1. Minimally Invasive Surgery Symposium Modest Weight Loss in T2 DM: Lessons from the Look AHEAD Trial Donna H. Ryan, MD Pennington Biomedical Research Center Baton Rouge, LA Donna.Ryan@pbrc.edu

2. OUTLINE  The relationship between weight and diabetes  Look AHEAD – what it means for obesity and for diabetes  Looking ahead – what have we learned to date from the study?

3. There is a diabetes epidemic. Crude and Age-Adjusted Prevalence of Diagnosed Diabetes per 100 Population, US, 1980-2005 Source: CDC website

4. There is an obesity epidemic. Prevalence of Overweight and Obesity by Age, 1960-2004 Source CDC/NCHS, Health, US, 2006

5. Relationship Between BMI and Risk of Type 2 Diabetes Chan J et al. Diabetes Care 1994;17:961. Colditz G et al. Ann Intern Med 1995;122:481. Age-Adjusted Relative Risk Body Mass index (kg/m 2 ) MenWomen <22<2323 - 23.9 24 - 24.9 25 - 26.9 27 - 28.9 29 - 30.9 31 - 32.9 33 - 34.9 35+ 1.0 2.9 1.0 4.3 1.0 5.0 1.5 8.1 2.2 15.8 4.4 27.6 40.3 54.0 93.2 6.7 11.6 21.3 42.1

6. Relationship Between Weight Gain in Adulthood and Risk of Type 2 Diabetes Mellitus Relative Risk Weight Change (kg) Willett et al. N Engl J Med 1999;341:427. -10-505101520MenWomen

7. Weight Loss Benefits  For acute weight loss phase: Strong benefit in glycemic control Reduction in LDL, reduction in HDL, reduction in BP  For reduced stable weight: Strong benefit in glycemic control Increase in HDL, reduction in BP; ~20% weight loss is needed to see reduction in LDL

8. Mechanisms of Glycemia Improvement with Weight Loss  Negative energy balance during acute weight loss improves glycemia  After weight loss plateaus, reduced state with less visceral adiposity improves glycemia  The behaviors that promote weight loss maintenance, low fat diet, energy neutral diet, & physical activity improve glycemia.

9. Insulin Sensitivity Improves with Weight Loss in Patients with Type 2 Diabetes Insulin (pmol/L) Before Weight Loss at 1 Year (%) Wing et al. Arch Intern Med 1987;147:1749. *P<0.01 vs before. * * * 0-2.42.5-6.97.0-14.0>15

10. DPP Results Diabetes Prevention Program Research Group. N Engl J. Med 2002: 346, 393. Diet + Exercise Diabetes Incidence per 100 Persons-Years Placebo Metformin 58% reduction 4.8 7.8 11

11. Redrawn from: Hamman, et al Diabetes Care 29:2102-2107, 2006 Change in weight from baseline (kg) 0-10-5+5 Incidence rate per 100 person-years 10 20 15 5 0 How much weight loss is needed to prevent type 2 diabetes – the DPP experience

12. Adding it up  Being obese is bad for you. Overweight and obesity are associated with increased mortality.  Is losing weight good for you? Losing weight is associated with Improvements in risk factors Prevention of diabetes But what about reduction in mortality? The SOS study showed mortality reduction with intentional, surgical weight loss, but many epi studies show that weight loss is associated with increased mortality.

13. OUTLINE  The relationship between weight and diabetes  Look AHEAD – what it means for obesity and for diabetes  Looking ahead – what have we learned to date from the study?

14. Why conduct the Look AHEAD Study?  Randomized clinical trial of a lifestyle intervention designed to produce and maintain weight loss and effects on so-called hard endpoints – cardiovascular events and mortality. Look AHEAD also gathers data on benefits/risks over 14 years in diabetics.  Look AHEAD is important to everyone in the weight loss community.  Look AHEAD is important to everyone in the diabetes community.

15. OUTLINE  The relationship between weight and diabetes  Look AHEAD – what it means for obesity and for diabetes  Looking ahead – what have we learned to date from the study?

16. Study Design  5145 overweight subjects with type 2 diabetes  2 arms Usual care (Diabetes Support and Education) Usual care + Lifestyle Intervention  Study duration: up to 13.5 years (with 4 years of intensive intervention).  Primary outcome: Cardiovascular death (fatal MI and stroke), nonfatal MI, and stroke; hospitalization for angina Look AHEAD Research Group. Controlled Clin Trials. 2003;24:61-28.

