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Prevention of

Type 2 Diabetes Mellitus


Key Questions
and
A Call to Action

Prevention of Type 2 Diabetes


Mellitus: Table of Contents
Section

Topic

Slide No.

Why is prevention of type 2 diabetes imperative?

3-5

What is the evidence that type 2 diabetes can be


prevented or delayed?

6-23

Do prevention interventions have sustained


effects?

24-30

Are we preventing type 2 diabetes or delaying it?

31-32

Is diabetes prevention cost-effective?

33-36

Can evidence-based interventions be delivered


effectively in lower-cost settings?

37-40

Will diabetes prevention bend the curve of the


epidemic?

41-42

How can we most effectively prevent or delay


type 2 diabetes?

43-51

Conclusions: call to action

52-53

Section 1

WHY IS PREVENTION OF
TYPE 2 DIABETES
IMPERATIVE?

U.S. Population with


Diabetes (%)

Projecting the Future Diabetes


Population: The Imperative for Change

Boyle JP, et al. Popul Health Metr. 2010;8(29):1-12.

Percentage of U.S. Adults Who Were


Obese or Had Diagnosed Diabetes
Obesity (BMI 30 kg/m2)
1994

No Data

2000

<14.0%

14.0-17.9%

18.0-21.9%

2008

22.0-25.9%

26.0%

Diabetes
1994

No Data
9.0%

2000

<4.5%

4.5-5.9%

6.0-7.4%

2008

7.5-8.9%

Centers for Disease Control and Prevention: National Diabetes Surveillance System.
Available online at: http://apps.nccd.cdc.gov/DDTSTRS/default.aspx. Accessed 10/3/2011.

Section 2

WHAT IS THE EVIDENCE


THAT TYPE 2 DIABETES
CAN BE PREVENTED OR
DELAYED?

Lifestyle Interventions
Can Prevent Type 2 Diabetes Onset
Several randomized trials have shown
interventions (lifestyle, medications) can
decrease rate of onset of diabetes
Lifestyle: Da Qing, Finnish Diabetes
Prevention Study, Diabetes Prevention
Program
Medications: Diabetes Prevention Program
(metformin), The Stop-NIDDM (acarbose),
DREAM (rosiglitazone), ACT-NOW
(pioglitazone)

Lifestyle Interventions
Da Qing Study Methods
110,660 adults from 33 Da Qing, China,
health care clinics screened in 1986 for IGT,
type 2 diabetes mellitus
577 adults with IGT (WHO criteria)
randomized to control (n=138) or one of three
lifestyle interventions (n=438)
Diet only
Exercise only
Diet + exercise

Follow-up at 2-year intervals over 6 years to


identify those who developed diabetes
Pan XR, et al. Diabetes Care. 1997;20:537-544.

Lifestyle Interventions
Da Qing Study Results
Cumulative incidence of diabetes at
6 years was significantly decreased in the
active intervention groups (P<0.05)
Control

67.7% (95% CI, 59.8-75.2)

Diet

43.8% (95% CI, 35.5-52.3)

Exercise

41.1% (95% CI, 33.4-49.4)

Diet + exercise

46.0% (95% CI, 37.3-54.7)

When analyzed by clinic, each active


intervention group differed significantly from
the control (P<0.05)
Pan XR, et al. Diabetes Care. 1997;20:537-544.

Lifestyle Interventions
Da Qing Study Results
When stratified as lean or overweight
(BMI < or 25 kg/m2), relative decrease
in rate of development of diabetes in
lifestyle intervention groups was similar
After adjusting for differences in baseline
BMI and fasting glucose, all interventions
were associated with diabetes risk
reduction
Diet

31% (P<0.03)

Exercise

46% (P<0.0005)

Diet + exercise

42% (P<0.005)
Pan XR, et al. Diabetes Care. 1997;20:537-544.

