Diabetes Prevention for a Diabetes Prevention for a Heterogeneous PopulationHeterogeneous Population

Richard Arakaki, M.D.Richard Arakaki, M.D.

Professor of Medicine and Professor of Medicine and

Chief, Division of Endocrinology and MetabolismChief, Division of Endocrinology and Metabolism

John A. Burns School of MedicineJohn A. Burns School of Medicine

September 30, 2011September 30, 2011

Type 2 Diabetes Prevention: Type 2 Diabetes Prevention: A Few QuestionsA Few Questions

• UNEQUIVOCALLY SHOWN TO BE UNEQUIVOCALLY SHOWN TO BE PREVENTED AND/OR DELAYED!PREVENTED AND/OR DELAYED!

• How should we identify people at-risk?How should we identify people at-risk?

• What interventions are appropriate?What interventions are appropriate?

• How do we implement the interventions?How do we implement the interventions?

Da Qing IGT and Diabetes StudyDa Qing IGT and Diabetes StudyDa Qing IGT and Diabetes StudyDa Qing IGT and Diabetes Study

• Screened 110,660 persons in Da Qing, China Screened 110,660 persons in Da Qing, China for IGT for IGT

• Randomized 577 persons with IGT at 33 local Randomized 577 persons with IGT at 33 local health centershealth centers

• Four arm study over 6 years (group Four arm study over 6 years (group intervention for weight loss)intervention for weight loss)– Diet (modest weight reduction due to low BMI)Diet (modest weight reduction due to low BMI)– ExerciseExercise

– Diet + Diet + Exercise– ControlControl

Pan et al. Diabetes Care 1997;20:537-44

Da Qing IGT and Diabetes StudyDa Qing IGT and Diabetes StudyDa Qing IGT and Diabetes StudyDa Qing IGT and Diabetes Study

a Adjusted for BMI and fasting glucosePan et al. Diabetes Care 1997;20:537-44

Intervention 6 yr Incidence of

NIDDM

% reduction from controla

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)

Mean change in BMI for intervention -0.69; Control -0.34

Diabetes Prevention ProgramDiabetes Prevention Program

• Primary Goal: Primary Goal: • To prevent or delay the development of type 2 diabetes in To prevent or delay the development of type 2 diabetes in

persons with impaired glucose tolerance (IGT)persons with impaired glucose tolerance (IGT)

Randomized (3,819 people)Randomized (3,819 people)

Standard lifestyle teachingStandard lifestyle teaching

Intensive Intensive LifestyleLifestyle(1079 people)(1079 people)

MetforminMetformin(1073 people)(1073 people)

PlaceboPlacebo(1082 people)(1082 people)

TroglitazoneTroglitazone585 people585 peopleUntil 6/98Until 6/98

• Study Interventions: Study Interventions:

0 1 2 3 4

0

10

20

30

40Placebo (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

ula

tive in

cidence

(%

)

Placebo (n=1082)

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

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

Incidence of Diabetes Incidence of Diabetes

Risk reductionRisk reduction31% by metformin31% by metformin58% by lifestyle58% by lifestyle

N Engl J Med 346:393-403, 2002

Effect of Treatment on Incidence of DiabetesEffect of Treatment on Incidence of Diabetes

PlaceboPlacebo MetforminMetformin LifestyleLifestyle

IncidenceIncidence of diabetes 11.0% 7.8% of diabetes 11.0% 7.8% 4.8% 4.8%

(percent per year)(percent per year)

ReductionReduction in incidence in incidence -------- 31%31% 58%58%

compared with placebo/metformincompared with placebo/metformin 39%39%

Number needed to treatNumber needed to treat -------- 13.9 13.9 6.9 6.9

to prevent 1 case in 3 yearsto prevent 1 case in 3 years

N Engl J Med 346:393-403, 2002

Diabetes Incidence Rates by EthnicityDiabetes Incidence Rates by Ethnicity

0

4

8

12

Caucasian(n=1768)

AfricanAmerican(n=645)

Hispanic(n=508)

AmericanIndian

(n=171)

Asian/PI(n=142)

Cases/1

00 p

ers

on

-yr

Lifestyle Metformin Placebo

N Engl J Med 346:393-403, 2002

71%

51%

0

5

10

15

20

95-109 (5.3- 6.0)(n=2174)

110-125 (6.1-6.9)(n=1060)

Ca

se

s/1

00

pe

rso

n-y

r

Lifestyle

Metformin

Placebo

Diabetes Incidence Rates by Fasting GlucoseDiabetes Incidence Rates by Fasting Glucose

Fasting Plasma Glucose: mg/dl (mmol/l)

N Engl J Med 346:393-403, 2002

0

4

8

12

16

140-153(n=1049)

154-172(n=1103)

173-199(n=1082)

Ca

se

s/1

00

pe

rso

n-y

r

Lifestyle Metformin Placebo

Diabetes Incidence Rates by 2-hr GlucoseDiabetes Incidence Rates by 2-hr Glucose

2-Hour Plasma Glucose (mg/dl)

N Engl J Med 346:393-403, 2002

DPPOS Incidence of DiabetesDPPOS Incidence of Diabetes

0 2 4 6 8 10

01

02

03

04

05

06

0

Year since DPP Randomization

Cu

mu

lativ

e I

nci

de

nce

(%

)A. All Participants

PlaceboMetforminLifestyle

DPP Research Group. Lancet. 2009; 374:1677-1686 (Figure 4)

DPPOS Diabetes Risk Reduction

• Delay in diabetes onset after 10 years follow-up:–4 years for Lifestyle; 34% lower risk–2 years for Metformin; 18% lower risk

• The key factors for lower rate of diabetes development for lifestyle and metformin.

