2. Prevention of Type 2 Diabetes Marshall H. Chin, MD Carol M. Mangione, MD Assoc. Prof. Of MedicineProf. Of Medicine University of ChicagoDavid Geffen School of Medicine at UCLA

3. Outline Background and Study Questions Intervention and Measures 2 Study Designs –RCT with randomized encouragement –Quasi-experimental with staggered enrollment Tradeoffs Discussion

4. Diabetes in the United States More than 16 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 35% of persons with diabetes are undiagnosed 798,000 new cases are diagnosed every year CDC National Diabetes Fact Sheet 1998

5. Estimated Growth in Type 2 Diabetes and US Population From 2000-2050 Bagust A, et al. Diabetes 50, Suppl 2 A205, 2001

6. Age Obesity Body fat distribution Physical inactivity Family history of diabetes Race/ethnicity Previous gestational diabetes (GDM) Elevated fasting glucose levels Impaired glucose tolerance (IGT) Risk Factors for Type 2 Diabetes

7. Every 1 kilogram (2.2 pounds) of weight gain per 10 years is associated with a 4.5% increased risk to develop diabetes. Ford et al. Amer J Epidemiol 146:214,1997 Weight Gain and Sedentary Life-style Increase Risk of Developing Diabetes 68 - 72 % of diabetes risk in the U.S. is attributable to or associated with excess weight. Numerous studies have documented an association between low levels of physical activity and risk to develop diabetes

8. Impaired Glucose Tolerance Major risk factor for cardiovascular disease IGT may be optimal time for intervention –Asymptomatic –Potentially reversible –Diabetes-specific complications have not developed

9. Preclinical state Normal IGT Clinical disease Type 2 Diabetes Disability Death Complications Primary Secondary Tertiary Primary Secondary Tertiary prevention prevention prevention Stages in the History of Type 2 Diabetes 20,000,000 16,000,000

10. 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 Feasibility of Prevention Prevention of Type 2 diabetes should be feasible since:

11. Modifiable Risk Factors for Type 2 Diabetes Obesity Body fat distribution Physical inactivity Elevated fasting and 2 hr glucose levels

12. Study Interventions Eligible participants Randomized Standard lifestyle recommendations IntensiveLifestyle (n = 1079) Metformin (n = 1073) Placebo (n = 1082)

13. Primary Outcomes Annual fasting plasma glucose (FPG) and 75 gm Oral Glucose Tolerance Test – FPG > 126 mg/dL (7.0 mmol/L) or – 2-hr > 200 mg/dL (11.0 mmol/L), Either confirmed with repeat test Semi-annual FPG – > 126 mg/dL, confirmed

14. Screening and eligibility Step 1 screening Step 2 OGTT Step 3 start run-in Step 3 start run-in Step 4 randomization Number of participants 158,177 30,985 4,719 4,080 3,819* Step 3 end run-in Step 3 end run-in * 3,234 in 3 arm study (585 in troglitazone arm)

15. 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

16. 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 –Behaviorist –Exercise physiologist

17. The Core Curriculum 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, and social support –Frequent contact with case manager and DPP support staff

18. Mean Weight Change 0 6 12 18 24 30 36 42 48 Months Lifestyle Metformin + Placebo

19. Lifestyle Intervention 74% of volunteers assigned to intensive life style achieved the minimum study goal of > 150 minutes of activity per week Mean activity level: –At end of core curriculum: 224 minutes –At most recent visit: 189 minutes Summary

20. 0 1 2 3 4 0 10 20 30 40 Placebo (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 Years from randomization Cumulative incidence (%)

21. “Pre-diabetes” A new post-DPP term, includes those with: Impaired fasting glucose: –FPG 100–125 mg/dl (5.6–6.9 mmol/l) Impaired glucose tolerance: –2-h postload glucose 140–199 mg/dl (7.8–11.1 mmol/l) 40,000,000 with pre-diabetes! From the 2004 American Diabetes Association Guideline

22. Background Diabetes Prevention Program (DPP): Intensive lifestyle intervention (diet and exercise) reduces relative risk of DM by 58% over 3 years But, can it be translated to real world settings??

