Diabetes Treatments

Joslin Diabetes Center, Harvard. University of Hawaii. University of New Mexico their diabetes. Program Format. 1. Pre-lesson: Written consent, written pre …

Current Knowledge of Prevention of Diabetes and Obesity
David G Marrero, PhD

Session: Plenary B

Preventing Type 2 Diabetes: What do we know, what can we do?
David G Marrero, PhD JO Ritchey Chair of Medicine Director, Diabetes Translation Research Center Division of Endocrinology Metabolism Indiana University School of Medicine

1

Diabetes: How Serious is the Problem?

Diabetes in the United States
More than 22 million people in the US have diabetes 90 have Type 2 diabetes 6 of the population 13 of the population older than age 40 19 of the population older than age 65

2

How Quickly is the Problem Growing?
In 2004, every 24 hours: 3600 new cases of diabetes 580 deaths 225 amputations 120 persons enter kidney failure 55 new cases of blindness

What is the Current Lifetime Risk for Diabetes in the US?
For individuals born in 2000, the lifetime risk for diabetes is
328 for males 385 for females

Lifetime risk higher among minority groups at birth and all ages
Narayan et al, Jama 29014, 2003

3

Lifetime Risk at Birth
For males: 454 for Hispanics to 267 for non-Hispanic whites For females: 525 for Hispanics to 312 for non-Hispanic whites Rates remain high even at older
ages
Narayan et al, Jama 29014, 2003

Why is Diabetes Increasing at Epidemic Rates?

4

But wait a bit, the Oysters cried, Before we have our chat; For some of us are out of breath, And all of us are fat
Lewis Carroll

The Walrus and the Carpenter

Obesity Trends Among US Adults BRFSS, 1991, 1996, 2003
BMI 30, or about 30 lbs overweight for 54 person 1991 1996

2003

Source: Behavioral Risk Factor Surveillance System, CDC

No Data

10

10-14

15-19

20-24

25

5

Why are We Gaining so Much Weight?

Were Eating More
Daily caloric intake increased by 523 calories from 1970 to 2003
- Bigger portion sizes - More eating out/fast food consumption - Fat-free foods perceived Fatas low calorie

Ernst N Am J Clin Nutr 1997;66suppl:965S-72S

6

We are Eating Worse
Between 1977 and 2001: Sweetened beverage consumption up 135 38 reduction in milk consumption 278 total calorie increase from drinks alone Percent of calories from fat increased by 531 calories per day

US Food Consumption Up 16 Percent Since 1970

7

Majority Of Americans Do Not Follow A Healthy Lifestyle
2000 Behavioral Risk Factor Surveillance System, N 153,805
100 80 599 Respondents 60 40 240 20 0 767 778

Smokers

BMI 25
kg/m2

Consumes fruits/vegetables 5x/day

Infrequent exercise 5x/week

Reeves MJ and Rafferty AP Arch Intern Med 2005;165:854-7

Were Moving Less
More automation / less activity at work Less energy to get to work, school shop Remote controls, drive-through windows, garage door openers, etc

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Can Current Diabetes Trends In The US Be Changed?
The only way to really stay out

of trouble is to avoid it
-My Dad,1960

9

Stages in the History of Type 2 Diabetes
Normal

IGT
Preclinical state

Type 2 Diabetes
Clinical disease

Complications

Disability Death

Complications

70,000,000 22,000,000 Primary prevention Secondary prevention Tertiary prevention

Impaired Glucose Tolerance
Identified with a 75 gram oral glucose tolerance test OGTT: defined as 2-hour value of 140-199 mg/dL 2140mg/dL Risk factor for type 2 diabetes Increases risk of type 2 diabetes by 5 - 8 fold 1- 12 per year develop type 2 diabetes Obesity, higher fasting glucose level, prior history of GDM, and other factors increase the rate of progression

10

Pre-Diabetes Raises Short-term Risk of Type-2 Diabetes by 7 to 15 Fold
Incidence of diabetes by glucose status: Annual 6-year
Normal 84: IFG 8: IGT 6: IFGIGT 2: 07 51
58 112 45 33 34 65

