Comparison of the Effect of Intense-Exercise/Moderate-Calorie, Topiramate-Phentermine and Cognitive Behavioral Therapy on Obesity

Background. Obesity is prevalent disorder; up to 60% of US population that is associated
with significant morbidity and mortality through inflammation, insulin resistance,
dyslipidemia, obstructive sleep apnea, and atherosclerosis. The economic burden of
obesity-related illnesses is substantial, with estimates ranging from 2% to 7% of the total
US health care expenditures and billions of dollars in direct and indirect costs to society.
This randomized clinical trial will compared the effectiveness of Intense Exercise/Moderate
Calorie Restriction (IE-MCR), Topiramate-Phentermine (TP) and cognitive behavioral therapy
(CBT) on obesity and atherosclerosis in morbidly obesity individuals (body mass
index(BMI)>40 kg/m2 or BMI>35 kg/m2 with associated comorbidities) with diabetes mellitus
(DM).

Importance/Significance. There is a cumulative increase in the rate of obesity, up to 60% of
the US population. This randomized clinical trial will compare: 1) the change in fat mass
and atherosclerosis and, 2) the change in psychological status and quality-of-life as well
as economic burden in response to IE-MCR, TP and CBT in morbidly obese individuals with DM.
Furthermore, 3) exploratory analyses evaluating the different underling adipocyte molecular
mechanisms will be conducted. This will investigate the underlying genomic determinants and
characterizes the management of obesity by comparing biologic, clinical phenotype, and cost
effectiveness of these two interventions. These aims will provide fundamental information to
assess the beneficial effects within and across interventions on obesity and atherosclerosis
management which will help provide individualized intervention models to improve management
of morbidly obese individuals Method. A significant difference in reduction of fat mass,
carotid/coronary atherosclerosis, improve in psychological, quality of life and economic
burden measures, as well as exploratory mechanism of action across IE-MCR, TP and CBT
methods, are hypothesized. Over a 5 year period, 60 morbidly obese individuals with diabetes
mellitus aged 18 or older and free of clinical cardiovascular disease will be recruited from
the Obesity Clinic of the Greater Los Angeles VA Health Care System, University of
California Los Angeles and Captain Lovell Federal Healthcare Center. Eligible subjects will
be randomized to either of intense exercise/moderate calorie restriction,
Topiramate-Phentermine or cognitive behavioral therapy (20 in each group) and receive these
intervention for 12-months. Intense exercise/moderate calorie restriction group will receive
lectures on exercise and general dietary measures including calorie counting. They will
prepare their own food, with protein:carbohydrate:fat ratio of 30:45:25 and over 70% of
their resting daily energy expenditure (RDEE), and completed daily food and exercise
journals. They will exercise ~2.5 hours/day, about 1/4 supervised, for a year.
Topiramate-Phentermine group will receive full dose of TP (15/92mg) pills daily for a period
of 1-year. Furthermore, CBT group as well as IE-MCR and TP will receive weekly cognitive
behavior therapy for a year. All subjects will undergo carotid ultrasound; coronary computed
tomography angiography, bioelectric impedance spectroscopy, dual-energy X-ray
absorptiometry, ambulatory calorimetry, serial home resting metabolic rate serial home
(RMR),sleep apnea assessment and abdominal fat pad fine-needle aspiration biopsy (FNAB), as
well as measurement of oxidative stress/inflammatory/metabolic biomarkers at baseline and at
1-year follow-up. Quality of life, psychological health and economic burden will be assessed
using standardized questionnaires. Participants will complete quarterly trial visits for
physical exam, compliance to intervention as well as ascertainment of adverse effects.

Inclusion Criteria:

- Age 20-70 years

- Competent to give informed consent

- Obesity (BMI>40) or BMI>35 kg/m2 with associated co-morbidities

- Diabetes Mellitus Type II

Exclusion Criteria:

- History of coronary artery disease, myocardial infarction, coronary angioplasty or
bypass surgery

- Prior non-cardiac illness with an estimated life expectancy <4 years

- Unable to give informed consent

- Women who are pregnant or lactating

- Prior bariatric surgery or receiving anti-obesity drugs