23. Challenge of Translating DPP to the Community Enrolling more generalizable population –Funnel of study enrollment for DPP Measurement of Impaired glucose tolerance in the community: FBS versus OGTT DPP lifestyle intervention intensive – realistic? –Training of study personnel –Intensity of intervention and F/U Sustainability

24. General Translation Challenges in Minority Communities Trust Enrollment Value of the “placebo” or “low intensity” study arm Is losing weight and diabetes prevention a community priority?

25. Primary Study Question Can community interventions designed to increase physical activity and change diet prevent the onset of type 2 diabetes among overweight and obese persons with pre-diabetes?

26. Subquestion What intensity of implementation occurs when organizations are presented with a menu of choices in a program to increase physical activity and cause dietary change?

27. Common Elements of Study Design: Community-based Participatory Research Community and researchers are equal partners Build on existing strengths / infrastructure in community Community / patient empowerment Improving community health overriding goal Takes into account community and individual preferences

28. Study Population Study setting: Churches in African American and Latino communities of Chicago and Los Angeles; Aim 50 people per church Pre-diabetes: Impaired fasting glucose (> 100 to 125 mg/dl), age > 50 yrs, BMI > 30 –Fallback: Overweight or obese with DM risk factors? Exclusions: DM, severe disability, dementia, short life expectancy

29. Enrollment and Study Period Work with local PIs with longstanding community church ties Pastor Church senior ambassador / opinion leader –Respected senior citizen with condition

30. Length of Study Intensive intervention: Weekly x 16 weeks Maintenance intervention: Monthly x 8 months Follow-up 3 years

31. Intervention: Menu of Choices Physical Activity Goal: Increase walking –Guideline goal: 150 minutes/week of walking –In practice, patient selects own goals

32. Physical Activity Menu Self-monitoring, pedometer Buddy system walking program Group walking sessions Collaborate with local Y or public parks Exercise classes taught by high school / college congregants Other suggested by community participants Particpants are encouraged to select activities from the list that they feel will work best for them

33. Nutrition / Diet Intervention Goal: Decrease calories Decrease fat / sugar Goals based upon weight and personal tailoring (Age, BMI, readiness to change) Health educator facilitator and 4-5 volunteer lay coaches

34. Nutrition / Diet Menu 1-on-1 individual sessions – health educator, lay coach, home visits Group classes Church social marketing campaign Support groups – problem-solving & goal setting Buddy system Involve family Other suggested by community participants Participants are encouraged to select activities from the list that they feel will work best for them

35. Outcome Primary – onset of DM (fasting plasma glucose greater than 125 mg/dl) Secondary –Physical activity- Weight, BMI –Dietary change- Knowledge –HgbA1c, lipids - Blood pressure –Self-efficacy- Quality of life

36. Process Assessment Fidelity of the Intervention Checklists – content and intensity of intervention –When given a choice, what do participants select to participate in? –Do certain elements in the intervention have better “uptake”? Qualitative interviews of participants

37. Randomized Controlled Trials Considered to be the gold standard –randomly allocated to either intervention or control group –best way to insure that both known and unknown factors that may influence the effectiveness of the intervention are balanced in the 2 comparison groups Time consuming, expensive, complex, may require a large number of clusters, tight inclusion criteria limit generalizabilty Unlikely to tell you whether an intervention will improve routine practice

38. Study Design Selection Challenge is translation research is that the interventions are usually complex (multifaceted with simultaneous changes in different parts of the community) Researcher has variable control over how the intervention is implemented In translation research there can be political, practical, and ethical barriers to randomized designs and other choices may be the best options Eccles M, et al. Qual Saf Health Care 2003;12;47-52