16 of the population accounted for 55 of the new cases of diabetes de Vegt F et al JAMA 2001;285:2109-2113

If that wasnt bad enough
In people with pre-diabetes: 5-year risk of Total Mortality 5060 5-year risk of CVD Mortality 150
Barr et al Circulation 2007;116: July 18 online

Prevalent retinopathy 8
DPP Diabet Med 2007; 24:137-144 Diabet 24:137-

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Prevention of Type 2 diabetes should be feasible since:
There is a long period of glucose intolerance that precedes the development of diabetes Most DM-specific complications have not yet DMdeveloped Screening tests can identify persons at high risk There are safe, potentially effective interventions

Diabetes Prevention Program Sites

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DPP Study Population
Asian 4 American Indian 5

Caucasian African-American Hispanic-American Asian-American Pacific Islander American Indian

1768 645 508 142

African American 20

Hispanic American 16

Caucasian 55

171

Participant Characteristics n3,234
BMI kg/m2 Fasting glucose mg/dL Blood pressure mm Hg Systolic Diastolic 34 106

124 76

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Study Interventions
Eligible participants Randomized Standard lifestyle recommendations

Intensive Lifestyle n 1079

Metformin
Placebo Troglitazone n 1073 n 1082
Discontinued 6/98 n 585

Lifestyle Intervention
An intensive program with the following specific goals:
7 loss of body weight and maintenance of weight loss Fat gram goal — 25 of calories from fat Calorie intake goal — 1200-1800 kcal/day

150 minutes per week of physical activity

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Intensive Lifestyle Intervention
16 session course conducted over 24 weeks Education and training in diet and exercise methods and behavior modification skills Emphasis on: Self monitoring techniques Problem solving Individualizing programs Self esteem, empowerment, social support Frequent contact with case manager and DPP support staff

Mean Weight Change from Baseline
1 0 -1 -2 -3 -4 -5 -6 -7 -8

Weight Change Kg

Placebo Metformin Lifestyle

N 3051

2865

1500

385

0

6

12

18

24

30

36

42

48

Months

15

Leisure physical activity change

Mean change in leisure physical activity Met hours per week 8
7 6 5 4 3

Lifestyle

Metformin
2 1 0
0 1 2 3 4

Placebo

Years from randomization

Development of Diabetes
Placebo, Life-Style and Metformin
Placebo Development of diabetes percent per year Reduction of diabetes compared with placebo Number needed to
treat —to prevent 1 case in 3 yrs 110 Metformin Life-style Life78 48

—-

31

58

139

69

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DPP Lifestyle Intervention Worked for:
All ethnic/racial groups Men and women, lean, plump or fat All adults, especially those over age 60

Was This an Isolated Finding?

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Reduction in Type 2 Diabetes Lifestyle Intervention Trials
100 80
Risk Reduction

71 58 39 25 60 48 38 51

60 40 20 0
Q in g

D PP Fi nD PS Fa ng

ID D P K os ak a

D a

RCTs of Diet Physical Activity Interventions to Prevent Diabetes
Adapted from Gillies, C L et al BMJ 2007;334:299

Reduction in Type 2 Diabetes Medication Intervention Trials
100 80 73
Risk Reduction

82 57 40 25 31 35 51 30 60

60 40 20 0

ST O

Adapted from Gillies, C L et al BMJ 2007;334:299

Fa ng P- Pa ac N n ar ID a bo Dcs Fa M arb e ng a c os Er a ik fl rb e ss um os e o D n am PP g in lip e ID m iz D P etf ide m or Li etf min D m or R e t mi EA fo n M rm r os P in ig oo lit le az d on e

RCTs of Medications to Prevent Diabetes

Po ol ed

Li ao

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Medication Intervention Caveats
Most trials assessed progression to diabetes on drug Are lower glucose values on glucose lowering agents the same as diabetes prevention? Following a
3-month run-out for the DREAM Trial, there was NO DIFFERENCE in incident diabetes between placebo and rosiglitazone treatment groups IDF, December 2006

Summary of Prevention Studies
Diabetes can be prevented by lifestyle modification 5-7 weight loss, 30 5minutes/day of exercise such as walking in high risk individuals Diabetes can be prevented by medications that reduce insulin resistance metformin, TZD or reduce beta cell effort acarbose acarbose

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Can We Get Patients to Change Their Lifestyles in Real World Practice?

