Post on 05-Jan-2016
description
Type 2 Diabetes in the Elderly: Lessons from the Diabetes Primary Prevention
Program
Andrew P. Goldberg, MDBaltimore VA GRECC
University of Maryland School of Medicine
410-605-7183 agoldber@grecc.umaryland.edu
Oral Glucose Tolerance TestFasting (2-Hour Glucose During
OGTT)(mg/dL) (mg/dL)
Normal <110 <140
Impaired 110-125 140-199
Diabetes >125 >199
Glucose Tolerance Categories
Adapted from The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 1997;20:1183-97.
High Prevalence of Type 2 Diabetes Among Elderly People
0
5
10
15
20
40-49 50-59 60-74
Age (years)
Previously diagnosed diabetes
Newly diagnosed diabetes by FPG
Newly diagnosed diabetes by OGTT (IPH)
Harris MI, et al. Diab Care. 1998;21:518-524.Resnick HE, et al. Diab Care. 2000;23:176-180.
Per
cen
tag
e o
f P
op
ula
tio
n
NHANES III
0
10
20
30
40
BMI (kg/m2)<22
22-2526-30
31-35
>35 <22
22-2526-30
31-35
>35
Per
cen
t D
iab
etic
Age (years) 20 - 54 60 - 74
Prevalence of Diabesity by Age
Increased adiposity
Age effects on insulin action
Medications
Age effects on Muscle metabolism
and cells
Coexisting illness
Genetics
INSULIN RESISTANCE
Impaired adaptation:No insulin
Progression to IGT
and type 2 diabetes
DECREASED INSULIN
SECRETION
Diabetes Risk Factors in Aging
Model for Age-Related Hyperglycemia
Decreased physical activity
*Chang & Halter. AJP 284:E7-E12, 2003
Compensatory hyperinsulinem
ia
Maintenance of
euglycemia
Insulin resistance
(of any cause)
Adaptation of -cell function
Normal Adaptation to Insulin Resistance
Aging and Diabetes Comparison Aging
Diabetes
Inactivity/Deconditioning + +Body Fat, Muscle + +Central Adiposity + +Atherosclerosis + +Renal failure + +Vision problems + +Cognitive problems + +Neuropathy + +Hypertension + +Insulin signaling/resistance + +Mortality + +Response to CR + +
National Diabetes Data Group. Diabetes in America. 2nd ed. NIH;1995.
Atherosclerosis in Diabetes
• ~80% of all diabetic mortality– 75% from coronary atherosclerosis– 25% from cerebral or peripheral vascular
disease• >75% of all hospitalizations for diabetic
complications• >50% of patients with newly diagnosed
type 2 diabetes have CHD
SMC=smooth muscle cell.Adapted from Bierman EL. Arterioscler Thromb. 1992;12:647-656.
Mechanisms of Atherogenesis in Diabetes
• Abnormal lipoproteins and apolipoproteins• Hypertension• Glucose toxicity
– Protein glycosylation and glycation– Glycoxidation and oxidation
• Insulin resistance and hyperinsulinemia• Procoagulant state• Hormone-, growth-factor–, and cytokine-
enhanced SMC proliferation and foam cell formation
Aging
Energy Flux
Energy Intake
Body Fat
Energy Flux
Energy Expenditure
Maintain Muscle Mass
“Health-Related Fitness”
Exercise
Hypocaloric Diet
Weight LossExercise
Nutritional Balance
Age, Physical Inactivity, and Obesity
Physical Characteristics of Subjects
Normal Lean Men (10)
Insulin Resistant Men ( 17)
Variable Baseline After Intervention
Age (yr)
Weight (kg)
Percent body Fat (%)
Fat-Free Mass (kg)
Waist:Hip Ratio
Waist Girth (cm)
Maximal Oxygen Uptake:
L•min-1
mL•kg-1 •min-1
62 ± 2
75 ± 3
19 ± 2
61 ± 3
0.88 ± 0.02
86 ± 3
2.6 ± 0.1
35 ± 2
57 ± 1†
97 ± 4 †
32 ± 1 †
66 ± 3
0.96 ± 0.01 †
106 ± 3 †
2.7 ± 0.2
28 ± 1 †
88 ± 4**†
25 ± 1**†
66 ± 3
0.93 ± 0.01** †
96 ± 2** †
3.1 ± 0.2**
36 ± 2**
Dengel, DR. et al. Metabolism, 1998;47(9):1075-1082Significantly different from Normal Lean men † P < 0.01, Significantly different from Baseline value: * P < 0.05; ** P < 0.01.
