Preventing Heart Disease (…and cancer…and dementia) 2016€¦ · Prediction of weight loss...

Preventing Diabetes2018

K A R O L E . W A T S O N , M D , P H D , F A C C

P R O F E S S O R O F M E D I C I N E / C A R D I O L O G Y

D A V I D G E F F E N S C H O O L O F M E D I C I N E A T U C L A

C O - D I R E C T O R , U C L A P R O G R A M I N P R E V E N T I V E C A R D I O L O G Y

DisclosuresResearch grants: NHLBI, NIDDK, NIH BD2K

Consultant: Amarin, Amgen, Boehringher Ingelheim and Kowa

Speaker’s Bureau: Boehringher Ingelheim

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%

Diabetes Atlas Committee. Diabetes Atlas 2nd Edition: IDF 2003.

Global Projections for the Diabetes Epidemic: 2003-2025

World2003 = 194 M2025 = 333 M↑ 72%

AFR

19.2 M39.4 M↑105%

2003 2025

DIABETES

PRE-DIABETES

30.3 million

Americans

have diabetes*

84 million American

adults have

prediabetes*

That’s more than 1 in 3

adults

9 out of 10 adults with

prediabetes don’t know

they have it

*Source: Centers for Disease Control and Prevention. National diabetes statistics report: estimates of diabetes and its burden in the United States, 2014. Atlanta, GA:

US Department of Health and Human Services, Centers for Disease Control and Prevention, 2014.

Prediabetes: Targeting a population at risk

Prediabetes: A reversible cardio-metabolic risk factor in which plasma glucose levels are above normal but not high enough to diagnose type 2 diabetes.

◦ 3-5 times higher risk of developing type 2 diabetes*

◦ Increased risk of cardiovascular disease and death



Prediabetes: Targeting a population at risk



Natural History of Type 2 Diabetes

Adapted from: International Diabetes Center (Minneapolis, Minnesota).

Years

Glucose

(mg/dL)

-15 -10 -5 0 5 10 15 20 25

Fasting glucose

Post-meal glucose

350

250

100

300

200

150

There is a long period of glucose intolerance that precedes the development of diabetes

Screening tests can identify persons at high risk

There are safe, potentially effective interventions that can address modifiable risk factors

Feasibility of Preventing Diabetes

NIH-NIDDK sponsored study

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

diabetes in persons with impaired glucose tolerance (IGT)

Diabetes Prevention Program

Diabetes Prevention Program

..

...

.

.

. ..

. .

. ..

.

.... ..

.. ..

Age > 25 years

Elevated fasting and post prandial glucose

Body mass index > 24 kg/m2

All ethnic groups

goal of up to 50% from high risk populations

DPP Eligibility Criteria

DPP Study Interventions

Eligible participants

Randomized

Standard lifestyle recommendations

Intensive Metformin Placebo

Lifestyle

(n = 1079) (n = 1073) (n = 1082)

Metformin- 850 mg per day escalating after

4 weeks to 850 mg twice per day

Placebo- Metformin placebo adjusted in

parallel with active drugs

Metformin

DPP Lifestyle Intervention

An intensive program with the following specific goals:

• > 7% loss of body weight and maintenance of weight loss

– Dietary fat goal -- <25% of calories from fat

– Calorie intake goal -- 1200-1800 kcal/day

• > 150 minutes per week of physical activity

Mean Change in Leisure Physical Activity

0

2

4

6

8

0 1 2 3 4

ME

T-h

ou

rs/w

ee

k

Years from Randomization

Placebo

Metformin

Lifestyle

The DPP Research Group, NEJM 346:393-403, 2002

-8

-6

-4

-2

0

0 1 2 3 4

Weig

ht

Ch

an

ge (

kg

)

Years from Randomization

Placebo

Metformin

Lifestyle

Mean Weight Change


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

Risk reduction

31% by metformin

58% by lifestyle


0 1 2 3 4

0

10

20

30

40

Years from randomization

Cu

mu

lative

in

cid

en

ce

(%

)

0

4

8

12

Male (n=1043) Female (n=2191)

Cas

es/1

00 p

erso

n-y

r

Lifestyle

Metformin

Placebo

Diabetes Incidence Rates by Sex


0

4

8

12

25-44 (n=1000) 45-59 (n=1586) > 60 (n=648)

Ca

se

s/1

00

pe

rso

n-y

r

Lifestyle Metformin Placebo

Diabetes Incidence by Age

Age (years)


Diabetes Incidence Rates by Ethnicity

0

4

8

12

Caucasian

(n=1768)

African

American

(n=645)

