Valued EpiGenetic Glycemic ImprovEments Through Weight Loss

The investigators plan to recruit a total of 200 middle-aged (40-65 years) obese (BMI=30-39.9
kg/m2), sedentary, pre-diabetic participants who will be randomized to either a 18-week
dietary weight loss (n=100) followed by a 8-week transition and then 26 weeks of maintenance
(Weight Loss group) or a delayed weight loss (Control group, n=100) intervention.

During the screening visit, eligible participants who provided informed consent will complete
a 3-day food record and then start a 3-day run-in period using the Medifast® meal replacement
products to be used for the weight loss intervention. At the next visit the participant will
meet with the Registered Dietitian (RD) to undergo an assessment of Readiness to Change (18).
All participants must be approved for eligibility by the RD based on her clinical judgment of
likelihood of success for weight loss, likelihood of compliance to the Medifast® meal plan,
and willingness to be randomized to either group.

Control/Delayed Weight Loss Group: (18 weeks) Participants randomized to the delayed weight
loss intervention (n=100) will serve as a no-weight loss control to the weight loss group
during the first 18 weeks of the study. During the control (18 weeks) phase these
participants will receive a monthly phone call visit from staff to maintain contact and
interest in the study. At the end of the initial 18 weeks participants will complete all
follow up assessments prior to being offered the opportunity to participate in a weight loss
program. This weight loss program will involve 18 weekly, group dietary and exercise sessions
led by the study staff in which participants will follow a modified Diabetes Prevention
Program. Participants will be given an individual introduction session to the weight loss
program by study staff and will be guided by the RD on their food purchasing and preparation
of their meals, but no meal replacements or supplements will be provided.

Weight Loss group: Phase 1 (18 weeks): Participants assigned to this group will undergo a
dietary intervention for the first 18 weeks of the study designed to elicit an approximate
8-10% weight loss. The intervention will incorporate partial meal replacements, nutrition
education, and some behavior modification.

This level of weight loss will be achieved through the combination of a partial meal
replacement (MR) program and individual and group nutrition/behavioral counseling.
Participants will be provided with and asked to consume 4 Medifast® MR per day. All
participants will follow the Medifast Achieve TM 4 & 2 & 1 Plan® which includes the 4 MR
products per day, with the addition of 2 Lean and Green™ Meals and 1 Healthy Snack. The Lean
and Green™ Meals will be prepared by the participants and each will consist of 5-7 oz. lean
protein, 3 servings of non-starchy vegetables and up to 2 servings of healthy fat. The
Healthy Snack will consist of one serving of fruit, dairy, or grain. Each MR from Medifast®
contains ~90-110 kcals and 10-15 g protein. Participants will be given an individual
introduction on the meal plan prior to starting and will be guided by the RD on their food
purchasing and preparation of the other Lean and Green TM meals. They are encouraged to
consume only what is approved on the Medifast Achieve TM 4 & 2 & 1 Plan®.

Phase 2 (8 weeks): After completion of the active weight loss phase, participants in this
group will attend bimonthly group meetings to discuss increasing their activity. The goal is
for participants to slowly increase their activity to 150 minutes per week and then continue
at 150 minutes per week to help them maintain their weight. Activity logs will be dispensed
and topics such as tracking activity, finding time for fitness and getting active will be
discussed.

Participants will have the option to transition off the meal replacements and potentially
continue on a select few during the transition phase. Additional dietary guidance will be
available to help participants transition off MR and maintain their weight. The RD will
calculate individual maintenance calorie goals to be discuss with participants at a brief
individual session prior to starting the transition phase. At this session an introduction to
the transition phase and information on how to track their activity will also be discussed.

Phase 3 (26 weeks): After completion of phase 2, participants will be called monthly for 26
weeks and then asked to return for a maintenance visit at the end of the 52 weeks from study
start. Participants will be offered an optional session with a staff member at the time of
their exit to discuss long term goals and strategies and provide closure.

Inclusion Criteria:

- BMI=30-45.0 kg/m2 OR BMI 27-30, if waist circumference is ≥ 40in in men or ≥ 35in in
women

- Sedentary for past 6 mos (<20 min; 2 d/wk of resistance or aerobic exercise)

- Normal cognitive function:

Greater than 12 years education:

Caucasian - MOCA ≥ 24 African American/Hispanic/Other- MOCA ≥ 22

12 years or less education: Caucasian- MOCA ≥22 African American/Hispanic/Other- MOCA ≥20

- No evidence of clinical depression

- Fasting blood glucose 100-125 mg/dl OR Hemoglobin A1c 5.7% - 6.4%

- No contraindications for participation in weight loss

- Able to provide own transportation to study visits and intervention

- Approved for participation by Medical Director

- Negative pregnancy test or confirmed post-menopausal/surgically sterile status (Women
Only)

- Not involved in any other research study

- Willing to provide informed consent

Exclusion Criteria:

- Weight loss (±5%) in past 6 months

- Uncontrolled arrhythmias

- Cancer requiring treatment in past year, except non-melanoma skin cancers

- Regular smoker (>1 cigarette/day) or heavy drinker (>9 alcoholic drinks/wk) within
past year

- Insulin dependent or uncontrolled diabetes (FBG>126 mg/dl) OR (Hemoglobin A1c 6.5% or
greater)

- Uncontrolled hypertension (BP>160/90 mmHg)

- Elevated triglyceride (TG>400 mg/dl)

- Clinically evident liver disease, kidney disease, edema or anemia

- Past or current ischemic heart disease, uncontrolled angina, heart failure, PAD,
stroke, chronic respiratory disease, endocrine or metabolic disease, neurological or
hematological disease

- Regular use growth/steroid hormones, including estrogen replacement, weight loss
medications, diabetes medications including insulin and/or blood thinners

- History of any type of bariatric or weight loss surgery or bilateral oophorectomy
requiring long term hormone replacement therapy use