Lifestyle Interventions
Da Qing Study Conclusions
Active intervention with diet and/or
exercise led to a significant decrease in
incidence of diabetes over a 6-year period
(1986-1992) among those with IGT
Diabetes incidence (per 100 person years)
per year
Control: 14.1 (95% CI 11.2-17.0)
Lifestyle intervention: 7.9 (95% CI, 6.8-9.1)

Pan XR, et al. Diabetes Care. 1997;20:537-544.

Lifestyle Interventions
Finnish Diabetes Prevention Study
522 subjects, 40-65 years of age
BMI 25 kg/m2; IGT: 2-h PPG 140-200 mg/dL

Control group: general oral and written


information diet and exercise
Intervention group: individualized

Reduce weight 5%
Decrease fat 30%, saturated fat 10% energy
Increase fiber to at least 15 g/1000 kcal
Moderate exercise 30 minutes/day

Primary end point: diagnosis of diabetes


Tuomilehto J, et al for the Finnish Diabetes Prevention Study Group.
N Engl J Med. 2001;344:1343-1350.

Lifestyle Interventions
Finnish Diabetes Prevention Study
172 men, 350 women; mean age 55 y
Mean BMI 31 kg/m2
Mean duration of follow-up 3.2 years
Weight Loss, Kg
Mean SD

Cumulative
Incidence of
Diabetes
After 4 Years

Year 1

Year 2

Control

0.83.7

0.84.4

23%
(95% CI, 17-29)

Intervention
*

4.25.1*

3.55.5*

11%
(95% CI, 6-15)

P<0.001

Risk Reduction

58%

*
Tuomilehto J, et al for the Finnish Diabetes Prevention Study Group.
N Engl J Med. 2001;344:1343-1350.

Lifestyle Interventions
Finnish Diabetes Prevention Study
Reduction in incidence of type 2 diabetes
was directly associated with changes in
lifestyles of high-risk subjects (ie, those
with IGT)
Modifiable risk factors such as obesity, physical
inactivity, suggested as main nongenetic
determinants of diabetes

These results demonstrate that 22 subjects


with IGT must be treated with lifestyle
intervention for 1 year (or 5 subjects for 5
years) to prevent 1 case of diabetes

Tuomilehto J, et al for the Finnish Diabetes Prevention Study Group.


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

Lifestyle Interventions
Diabetes Prevention Program
3,234 nondiabetic persons in 27 clinical
centers
BMI 24 kg/m2 (22 kg/m2 in Asians)
IGT: FPG 95-125 mg/dL or 2-h PPG 140-199
mg/dL

From 1996-1999, randomly assigned to


Standard lifestyle + placebo (n=1082)
Standard lifestyle + metformin, initiated at 850
mg orally once daily; at 1 month, increased to
850 mg twice daily (n=1073)
Intensive lifestyle intervention (n=1079)
Knowler WC, et al. for the Diabetes Prevention Program Research Group.
N Engl J Med. 2002;346:393-403.

Lifestyle Interventions
Diabetes Prevention Program
Goals of intensive lifestyle intervention
7% loss of body weight
Dietary fat goal: 25% of calories from fat
Calorie intake goal: 1200-1800 kcal/day based
on initial body weight

>150 minutes of physical activities weekly


Similar in intensity to brisk walking; at least
700 kcal/week

Group received 16-lesson curriculum


Knowler WC, et al. for the Diabetes Prevention Program Research Group.
N Engl J Med. 2002;346:393-403.

Lifestyle Interventions
Diabetes Prevention Program
Mean age 50.6 years
67.7% women; 45.3% members of
minority groups
Mean BMI 34.0 kg/m2
69.4% had a family history of diabetes
Average follow-up: 2.8 years
(range, 1.8-4.6)

Knowler WC, et al. for the Diabetes Prevention Program Research Group.
N Engl J Med. 2002;346:393-403.

Lifestyle Interventions
Diabetes Prevention Program
Those assigned to lifestyle intervention
had greater weight loss and increase in
physical activity than participants receiving
metformin or placebo
Lifestyle intervention more effective in
restoring normal post-load glucose values
Results: average weight loss (P<0.001)
Lifestyle

Metformin

Placebo

5.6 kg

2.1 kg

0.1 kg

Knowler WC, et al. for the Diabetes Prevention Program Research Group.
N Engl J Med. 2002;346:393-403.