Hispanic

(n=508)

American

Indian

(n=171)

Asian

(n=142)

Cas

es/1

00 p

erso

n-yr



0

4

8

12

16

24 - < 30 30 - < 35 > 35

Ca

se

s/1

00

pe

rso

n-y

r Lifestyle Metformin Placebo

Diabetes Incidence Rates by BMI

Body Mass Index (kg/m2)


Key Lesson # 1

Lifestyle trumps medication for preventing diabetes

DPP Lifestyle Intervention Structure

16 session core curriculum (over 24 weeks)

Long-term maintenance program

Supervised by a case manager

Access to lifestyle support staff

◦ Dietitian

◦ Behavior counselor

◦ Exercise specialist

The Core Curriculum (16 sessions)

Education and training in diet and exercise methods and behavior modification skills

Emphasis on:

◦ Self monitoring techniques

◦ Problem solving

◦ Individualizing programs

◦ Self esteem, empowerment, and social support

◦ Frequent contact with case manager and DPP support staff

DPP Post Core Program

Self-monitoring and other behavioral strategies

Monthly visits

Supervised exercise sessions offered

Periodic group classes and motivational campaigns

Tool box strategies

◦ Provide exercise videotapes, pedometers

◦ Enroll in health club or cooking class

Key Lesson # 2

Lifestyle interventions to prevent diabetes should be comprehensive

9 8.9

14.3

8.8

7.67.0

3.33.7

7.3

-1.5

0.5

2.5

4.5

6.5

8.5

10.5

12.5

14.5

22 to <30 30 to <35 ≥35

Placebo

Metformin

Lifestyle

Effect of Weight on T2DM Incidence in DPPT

2D

M in

cid

en

ce

pe

r 1

00

pe

rso

n-y

ea

rs

65%

BMI (kg/m2)

51%

61%

.

DPP Research Group. N Engl J Med. 2002;346:393-403.

1996-2002: To prevent or delay the development of type 2 diabetes

in persons with impaired glucose tolerance (IGT)

2002-2013: Prevention of diabetes complications such as

kidney, eye and nerve problems, and heart disease

DPP and DPPOS

ALL participants offered lifestyle seesions in between DPP and DPPOS

DPP vs. DPPOS Diabetes Rates

0

2

4

6

8

10

12

DPP (n=3234) DPPOS (n=1994)

Cru

de R

ate

per

100 P

YR Placebo

Metformin

Lifestyle

DPP DPPOS

Diabetes Development in DPPOS

Original Lifestyle participants continue to develop diabetes at about

the same lower rate they developed diabetes during DPP.

Original Placebo and Metformin participants lowered their rate of

diabetes development to a similar rate as the Lifestyle group.

DPPOS Diabetes Risk Reduction

Delay in diabetes onset after 10 years follow-up:

◦ 4 years for Lifestyle

◦ 2 years for Metformin

The lower rate of diabetes development means:

◦ Original Lifestyle participants have a 34% lower risk of diabetes

◦ Original Metformin participants have a 18% lower risk of diabetes

Diabetes Frequency After 10 years

52% of Placebo participants developed

diabetes

47% of Metformin participants developed

diabetes

42% of Lifestyle participants developed

diabetes

Lancet. 2009 Nov 14;374(9702):1677-86.

Cost Effectiveness

•Over 10 years, metformin treatment reduced the costs of

medical care by $1700 per person

•Over 10 years lifestyle treatment reduced the costs of medical

care by $2600 per person

‘(These data) put diabetes prevention in the category of prenatal care or pediatric immunizations... It’s dramatic when an intervention can improve the health of the population and potentially save money at the same time.’

William H. Herman -health services researcher with expertise is in the

area of diabetes, University of Michigan

Key Lesson # 3

Preventing diabetes is cost-effective

Keys to DPP Lifestyle Success

Weight loss was the key to diabetes prevention

-Every 2.2 pounds of weight loss decreased risk by 13%

Reduction of total calories, especially fat calories

Achieving 150 minutes of activity each week

DPP intervention was key to prevention

Weight Change Over Time

0 1 2 3 4 5 6 7 8 9 10

-8-6

-4-2

02

Year since DPP Randomization

Ch

an

ge

in W

eig

ht (k

g)

Placebo Metformin Lifestyle

Key Lesson # 4

Weight loss is very difficult to sustain

Key findingsPrediction of weight loss

Improvements in diet (calories and fat grams, or percent of calories from fat) predicted weight loss up to year 3 in DPP

Increased activity became a stronger predictor of weight loss at each subsequent year so that by year 3 and beyond, an increase of 5 met-hours/week (approximately 1 hours walking/week) resulted in a .43 kg weight loss.

