presenter disclosure information - diabetes association of atlanta · 2009. 10. 23. · 1 presenter...

1

Presenter Disclosure Information

In compliance with accrediting board policies, the American Diabetes Association requires the following disclosure to participants:

Lawrence S Phillips, MDAdvisory Panel/Board Member: Amylin, Bristol-Myers Squibb, Daiichi Sankyo, Sanofi-Aventis, Merck, Boehringer-Ingelheim, Takeda, Eli Lilly

2

Prevention of Type 2 Diabetes: A Review of Past, Present, and

Future Intervention Trials

Lawrence S. Phillips, M.D.Medical Director, Clinical Studies Center

Atlanta VA Medical Center

Professor of MedicineEmory University School of Medicine

Atlanta, Georgia

3

So Why Does Diabetes Continue to Command Our

Attention?Because EVERY 24 HOURS there are, in the USA alone approximately:• 4,100 new cases of diabetes,• 810 deaths due to diabetes,• 230 amputations,• 120 kidney failures, and• 55 new cases of blindnessSource: NIDDK, National Diabetes Statistics fact sheet. HHS, NIH, 2005.

4

23.0 M36.2 M↑57.0%

14.2 M26.2 M↑85%

48.4 M58.6 M↑21% 43.0 M

75.8 M↑79%

7.1M15.0 M↑111%

39.3 M81.6 M

↑108%

M = million, AFR = Africa, NA = North America, EUR = Europe, SACA = South and Central America, EMME = Eastern Mediterranean and Middle East, SEA = South-East Asia, WP = Western PacificDiabetes Atlas Committee. Diabetes Atlas 2nd Edition: IDF 2003.

Global Projections for the Diabetes Epidemic: 2003-2025

World2003 = 194 M2025 = 333 M

↑ 72%

AFR

NA

SACA

EUR

SEA

WP19.2 M39.4 M↑105%

EMME

2003 2025

5

Diabetes is the epidemic of our times:

• 24 million Americans have diabetes• 7.8% of adults have diabetes• 213,000 people die each year from diabetes• >60 million people have pre-diabetes

Diabetes increased 70% among people age 30-39 in approximately the last decade

6

Pre-Diabetes

Type 2 diabetes

Years from Years from diagnosisdiagnosis

0 5-10 -5 10 15

Pre-diabetes

Onset Diagnosis

Insulin secretionInsulin resistanceInsulin resistance

Ramlo-Halsted BA, Edelman SV. Prim Care. 1999;26:771-789 Nathan DM. N Engl J Med. 2002;347:1342-1349

Post-Meal glucose

Fasting glucoseFasting glucose

β-Cell function

Progressive β-Cell Failure

Natural History of Type 2 DiabetesNatural History of Type 2 Diabetes

7

4.0

4.5

5.0

5.5

6.0

6.5

7.0

7.5

1990 1992 1994 1996 1998 200072

73

74

75

76

77

78

Prevalence of obesity increased by 61% since 1991More than 50% of US adults are overweightOnly 43% of obese persons advised to lose weight during checkupsBMI and weight gain major risk factors for diabetesBlunting the obesity epidemic is necessary but not sufficient to prevent T2DM

Prev

alen

ce (%

)

DiabetesMean body weight

kg

Year

The Prevalence of Diabetes and Obesity

Mokdad et al. Diabetes Care. 2000;23:1278.Mokdad et al. JAMA. 1999;282:1519.Mokdad et al. JAMA. 2001;286:1195.

8

Obesity and its impact on the type 2 diabetes epidemic

The diabetes epidemic is linked to the obesity epidemicObesity alone is insufficient to cause diabetesWhile the prevalence of obesity is ~33% among adults, the prevalence of T2DM is 7.8%Thus, while obesity may be necessary for many to develop disease, it is not sufficientFundamentally, development of T2DM is about failure of the beta cellDiabetes prevention depends on the ability to preserve/improve beta cell function in the susceptible

9Weyer C et al. J Clin Invest 1999;104:787–94.

NGTNGT

500

400

300

200

100

0 0 1 2 3 4 5

NGT Normal glucose toleranceIGT Impaired glucose toleranceDM Diabetes mellitus

IGT

DM

ProgressorsProgressors

NGTNGT NonNon--ProgressorsProgressors

Glucose Disposal ( Insulin Sensitivity )(mg/kg EMBS/min)

Acu

te I

nsulin R

espo

nse

(μU/m

L)

Progression: NGT to IGT to DiabetesProgression: NGT to IGT to DiabetesEarly Insulin Early Insulin SecretorySecretory DefectDefect

10

-12 -6 0 6 120

20

40

60

80

100

β-ce

ll Fu

nctio

n(%

β)

Based on data of UKPDS 16: conventional (diet) treatment group. Diabetes. 1995.