Overweight and Obesity
Multicenter weight loss program: 5 year follow-up
30 wt reduction 25 20 15 10 5 0 baseline 2 3 years 4 5 men women

Wadden et al I J Eat Disorders; 22:203-212,1997

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Overweight and Obesity
Multicenter weight loss program: 5 year follow-up
100 80 of pts 60 40 20 0 0 5 10 20 weight reduction 30 men women

Wadden et al I J Eat Disorders; 22:203-212,1997

Patients Expectations and Evaluations of Obesity Treatment and Outcome
Study design 60 obese women, age 40 87 yrs BMI 363 43 kg/m2 Subjects questioned about their goal weight goal Dream weight Happy weight Acceptable weight Disappointed weight
Foster GD, et al J Consult Clin Psychol
1997;65:79-85

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Subjects Perceptions of Goals
Defined Weights
Dream Happy Acceptable Disappointed

Reduction
38 31 25 17

Foster GD, et al J Consult Clin Psychol 1997;65:79-85

Percent Achieving Defined Weight at Week 48 n45
Happy 9 Acceptable 24

Dream 0

Weight loss: 163 72 kg
Disappointed 20

Did not Reach Disappointed Weight 47

Foster GD, et al J Consult Clin Psychol 1997;65:79-85

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So what can we do?

What Works in Obesity Management
Behavior modification:
Self-monitoring food diaries, regular body weights, exercise log Stimulus Control eat when hungry, stop when full, always eat at table, dont buy unhealthy snack foods, lay out exercise clothes Cognitive restructuring realistic goals, changing internal response to slip-ups

23

What Works in Obesity Management
Stress management other outlets for stress than eating, eg exercise, meditation, hobby Social support involve family in lifestyle changes, peer support such as Weight Watchers, TOPS, exercise partner Accountability

What Works in Obesity Management: Diet
Modest reduction of calories 500-1000 cals less per day leads to 1-2 pounds/wk of weight loss Rapid weight loss with severely hypocaloric diets unlikely to be
sustained Reduction in fat is healthiest and most practical way to cut calories; strategy used in DPP and Finnish study

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Of course, there may be some risks with adopting a healthier diet plan

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Can The Important Evidence-based Clinical Findings And Lessons Be Translated Into Practice And Effective Self-management Approaches? Yes—but Only Through Organized And Effective Partnerships And Collaborations

Diabetes Education Prevention with a Lifestyle Intervention Offered at the YMCA

DPLOY E

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Primary Aim
To determine if a group-based adaptation of the DPP lifestyle intervention can be implemented at a YMCA facility

The IUMC-YMCA Collaboration
Why the Y?
Reach:
2,400 YMCA facilities with 18 million members serving over 10,000 communities

Access:

Services provided for persons from diverse social and economic positions Over 40 million persons within a 5 minute drive to a Y Policy of not turning anyone away from a program offering due to their ability to pay History of promoting healthy lifestyles through a combination of education and physical activity They have translated clinical programs into community facilities on a national scale

Experience:

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Steps we followed
to Create a YMCA-based DPP
1 2 3

4

Adapted the DPP for feasible delivery in the Y broader population, Y coaches, group-based groupIdentified Y staff to lead groups Trained staff to deliver the group-based DPP groupFormal training certification Designed and offered by IUSM Developed an IUSM YMCA partnership to: Educate the community about diabetes Identify pre-diabetes risk factors in residents preStudy the strengths weaknesses of Y-DPP YDevelop a model to move DPP nationally through the Y

Design and Participants
Cluster-randomized YMCAs pilot trial Direct-mailing to households in Primary Market Areas of two matched YMCAs
Introduce risk factors for diabetes Invite attendance at one of several screening events
All attendees receive 3-step diabetes risk screening and 3advice Advice tailored to risk low, moderate, high

Recruit and enroll 200 high-risk adults over 1 yr
BMI 24 kg/m2 ADA Risk Score 10 AND CCBG 110-199 mg/dl 110-