Preventing Diabetes

Weight loss, largely determined by changes in diet and exercise, is the primary factor resulting in reduced diabetes incidence.

An increase in physical activity helps sustain weight loss and independently reduces diabetes risk among those who do not lose weight.

But exercise alone rarely results in weight loss

Interventions to reduce the incidence of diabetes should aim at weight loss as the primary determinant of success.

Key Lesson # 5

Dietary changes are essential for weight loss; Regular physical activity is essential for weight maintenance

DPP Lifestyle Intervention Structure

16 session core curriculum (over 24 weeks)

Long-term maintenance program

Supervised by a case manager

Access to lifestyle support staff

◦ Dietitian

◦ Behavior counselor

◦ Exercise specialist

The Core Curriculum (16 sessions)

Education and training in diet and exercise methods and behavior modification skills

Emphasis on:

◦ Self monitoring techniques

◦ Problem solving

◦ Individualizing programs

◦ Self esteem, empowerment, and social support

◦ Frequent contact with case manager and DPP support staff

DPP Post Core Program

Self-monitoring and other behavioral strategies

Monthly visits

Supervised exercise sessions offered

Periodic group classes and motivational campaigns

Tool box strategies

◦ Provide exercise videotapes, pedometers

◦ Enroll in health club or cooking class

Key Lesson # 6

Regular contact with the health care system appears essential for sustaining lifestyle changes

DPP Change in Blood Pressure

-3.4

-0.91 -0.9

-4

-3.5

-3

-2.5

-2

-1.5

-1

-0.5

0


-3.6

-1.3

-0.89

-4

-3.5

-3

-2.5

-2

-1.5

-1

-0.5

0


Ch

an

ge i

n B

P(m

m H

g)

Baseline BP 124 124 124 79 78 78

Systolic Diastolic

BP, blood pressure; DPP, Diabetes Prevention Program.

Ratner R, et al. Diabetes Care. 2005;28:888.

DPP Change in Total and LDL Cholesterol

DPP, Diabetes Prevention Program; LDL-C, low-density lipoprotein.DPP Research Group. Diabetes Care. 2005;28:2472–2479.

Ratner R, et al. Diabetes Care. 2005;28:888-894.

-2.3

-0.9

-1.2

-2.5

-2

-1.5

-1

-0.5

0


-0.7

-0.3

-1.3-1.4

-1.2

-1

-0.8

-0.6

-0.4

-0.2

0


Ch

an

ge i

n L

ipid

s(%

)

Baseline (mg/dL) 202 127

Total Cholesterol LDL-C

DPP Change in Triglycerides and HDL

DPP, Diabetes Prevention Program.DPP Research Group. Diabetes Care. 2005;28:2472–2479.

Ratner R, et al. Diabetes Care. 2005;28:888-894.

-25.4

-7.4

-11.9

-30

-25

-20

-15

-10

-5

0


1

0.3

-0.1-0.2

0

0.2

0.4

0.6

0.8

1

1.2


Ch

an

ge i

n L

ipid

s(m

g/d

L)

Baseline (mg/dL) 172 40

Triglycerides HDL-C

Cardiovascular Risk Factors in DPPOSLifestyle

(n=910)

Metformin

(n=924)

Placebo

(n=932)

Antihypertensive drugs 33% 37% 36%

Lipid-lowering drugs 18% 23% 23%

Blood pressure (mmHg) 120·8 / 74·4 122·4 / 75·6 122·3 / 75·6

Serum cholesterol (mmol/L) 4·92 4·93 4·97

Geometric serum triglycerides

(mmol/L)

1·37 1·45 1·45

DPP Research Group. Lancet. 2009; 374:1677-1686

Key Lesson # 7

Prevention of diabetes is associated with improvement in almost all cardiovascular risk factors

Cardiovascular Risk in DPPOS

All treatment groups have decreased blood pressure,

cholesterol and triglycerides.

Lifestyle participants had the same or lower blood pressure

and lipid levels over time than other participants with less use

of medicines.

Weight Change Over Time

0 1 2 3 4 5 6 7 8 9 10

-8-6

-4-2

02

Year since DPP Randomization

Ch

an

ge

in W

eig

ht (k

g)


BMI Change Over Time YOUNG people (25-44 y.o.)



BMI Change Over Time MIDDLE AGE (45-59 y.o.)


BMI Change Over Time OLDER ADULTS (> 60 y.o.)