Years

DiagnosisDiagnosis

Natural History of Type 2 DMNatural History of Type 2 DMββ--cell functioncell function

11

StudyStudy PopulationPopulation Index of insulin Index of insulin secretion secretion

RatioRatioIFG/NGTIFG/NGT

WasadaWasada JapaneseJapaneseWeyerWeyer Pima Pima

IndiansIndiansAIRAIR

FestaFesta MixedMixed AIRAIRAbdulAbdul--GhaniGhani HispanicHispanicSnehalathaSnehalatha IndianIndianCarnevale Carnevale SchiancaSchianca

CaucasianCaucasian HOMAHOMA--ββ

PichePiche CaucasianCaucasianHanefeldHanefeld CaucasianCaucasian

AbdulAbdul--GhaniGhani ArabsArabsTripathyTripathy SwedesSwedesNovoaNovoa SpanishSpanish HOMAHOMA--ββ

IFGIFG IGTIGT

ΔΔI 0I 0--30/ 30/ ΔΔG0G0--3030

RatioRatioIGT/NGTIGT/NGT

MEANMEAN

0.410.410.670.67

0.640.640.770.771.031.030.420.42

1.031.030.780.780.510.510.920.921.001.00

0.740.74

0.720.720.920.92

0.820.820.370.370.930.931.471.47

0.570.570.630.630.220.220.600.601.501.50

0.780.78

ΔΔI 0I 0--30/ 30/ ΔΔG0G0--3030ΔΔI 0I 0--30/ 30/ ΔΔG0G0--3030



AbdulAbdul--Ghani MA et al., Ghani MA et al., Diabetes CareDiabetes Care, 2006, 2006

12

FerranniniFerrannini E et al., E et al., J J ClinClin EndocrinolEndocrinol MetabMetab, , 20052005

ββ--cell glucose cell glucose sensitivity sensitivity modeledmodeledfrom the oral from the oral glucose tolerance glucose tolerance test in 188 subjectstest in 188 subjects

Lean NGT

Obese NGT

IGT

Type 2 DM

3019128531

10

100

1000

2-Hour Plasma Glucose (mmol/L)

β-ce

ll G

luco

se S

ensi

tivity

(p

mol

min

−1m

2m

M−1

)

13

~50%~50%

00 11 22 33 44 55 66

7575

100100

125125

150150

175175 Obese DiabeticObese DiabeticImpaired Fasting GlucoseImpaired Fasting GlucoseObese NonObese Non--DiabeticDiabetic200200

250250300300

88 1212BetaBeta--Cell Volume [%]Cell Volume [%]

FPG

[mg/

dl]

FPG

[mg/

dl]

R.A. Ritzel et al. Diabetes Care 29: 717, 2006

ControlsControls

14

CAN CURRENT DIABETES TRENDS IN THE U.S. BE

CHANGED?---Can we stop the onslaught of pre-diabetes?

“The only way to really stay out of trouble is to avoid it”-My Daddy,1955

15

Pre-Diabetes

Type 2 diabetes


0 5-10 -5 10 15

Pre-diabetes

Onset Diagnosis

Insulin secretionInsulin resistanceInsulin resistance


Post-Meal glucose


β-Cell function

Progressive β-Cell Failure


16

Management of PreManagement of Pre--DiabetesDiabetes

What is the Natural History of PreWhat is the Natural History of Pre--diabetes?diabetes?

• At the stage of IGT, individuals have lost more than 80% of their beta-cell function

• The results of Butler suggest that participants with IFG have lost approximately half of their beta-cell volume

Annual Risk of conversion

Normoglycemia – 0.7%

IFG or IGT (“Pre-diabetes”)– 5-10%

17

CHD Risk Appears to Correlate With Increasing Blood Glucose Levels

83 mg/dL

1.6

1.2

0.8

0.4

0.0

–0.454 72 90 108 126 144 162 180

2-hour OGTT blood glucose(mg/dL)

CH

D M

orta

lity,

log

haza

rd ra

tiosa

Whitehall Study—17,869 men, aged 40–64 years; follow-up 33 years

CHD=coronary heart disease; OGTT= 50-g oral glucose tolerance test.a Relative to baseline group of all men below a blood glucose of 83 mg/dL.

