35

30

25

20

15

10

5

0

9080706050403020100 1009080706050403020100

RiskRisk of of TypeType 2 2 DiabetesDiabetes AccordingAccording toto TertilesTertiles ofof

BaselineBaseline InsulinInsulin SensitivitySensitivity and and BaselineBaseline InsulinInsulin

SecretionSecretion in the DPPin the DPP

InsulinInsulin SensitivitySensitivity (1/FL)(1/FL)

InsulinInsulin SecretionSecretion (IGR)(IGR)

LowLowMediumMedium

HighHigh

00

55

1010

1515

2020

2525

3030

LowLowMediumMediumHighHigh

LowLowMediumMedium

HighHighLowLow

MediumMediumHighHigh

Diabetes

Diabeteshazard

hazardrate

rate

(per 100

(per 100 pyrpyr ))

DPP DPP ResearchResearch GroupGroup, , DiabetesDiabetes,, 20052005

PlaceboPlacebo

MetforminMetformin

LifestyleLifestyle

PlaceboPlacebo TroglitazoneTroglitazone

Cumulative


Incidenceof

of Diabetes

Diabetes(%)

(%)

00

55

1010

1515

2020

2525

PlaceboPlacebo TroglitazoneTroglitazone

8 8 MonthsMonths aafter fter TxTx SospensionSospension

Cumulative


Incidenceof

of

Diabetes

Diabetes(%) in

(%) in NonNon-- progressor

progressor

After After TxTx forfor 12 12 MonthsMonths

00

22

44

66

88

1010

1212

1414

Cumulative Cumulative IncidenceIncidence of of DiabetesDiabetes in the in the TRIPOD TRIPOD StudyStudy

Buchanan TA et al, Buchanan TA et al, DiabetesDiabetes, 2002 , 2002

PlaceboPlacebo


TROG TROG discontinueddiscontinued 4 4 JuneJune 1998 1998

JulyJuly 19961996

MayMay 19981998JuneJune 19981998



JulyJuly 20012001

00

33

66

99

1212

Incid

ence

Incid

ence

(( cases

cases /

100

/100 pp

-- yryr ))

YearsYears sincesince 4 4 JuneJune 19981998

EffectEffect of of WithdrawalWithdrawal fromfrom TroglitazoneTroglitazone on the on the

DevelopmentDevelopment of of DiabetesDiabetes in the DPPin the DPP

KeyKey ClinicalClinical

RecommendationRecommendation

A A lifestylelifestyle interventionintervention aimedaimed at at

inducinginducing 5%5%--7% 7% weightweight lossloss can can preventprevent

typetype 2 2 diabetesdiabetes in in subjectssubjects withwith IGTIGT

TZDsTZDs can help can help toto preventprevent typetype 2 2

diabetesdiabetes in in subjectssubjects withwith IGTIGT

MetforminMetformin can help can help toto preventprevent typetype 2 2

diabetesdiabetes, , especiallyespecially in in youngeryounger, ,

more obesemore obese patientspatients withwith IGTIGT

AcarboseAcarbose can help can help toto preventprevent typetype 22

diabetesdiabetes in in subjectssubjects withwith IGTIGT

OrlistatOrlistat can help can help toto preventprevent typetype 22

diabetesdiabetes in in obeseobese patientspatients withwith IGTIGT

CommentComment

RecommendationRecommendation basedbased on on twotwo

largelarge randomizedrandomized clinicalclinical trialstrials

RecommendationRecommendation basedbased on on threethree

largelarge randomizedrandomized clinicalclinical trialstrials

RecommendationRecommendation basedbased on on oneone

largelarge randomizedrandomized clinicalclinical trialtrial


randomizedrandomized clinicalclinical trialtrial


randomizedrandomized clinicalclinical trial and trial and oneone

metameta--analysisanalysis of of threethree otherother clinicalclinical trialstrials

StrengthStrength ofof

RecommendationRecommendation

AA

AA

BB

BB

BB

StrategiesStrategies ToTo PreventPrevent TypeType 2 2 DiabetesDiabetes

Effetti dell’Acarbosio sull’Incidenza di Eventi CVEffetti dell’Acarbosio sull’Incidenza di Eventi CV

in Pazienti con Alterata Tolleranza Glicidica (IGT)in Pazienti con Alterata Tolleranza Glicidica (IGT)

STOPSTOP--NIDDM TrialNIDDM Trial

Chiasson JL, Chiasson JL, JAMAJAMA 20032003

--49% (RR)49% (RR)

Pl A

IMA 12 1

Angina 12 5

Riv Mioc 20 11

STUDYSTUDY MeanMean ChangeChange (95% CI)(95% CI)

Ebeling 2001Ebeling 2001 1.3 (1.3 (--11.24.24, 3.83), 3.83)

Haffner (4 mg) 2002Haffner (4 mg) 2002 --3.70 (3.70 (--55.90.90, , --11.50.50))

Haffner (8 mg) 2002Haffner (8 mg) 2002 --33.90.90 ((--44.46.46, , --33.34.34))

Kernan 2003Kernan 2003 --00.14.14 ((--11.31.31, 1.03), 1.03)

Satoh 2003Satoh 2003 --0.40 (0.40 (--0.57, 0.57, --00.23.23))

Sidhu 2003Sidhu 2003 --0.19 (0.19 (--0.23, 0.23, --0.15)0.15)

Choi 2004Choi 2004 --2.08 (2.08 (--2.21, 2.21, --1.95)1.95)

Hallsten 2004Hallsten 2004 0.5 (0.03, 1.03)0.5 (0.03, 1.03)

Natali 2004Natali 2004 0.15 (0.15 (--0.03, 0.33)0.03, 0.33)

Sidhu 2004Sidhu 2004 --0.07 (0.07 (--0.11, 0.11, --0.03)0.03)

Sutinen 2004Sutinen 2004 --0.50 (0.50 (--0.83, 0.83, --0.17)0.17)

Wang 2004Wang 2004 --1.09 (1.09 (--1.41, 1.41, --0.77)0.77)

Mattoo 2005Mattoo 2005 --1.47 (1.47 (--3.05, 0.11)3.05, 0.11)

Wang 2005Wang 2005 --0.94 (0.94 (--1.60, 1.60, --0.28)0.28)

Total (95% CI)Total (95% CI) --0.82 (0.82 (--1.15, 1.15, --00.49.49))

Test for overall effect: Test for overall effect: Z=Z= 4.89 (P<0.00001)4.89 (P<0.00001) Test Test forfor heterogeneityheterogeneity: Chi: Chi22=1120=1120.60.60, df=13 (p<0.00001), df=13 (p<0.00001)

MetaMeta--Analysis of Analysis of ThiazolidinedionesThiazolidinediones EffectsEffects

on Serum Con Serum C--Reactive Protein (CRP) LevelsReactive Protein (CRP) Levels

-4 -2 0 2 4

QayyumQayyum R. et al,R. et al, Am J Am J CardiolCardiol 2006; 97, 6552006; 97, 655--658658

EffectsEffects of of MetforminMetformin on on TriglycerideTriglyceride LevelsLevelsMetaMeta--analysisanalysis of 41 of 41 studiesstudies (n = 3074)(n = 3074)

WulffeleWulffele MG,MG,

J J InternIntern MedMed, 2004, 2004

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