Lifestyle Interventions
Diabetes Prevention Program
Results: intensive lifestyle intervention

Weight loss 7%

50%

At Final
Study Visit
38%

Exercise >150
minutes/week

38%

58%

At 24 Weeks

Knowler WC, et al. for the Diabetes Prevention Program Research Group.
N Engl J Med. 2002;346:393-403.

Medications
DPP: Metformin Intervention
Metformin, intensive lifestyle modification
delayed or prevented type 2 diabetes vs
placebo (11%/year incidence)
Placebo: 11%/year incidence
Metformin: 7.8%/year incidence*
Lifestyle intervention: 4.8%/year incidence*

Risk reduction:
31% by metformin
58% by lifestyle
39% lifestyle vs metformin
P<0.001 vs placebo

Knowler WC, et al. for the Diabetes Prevention Program Research Group.
N Engl J Med. 2002;346:393-403.

Medications
DPP: Metformin Intervention
Intensive lifestyle intervention more
effective than either metformin or placebo
By subgroup, metformin more effective if:
FPG >110 mg/dL
Age <60 years
BMI >35 kg/m2

Gender, ethnicity, 2-h PGG, NOT predictive


of response
Use metformin in high-risk individuals
Knowler WC, et al. for the Diabetes Prevention Program Research Group.
N Engl J Med. 2002;346:393-403.

Medications
The STOP-NIDDM: Acarbose
Acarbose
100 mg TID
n=682

Placebo
n=686
25% Relative
Risk Reduction
P=0.0022

Acarbose reduced
risk of new
Hypertension
>140/90; 5.3%
absolute risk
reduction
(P=0.006)
Myocardial
infarction
(P=0.02)
Any CVD event:
CHD, CV death or
stroke, CHF, PVD
(P=0.03)

Reprinted with permission from Chiasson JL, et al. Lancet. 2002;359(9323): 2072-2077;
Chiasson JL, et al. JAMA. 2003;290(4):486-494.

Medications
DREAM: Rosiglitazone
60%
Relative Risk
Reduction
HR 0.40
(0.350.46)
P<0.0001

Reprinted with permission from DREAM Trial Investigators. Lancet. 2006;368(9541):1096-1105.

Medications
ACT NOW: Pioglitazone
Pioglitazone reduced risk of type 2 diabetes
mellitus by 72% vs placebo (HR 0.28; 95%
CI 0.160.49 P<0.001)
Conversion to normal glucose tolerance:
48% of patients with pioglitazone vs 28%
with placebo (P<0.001)
Pioglitazone reduced fasting glucose,
2-hour glucose, HbA1c
Weight gain, edema observed in the
pioglitazone arm
DeFronzo RA, et al, for the ACT NOW Study. N Engl J Med. 2011;364:1104-1115.

Section 3

DO PREVENTION
INTERVENTIONS HAVE
SUSTAINED EFFECTS?

Lifestyle Interventions
Da Qing Study 20-Year Follow-Up
Combined lifestyle intervention vs control
51% lower incidence of diabetes during
active intervention
43% lower incidence over 20 years
3.6 years fewer with diabetes

Controls
Combined lifestyle
intervention

Average
Annual
Incidence
11%

20-Year
Cumulative
Incidence
93%

7%

80%
Li G, et al. Lancet. 2008;371:1783-1789.

Lifestyle Interventions
Da Qing Study 20-Year Follow-Up
No significant difference in rate of
First CVD event (HR 0.98; 95% CI, 0-71-1.37)
CVD mortality (HR 0.83; 0.48-1.40)
All-cause mortality (HR 0.96; 0.65-1.41)

Study had limited statistical power to detect differences


in these outcomes
Lifestyle interventions over 6 years can prevent, delay
diabetes for up to 14 years after active intervention
Unclear whether lifestyle interventions also lead to
reduced CVD, mortality

Li G, et al. Lancet. 2008;371:1783-1789.