Copyright © 2006 American Diabetes Association From Diabetes Care®, Vol. 29, 2006; 26–31 Reprinted with permission from The American Diabetes Association.

18

DPP Research Group. Diabet Med. 2007;24:137-144. Diabetes Care. 2001;24:1148-1153.Ziegler D, et al. Diabetes Care. 2008;31:464-469.

Diabetic Peripheral Neuropathy (%):Incidence in IGT…………5%-10%

Diabetic Retinopathy (%):

IGT (A1C = 5.9%) IGT…………7.9%IGT (A1C = 6.1%) T2DM………12.6%

Incidence of Incidence of MicrovascularMicrovascular Complications Complications in IGTin IGT------the trouble starts early!the trouble starts early!

19


•• Prevent BOTH the Prevent BOTH the microvascularmicrovascular and and the the macrovascularmacrovascular complicationscomplications

•• Must intervene early (IGT/IFG) InterventionsMust intervene early (IGT/IFG) Interventions

•• Should target both pathogenic mechanisms Should target both pathogenic mechanisms -- Insulin resistanceInsulin resistance-- ββ--cell failurecell failure

Goals of Management:

20

Type 2 diabetes


0 5-10 -5 10 15

Pre-diabetes

Onset Diagnosis

Insulin resistanceInsulin resistance


Post-Meal glucose



““Lifestyle (Preventive)Lifestyle (Preventive)StrategiesStrategies””

21

Lifestyle ChangesMalmo Study Da Qing StudyFinnish Diabetes Prevention StudyDiabetes Prevention Program

MedicationsDiabetes Prevention Program: metformin, (troglitazone)TRIPOD: troglitazoneSTOP-NIDDM: acarboseNAVIGATOR: nateglinide and valsartanDREAM: rosiglitazone and ramiprilXENDOS: orlistatORIGIN: glargine insulinACT NOW: pioglitazoneCANOE; rosi/metformin

TRIPOD = Troglitazone in Prevention of Diabetes Study; STOP-NIDDM = Study to Prevent Non–Insulin-Dependent Diabetes Mellitus; NAVIGATOR = Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research; DREAM = Diabetes Reduction Approaches with Ramipril and Rosiglitazone; XENDOS = Xenical in the Prevention of Diabetes in Obese Subjects; ORIGIN = Outcomes Reduction with Initial Glargine Introduction.

Trials to Prevent/Delay Progression Trials to Prevent/Delay Progression from IGT to Type 2Diabetesfrom IGT to Type 2Diabetes

22Hu et al. Arch Intern Med. 2001;161:1542.

Sedentary Lifestyle and Development of Diabetes

Quartiles of no. of hourswatching TV per week

Quartiles of MET-hours per week

2.922.36 2.23

1.922.12

1.83 1.71 1.551.67

1.29 1.361.11

1.371.09 1.26

1.00

0.00.51.01.52.02.53.0

>15.0 8.1-15.0 3.6-8.0 <3.5

>46.0

23.6-45.9

10.0-23.5

<10.0

RR

23

The Finnish Diabetes Prevention Study: Lifestyle Modifications

522 overweight individuals with IGT randomized to– Diet and exercise instructions at baseline and annual visits– Individualized advice given 7 times in the first year and

every 3 months thereafter with goals of• Weight loss ≥5% • Reducing fat intake to <30% of energy

consumption• Increasing fiber intake to ≥15 g/1000 kcal • Exercising at a moderate level for 30 min/d

Primary end point: Prevention of diabetes, as assessed by annual OGTT

24

The Finnish Diabetes Prevention Study: Lifestyle Modifications

-30

-20

-10

0

10FPG 2-h PG Fasting insulin 2-h insulin

Control (n=250) Diet intervention (n=256)

Cha

nge

from

bas

elin

e

P<0.001 P=0.003 P=0.001(mg/dL) (mg/dL) (μg/mL) (μg/mL)

Tuomilehto et al. N Engl J Med. 2001;344:1343.

25

Cumulative probability of

remaining free of diabetes

0.5

0.6

0.7

0.8

0.9

1.0

0 1 2 3 4 5 6Years on trial

Intensive Lifestyle (11%)Control (23%)

58% Relative Risk

Reduction

Tuomilehto J et al. N Engl J Med. 2001;344:1343-1350.

