Primary Prevention of Type 2 Diabetes Mellitus K.M.Venkat Narayan

1
Primary Prevention of Type 2 Diabetes
MellitusK.M.Venkat Narayan
2
Burden of Diabetes in the U.S.

• Affects more than 16 million persons
• Increases the risk of heart attack and stroke by
  at least 3-fold
• The leading cause of new blindness, end stage
  renal disease, and amputation
• Accounts for 17 of all deaths after age 25
• Costs 100 billion per year

3
GLUCOSE INTOLERANCE IN THE U.S.
AGE 20-74
NORMAL 81
DIABETES 8
IGT 11
NHANES III
4
Rationale for a Prevention Trial

• The incidence of type 2 of diabetes is increasing
  in epidemic proportions throughout the world.
• Once type 2 diabetes develops, it is difficult to
  treat.
• Prevention of type 2 diabetes would result in a
  significant reduction in social and economic
  costs.

5
Feasibility of Prevention

• Prevention of type 2 diabetes should be feasible
  since
• There is a long asymptomatic period in the
  natural history
• Screening tests can identify high risk
  persons
• There are safe, potentially effective
  interventions

6
Weight gain
Each unit increase in BMI (about 2.7 - 3.6 kg)
increases Type 2 diabetes risk by 12.1 percent !
68 - 72 of diabetes risk in the U.S. is
attributable to or associated with excess weight
For every kilogram increase in weight over 10
years, Type 2 diabetes risk increases 4.5
Ford et al. Amer J Epidemiol 146214,1997
7
Studies of Physical Activity and Type 2 Diabetes
Risk

• US Nurses 27
• U Penn Alumni 31
• Malta 51
• US Physicians 30
• Jap-Amer Hawaii 51
• E Boston elderly 23
• England 60
• San Antonio, M 59
• San Antonio, F 43

• Sweden, men 49
• Jap-Amer LA 40
• Jap-Amer Hawaii 25
• Finland, M 54
• Harvard alumni, M 28
• Finland, M 21
• Finland, F 53

Hamman RF, Evidence Base for Diabetes, Wiley,
2000, In Press
8
Risk of type 2 diabetes associated with level of
physical activity
Relative Risk
U.S. Nurses Health Study
Adjusted for age, smoking. hypertension, family
history, menopause, high cholesterol
8 year follow-up
Quartile of physical activity vs Q1
Hu et al., JAMA 2821433, 1999
9
Type 2 Diabetes Prevention Randomized Controlled
Trials of Drugs

• Sulfonylureas
• Seattle, WA, 1967
• Humble Oil, 1967
• New York, 1967
• Kaiser Permanente, 1967
• Bedford, UK, 1968-1982
• Karolinska, Sweden, 1970
• Joslin Clinic, Boston, 1977
• Malmöhus, Sweden, 1980
• Oxford pilot, UK, 1993
• Fasting Hyperglycemia Study II, UK, France 1997
• Acarbose
• Montreal, CA, 1996

• Biguanides
• Hotel Dieu, France, 1978
• Whitehall, London, 1979
• Warsaw, Poland, 1986
• BIGPRO1, France, 1996
• BIGPRO 1.2, France,1999
• Bejing, China, 1999
• Thiazolidendiones
• San Diego, CA 1994
• Los Angeles, GDM, 1996
• US multicenter IGT, 1997
• ACE inhibitors
• Captopril Prevention Project (CAPPP), 1999
• Heart Outcomes Prevention Evaluation (HOPE), 1999

10
BIGuanides and Prevention of the Risks in Obesity
(BIGPRO1) Trial

• Metformin treated group vs Placebo
• 457 subjects - over 30 dropped out at 1 year
• 2 kg weight loss
• Less rise in fasting glucose (p 0.05)
• Only in subjects with abnormal glucose tolerance
  at baseline
• Lower 2 hr insulin level (p 0.06)
• Lower t-PA antigen (p 0.02)
• No change in Total-, HDL-, LDL-cholesterol,
  triglycerides, blood pressure or 2 hour glucose
  level
• No cases of diabetes in metformin group vs 5 in
  placebo group (p0.06)

