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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
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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.
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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.
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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
ΔΔI 0I 0--30/ 30/ ΔΔG0G0--3030ΔΔI 0I 0--30/ 30/ ΔΔG0G0--3030
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
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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
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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!
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Management of PreManagement of Pre--DiabetesDiabetes
•• 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:
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Type 2 diabetes
Years from Years from diagnosisdiagnosis
0 5-10 -5 10 15
Pre-diabetes
Onset Diagnosis
Insulin 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
Natural History of Type 2 DiabetesNatural History of Type 2 Diabetes
““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.
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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)
Pan et al. Diabetes Care. 1997;20:537.
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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
Pan et al. Diabetes Care. 1997;20:537.
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
The Diabetes Prevention Program Research Group. N Engl J Med. 2002;346:393.
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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%
The Diabetes Prevention Program Research Group. N Engl J Med. 2002;346:393.
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
For Health Care Providers:Patient Handouts
42
For Health Care Providers:Patient Handouts
43
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?
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