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Randomization
Adults with DPP characteristics N ? Attend, screen high-risk, enroll high- risk N 200

Intervention YMCA Site N 100 Enroll in YMCA DPP GLS N 70 Weight loss and PA 4 mo; 12 mo

Control YMCA Site N 100

Weight loss and PA 4 mo; 12
mo

Intervention and Controls
Control Interventi Site on Site

Community marketing of YMCA risk-screening riskevents Standard risk assessment protocol Brief advice about risk reduction using NDEP materials Recruitment of high-risk individuals for study highAccess to existing YMCA resources for weight loss Access to group-based DPP intervention at YMCA groupFollow-up risk assessment advice at 4 12 Followmonths

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Measures and Outcomes
Patient characteristics Self-report physical activity and diet Body mass BP, TC, HDL, A1c, Framingham Costs and QoL EQ5 Internal direct program observation mole Predictors of enrollment, participation, attendance, and success in program

Subjects to Date
Age Male White Income 50K Weight lbs Controls n87 60 40 77 46 201 DEPLOY n92 56 49 89 39 209

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So if the DPP achieved 7 weight loss with all the bells and whistles What do you think the Y can achieve for 1/3 of the cost?

Preliminary Results
2100 2050 Body Weight 2000 1950 1900 1850 1800 1750 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
Week Number

Average Weight Loss 65 p001

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Percent weight loss by Group
7 6

Weight SBP A1c

Total Chol 8 HDL 16

Weight loss

5 4 3 2 1 0 post program 6 months 12
months Intervention Control

Change Results
Controls -19 -20 -01 DEPLOY -60 -23 -01 -23 17 P-value 0001 085 069 0001 071

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How much should a lifestyle program for prevention of type-2 diabetes cost?

The YMCA has estimated the total cost for supplies, personnel time, and program administration during year 1 to be 275 to 325 per participant participant

Ackermann RT, Marrero DJ The Diabetes Educator 2007; 33; 69

What if costs were shared?

RESULTS– Compared with placebo, providing the lifestyle RESULTS– intervention at age 50 years could prevent 37 of new cases of diabetes before age 65, at a cost of 1,288 per QALY gained A private payer could reimburse 655 24 of the 2,715 in total discounted intervention costs during the first 3 intervention years and still recover all of these costs in the form form of medical costs avoided If Medicare paid up to 2,136 in intervention costs over the 1515year period before participants reached age 65, it could recover those costs in the form of future medical costs avoided beginning at age 65 65

Ackermann RT et al Diabetes Care 29:12371241, 2006 29:1237

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Conclusions
There are linked epidemics of type 2 DM and obesity Morbidity and cost
can be reduced more effectively with prevention than with treating the disease once it is diagnosed Type 2 can be prevented with modest weight loss and increases in physical activity in high-risk populations

Conclusions
Type 2 DM can also be prevented, to a lesser extent, with metformin, acarbose, and possibly with TZDs ??Combination of lifestyle and meds Society and the health care system need to support interventions to ameliorate weight gain and sedentary lifestyles

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Conclusions
The DPP lifestyle intervention can be adapted for delivery by lay persons in community settings
Weight loss comparable to what was achieved in the DPP

Community-based programs are well received by participants Can be implemented at 1/3 the cost Risk assessment may create a teachable moment

Thank You

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Orlistat Xenical
Binds to gastrointestinal lipases preventing hydrolysis of dietary triglycerides Results in loss of one third of dietary fat Approximately 9 reduction of body weight compared with 58 for placebo Side effects include flatulence with discharge, fecal urgency, fecal incontinence, steatorrhea, oily spotting, and decreased absorption of fat-soluble vits

Slides if questions about
weight loss drugs

36

Drug Therapy for Obesity
Approved for use in adults who have BMI 27 plus obesity-related medical conditions type 2 DM, hypertension, hyperlipidemia, coronary artery disease, sleep apnea have BMI 30 in the absence of such conditions Two general classes Appetite suppressants: noradrenergic, serotonergic, combined sibutramine Decrease nutrient absorption orlistat