Key Lesson # 8

After 60 years of age people tend to begin to lose weight

11.6

10.8 10.8

6.7

7.6

9.6

6.2

4.7

3.1

0

2

4

6

8

10

12

14

25-44 45-59 ≥60

Placebo

Metformin

Lifestyle

Effect of Age on Diabetes incidence in DPPT

2D

M in

cid

en

ce

pe

r 1

00

pe

rso

n-y

ea

rs

48%59%

Age (years)

71%

DPP Research Group. N Engl J Med. 2002;346:393-403.

Key Lesson # 9

Lifestyle appears to have the greatest impact on older patients (possibly due to greater weight loss)

Now what about the age old question: What is more imporant… our genes…or our environment?

Common genetic variants of the gene “TCF7L2” have been found to be associated with development of type 2 diabetes

Florez et al., N Engl J Med. 2006 Jul 20;355(3):241-50.

Genetic Variants and Progression to Diabetes

We found that DPP participants with the TT genotype were more likely to develop diabetes than participants with the CC genotype

We found that both metformin and lifestyle could mitigate the genetic risk

In other words, if you had the TT genotype, you could reduce your chances of developing diabetes with lifestyle changes or with metformin

Key findings

0

5

10

15

20


Ca

se

s/1

00

pe

rso

n-y

r

CC CT TT

Florez et al., N Engl J Med. 2006 Jul 20;355(3):241-50.

Key Lesson # 10

Lifestyle (and metformin) can mitigate some of the genetic risk for development of diabetes

Preventing diabetes in community based settings

Group Lifestyle Balance Program Intervention

• DPP lifestyle intervention was

adapted to a 12-session group-

based program

• Implemented in a community

setting

• Significant decreases in weight,

waist circumference, and BMI

were found

• Average combined weight

loss over the 3-month

intervention was 7.4 pounds

(3.5% relative loss, P<0.001)

0

10

20

30

40

50

60

70

Phase 1 Post(n=51)

Phase 2 Post(n=42)

CompletersBoth phases

(n=67)

Phase 26 mo

Phase 212 mo

Pe

rce

nt

Weight Loss Achieved

Weight Loss > 3.5% Weight Loss > 5% Weight Loss >7%

DPP, Diabetes Prevention Program; mo, month.

Kramer MK, et al. Am J Prev Med. 2009;37:505-511.

6

-21.6

11.8

-13.5

-25

-20

-15

-10

-5

0

5

10

15

To

tal C

ho

lest

ero

l (%

)

Standard (4-6 months) DPP (4-6 months) Standard (12-14 months) DPP (12-14 months) • Pilot, cluster-randomized

trial

• Group-based DPP lifestyle

intervention vs brief

counseling alone (control)

among high-risk adults who

attended a diabetes risk-

screening event at one of

two semi-urban YMCA

facilities

DEPLOY, Diabetes Education & Prevention with a Lifestyle Intervention Offered at the YMCA; DPP, Diabetes Prevention

Program; YMCA, Young Men’s Christian Association.

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

Translating the DPP Into the CommunityThe DEPLOY Pilot Study

P<0.001

P=0.002

Translating DPP into the community

Four additional studies utilizing the DPP lifestyle interventions in

community settings demonstrated that:

◦ Weight loss could be achieved

◦ Reduction in glucose levels and HbA1c could be achieved

◦ Benefits were seen in high risk, underserved populations

◦ A new model of chronic, disease management is needed

Ruggiero L, et al. Diabetes Educ. 2011;37:564-572.

Santoyo-Olsson J, et al. Gerontologist. 2011;51(Suppl 1):S82-93.DPP, Diabetes Prevention Program.

Boltri JM, et al. J Natl Med Assoc. 2011;103:194-202.Katula JA, et al. Diabetes Care. 2011;34:1451-1457.

.

LA County Diabetes Prevention Program

Key Lesson # 11

It is very feasible to translate a DPP-like intervention into the community

Kim et al., Diabetes Care, 2002

Gestational Diabetes and future DM risk

JAMA 2008; 300(24): 2886-2897

Low birth weight is associated with Type 2 DM

Incidence of Diabetes by Category of Glucose Intolerance

Number of studies

Regress to normal (%)

Progress to Diabetes (%)

Relative Risk of

Diabetes

Impaired Glucose Tolerance

26 8% 7% 6.4 (4.9 – 7.8)

IGT only on 1 occasion 3 n/a 6% 5.5 (3.1 – 7.9)

Impaired Fasting Glucose 6 13 – 29% 5-20%* 4.7 (2.5 – 6.9)

IFG only on 1 occasion 3 n/a 7% 7.5 (4.6 – 10.5)

IGT and IFG 3 n/a 10-15% 12.1 (4.3 – 20)