Lifestyle Interventions
Finnish DPS 7-Year Follow-Up

43%
Relative
Risk
Reduction

Reprinted with permission from Lindstrm J, et al. Lancet. 2006;368(9548):1673-1679.

DPP: Metformin Had Sustained Effect


After Drug Washout
Brief (1-2 week) drug washout study at end
of Diabetes Prevention Program trial
After washout, diabetes was more frequently
diagnosed in metformin vs. placebo (1.49;
0.93, 2.38; P=0.098)
DPP primary analysis: metformin decreased
diabetes risk by 31%
Washout: 26% accounted for by
pharmacological effect of metformin
Postwashout: diabetes reduced by 25%
Diabetes Prevention Program Research Group. Diabetes Care. 2003;26:977-980.

Rosiglitazone Had No Sustained Effect


After Drug Washout: DREAM
During rosiglitazone vs placebo washout
Primary outcome, new-onset diabetes or
death: 10.5% vs 9.8% (P=0.59)
Secondary outcome, regression to
normoglycemia: 21.5% vs 23.8% (P=0.33)
Median follow-up: 71 days (range, 63-86 days)

Rosiglitazone substantially reduced


incidence of type 2 diabetes (DREAM);
however, when withdrawn, this effect is
not sustained
The DREAM Trial Investigators. Diabetes Care. 2011;34:1265-1269.

Lifestyle Interventions
Summary
Lifestyle intervention continues to have an
effect; most drugs do not

Pharmacologic

Lifestyle

Study

Intervention

Treatment

Risk
Reduction
34% - 69%

Da Qing

IGT

577

Lifestyle

6 years
20 years

Finnish DPS

IGT

523

Lifestyle

3+ years
7 years

58%

DPP

IGT

3324

Lifestyle

3 years

58%

Intervention

Treatment

Risk
Reduction

Study
DPP

IGT

3324

Metformin

3 years

31%

DREAM

IGT

5269

Rosiglitazone

3 years

60%

STOP-NIDDM

IGT

1429

Acarbose

3 years

21%

ACT NOW

IFG

~600

Pioglitazone

3 years

81%

Diabetes Care. 1997;20:537-544; N Engl J Med. 2002;344:1343-1350;


N Engl J Med. 2002;346;393-403; Diabetes Care. 2011;34:1265-1269;
Lancet. 2002;359(9323): 2072-2077 N Engl J Med. 2011;364:1104-1115.

Section 4

ARE WE PREVENTING TYPE 2


DIABETES OR DELAYING IT?

Diabetes Prevention Program


10-Year Follow-Up Study
During 10-year follow-up since
randomization
Original lifestyle group lost, then partly
regained weight
Modest weight loss with metformin maintained

Diabetes incidence per 100 person-years


Lifestyle

5.9 (5.1, 6.8)

34%* (24, 42)

Metformin

4.9 (4.2, 5.7)

18%* (7, 28)

Placebo

5.6 (4.8, 6.5)

vs placebo

Diabetes Prevention Program. Lancet. 2009;374:1677-1686.

Section 5

IS DIABETES PREVENTION
COST-EFFECTIVE?

Cost-Effectiveness of Lifestyle
Modification or Metformin: DPP
Active interventions (vs placebo) would:
Intensive
Lifestyle

Metformin

11.1 years

3.4 years

20%

8%

Increase life
expectancy by

0.5 years

0.2 years

Cost per QALY

$1,124

$31,286

Delay onset of
type 2 diabetes by
Reduce incidence of
type 2 diabetes by

QALY = Quality Adjusted Life Years


Herman WH, et al for the Diabetes Prevention Program Research Group.
Ann Intern Med. 2005:142:323-332.

Diabetes Prevention Program


10-Year Cost-Effectiveness
10-year within-trial cost-effectiveness of
the interventions
Intensive lifestyle
Metformin

Data on resource utilization, cost, and


quality of life collected prospectively
Economic analyses performed from health
system and societal perspectives

Diabetes Prevention Program Research Group. Diabetes Care. 2012;35:723-730.