17. Lifestyle Intervention: Phase I, Weight Loss Induction Months 1-6 Weekly contact  3 group sessions/month  1 individual session/month Personal weight loss goal = 10% Study weight loss goal > 7% Phase II, Weight Loss Maintenance Months 7-12 Reduced contact  2 group sessions/month  1 individual session/month  2 face-to-face contacts/month required; 3 recommended Individual weight loss goal  continue weight loss if < 10%  weight maintenance if > 10%

18. Diabetes Support and Education  3-4 meetings / year to promote retention  health education topics diet exercise social support

19. Attendance At Year 1 Examination ILI Cohort: 97% DSE Cohort: 96% P=0.004

20. % Weight Loss at 1-Year -9 ILI 0 -2 -3 -4 -5 -6 -7 -8 DSE p < 0.0001 % Weight Change 8.6% 0.7%

21. % Reduction in Initial Weight by Gender N=872 N=1229 N=1197 N=830 -12 -10 -8 -6 -4 -2 0 024681012 Months % Reduction in Initial Weight Men Women P<0.001

22. Weight Loss in Insulin Users vs. Non- Users within ILI Group Mean % Weight Loss 7.6% 8.7% Medication Use At Baseline P=0.002

23. Fitness Change (%) at 1-Year Mean % Fitness Change Unadjusted P<0.001 Adjusted for 1 Year Weight Change P<0.001 5.8 20.9 10.8 15.9 DSEILI DSE

24. 1-Year Changes in Markers of Diabetes Control Markers of Diabetes Control ILIDSEP-value Hemoglobin A1c (%), BL Hemoglobin A1c (%), Y1 Y1 – Baseline 7.25 6.61 -0.64 7.29 7.15 -0.14 0.26 <0.001 Fasting glucose (mg/dl), BL Fasting glucose (mg/dl), Y1 Y1 – Baseline 151.9 130.4 -21.5 153.6 146.4 -7.2 0.21 <0.001 Diabetes medications, BL Diabetes medications, Y1 Y1 – Baseline 86.5% 78.6% -7.8% 86.5% 88.7% 2.2% 0.93 <0.001

25. 1-Year Changes in Markers of Blood Pressure Control Markers of Blood Pressure Control ILIDSEP-value Systolic BP (mmHg), BL Systolic BP (mmHg), Y1 Y1 – Baseline 128.2 121.4 -6.8 129.4 126.6 -2.8 0.26 <0.001 Diastolic BP (mmHg), BL Diastolic BP (mmHg), Y1 Y1 – Baseline 69.9 67.0 -3.0 70.4 68.6 -1.8 0.11 <0.001 Antihypertensive medications, BL Antihypertensive medications, Y1 Y1 – Baseline 75.3% 75.2% -0.1% 73.7% 75.9% 2.2% 0.23 0.54 0.02

26. 1-Year Changes in Markers of Lipid Control Markers of Lipid ControlILIDSEP-value LDL-cholesterol (mg/dl), BL LDL-cholesterol (mg/dl), Y1 Y1 – Baseline 112.2 107.0 -5.2 112.4 106.7 -5.7 0.78 0.74 0.49 HDL-cholesterol (mg/dl), BL HDL-cholesterol (mg/dl), Y1 Y1 – Baseline 43.5 46.9 3.4 43.6 44.9 1.4 0.80 <0.001 Triglycerides (mg/dl), BL Triglycerides (mg/dl), Y1 Y1 – Baseline 182.8 152.5 -30.3 180.0 165.4 -14.6 0.38 <0.001 Lipid lowering medications, BL Lipid lowering medications, Y1 Y1 – Baseline 49.4% 53.0% 3.7% 48.4% 57.8% 9.4% 0.52 <0.001

27. 1-Year Changes in Percent of Participants Meeting ADA Goals ADA GoalILIDSEP-value Hemoglobin A1c < 7%, BL Hemoglobin A1c < 7%, Y1 Y1 – Baseline 46.3% 72.7% 26.4% 45.4% 50.8% 5.4% 0.50 <0.001 Blood pressure < 130/80 mmHg, BL Blood pressure < 130/80 mmHg, Y1 Y1 – Baseline 53.5% 68.6% 15.1% 49.9% 57.0% 7.0% 0.01 <0.001 LDL-cholesterol < 100 mg/dl, BL LDL-cholesterol < 100 mg/dl, Y1 Y1 – Baseline 37.1% 43.8% 6.7% 36.9% 44.9% 8.0% 0.87 0.45 0.34 All three goals, BL All three goals, Y1 Y1 – Baseline 10.8% 23.6% 12.8% 9.5% 16.0% 6.5% 0.13 <0.001

28. Trying Look AHEAD at Home  The ILI was a program Derived from DPP Manuals for interventionists and participants  Dietary Intake 1200-1500 kcal/day < 250 lb 1500-1800 kcal/day > 250 lb < 30% calories from fat Meal replacements Menu plans provided  Physical Activity Gradual increases to 175 min/wk 10,000 steps

29. Trying Look AHEAD at Home Algorithm for medication management while in negative energy balance. Obesity Vol 14 No 5 May, 2006

30. Thank you www.pbrc.edu donna.ryan@pbrc.edu