–Weight loss is the predominant factor; 16% RR per kg weight loss

–Metformin compliance

Summary of Treatment EffectsSummary of Treatment Effects

• Lifestyle intervention was beneficial regardless of ethnicity, age, BMI, or sex

• The efficacy of lifestyle relative to metformin was greater in older persons and in those with lower BMI

• The efficacy of metformin relative to placebo was greater in those with higher baseline fasting glucose and BMI

Li et al. Lancet 2008;317:1783-89

Cumulative incidence of DM during follow-up in Cumulative incidence of DM during follow-up in China Da Qing Diabetes Prevention Outcome StudyChina Da Qing Diabetes Prevention Outcome Study

Study NStudy

populationDuration of intervention

Cumulative incidence in

controls

Risk reduction(95% CI)

DPP Research Group

API Subgroups

1079 active1082 control

57 L/S, 49 P

IGTBMI 34

BMI 29.3

2.8 years

28.9% at 3 years

36% at 3 yrs

58%(48-66)

71%

Da Qing IGT and DiabetesStudy

133 control;130 diet;141 ex; 126 both

IGT BMI 26

6 years68 %

(15.7% per year)

31% (diet)46% (ex)

42% (both)

Japan Diabetes Study

356 control102 active

IGT (*)BMI 24

4 years 9.3 (FPG >140mg/dl)

67.4%

Indian Diabetes Prevention Programme

133 active136 control

IGTBMI 26

3 years 55 %28.5%(20-37)

Zensharen Study330 control311 active

IFG, IGTBMI 27

3 years 16.6 % 44%

Lifestyle Intervention/Prevention DM Asian StudiesLifestyle Intervention/Prevention DM Asian Studies

Knowler W et al, N Engl J Med 2002;346:393-403, 2002; Pan XR et al, Diabetes Care 1997;20:537-544; Kosaka Diabetes Res Clin Pract 2005;67:152-62K et al,; Ramachandran A et al, Diabetologia 2006;49:289-97; Saito T et al Arch Intern Med 2011;171:1352-60.

Saito T et al Arch Intern Med 2011;171:1352-60.

Zensharen Study: Cumulative Diabetes Incidence by baseline glucose tolerance status

Study and Medication

NStudy

populationDuration of intervention

Cumulative incidence in

controls

Risk reduction(95% CI)

DPP Research GroupMetformin 850 BID

API Subgroup

1073 active1082 placebo

36 Met, 49 Pla

IGTBMI 34

BMI 29.3

2.8 years

28.9% at 3 years

36% at 3 yrs

31%

38%Chinese Diabetes Metformin 250 TID

42 active43 control

IGTBMI 26

1 year 14.0 % 50%

Indian Diabetes PPMetformin 250 BID

133 active136 control

IGTBMI 26

2.5 years 55% 26%

Indian Diabetes PPPioglitazone 30 + LS

204 active203 control

IGTBMI 26

3 years 31.6 % 8% (NS)

DREAM Trial Indian Cohort

Rosiglitazone 8 mg

330 active332 placebo

IGT /IFG/bothBMI 28

3.0 years 8 % per year 40 %

Japan DiabetesStudyVoglibose 0.2 mg TID

110 control112 active

IGTBMI 26

3 years 9.3 % 58 %

Knowler W et al, N Engl J Med 2002;346:393-403, 2002; Ramachandran A et al, Diabetologia 2009;52:1019-26; Li, CL et al Diabetic Med 1999;16:477-481; DREAM Trial Investigators Lancet 2006;368:1096-1105; Kawamori R et al, Lancet 2009;373:1607-14.

Medication DM Prevention Studies in AsiansMedication DM Prevention Studies in Asians

10% Estimate of diabetes associated with known genetic risk (Jablonski K et al Diabetes 2010)Primarily related to beta-cell function

Overall genetic markers (SNPs by GWAS) associated with increased rates of DM are similar across all ethnic groups (Europeans, Asians, etc; Tan JT et al, J Clin Endocrinol Metab 2010;95:390-397).

Allele frequency may reduce usefulness of SNPs for screening at-risk individuals

TCF7L2 Polymorphisms and progression to diabetes in the Diabetes Prevention Program (N Engl J Med, July 2006); high risk SNP but still responsive to lifestyle

intervention

Genetics Risk for Diabetes

Type 2 Diabetes Prevention: Type 2 Diabetes Prevention: A Few Answers?A Few Answers?

• How should we identify people at-risk?How should we identify people at-risk?

• Pathophysiologic and physical characteristics • low insulinogenic index (beta cell function) • high HOMA IR (insulin resistance)• higher BS levels; fasting > 110 mg/dl;

A1c>6.0%• Zensharen Study- need for OGTT

• GWAS; look for multiple SNPs, additive risk

Type 2 Diabetes Prevention: Type 2 Diabetes Prevention: A Few Answers?A Few Answers?

• What interventions are appropriate?What interventions are appropriate?• ANY effective Weight loss interventions

• Lower BMI group• More weight loss-greater effect

• Effective Exercise interventions• 150 min/week or more?

• Medications • Metformin 250 BID/TID (lower doses)• TZDs at high dose• Alpha-glucosidase inhibitors-preferred?Alpha-glucosidase inhibitors-preferred?

Type 2 Diabetes Prevention: Type 2 Diabetes Prevention: A Few Answers?A Few Answers?

• How do we implement the interventions?How do we implement the interventions?

• Community-Based Interventions• Physicians/physician’s groups• Medicare/ Other Insurers• Government-Federal/State

• Are we even there yet?

Thank you for your attentionThank you for your attention