Intermittent Fasting Versus Daily Caloric Restriction for Weight Loss

Restricting daily calorie intake is the primary dietary strategy currently used to treat
obesity. However, this approach is not effective for all individuals. Further, adherence to
daily caloric restriction (DCR) typically decreases over time and many individuals who lose
weight with this strategy will regain. Thus, novel dietary interventions are needed to
provide a broader range of treatment options. The objective of this proposal is to determine
if intermittent fasting (IMF) is an effective dietary strategy for treatment of obesity. IMF
is an alternative method of reducing energy intake (EI) which has gained lay popularity in
recent years as a strategy for weight loss. Short-term studies suggest IMF produces 3-8%
weight loss in individuals with overweight and obesity. However, few studies have compared
IMF to DCR and no studies have evaluated whether IMF is an effective long-term (≥1 year)
weight loss strategy. Data from an 8-week pilot study comparing IMF to DCR suggests IMF is
safe, tolerable, and produces similar short-term weight loss. After 6 months of unsupervised
follow-up, changes in body composition tended to be more favorable with IMF and almost twice
as many IMF participants maintained a ≥5 kg weight loss. Thus, IMF may be a more effective
dietary strategy for sustaining weight loss than DCR. However, longer-term data are needed
and little is known about adherence to IMF or the impact of IMF on energy expenditure (EE).
Short-term studies suggest adherence to IMF may be superior to DCR, however, energy intake
(EI) was based on self-report which may have significant limitations. Pilot data suggests
resting energy expenditure (REE) was preserved during IMF-induced weight loss, which could
decrease risk for weight regain. However, the impact of IMF on other components of EE
including physical activity (PA) is largely unexamined. The study design is a pragmatic
randomized trial to compare weight loss generated by IMF vs DCR. The targeted weekly energy
deficit will be equivalent: DCR will be prescribed a ~30% daily energy restriction and IMF
will be prescribed a modified fast (~80% energy restriction) on 3 non-consecutive days per
week. The hypothesis is that a weight loss program based on IMF as the primary dietary
strategy will result in greater weight loss at 1 year compared to a program based on
traditional DCR. The approach is innovative as the targeted energy deficit will be matched
between groups and EI will be assessed objectively (using doubly-labeled water) to provide an
accurate comparison of adherence. In addition, both intervention groups will receive
guidelines-based behavioral support to compare IMF to the current standard of care (DCR) in a
more robust fashion. This study is significant as it could identify an effective alternative
dietary strategy to help more people achieve and sustain weight loss.

Inclusion Criteria:

- Female or Male

- Age 18-55 years

- Body Mass Index 27-46 kg/m2

- Sedentary: defined as <150 minutes per week of voluntary exercise at moderate
intensity or greater and < 60 min per day of total habitual physical activity (i.e.
work related, transportation related) at moderate intensity or greater, over the past
3 months.

- No self-report of acute or chronic disease (cardiovascular disease (CVD), diabetes,
gastrointestinal disorders and orthopedic problems in particular)

- No plans to relocate within the next 12 months

- No plans for extended travel (> 2 weeks) within the next 12 months

- No nicotine use

- Live or work within 30 minutes of the Anschutz Health and Wellness Center (AHWC)
(exceptions may be made at the discretion of the Study PI on a case by case basis for
highly motivated subjects).

- Capable and willing to give informed consent, understand exclusion criteria, and
accept the randomized group assignment.

- Have a primary care physician (or are willing to establish care with a primary care
physician prior to study enrollment) to address medical issues which may arise during
screening or study procedures/interventions.

- For Females

- Not currently pregnant or lactating

- Not pregnant within the past 6 months

- Not planning to become pregnant in the next 12 months;

- Sexually active women of childbearing potential may be enrolled if they have had
a tubal ligation or use a reliable means of contraception

Exclusion Criteria

- Diastolic blood pressure > 100 mm of Mercury (HG) or systolic blood pressure > 160 mm
HG.

- Resting heart rate >100

- Diabetes (fasting glucose ≥126 mg/dL or Glycated Hemoglobin (A1C) ≥6.5%)

- Undiagnosed hypo- or hyper-thyroidism (TSH outside of the normal range) or history of
uncontrolled thyroid disorder. History of thyroid disease or current thyroid disease
treated with a stable medication regimen for at least 6 months is acceptable.

- Hematocrit, white blood cell count or platelets significantly outside the normal
reference range.

- Triglycerides > 400 mg/dL

- LDL cholesterol > 190 mg/dL

- Abnormal resting electrocardiogram (ECG): serious arrhythmias, including multifocal
Premature Ventricular Contractions (PVC's), frequent PVC's (defined as 10 or more per
min), ventricular tachycardia (defined as runs of 3 or more successive PVC's), or
sustained atrial tachyarrhythmia; 2nd or 3rd degree A-V block, QTc (Q-T Corrected)
interval > 480 msec or other significant conduction defects.

- Presence or history of any metabolic or chronic health problems which would affect
appetite, food intake, energy metabolism, or ability to optimally participate in the
exercise component including: CVD, peripheral vascular disease, cerebrovascular
disease, significant cardiac arrhythmias or cardiac valve disease, diabetes,
uncontrolled hyper- or hypothyroidism, uncontrolled hypertension, cancer (within the
last 5 years, except skin cancer or other cancers considered cured with excellent
prognosis), HIV infection, significant gastrointestinal disorders (described below),
significant pulmonary disorders (described below), significant renal, musculoskeletal,
neurologic, hematologic, or psychiatric disease.

- Significant gastrointestinal disorders including: chronic malabsorptive conditions,
peptic ulcer disease, Crohn's disease, Ulcerative Colitis, chronic diarrhea, or active
gallbladder disease.

- Significant pulmonary disorders including: chronic obstructive pulmonary disease
(COPD), interstitial lung disease, cystic fibrosis, or uncontrolled asthma.

- Symptoms suggestive of CVD: chest pain, shortness of breath at rest or with mild
exertion, syncope.

- Regular use of prescription or over-the-counter medications known to significantly
impact appetite, weight, or energy metabolism

- Regular use of systemic steroids (other than Oral Contraceptive Pills).

- Regular use of obesity pharmacotherapeutic agents within the last 6 months.

- Previous obesity treatment with surgery or weight loss device, except: (1) liposuction
and/or abdominoplasty if performed > 1 year before screening, (2) lap banding if the
band has been removed > 1 year before screening, (3) intragastric balloon if the
balloon has been removed > 1 year before screening (4) duodenal-jejunal bypass sleeve,
if the sleeve has been removed > 1 year before screening or 5) AspireAssist or other
endoscopically placed weight loss device if the device has been removed > 1 year
before screening.

- Current alcohol or substance abuse

- Nicotine use (past 6 months)

- History of clinically diagnosed eating disorders including anorexia nervosa, bulimia,
binge eating disorder.

- Current severe depression or history of severe depression within the previous year,
based on Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) criteria
for Major Depressive Episode.

- History of other significant psychiatric illness (e.g. psychosis, schizophrenia,
mania, bipolar disorder) which in the opinion of the Study MD would interfere with
ability to adhere to dietary or exercise interventions.

- Currently participating in or planning to participate in any formal weight loss or
physical activity programs or clinical trials.

- Weight loss or gain >5kg in past 3 months.