Finnish Diabetes Prevention Study: Effect of Lifestyle Intervention

26

Da Qing IGT and Diabetes Study

Screened 110,660 persons in Da Qing,China for IGT Randomized 577 persons with IGT at 33 local health centers4-arm study over 6 years– Diet– Exercise– Diet + exercise– Control

Pan et al. Diabetes Care. 1997;20:537.

27

Da Qing IGT and Diabetes Study(cont’d)

*Adjusted for BMI and fasting glucose.

Intervention

6-y Incidence of NIDDM (%)

% Reduction From Control*

Control 67.7 —

Diet 43.8 31 (P<0.03)

Exercise 41.1 46 (P<0.0005)

Diet + exercise 46.0 42 (P<0.005)


28

Da Qing: Incidence of Diabetes at 6-Year Evaluation

02468

101214161820

Control Diet Exercise Diet +exercise

TotalLeanOverweight

Per 1

00 p

erso

n-ye

ars

Intervention group


29

Diabetes Prevention Program

Metformin titrated to 850 mg bidPlaceboIntensive lifestyle intervention with at least monthly contact with case managers; intervention goals were– ≥7% weight reduction through healthy eating and physical

activity– ≥150 min/wk moderate-intensity physical activity

Primary end point: prevention of diabetes diagnosed by annual OGTT or semiannual FPG

The Diabetes Prevention Program Research Group. Diabetes Care. 1999;22:623.

3234 high-risk individuals with IGT and elevated FPG randomized to

30

Diabetes Prevention Program:Randomization Scheme

3234 Randomized

Standard lifestyle recommendations

The Diabetes Prevention Program Research Group. N Engl J Med. 2002;346:393.

Intensive lifestyle (n=1079)

Metformin850 mg bid(n=1073)

Placebobid

(n=1082)

31

DPP Study Population

Caucasian55%

AfricanAmerican

20%

HispanicAmerican

16%

Asian4% American

Indian5%

Caucasian 1768

African-American 645

Hispanic-American 508

Asian-American & 142Pacific Islander

American Indian 171

32

DPP Study Population

Age Distribution

40-59 years64%

<39 years16%

> 60 y20%

33

0 1 2 3 4

0

10

20

30

40 Placebo (n=1082)Metformin (n=1073, p<0.001 vs. Plac)Lifestyle (n=1079, p<0.001 vs. Met , p<0.001 vs. Plac )

Percent developing diabetes

All participants

All participants

Years from randomization

Cum

ulat

ive

inci

denc

e (%

)

Placebo (n=1082)Metformin (n=1073, p<0.001 vs. Placebo)Lifestyle (n=1079, p<0.001 vs. Metformin ,

p<0.001 vs. Placebo)

Risk reductionRisk reduction31% by 31% by metforminmetformin58% by lifestyle58% by lifestyle

DPP: Progression to DiabetesDPP: Progression to Diabetes

34

Diabetes Prevention Program:Progression to Type 2 Diabetes by Age

0

3

6

9

12

15 PlaceboMetforminIntensive lifestyle

Cas

es/1

00 p

erso

n-ye

ars

Baseline age (y) 25 to <45n=1000 (31%)

45 to <60n=1586 (49%)

≥60n=648 (20%)

↓44%↓48%

↓31%

↓59%

↓11%

↓71%

80% of patients


35

Diabetes Prevention Program:Progression to Type 2 Diabetes by BMI

0

3

6

9

12

15 PlaceboMetforminIntensive lifestyle

Cas

es/1

00 p

erso

n-ye

ars

Baseline BMI (kg/m2)

24 to <30n=1045

30 to <35n=995

≥35n=1194

↓3%

↓65%

↓16%

↓61%

↓53%↓51%


36

Diabetes Prevention Program: Conclusions

Intensive lifestyle modifications and metformineach reduced the risk of developing type 2 diabetes among a high-risk population of persons with IGTLifestyle modification was most effective for individuals 60 years and older and for those with lower baseline BMIMetformin reduced the risk of developing type 2 diabetes most effectively in the DPP participants younger than 60 years and those with a baseline BMI >35 kg/m2

37

NDEP Prevention Campaign

38

Target Audience

39

For Health Care Providers:GAME PLAN Toolkit

40

For Health Care Providers:Patient Handouts

41


42


43


•• Use of other Pharmaceutical Agents?Use of other Pharmaceutical Agents?

