Post on 26-May-2020
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
*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
*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.
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
The DPP Research Group, NEJM 346:393-403, 2002
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
The DPP Research Group, NEJM 346:393-403, 2002
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
The DPP Research Group, NEJM 346:393-403, 2002
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)
The DPP Research Group, NEJM 346:393-403, 2002
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
Lifestyle Metformin Placebo
The DPP Research Group, NEJM 346:393-403, 2002
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)
The DPP Research Group, NEJM 346:393-403, 2002
The DPP Research Group, NEJM 346:393-403, 2002
Key Lesson # 1
Lifestyle trumps medication for preventing diabetes
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
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
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
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
Lifestyle Metformin Placebo
-3.6
-1.3
-0.89
-4
-3.5
-3
-2.5
-2
-1.5
-1
-0.5
0
Lifestyle Metformin Placebo
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
Lifestyle Metformin Placebo
-0.7
-0.3
-1.3-1.4
-1.2
-1
-0.8
-0.6
-0.4
-0.2
0
Lifestyle Metformin Placebo
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
Lifestyle Metformin Placebo
1
0.3
-0.1-0.2
0
0.2
0.4
0.6
0.8
1
1.2
Lifestyle Metformin Placebo
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)
Placebo Metformin Lifestyle
BMI Change Over Time YOUNG people (25-44 y.o.)
DPP Research Group. Lancet. 2009; 374:1677-1686
DPP Research Group. Lancet. 2009; 374:1677-1686
BMI Change Over Time MIDDLE AGE (45-59 y.o.)
DPP Research Group. Lancet. 2009; 374:1677-1686
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
Placebo Metformin Lifestyle
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
Calorie Difference: 290 calories
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
Calorie Difference: 400 calories
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?