Fontbonne, et al. Diabetes Care 1996 19920-926
11
Primary prevention trial among Chinese persons
with IGT
RR 0.51 (0.14-1.91)
N42 N43
Li, et al., Diabetic Medicine, 16477-481,1999
12
Captopril Prevention Project (CAPPP)

• 10,985 patients in 536 centers in Sweden, Finland
• Aged 25-66 at entry
• BP gt 100 mm Hg x 2
• Randomized to Captopril (ACE inhibitor) vs
  conventional therapy (diuretics, beta-blockers)
• 10,410 non-diabetic persons at entry
• Average follow-up 6.1 years
• RR for incident diabetes 0.86 (0.74-0.99) p
  0.039
• On treatment RR 0.79 (0.67-0.94)

Hansson et al., Lancet 353 611 1999
13
Heart Outcomes Prevention Evaluation (HOPE)

• 9,297 patients in 267 centers in Europe, Americas
• Aged 55 at entry
• History of CVD or stroke or PVD or diabetes and 1
  other risk factor
• Randomized to Ramipril (ACE inhibitor) or Vitamin
  E (2 x 2 factorial) (No effect of Vitamin E)
• 5,720 non-diabetic persons at entry
• Average follow-up 5 years
• RR for incident diabetes 0.66 (0.51-0.85) p lt
  0.001

New Engl J Med 342145-153, 2000
14
Type 2 Diabetes Prevention Randomized Controlled
Trials of Lifestyle

• Uppsala, Sweden 1985
• Dalby, Sweden, 1992
• Oxford, UK pilot 1992
• Indian Diet Heart, 1993
• Baltimore, MD, 1995
• Sollentuna, Sweden, 1995
• Baltimore, MD, 1995
• Oslo Diet and Exercise Study (ODES), 1996
• DaQing IGT and Diabetes Study, 1997

• Fasting Hyperglycemia Study II UK, France, 1997
• Pittsburgh, PA, 1998
• Pima Indian pilot, 1998
• Syracuse, NY, 1998
• Womens Healthy Lifestyle Project, Pittsburgh,
  PA, 1998
• Community Diabetes Prevention Project, Minnesota,
  1998

15
Stages in the natural history of Type 2 diabetes
Disability Death
Normal
IGT
NIDDM
Complications
Genetic predisposition
Preclinical state
Clinical disease
Disability Death
Complications
Primary Secondary
Tertiary prevention prevention
prevention
16
Impaired Glucose Tolerance

• Risk factor for type 2 diabetes
• Increases risk of type 2 diabetes 5 - 8 fold
• 1-5 per year develop type 2 diabetes
• Risk factor for cardiovascular disease (CVD)
• IGT may be optimal time for intervention
• Asymptomatic
• Few, if any complications present
• Potentially reversible

17
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 centers
• Four arm study over 6 years
• Diet
• Exercise
• Diet Exercise
• Control

Pan et al. Diabetes Care 20 537, 1997
18
Da Qing IGT and Diabetes Study
a Adjusted for BMI and fasting glucose
Pan et al. Diabetes Care 20 537, 1997
19
Type 2 Diabetes Primary Prevention Randomized
Controlled Trials Underway as of 2000

• Diabetes Prevention Study (DPS) Start
  Finish
• Finland 523 MF IGT Lifestyle
  1993 - 2002-03
• Community Diabetes Prevention Project
• Minneapolis, MN 418 MF Limited
  lifestyle 1995 - 2000-01
• TRIPOD (Troglitazone in the Prevention of
  Diabetes)
• Los Angeles, CA 150 F with GDM
  Troglitazone 1996 - 2000
• EDIT (Early Diabetes Intervention Trial)
• 9 centers in UK 631 MF FPG 5.5-7.0 mmol/L
  acarbose and metformin 2 x 2 factorial design
  with placebo 1994 - 2002

