Look AHEAD Study Lukasz Materek Endocrinology Rounds May 20, 2012

Objectives Review the Look AHEAD study design Understand the outcome measures Review currently available evidence and implications in clinical practice

Background Overweight and obesity are major health problems in the United States, affecting more than 50% of adults, with 22.5% classified as obese (body mass index > 30 kg/m2) Long-term consequences of being overweight include increased mortality and increased morbidity

Look AHEAD Objective Assess the long-term effects of an intensive lifestyle intervention program designed to achieve and maintain weight loss by decreased caloric intake and increased physical activity Population: overweight volunteers with type 2 diabetes

Study Population ~ 5,000 volunteers with type 2 diabetes years of age overweight or obese (body mass index > 25 kg/m2) Potential volunteers who are unlikely to be able to carry out the components of the weight loss intervention will be excluded

Study Interventions Intensive lifestyle intervention or to diabetes support and education Treatment assignments are unmasked Lifestyle intervention is implemented with individual supervision and group sessions and is aimed at achieving and maintaining: – at least a 7% decrease in weight from baseline and – 175 minutes per week in physical activity

implemented during a four-year period most intensive application during the first year less frequent attention during the next three years minimum of twice yearly contacts during an extended follow-up period

Control Participants assigned to diabetes support and education are offered three sessions each year in diabetes management and social support

Intervention variety of diet strategies (e.g. prepared meals and liquid formula), exercise strategies, and optional weight loss medications are utilized

Outcomes primary outcome is the aggregate occurrence of major cardiovascular events – fatal and non-fatal myocardial infarctions – strokes – hospitalizations for angina – cardiovascular deaths over a planned follow-up period of up to 13.5 years

Three composite secondary outcomes have also been defined: 1. cardiovascular deaths, myocardial infarctions (fatal or non- fatal), and strokes (fatal or non-fatal) 2. deaths (all causes), myocardial infarctions, strokes, and hospitalizations for angina 3. deaths (all causes), myocardial infarctions, strokes, hospitalizations for angina, coronary artery bypass graftings, percutaneous coronary angioplasty, hospitalizations for congestive heart failure, carotid endarterectomies, or peripheral vascular procedures such as bypass or angioplasty

Design The study is a two-armed randomized, controlled clinical trial With 5,000 participants, the study has a >80% probability of detecting an 18% difference in major cardiovascular disease events between the two intervention groups

Design Modification actual event rate in the Diabetes Support and Education group was about 0.7% per year trial lacked the statistical power necessary to detect the originally hypothesized effect primary endpoint was expanded to include hospitalized angina and the duration of the trial should be increased by two years.

Intervention Group diet modification and increased physical activity with a goal of sustained weight loss intervention has been designed to allow individual flexibility of treatment strategies portion-controlled diet behavioral techniques, diet modification, physical activity, and social support

Phase I (year 1) participants are seen in clinic weekly with three group meetings and one individual counseling session per month total of 24 visits during the first 26 weeks months 7-12, participants are seen in clinic at least twice a month group sessions are provided every-other-week, with participants encouraged to attend at least one group meeting per month monthly one-on-one meetings with individual counselors

Phase II (Months 13-48) minimum of two contacts per month are expected during this phase refresher groups will be offered once a week for up to six weeks and will be designed to reverse weight gain or promote weight maintenance.

Phase III (Months 49+) participants will be offered monthly on-site individual contact with a counselor open groups will be offered one time per month

Goals

Diet restriction of caloric intake is the primary method of achieving weight loss – kcal/day for individuals weighing 250 lbs (114 kg) or less at baseline – kcal/day for individuals who weigh more than 250 lbs – These goals can be reduced to kcal/day and kcal/day, respectively, if participants do not lose weight – These calorie levels should promote a weight loss of approximately one to two lbs/week

Diet maximum of 30% of total calories from total fat maximum of 10% of total calories from saturated fat minimum of 15% of total calories from protein

Portion-controlled diets provide patients servings of food with a fixed calorie and macronutrient content Participants choose from two prototype diets