39. Design 1: Randomized Encouragement Trial (RET) Retains experimental structure but emphasizes a pragmatic public health perspective Combines strengths of the RCT and Observational studies Instead of mandating treatment assignment, randomizes participants to encouragement for the target intervention Promotes a more equitable relationship between the researcher and the participant/community Duan N, et al. Randomized Encouragement Trial: A Pragmatic, Public Health Oriented Paradigm for Clinical Research. In preparation 2004

40. Randomized Encouragement Trial (RET) Facilitates participants’ autonomy with regard to treatment decisions -- may be an important feature for sustaining a life style intervention over time Maintains many of the real world aspects of facilitation of behavioral change in community and medical settings. Unit of randomization can be at the participant level or at a higher level

41. Randomized Encouragement Trial (RET) Requires recruitment, consent, enrollment, and randomization Intervention group: –Randomized to encouragement rather than mandatory treatment assignment Control group: –no encouragement Maintaining personal choice, much as one would have to in practice or community settings is a critical element of this design

42. What is Encouragement? Offer of resources, incentives, education, and communication (persuasive messages) designed to increase the probability that a participant will want to adopt the treatment Various encouragement strategies can be tested in a bundle, in combinations, or individually Encouragement strategies can be developed collaboratively with communities and the population of interest

43. Why Encouragement? Attempts to influence treatment adoption through participants’ autonomous choice, leaving ultimate decisions to the participants Choices are voluntary Some participants might reject all menu choices in the intervention, some might select some Some controls may figure out how to get access to the intervention through other means

44. Randomized Encouragement Trial Analyses Assuming that the encouragement increases treatment adoption, it can provide an evaluation of treatment effectiveness using an intent-to-treat analysis Provides important qualitative and quantitative findings with regard to adoption and what is desirable and feasible in the community context Pragmatic by nature –stronger external validity than the RCT –stronger internal validity than observational studies

45. Randomized Encouragement Trial Strengths Retains aspects of naturalist treatment delivery May enhance the appeal of participation in effectiveness and translational research by maintaining autonomous choice which will enhance recruitment of more representative samples Rather than viewing treatment choice as a threat to internal validity, it is part of the primary data collection that informs the researcher about participant decision processes

46. Randomized Encouragement Trial Strengths Can provide important information about what can actually be delivered in real world settings

47. Randomized Encouragement Trial Weaknesses Internal validity is lower than in RCTs but higher than in observational designs By its less controlled nature RETs tend to have smaller effect sizes and greater within group variance therefore require bigger sample sizes.

48. RET Strengths and Weaknesses > Moderate dominance, >> strong dominance Duan N., et al. Personal Communication

49. RET Sample Size Considerations DPP, assume that the treatment effect is prevention of 6.2 cases of DM per 100 person-years Then in the RET, if adoption P d =0.5, then RET treatment effect is 3.1 cases of DM per 100 person years Then inflation factor is (1/0.5) 2 = 4 times more sample needed for the same power!

50. Sample size needed based on the observed effect size in the DPP

51. Design 2: Quasi-Experimental with Staggered Enrollment Randomization of initial assignment into intervention or control arm After 1 year, control participants transfer into intervention arm

52. Staggered Enrollment Analyses Intervention vs. control Among control subjects that crossover into intervention, each subject can serve as own control

53. Staggered Enrollment Strengths Increased enrollment compared with std RCT Increased subject retention compared with std RCT Intervention and control subjects drawn from same population Subjects initially randomized to control group can serve as own controls

54. Staggered Enrollment Weaknesses Secular trends Possible contamination of control groups Learning effects – control group has 1 more year in study Shorter F/U time in initial control group

55. Back-up slides

56. RET Sample Size Considerations RET: P 1 Adoption rate in the intervention group P 0 Adoption rate in the control group RET the incremental adoption rate is: P d = P 1 -P 0 RCT Q 1 Adoption rate in the intervention group Q 0 Adoption rate in the control group RCT with perfect adherence adoption rate is: Q d = Q 1 Assume treatment effect is constant M, then RET intervention effects are P d X M and RCT effects are Q d X M and the inflation factor is: (Q d / P d ) 2