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