Sibutramine Meridia
Inhibits both norepinephrine and serotonin reuptake Results in 5 to 8 weight loss compared with 1 to 4 percent for placebo Safety data not available beyond 2 years May improve maintenance of weight lost via lifestyle intervention Side effects include mild increases BP, HR; dry mouth, headache, insomnia, and constipation

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Obesity Drugs - Clinical Application
Consider if wt loss 1 pound per week during 6 months of diet and exercise Individual patients may have better response Most effective if used in conjunction with lifestyle modification program If weight loss 20 kg during the first month of treatment, assess adherence to medication, diet, and exercise and consider adjustment in dosage If minimal response continues, discontinue or substitute

What does this mean to the
practicing physician diabetes educator?

38

Three Main Translation Questions
How do we identify persons who should receive a DPP-style intervention? What do we do with persons identified as being at risk? How do we sustain an intervention program?

Methods for Identifying People At Risk
New Category of pre-diabetes was introduced pre- diabetes This category targets fasting plasma glucose levels of 100-125 mg/dl or a 2 hour value of 140100140199 mg/dl during an oral glucose tolerance test OGTT OGTT is emphasized because it is more sensitive and specific for diagnosing pre-diabetes preUsed by DPP to define high risk status Potential barrier due to difficulty

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Strategies for Identifying People At Risk
Activate the public
Educate about risk factors, pre-diabetes, preand encourage follow-up with health care followproviders

Activate health care providers
Educate about modifiable risk factors Describe methods for identifying persons at increased risk Provide support for assisting high risk persons to initiate risk reducing behaviors

An Example of Activating Public Providers
National Diabetes Education Program NDEP developed the Small Steps Big program Multimedia Campaign
Implementation toolkit for use by health care providers

Rewards, Prevent Type 2 Diabetes

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Strategies for Identifying Persons at Risk
Screening by PCPs Screening at worksites Screening at community centers

Identifying Persons at Risk: Using Healthcare settings
Healthcare settings are uniquely suited to screen for IGT, especially using OGTT Restricts availability of risk screening to persons with access to a healthcare system If it is necessary for a healthcare setting to provide interventions, the numbers identified and referred may be too small to justify costs associated the modification programs

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Identifying Persons at Risk: Using Worksite settings
Worksites can take advantage of a captive audience
Capitalize on internal communication channels Provide access to medical screening and follow-up Limited to employees
The working well well

Identifying Persons at Risk: Using Community Settings
Greater access by a broader segment of the at-risk population
Potentially limited access to laboratory based assessments May be more difficult to arrange follow-up testing or care after an abnormal screen

42

What do we do with persons at risk?

The Easy Approach: Write a
Prescription
Metformin, Acarbose, lower risk of diabetes in subjects with IGT Risk reductions 23-31 were half as great as those seen with lifestyle interventions 58 Need to consider cost, tolerability of meds Off label use May want to reserve for those unable to meet lifestyle goals

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Medications for DM Prevention: Metformin
850 mg bid Even with titration, 25 cannot tolerate Contraindications: renal insufficiency, CHF, liver disease Post-hoc analyses of DPP suggest no benefit in subjects 60 yrs or if BMI 30 kg/m2

Medications for DM Prevention: Acarbose
100 mg tid Requires slow titration due to GI side effects bloating, flatulence Even with titration, 20-30 cant tolerate Not absorbed; no systemic toxicity so perhaps most reassuring for long-term use

44

Medications for DM Prevention: What about TZDs?
Since insulin resistance key, strong rationale for use of this class Troglitazone off the market; little data on newer TZDs and prevention Costly 120/month No data on long-term safety Looks promising, but not ready for prime time

Overweight and Obesity
Goals of therapy: general
prevent further weight gain

reduce body weight maintain lower body weight long
term

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Overweight and Obesity
Treatment strategies
dietary therapy physical activity behavior therapy combined therapy pharmacotherapy weight loss surgery

Lifestyle Changes
Most effective 58 reduction in DM risk Low cost Safe Have other benefits HTN, CVD, cancer, quality of life

HOWEVER

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Source:emnet-usa.org