•• Efficacy? Safety? Efficacy? Safety?

•• Change the Natural History? Mask Change the Natural History? Mask the disease? the disease?

44

AcarboseAcarbose Reduces Risk of Reduces Risk of Cardiovascular Events: Cardiovascular Events: STOPSTOP--NIDDMNIDDM

Effect of Acarbose on Probability of Any Cardiovascular Event

Chiasson JL et al. JAMA. 2003;290:486-494.

Probability of any Cardiovascular Event

Days After Randomization

Placebo

Acarbose

0

0.01

0.02

0.03

0.04

0.05

0.06

0 100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400

STOP-NIDDM = Study to Prevent Non-Insulin Dependent Diabetes Mellitus

45

HOPE=Heart Outcomes Prevention Evaluation.RRR=Relative risk reduction. Yusuf S, et al. JAMA. 2001;286:1882-1885.

Cum

ulat

ive

Ris

k

Days of Follow-up

RRR=34% (P<0.001)

0.10

0.08

0.06

0.04

0.02

0.00

Placebo (n=2883)Ramipril (n=2837)

400 800 1200 1600

Meta-analysis of 12 randomized trials showed reductions in the risk of

diabetes in subjects receiving ACE inhibitors, as well as in those receiving

angiotensin-receptor blockers (27% and 23%)

Do Do ACEs/ARBsACEs/ARBs Prevent Progression DiabetesPrevent Progression DiabetesHOPE TrialHOPE Trial

Effect of ACEs NOT confirmedin DREAM Trial!!

46

Cum

ulat

ive

risk

Prevention of Diabetes With Therapies Not Targeting Hyperglycemia

Days of follow-up Years in study

HOPE Trial*

RRR=34% (P<0.001)

0.10

0.08

0.06

0.04

0.02

0

Placebo Ramipril

400 800 1200 1600

(n=2883)(n=2837)

0

2

6

4

New

dia

bete

s (%

) Placebo Pravastatin

RRR=30% (P=0.036)

0 1 2 3 4 5

WOSCOPS*(n=2975)

(n=2999)

*Patients without diabetes at baseline.Yusuf et al. JAMA. 2001;286:1882.Freeman et al. Circulation. 2001;103:357.

47

6.8 –

6.6 –

6.4 –

6.2 –

6.0 –

5.8 –

5.6 –

5.4 –

5.2 –

5.0 –

A1c

(%)

Baseline Switch 2-Year Check 3-Year Final

*

**

*

*

*

*

†

†Rosiglitazone (n=39)Pioglitazone (n=62)Control (n=71)

Durbin RJ. Diabetes Obes Metab. 2004;6:280-285.

*P<0.001 vs baseline.†P<0.001 vs rosiglitazone and pioglitazone.

19 (27%)

3 (3%)

Risk reduction of diabetes was 88.9% lower with TZDs group (p < 0.001)

Conversion toDiabetes

Early TZD Use in PreEarly TZD Use in Pre--diabetes diabetes

48

Rosiglitazone

Cum

ulat

ive

Haz

ard

0.1

0.6

0 1 2 3 4

Placebo

0.4

0.5

0.3

Number at Risk:2634 2470 2150 1148 177

0.2

0.0

Years

2635 2538 2414 1310 217PlaceboRosiglitazone

The Dream Trial. Lancet. 2006. Available at: http://www.thelancet.com/webfiles/images/clusters/thelancet/dream_article.pdf.

Early TZD Use in PreEarly TZD Use in Pre--diabetesdiabetesDREAM Trial DREAM Trial

49

Risk for Type 2 diabetes in women with history of GDM is 14.3 % per year

Rate varies as to ethnic background:– In Latino women, 50% progress to type 2

diabetes within 5 years

– If glucose intolerance remains in the post-partum period, the risk increases to 70-80%within 5 years

Buchanan, TA. Diabetes. 2000. 49:782.