Diabetes Prevention Program


10-Year Cost-Effectiveness
Lifestyle cost-effective, metformin
marginally cost-saving vs placebo
Investment in lifestyle, metformin
interventions for diabetes prevention in
high-risk adults provides good value
Societal
Perspective*

DPP Group
Lifestyle vs
Lifestyle vs
Metformin
Placebo

Lifestyle vs
Placebo

Metformin
vs Placebo

Undiscounted

11,274

Costsaving

44,562

Costsaving

Discounted

14,365

Costsaving

42,753

1,681

Incremental cost-effectiveness ratios from three different perspectives; cost/QALY


*Includes direct medical costs and direct nonmedical costs including participant time
Both costs and QALYs are discounted at 3%

Diabetes Prevention Program Research Group. Diabetes Care. 2012;35:723-730.

Section 6

CAN EVIDENCE-BASED
INTERVENTIONS BE
DELIVERED EFFECTIVELY IN
LOWER-COST SETTINGS?

DEPLOY Pilot Study: Diabetes


Prevention in the Community
Adults BMI 24 kg/m2, 2 diabetes risk
factors, blood glucose 110-199 mg/dL
Randomized to group-based DPP lifestyle
intervention or brief counseling (control)
Outcome,
4-6 months

Control
(n=38)

Intervention
(n=39)

P value
(vs control)

% change
in weight

2
(3.3, 0.6)

6
(7.3, 4.7)

< 0.001

% change
BMI

2.3
(3.7, 0.8)

5.8
(7.3, 4.4)

0.001

Change total
cholesterol

+6 mg/dL
(2.8, 14.8)

21.6 mg/dL
29.9, 13.3)

<0.001

Ackermann RT, et al. Am J Prevent Med. 2008;35:357-363.

Practice-Based Opportunities for


Weight Reduction (POWER)
Obese patients achieve, sustain significant
weight loss with behavioral interventions
2-Year
Outcome
Mean
change in
weight from
baseline
% patients
losing 5%
of initial
weight

Control

Remote
Support Only

In-Person
Support

0.8 kg

4.6 kg*

5.1 kg*

18.8%

38.2%

41.4%

*P<0.001 vs control arm


Appel LJ, et al. N Engl J Med. 2011;365:1959-68.

Diabetes TeleHealth Improves


Diabetes Self-Management
1-year remote DSME intervention, Diabetes
TeleCare (dietitian, nurse/certified diabetes
educator
Improved metabolic control, reduced CV risk
Reduction in
Glycated
Hemoglobin

Baseline

6 Months

12 Months

Diabetes
TeleCare
group

9.40.3

8.30.3*

8.20.4

Usual care
group

8.80.3

8.60.3

8.60.3

*P=0.003 vs. baseline


P=0.004 vs. baseline
Davis RM, et al. Diabetes Care. 2010;33:17121717.

Section 7

WILL DIABETES
PREVENTION BEND THE
CURVE OF THE EPIDEMIC?

CDC Modeling Study to Reduce


Future Diabetes Prevalence
Five-state model
Potential effect of hypothetical preventive
intervention delivered to all with IFG
If 50% participated and incidence reduced
by 50%, would equal 25% reduction in
annual incidence of diabetes in the
population with IFG
Would lower the increase in prevalence by
2050 to 1 in 4 (vs 1 in 3)

Boyle JP, et al. Popul Health Metr. 2010;8(29):1-12.

Section 8

HOW CAN WE MOST


EFFECTIVELY PREVENT OR
DELAY TYPE 2 DIABETES?

Most People with Diabetes Are


Unaware of Their Condition
Data analyzed from 1,402 adults without
diabetes
20052006 NHANES participants
Valid fasting plasma glucose, oral glucose
tolerance tests

Almost 30% of the US adult population


had prediabetes in 20052006; only 7.3%
were aware they had it
Adoption of risk reduction behaviors
suboptimal
Geiss LS, et al. Am J Prevent Med. 2010;38:403-409.

