Towards Diabetes PreventionTowards Diabetes Prevention

Leigh Perreault, MDAssociate Professor of Medicine

Endocrinology, Metabolism and DiabetesUniversity of Colorado Anschutz Medical Campus

Associate Professor of EpidemiologyColorado School of Public Health

Leigh Perreault, MDAssociate Professor of Medicine

Endocrinology, Metabolism and DiabetesUniversity of Colorado Anschutz Medical Campus

Associate Professor of EpidemiologyColorado School of Public Health

Diabetes Care 2008

Preventing Diabetes in People at Highest Risk

CDC Statement

January 26, 2011

“An estimated 79 million Americans - 35% of the population over 20 years of age - currently has pre-

diabetes.”

Screening

• Everyone >45 years old

• Anyone with a BMI>25 kg/m2 + 1 risk factor

• Risk factors: *physical inactivity *FDR with diabetes *high-risk ethnicity *women delivering a baby >9 lbs or h/o GDM or PCOS *HDL<35, TG> 250 mg/dl

*history of hypertension or CVD

American Diabetes Association: Glucose criteria for pre-diabetes

NGT IFG

IGT IFG/IGT

Fasting glucose (mg/dl)

2h glucose (mg/dl)

<100 100-125

<140

140-200

A1c = 5.7-6.4%

Risk of Diabetes for those withPre-diabetes

A1c(%)

Annual incidence of diabetes (%)

5

6

7

8

5 10 15 20 2520

25%/5 year risk

50%/5 year risk

Zhang, Diabetes Care 2010

Intervention Trials to Reduce Progression of IGT to Type 2 Diabetes

Rosi

FDPS2 DPP9DaQing1

DPP3

Lifestyle

Troglitazone

Non-thiazolidinedione Thiazolidinediones

Pio

DPP2

Met

IDPP4

Met Acarbose Orlistat

XEN-DOS6IDPP4

STOP-NIDDM5

ACTNOW11DREAM10

1Pan XR et al: Diabetes Care 20:537-544; 1997. 2Tuomilehto J et al: N Engl J Med 344:1343-1350; 2001. 3DPP Research Group: N Engl J Med 346:393-403; 2002. 4Ramachandran A et al: Diabetologia 49:289-297; 2006. 5Chiasson JL et al: Lancet 359:2072-2207; 2002. 6Torgerson JS et al: Diabetes Care27: 155-161; 2004. 7Holman RR et al: N Engl J Med 362:1463-1476; 2010. 8Buchanan TA et al: Diabetes 51:2796-2803; 2002. 9DPP Research Group:Diabetes 54:1150-1156; 2005. 10DREAM Trial Investigators: Lancet 368:1096-1105; 2006. 11DeFronzo RA et al: N Engl J Med 364:1104-1115; 2011.

Nateg

NAVIGATOR7

62%†

55%†

75%† 72%†

*vs control†vs placebo

58%*

42%*

58%†

29%†31%†

26%* 25%†

37%†

-7%

TRIPOD8

Diabetes Prevention Program (DPP)

Knowler, NEJM 2002

• Lose >7% body weight• Exercise 150 minutes/week• Consider metformin• Re-screen annually

Diabetes Care 2007

Diabetes Prevention Program Outcomes Study (DPPOS)

Knowler, Lancet 2010

0 1 2 3 4 5 6 7 8 9 10

intervention

intervention observation

The Alternate Explanation: Quasi-inertia

Pre-diabetes DiabetesNormoglycemia

The Alternate Explanation: Quasi-inertia

Pre-diabetes DiabetesNormoglycemia

New Goals for People with Pre-diabetes: Normal Glucose Regulation

Perreault, Lancet 2012

56%

Benefit of Maintaining NGR

Perreault, Lancet 2012

Does treatment modality matter?

Perreault, Lancet 2012

American Diabetes Association: Glucose criteria for pre-diabetes

NGT IFG

IGT IFG/IGT

Fasting glucose (mg/dl)

2h glucose (mg/dl)

<100 100-125

<140

140-200

QuickTime™ and a decompressor

are needed to see this picture.