20
Type 2 Diabetes Primary Prevention Randomized
Controlled Trials Underway as of 2000

• DPP (Diabetes Prevention Program)
  Start Finish
• 27 centers 3,234 MF IGT Lifestyle,
  Metformin/PLBO
  
  1996 - 2002
• STOP-NIDDM
• Europe, Canada 1,418 MF IGT Acarbose/PLBO
  
  1996 - 2001-02
• DAISI (Dutch Acarbose Trial)
• Hoorn, Netherlands 150 MF IGT Acarbose/PLBO
  
  1998 - 2002
• NANSY
• Sweden, Norway 2,224 MF IFG
  Glimepiride/PLBO
  
  2000 - 2007

21
Finnish Diabetes Prevention Study

• 4-year, multi-center (5 clinics), randomized
  controlled trial of lifestyle (diet activity)
• 523 persons with IGT (? 55 yrs, BMI 31, 33
  men)
• Two arm study
• Lifestyle wt loss, reduce kcal, total/sat.
  fat increase fiber, physical activity 1st year
  intensive, thereafter maintenance 7 sessions
  1st year, and quarterly thereafter 2-yr wt.
  change -7.7 lbs.
• Control general advice re diet/activity
  annually. 2-yr wt. change -1.7 lbs.

Tuomilehto et al. 60th Scientific Sessions, ADA
2000, San Antonio, TX June, 2000 (LB-12).
22
Changes after a 2-year intervention - DPS
Intervention Control
p for change Weight (kg) -3.5 -0.8
Waist circumference
(cm) -4.2 -1.3 fP-glucose
(mmol/l) -0.1 0.2 2h-P-glucose
(mmol/l) -0.8 0.0 fS-insulin
(µU/ml) -2 -1 ns 2h-S-insulin
(µU/ml) -29 -12 HbA1c
() -0.2 0.1 Systolic BP
(mmHg) -5 0 Diastolic BP
(mmHg) -5 -3 Total
cholesterol -0.09 -0.00 ns HDL
cholesterol 0.10 0.07
ns Triglycerides -0.20 0.00

23
Development of diabetes - DPS

Risk reduction 57
24
Success in achieving the lifestyle targets at
1-year examination
TARGET Intervention
Control () () Weight
reduction gt 5 43 13 Fat intake
lt 30E 47 26 Saturated fat intake lt 10
E 26 11 Fiber intake gt 15 g/1000
kcal 25 12 Exercise gt 4 hours/week
86 71
All plt0.0001
25
Diabetes Prevention Program (DPP)

• 27 center randomized controlled trial
• 3,234 people with IGT 45 minorities 25-85
  years average BMI 34 kg/msq
• Three groups
• Standard lifestyle
• Intensive lifestyle 7 weight loss through
  low-fat diet and 150 mins exercise per week
• Metformin

26
Diabetes Prevention Program (DPP)

• Conversion to diabetes att 3 years of follow-up
• Standard lifetsyle 29
• Intensive lifestyle 14 (-58)
• Metformin22 (-31)
• Intensive lifestyle participants achieved 7 (15
  lbs) weight loss in first year and sustained 5
  total loss during 3 years

27
Implications for Public Health?

• Identification of Those at Risk?
• Screening for Impaired Glucose Tolerance?
• Those with poor access to health care?
• Ethics of just screening without follow-up?
• Translation of Intervention(s)?
• What dose (frequency, intensity, duration) can
  be achieved in the real world
• What is minimally necessary compliance?
• Role of extra-clinical interventions?
• Environmental change to support lifestyle
• Community-level activities vs. go-it-alone
  lifestyle
• Evaluation of Overall Efforts
• Time-Place-Person Trends in Type-2 Diabetes
• e.g. population Surveillance
• Adequacy of the Intervention(s) Process
• e.g., population surveys of exposure