We Need to Test People at Risk


Categories of increased risk for diabetes
(Prediabetes)*
FPG 100-125 mg/dl (5.6-6.9 mmol/l): IFG
or
2-h plasma glucose in the 75-g OGTT
140-199 mg/dl (7.8-11.0 mmol/l): IGT
or

A1C 5.7-6.4%
*For all three tests, risk is continuous, extending below the lower limit of a range and becoming
disproportionately greater at higher ends of the range.
ADA. I. Classification and Diagnosis. Diabetes Care 2012;35(suppl 1):S13. Table 3.

Recommendations: Testing for


Diabetes in Asymptomatic Patients
Consider testing overweight/obese adults with
one or more additional risk factors
In those without risk factors, begin testing at age
45 years (B)

If tests are normal


Repeat testing at least at 3-year intervals (E)

Use A1C, FPG, or 2-h 75-g OGTT (B)


In those with increased risk for future diabetes
Identify and, if appropriate, treat other CVD risk
factors (B)

ADA. II. Testing in Asymptomatic Patients. Diabetes Care. 2012;35(suppl 1):S13.

Criteria for Testing for Diabetes in


Asymptomatic Adult Individuals (1)
1. Testing should be considered in all adults who are overweight
(BMI 25 kg/m2*) and have additional risk factors:
Physical inactivity
First-degree relative with
diabetes
High-risk race/ethnicity (e.g.,
African American, Latino,
Native American, Asian
American, Pacific Islander)
Women who delivered a baby
weighing >9 lb or were
diagnosed with GDM
Hypertension (140/90
mmHg or on therapy for
hypertension)

HDL cholesterol level


<35 mg/dl (0.90 mmol/l)
and/or a triglyceride level
>250 mg/dl (2.82 mmol/l)
Women with polycystic ovarian
syndrome (PCOS)
A1C 5.7%, IGT, or IFG on
previous testing
Other clinical conditions
associated with insulin
resistance (e.g., severe
obesity, acanthosis nigricans)
History of CVD

*At-risk BMI may be lower in some ethnic groups.


ADA. Testing in Asymptomatic Patients. Diabetes Care. 2012;35(suppl 1):S14. Table 4.

Criteria for Testing for Diabetes in


Asymptomatic Adult Individuals (2)
2. In the absence of criteria (risk factors on
previous slide), testing for diabetes should begin
at age 45 years
3. If results are normal, testing should be repeated
at least at 3-year intervals, with consideration of
more frequent testing depending on initial
results and risk status

ADA. Testing in Asymptomatic Patients. Diabetes Care. 2012;35(suppl 1):S14. Table 4.

DPP: Managing Prediabetes


For those found to have prediabetes, provide
support or referral to encourage
Weight loss of at least 7%
Moderate exercise of at least 150 minutes
per week
Consider metformin for certain patients
Obese (BMI 35 kg/m2)
<60 years (most effective, 25-44 years)
Lifestyle interventions feasible, more
cost-effective than medications
American Diabetes Association, 2012.

Clinical Tools Effective in Promoting


Lifestyle Modification: AGREE
Steps in the lifestyle change process: AGREE
Assess
Re-assess

Generate goals
Record

Evaluate and Empower

American Diabetes Association. 2008.

Clinical Tools Effective in Promoting


Lifestyle Modification: FIRM
Steps to setting behavioral goals, objectives
1. Focus on developing specific objectives
2. Let the patient take the lead
3. Keep the objectives FIRM
Few in number
Individualized
Realistic
Measurable (frequency and duration)
Saunders JT, Pastors JG. Curr Diabetes Rep. 2008;8;353-360.

Section 9

CONCLUSIONS:
CALL TO ACTION

Conclusions: Call to Action


We must identify patients at highest risk
(prediabetes)
Modest lifestyle changes are most effective
Sustain interventions
Increase opportunities for community
programs to support prevention
Delaying or preventing type 2 diabetes is
cost-effective and will help turn the tide on
the diabetes epidemic