Early TZD Use in High Risk Early TZD Use in High Risk Subjects: GDM Subjects: GDM

50

Resistant SensitiveInsulin Sensitivity

Preventing Diabetes After GDM:The Strategy

Workload Reductionfor the Pancreas

1

2

Insu

lin S

ecre

tion

51

Months on Study

Peop

le W

ith D

iabe

tes

53%

19%

RR=0.44Placebo12.3%/yr

TZDs5.4%/yr

60%

40%

20%

0%0 10 20 30 40 50 60

Preventing Diabetes: The TRIPOD Study

Buchanan TA et al. Diabetes. 2002 Sep;51(9):2796-803. Xiang AH et Diabetes. 2006

TZDsTZDs and Prevention of Diabetesand Prevention of DiabetesTRIPOD/PIPOD StudiesTRIPOD/PIPOD Studies

52

Summary of Subgroups

TZD

Large Change in SI

Small Fall inInsulin Levels

DM Rate5.8%/year

Large Fall inInsulin Levels

DM Rate0%/year

Small Changein SI

DM Rate9.8%/year

Placebo

Randomization

DM Rate12.3%/year

Early Metabolic Changes and Risk of Early Metabolic Changes and Risk of Diabetes with TZD Treatment Diabetes with TZD Treatment

Buchanan TA et al. Diabetes. 2002 Sep;51(9):2796-803. Xiang AH et Diabetes. 2006

53

Early Metabolic Changes and Risk of Early Metabolic Changes and Risk of Diabetes with TZD Treatment Diabetes with TZD Treatment

Xiang AH et Diabetes. 2006

54

On Trial Off Trial

Placebo

TZD(Protected)

Months After Randomization

Frac

tion

With

Dia

bete

s

Diabetes

Masking

Prevention

Observed=2.4%

37%Predicted

9%Predicted

40%

30%

20%

10%

0%

0 10 20 30 40

Can Pharmacologic Agents Alter Natural History?Can Pharmacologic Agents Alter Natural History?

55

Potential Lifetime Impact for PrePotential Lifetime Impact for Pre--Diabetes Diabetes Intervention Intervention

83%75%63%

% Developing Diabetes over Lifetime

Diabetes Onset

$1755$ 635

Aroda VR, Ratner R. JCEM 93(9):3259-65, 2008

56

Life Expectancy: Increase by 0.5 Years

Macrovascular Microvascular

Potential Lifetime Impact for PrePotential Lifetime Impact for Pre--Diabetes Diabetes Lifestyle Intervention Lifestyle Intervention

Aroda VR, Ratner R. JCEM 93(9):3259-65, 2008

Stroke

9%

Coronary Heart Disease

8%

Amputations

35%

Blindness

39%

End Stage Renal Disease

38%

57

GLP-1 and GIP are the two major incretins(Is there a role for prevention?)

58

GLPGLP--1 R1 R

cAMPcAMP

Insulin SecretionInsulin Secretion

AgonistAgonist

PKAPKA

EGF REGF R

EpacEpac

Proliferation / Inhibition of ApoptosisProliferation / Inhibition of ApoptosisDifferentiation of Differentiation of ββ--Cell ProgenitorsCell Progenitors

PI 3PI 3--KK

AKTAKT

Foxo1Foxo1CREBCREB

IRSIRS--22

PDXPDX--11

Insulin Gene ExpressionInsulin Gene Expression

BB--RafRaf

MEKMEK

ERKERK

Giorgino F et al, Giorgino F et al, Diabetes Res Clin PractDiabetes Res Clin Pract, 2006, 2006

59

RodentsRodents

Rapid increase of Rapid increase of ββ--cell mass:cell mass:

•• after glucose infusionsafter glucose infusions

•• in transplanted islets with in transplanted islets with induced induced hyperglycaemiahyperglycaemia

•• after partial after partial pancreatectomypancreatectomy

•• by midby mid--trimester of pregnancytrimester of pregnancy

•• with insulin resistancewith insulin resistance

Main mechanism seems to be Main mechanism seems to be replication, rather than replication, rather than neogenesisneogenesis

Involution, e.g., postInvolution, e.g., post--partum, is partum, is primarily by apoptosisprimarily by apoptosis

HumansHumans

Little evidence to support shortLittle evidence to support short--term modulationterm modulation

ββ--cell mass is related to obesitycell mass is related to obesity

Replication rate is difficult to Replication rate is difficult to measure and apparently lowmeasure and apparently low

Possible evidence of Possible evidence of neogenesisneogenesis

60

Recommendations for PreRecommendations for Pre--Diabetes Intervention Diabetes Intervention

Nathan DM et al. Diabetes Care 2007 30: 753; Indian Health Services 2008; Twig SM et al. Med J. Aust 207186: 461