Diet Option 1 commercially available liquid meal replacement that will replace two meals and snacks each day evening meal of either a frozen entrée or conventional table foods to provide a total of kcal/day depending on the individual’s baseline weight

Diet Option 2 consumption of a very structured meal plan, with the same calorie range, using foods that participants prepare themselves for those who do not accept or tolerate the liquid/prepared meal prototypes

Activity unsupervised exercise, with gradual progression toward a goal of 175 minutes of moderate intensity physical activity per week by the end of the first six months Moderate-intensity walking is encouraged as the primary type of physical activity

Activity Exercise bouts of ten minutes and longer are counted toward this goal Exercise is recommended to occur five days per week occupational activity will not be counted towards the physical activity goal

Cognitive Behavioral Strategies training in cognitive behavioral strategies to help produce and maintain changes in dietary intake and physical activity

Further Strategies After six months of lifestyle strategies alone, a toolbox of weight loss medications and advanced behavioral strategies may also be employed

Drugs are used only as an adjunct to an intensive program of exercise and dietary modification Only drugs that have received FDA approval for use in weight loss are included only drug originally approved for the toolbox was orlistat, however it was later voted to discontinue its use based on finding limited effectiveness

primary analyses in this article examined the relationships between categories of weight loss and changes in CVD risk factors – weight changes from baseline to 1 year: – gained >2% – remained weight stable (±2%) – lost ≥2 to <5% – lost ≥5 to <10% – lost ≥10 to <15% – lost ≥15%.

Baseline Charecteristics

ILI participants had a weight loss (means ± SD) of 8.7 ± 7.6 kg compared with 0.8 ± 5.0 kg in the DSE group (P < )

Table 1 60% of the participants were women, and 37% were from ethnic or racial minority groups. Participants were an average age of 58.7 ± 6.8 years and weighed ± 19.3 kg at study entry.

Weight changes were significantly correlated with changes in glycemic control, blood pressure, HDL cholesterol, and triglycerides greater the weight change, the greater the improvements in each risk factor in the full cohort and within the ILI and DSE group separately

A1C

Fasting Glucose

BP

TG

HDL and LDL

Lipid Profile – not on medications

six weight change categories, adjusted for age, sex, race, treatment group assignment, baseline weight, and baseline level of the risk factor strong graded association was seen for changes in glucose, HbA 1c, SBP, DBP, triglycerides, and HDL cholesterol (all P values <0.0001).

magnitude of improvement in LDL cholesterol did not differ across the weight categories, even in those not using lipid-lowering medications at baseline and 1 year

TG 0.5; LDL 0.25; HDL 0.13; glucose 1.1

Conclusion modest weight losses of 5–10% of initial weight are sufficient to produce significant, clinically relevant improvements in CVD risk factors in overweight and obese patients with type 2 diabetes examined effects at 1 year only

Conclusion The magnitude of weight loss at 1 year was highly related to the improvements in blood pressure, glycemic control, and lipids, with the notable exception of LDL cholesterol

assessment of the associations that weight- loss patterns during the first year of an intensive lifestyle intervention have with 4- year maintenance and health outcomes

Conclusions Greater month-to-month weight losses and more gradual and sustained weight losses during the 1st year were each associated with better longer term weight loss Associations were independent of each other and of a panel of participant characteristics: markers of demography, health, and lifestyle, including baseline BMI and diabetes control

Conclusions weight loss that is achieved through gradual and sustained increments, rather than a more rapid loss weight loss that is not sustained, is associated with better long-term maintenance

Greater month-to-month weight losses during the 1st year of the weight-loss intervention were associated with longer term benefits

Conclusions Look AHEAD strategy works in severely obese patients

Conclusions Improvement in markers Will this translate into mortality/events outcomes ???

Final Conclusions Key: – weight loss – diet – Exercise Wait for final results of the Look AHEAD Study – Completion 2014

Patient Goals Weight: – Weight loss goal: Lose 10% of initial weight – Continued loss or weight maintenance Activity – Exercise 175 min/wk by month 6 – Increase minutes per week of activity; 10,000 steps/day goal

Study information including educational materials published online

Thanks!