Gerstein et al., Diab Res Clin Pract, 2007

Selected risk factors for development of DM

Age ↑

Family History / genetics ↑

Gestational Diabetes ↑

Obesity / fat distribution ↑

Physical Activity / fitness ↓

Very low birth weight ↑

Antipsychotic medications ↑

Anti-Retrovial therapy ↑

Key Lesson # 13

Targeting interventions to “at risk” populations is important

COFFEE

20 Years AgoCoffee

(with whole milk and sugar)

TodayMocha Coffee (with steamed

whole milk and mocha syrup)

45 calories; 8 ounces 350 calories;16 ounces

Calorie Difference: 305 calories

20 Years Ago Today


500 calories

4 ounces

MUFFIN

210 calories

1.5 ounces

CHICKEN CAESAR SALAD

20 Years Ago Today

390 calories

1 ½ cups790 calories

3 ½ cups


Portion Sizes 1977-1996.

0

5

10

15

20

25

Fo

od

in

take

pe

r o

cca

sio

n, o

z

1977-78

1989-91

1994-98

Nielsen and Popkin, JAMA, 2003

Key Lesson # 14

We live in an “obesogenic” society

Key Lesson # 15

It takes a village

Statin Odds ratio (95% CI)

Overall (n=91 140) 1.09 (1.02–1.17)

Rosuvastatin only (n=24 714) 1.18 (1.04–1.33)

Atorvastatin only (n=7773) 1.14 (0.89–1.46)

Simvastatin only (n=18 815) 1.11 (0.97–1.26)

Pravastatin (n=33 627) 1.03 (0.90–1.19)

Lovastatin (n=6211) 0.98 (0.70–1.38)

Association between statins and development of diabetes

Sattar N et al. Lancet 2010;375:735-42.

Jupiter Trial: Statins and Diabetes

Ridker PM et al. Lancet 2012;380:565

Metabolic syndrome, IFG,

HbA1c >6%, or BMI ≥30 kg/m2

HR 1.28

(1.07-1.54)

p=0.01

134 deaths or vascular events prevented54 excess cases of diabetes

No major risk factors for diabetes Major risk factors for diabetes

HR 0.99

(0.45-2.21)

p=0.99

86 deaths or vascular events prevented0 excess cases of diabetes

CV Event Reduction vs. New-Onset Diabetes

Preiss D et al. JAMA 2011; 305:2556-64

Incident Diabetes

Incident CVD

PROVE-IT - TIMI 22

A to Z

TNT

IDEAL

SEARCH

Pooled odds ratio

315/1707 (18.4)

212/1768 (12.0)

647/3798 (17.0)

776/3737 (20.8)

1184/5398 (21.9)

3134/16,408 (19.1)

355/1688 (21.0)

234/1736 (13.5)

830/3797 (21.9)

917/3724 (24.6)

1214/5399 (22.5)

3550/16,344 (21.7)

0.85 (0.72-1.01)

0.87 (0.72-1.07)

0.73 (0.65-0.82)

0.80 (0.72-0.89)

0.97 (0.88-1.06)

0.84 (0.75-0.94)

PROVE-IT - TIMI 22

A to Z

TNT

IDEAL

SEARCH

Pooled odds ratio

101/1707 (5.9)

65/1768 (3.7)

418/3798 (11.0)

240/3737 (6.4)

625/5398 (11.6)

1449/16,408 (8.8)

99/1688 (5.9)

47/1736 (2.7)

358/3797 (9.4)

209/3724 (5.6)

587/5399 (10.9)

1300/16,344 (8.0)

1.01 (0.76-1.34)

1.37 (0.94-2.01)

1.19 (1.02-1.38)

1.15 (0.95-1.40)

1.07 (0.95-1.21)

1.12 (1.04-1.22)

0.5 1.0 2.0

0.5 1.0 2.0Odds ratio (95% CI)

Intensive dose Moderate dose OR (95% CI)

NTT: 155 patients to prevent 1 cardiovascular event

NNH: 498 patients to see 1 new case of diabetes

Conclusions

There are now an estimated 18 million people with DM in the USA and even more with pre-diabetes.

The lifetime risk of developing DM for people born in 2000 is 33% for men and 39% for women. For Hispanic women it is 50%.

In this population CVD is the major cause of death.

Preventing diabetes and cardiovascular disease is crucial

Questions?

Preventing Heart Disease (…and cancer…and dementia) 2016€¦ · Prediction of weight loss...

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Transcript of Preventing Heart Disease (…and cancer…and dementia) 2016€¦ · Prediction of weight loss...