ATPIII Criteria for Metabolic Syndrome
Metabolic Syndrome if 3 or More:
Abdominal Obesity: Waist >102 cm (men), > 88cm (women)
Triglyceride: >150 mg/dl
HDL-C: < 40 mg/dl (men), < 50 mg/dl (women)
BP: >135/85 mm Hg
Fasting Glucose: >100 mg/dl
AEX + WL in Metabolic SyndromeImproves Oral Glucose Tolerance
AE + WL in Metabolic Syndrome Improves Lipid Profiles
Variable Baseline AEX + WL
Cholesterol 177 ± 7 154 ± 7*
Total HDL-C 30 ± 1 34 ± 1*
HDL2-C 2 ± 0.4 5 ± 0.8**
HDL3-C 29 ± 1 29 ± 1
LDL-C 119 ± 6 103 ± 6*
Triglyceride 137 ± 18 92 ± 11**
Data are Mean ± SEM, mg/dl; *p < 0.05; **p < 0.01 vs Baseline
110
120
130
140
150
160
170
Sys
toli
c B
loo
d P
ress
ure
(m
m H
g)
70
80
90
100
110
Dia
sto
lic
Blo
od
Pre
ssu
re (
mm
Hg
)
AEX+WL in Metabolic Syndrome Reduces Blood
Pressure
= -8% = -10%
Effects of Exercise and Weight Loss on Components of Metabolic Syndrome
MetabolicAbnormality Baseline AEX+WL
Central Obesity 17 10
Hypertension 17 6
Insulin 17 10
Glucose Intolerance 10 5
Low HDL-C 17 10
TG 6 3
Totals 84 44
There are now a large number of prevention trials—some limited to
life-style intervention, some limited to anti-diabetic drug trials;
however, only rarely do studies include both types of potential
prevention.
• Da Qing IGT and Diabetes Study (Pan et al. Diabetes Care 1997).
Randomized 577 IGT subjects (283M/247F) mean age 45yrs –
diabetes incidence: control (15.7%) v diet (10%) v exercise
(8.3%) v diet + exercise (9.6%).
• Finnish Diabetes Prevention Trial (Tuomilehto et al., NEJM
2001). Randomized 422 IGT subjects age 40-64 ( 350F/172M,
mean 55 yrs ) to diet counseling and circuit-type weight training
vs. control. F/U 3.2 yrs. Diabetes incidence: 58% reduction
(19.8% control vs. 8.3% intervention.
Of importance to this talk, the Diabetes Prevention Program (NEJM,
2002) is the only one that includes old subjects (60–85 yr).
Diabetes Prevention Trials
Diabetes Prevention Program (DPP)
A Randomized Clinical TrialA Randomized Clinical Trialat 27 sites to Prevent Type 2 at 27 sites to Prevent Type 2
DiabetesDiabetes in Persons at High Risk in Persons at High Risk
DPP ClinicsDPP Clinics
..
...
.
.
. ..
. .
. ..
.
.... ..
.. ..
To prevent or delay the development
of type 2 diabetes in persons with
impaired glucose tolerance (IGT).