QuickTime™ and a decompressor

are needed to see this picture.

Can we do a better job preventing diabetes by targeting defects specific

to the subtypes of pre-diabetes?

Can we do a better job preventing diabetes by targeting defects specific

to the subtypes of pre-diabetes?

Matschinsky, Medicine Reports 2010

Hepatic Glucokinase

GlucoseG-6-P

glucokinase

G-6-Pase

Hepatic GlucokinaseGKRP

GlucoseG-6-P

glucokinase

G-6-Pase

Hepatic Glucokinase

GlucoseG-6-P

GKRP glucokinase

G-6-Pase

fructose

Demographics

NGT IFG

N= 17 17

M/W 8/9 8/9

BMI (kg/m2) 31±0.6 32±1.0

% Fat 37±1.5 36±2.2

Fasting glucose (mg/dl) 91±0.9* 102±1.1

2-hour glucose (mg/dl) 90±6.1* 111±6.1

*p<0.05 from IFG

Study Design

6,6 2H2-glucose isotope

somatostatin, glucagon, growth hormone, insulin

glucose

Hours0 2 5 7 9

fructose

*

*p<0.05 from IFG

#p<0.05 from prior stage

##

*

*p<0.05 from IFG#p<0.05 from prior stage

#

##

#p<0.05 from prior stage

##

#

0.75%

What’s changed in the past 50 years?

• Portion size explosion• High-fructose corn syrup• Trans fat• Processed foods• Environmental pollutants

Increasing Prevalence of Diabetes Tracks with Environmental Pollutants

Neel, Diabetes 2011

Diabetes Tracks with Gut Microbial Composition

Qin, Nature 2012

microbial gene clusters -T2DM microbial gene clusters +T2DM

Increasing Prevalence of Diabetes Tracks with Sleep Disorders:

NHANES 2008T2DM Sleep Disorders

Will achievement of normoglycemia improve outcomes in pre-diabetes? Will achievement of normoglycemia improve outcomes in pre-diabetes?

Can Glucose Lowering in Pre-diabetes Prevent Macrovascular Complications?

UKPDS ADVANCE VA-DT ACCORD

% re

duct

ion

in c

ompo

site

mac

rova

scul

ar d

isea

se

16%6% 12% 10%

None significant

Data from trials in type 2 diabetes

Glucose Lowering Decreases Carotid Intima Media Thickness in Pre-diabetes

PlaceboPioglitazone

Xiang, Athero 2008

PlaceboPioglitazone

Xiang, Athero 2008

DeFronzo, NEJM 2011

Carotid Intima-Media Thickness

Mea

n %

Cha

nge

0

2

4

Months0 12 24 36

p=0.047

PlaceboPioglitazone

Glucose Lowering Decreases Carotid Intima Media Thickness in Pre-diabetes

Chiasson, JAMA 2003

Glucose Lowering Decreases CVD in Pre-diabetes

49%

Should we expand our focus on CVD prevention to those with pre-diabetes? Should we expand our focus on CVD

prevention to those with pre-diabetes?

Conclusions

• Pre-diabetes represents a very high-risk state for diabetes and carries a higher incidence of related complications in and of itself.

• Prevention of diabetes - particularly when NGR can be attained - is key to lower risk.

• Additional risk can also be decreased through CVD risk stratification, but guidelines for lipid and BP goals specific to pre-diabetes are lacking.

• Consider the subtype of pre-diabetes when picking a glucose-lowering strategy.

• NGR should be the treatment goal with patients monitored for relapse.

• Applying lipid and BP standards-of-care in diabetes to pre-diabetes may be even more important than NGR for CVD prevention.

Bringing the Data to Patient Care

• Bryan Bergman, PhD

• Anna Kerege

• Samantha Bacon

• Richard Hamman, MD, DrPh

• Diabetes Prevention Program

• National Institutes of Health (5U01-DK048375-12)

Thank you!