American Diabetes Assoc1

Indian Health Services2

Australian Diab Soc/

ADEA3

DEFINITION:IFGIGT

FPG > 100,<126 mg/dl

2hPG: 140- 200 mg/dl

FPG > 100,<126 mg/dl

2hPG: 140- 200 mg/dl

FPG > 110,<126 mg/dl

2hPG: 140- 200 mg/dl

Screening Individuals with RF

Individuals with RF; annual testing

Incidental when screening for DM

Method - FPG- 2hr OGTT if Metforminconsidered

- FPG- 2hr OGTT (Optional)

As per DM

61

Recommendations for PreRecommendations for Pre--Diabetes Intervention Diabetes Intervention

Nathan DM et al. Diabetes Care 2007 30: 753; Indian Health Services 2008; Twig SM et al. Med J. Aust 207186: 461

American Diabetes Assoc1

Indian Health Services2

Australian DiabSoc/

ADEA3

Treatment 1) Lifestyle2) Lifestyle and/or metformin- if IFG and IGT, or additional RF

1) Lifestyle2) Metformin

in individualized cases

1) Lifestyle;2)Metformin after 6 months

Followup 1)Annual/semi-annual with Rx

Every 6 months 75 OGTT initially, retesting 1-3 years

62

Prevention of Type 2 diabetes

1Lindström J, et al. J Am Soc Nephrol 2003; 14:S108–S113. 2Pan XR, et al. Diabetes Care 1997; 20:537–544. 3Knowler WC, et al. N Engl J Med 2002; 346:393–403. 4Karunakaran S, et al. Metabolism 1997; 46(Suppl 1):56–60.

5Ramachandran A, et al. Diabetologia 2006; 49:289–297. 6Chiasson JL, et al. Lancet 2002; 359:2072–2207.7Torgerson JS, et al. Diabetes Care 2004; 27: 155–161. 8Knowler WC, et al. Diabetes 2005; 54:1150–1156.

9Buchanan TA, et al. Diabetes 2002; 51:2796–2803. 10DREAM Trial Investigators. Lancet 2006; 368:1096–1105.

62%†

Rosiglitazone

DREAM10

*vs control†vs placebo

DPS1

58%*

42%*

58%†

31%†

DPP8

26%*

50%†

0%

28%*25%†

37%†

Da Qing2 DPP3 DPP3FHSG4

Lifestyle

Gliclazide Met Met + lifestyle

IDPP5 IDPP5 STOP-NIDDM6

Acarbose Troglitazone

75%†

TRIPOD9

Orlistat+ lifestyle

XENDOS7

Non-thiazolidinedione

Met

Thiazolidinediones

63

Rosiglitazone plus metformin fixed-dose combination

Rosiglitazone+metformin

n = 152

Metformin

n = 150

Rosiglitazone

n = 155

0

10

20

30

40

50

60

70

80

90

Patie

nts

achi

evin

g H

bA1c

goal

s (%

)

77.0%

59.9%

58.1%†

35.5%†

57.3%*

38.7%**

AACE/IDF goal≤ 6.5%

ADAgoal < 7%

Adapted from Rosenstock J, et al. Diab Obes Metab 2006; 8:650–660.

Intent to treat with last observation carried forward*P < 0.001 vs rosiglitazone+metformin**P = 0.0001 vs rosiglitazone+metformin†P < 0.0001 vs rosiglitazone+metformin

64

Management of PreManagement of Pre--DiabetesDiabetes•• Use of other Pharmaceutical Agents?Use of other Pharmaceutical Agents?

•• Efficacy? Safety? Efficacy? Safety?

•• Change the Natural History? Mask Change the Natural History? Mask the disease?the disease?

•• Will we ever truly determine if a Will we ever truly determine if a pharmacologic approach can prevent pharmacologic approach can prevent development of diabetes as long as development of diabetes as long as we use agents that also we use agents that also treattreat the the disease?disease?

65

Diabetes Prevention Trials: Summary

Prevalence of diabetes and pre-diabetes increasingDevelopment of diabetes associated with sedentary lifestyle and obesityProven early prevention interventions– Intensive lifestyle modification with individualized counseling– Metformin– Troglitazone (patients with history of gestational diabetes)– Acarbose

Several trials with antihyperglycemic and other therapies are ongoing (combination approaches)Newer data with pioglitazone have proven compellingNewer agents with beta-cell trophic effects may prove transformational in diabetes prevention alone or in combination

presenter disclosure information - diabetes association of atlanta · 2009. 10. 23. · 1 presenter...

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