DPP Primary Goal
• Age > 25 years • Plasma glucose
– 2 hour glucose 140-199 mg/dl (7.8- <11.1 mmol/L)
and– Fasting glucose 95-125 mg/dl (5.3- <7.0 mmol/L)
• Body mass index > 24 kg/m2 • All ethnic groups
• Goal of up to 50% subjects from high risk populations – old,
African American, American Indian, Hispanic, Asian
Eligibility Criteria
NEJM 346:393-403, 2002
Study Interventions
Eligible ParticipantsEligible Participants
RandomizedRandomized
Standard Lifestyle RecommendationsStandard Lifestyle Recommendations
Intensive Metformin PlaceboIntensive Metformin PlaceboLifestyleLifestyle(n = 1079) (n = 1073) (n = 1082)(n = 1079) (n = 1073) (n = 1082)
DPP Population
Sex Distribution Age Distribution
25-44 31%
> 60 20%
45-59 49%
Men32%
Women68%
The DPP Research Group, Diabetes Care 23:1619-29, 2000
Base-Line Characteristics of the Study ParticipantsCharacteristic Placebo
(N=1082)
Metformin
(N=1073)
Lifestyle
(N=1079)
Sex – Male/Female (%) 31/69 34/66 32/68
Race or ethnic group (%)
White/African American 54/20 56/21 5419
Hispanic/American Indian/ Asian 16/6/5 15/5/3 17/6/5
Family history of diabetes (%) 70 68 70
History of gestational diabetes (%) 16 16 16
Age – yr 50 ± 10 51 ± 10 51 ± 11
Weight – kg 94 ± 20 94 ± 20 94 ± 21
Body-mass index 34 ± 7 34 ± 7 34 ± 7
Waist circumference – cm 105 ± 14 105 ± 14 105 ± 15
Plasma glucose – Fasting 107 ± 8 107 ± 8 106 ± 8
Two hours after an oral glucose load
165 ± 17 165 ± 17 164 ± 17
Glycosylated hemoglobin - % 6 ± 1 6 ± 1 6 ± 1
Leisure physical activity – MET-hr/wk¶
17 ± 29 16 ± 26 16 ± 22
* Values are means ± SD¶ Data are based on responses to the Modifiable Activity Questionnaire
N Engl J Med, 2002; 346(6):393-403
Lifestyle Intervention Structure
• 16 session core curriculum
• Long-term maintenance program
• Supervised by a case manager &
lifestyle support staff
– Dietician
– Behavioral specialist
– Exercise physiologist / trainer
Lifestyle Intervention Exercise Component
• Moderate intensity aerobic exercise• Structured classes offered 1-2 x per
week• Tool box strategies
– Pedometers, exercise videos, health club memberships
• Activity assessed by self-report– LoPAR (habitual physical activity)– MAQ (leisure activity)
Mean Change in Leisure Physical Activity
0
2
4
6
8
0 1 2 3 4
Years from Randomization
MET
-hou
rs/w
eek
PlaceboMetformin
Lifestyle
The DPP Research Group, NEJM 346:393-403, 2002
0 1 2 3 4
0
10
20
30
40Placebo (n=1082)Metformin (n=1073, p<0.001 vs. Plac)Lifestyle (n=1079, p<0.001 vs. Met , p<0.001 vs. Plac )
Percent developing diabetes
All participants
All participants
Years from randomization
Cum
ulat
ive
inci
denc
e (%
)
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 Incidence of Diabetes
Risk reductionRisk reduction31% by metformin31% by metformin58% by lifestyle58% by lifestyle
The DPP Research Group, NEJM 346:393-403, 2002
-8
-6
-4
-2
0
0 1 2 3 4
Years from Randomization
Wei
ght C
hang
e (k
g)
Placebo
Metformin
Lifestyle
Mean Weight Change
The DPP Research Group, NEJM 346:393-403, 2002
Intensive Lifestyle (ILS) Activities by Age
25-44 45-59 60+ p
Weight change (kg)
-4.09 -5.03 -6.42 < 0.001
WC change (cm) -4.30 -4.68 -6.69 < 0.001
% at wt. loss goal 33.4 38.9 55.7 < 0.0001
Recreational activity (met-hr/wk)
4.4 5.8 18.7 <0.001
% at exercise goal
68 74 81 < 0.05
Age in years
Changes in Body Fat Distribution
● Placebo; ▲ Metformin; ■ Lifestyle Intervention
Diabetes. 2007 Jun;56(6):1680-5.
0
5
10
15
20
-15 -10 -5 0 5
Change in weight from baseline (kg)
Haz
ard
rate
per
100
per
son-
year
s
Hazard Rate for Development of Diabetes in Relation to Weight Change
0
4
8
12
25-44 (n=1000) 45-59 (n=1586) > 60 (n=648)
Cas
es/1
00 p
erso
n-y
r
Lifestyle Metformin Placebo
Diabetes Incidence Rates by Age
Age (years)
NEJM 346:393-403, 2002
p = 0.007 ILS by age
p= 0.067 metformin by age
Diabetes Risk Reduction by Age
0
10
20
30
40
50
60
70
80
25-44 45-59 60+
* p< 0.05 ILS v. Metformin
Age in Years
ILS Metformin
NEJM 346:393-403, 2002
Percent Risk
Reduction
*
Percent Achieving Normal Glucose Tolerance by Age
0
10
20
30
40
25-44 45-59 60+
p=0.01 Metformin by age
Percent with NGT
ILS
Metformin
Placebo
Age in Years
DPP : Age 60+ Intensive Lifestyle Group
• Better success in achieving exercise goals
• Better success in achieving weight loss goals
• More likely to complete self-monitoring records
• Achieved greatest reduction in diabetes risk
• This suggests there are benefits from including
older subjects in clinical trials to prevent diabetes
Change in CVD Risk Factors
-4
-3.5
-3
-2.5
-2
-1.5
-1
-0.5
0
Systolic BP Diastolic BP
* p<0.001 ILS v P, M
Diabetes 2003; Suppl 1:A169
Lifestyle Metformin Placebo
Blood pressure
mm Hg
-30
-25
-20
-15
-10
-5
0
Chol TG LDL
mg/dl
Lipids
*
*
* p<0.001 ILS v P, M
*
Change in Non-traditional CVD Risk Markers
-35
-30
-25
-20
-15
-10
-5
0
5
TPA Fibrinogen CRP
Percent Change at 1 year
p< 0.01 Met v Placebo p<0.001 ILS v Placebo
Lifestyle Metformin Placebo
Diabetes 2003; Suppl 1:A169
Weight Loss vs. Exercise in Diabetes Prevention
• Weight loss was strongest variable associated with
reduced diabetes and CVD risk.
• For every kg lost, 16% reduction in diabetes risk.
• Increased activity, in the absence of weight loss,
had minimal effect on diabetes prevention in DPP.
• In contrast, Finnish DPS reported those who met
physical activity goal, but not wt loss goal, had 70%
reduction in DM risk.
NEJM 2001;344:1343-50; Cox, et al. Am J Clin Nutr 2004:80:308-16
Summary - DPP
• Lifestyle modification can prevent diabetes
in high risk older adults
• The robust effect in 60+ older subjects was
due to greater ILS participation (intensity
too low in young and middle-age?)
• ILS program preferred over medication in
older individuals
• Additional benefits of ILS – lower CVD risk
factors
Progression to Diabetes Distinct Phenotypes?
IGT
Fasting Hyperglycemia
Post-challenge Hyperglycemia
DIABETESMetformin ILS
Older, more sedentary
Younger, fitter ?
+ +
>intensity?
Prevention of Diabetes
• Weight Loss and Exercise :• Increase Aerobic Capacity• Reduce Obesity (central)• Decrease Hyperglycemia• Lower Blood Pressure• Benefit Dyslipidemia • Increase Insulin Sensitivity
But also,• Stop Cigarette smoking• Insulin Sensitizers – TZDs, Metformin
Treatment of Type 2 Diabetes
Organ Goal Long-Term Effect Action
Eyes Annual Exam Prevent Retinopathy Laser
Heart, Brain Semiannual CVA, CAD, PAD Ex+WLBlood Pressure, MI, Deaths ACE-I, Lipid RxLipids
Kidney Annual Microalbumin ESRD ACE-I Dialysis Lipid Rx Transplant
Legs Check Feet Charcot Joint Footcare, Pulses, Doppler Revascularize Exercise,Sensory Exam Amputation Stents, Bypass
Whole Body Quarterly HbA1c Vascular, Cardiac, Exercise/WL, Neuropathic Intensive Complications Glucose
Control