Effects of Low and Moderate Fat Diets on Lipids, Inflammation and Vascular Reactivity in the Metabolic Syndrome

The Metabolic Syndrome is characterized by elevated insulin levels, excess body fat in the
waist, and elevated levels of glucose and blood pressure, and dyslipidemia. Dyslipidemia in
the Metabolic Syndrome is characterized by high levels of triglycerides, low levels of HDL
cholesterol, and above average LDL and non-HDL cholesterol. Individuals with elevated LDL
cholesterol have traditionally been advised to follow a low fat, high carbohydrate diet.
However, research has shown that this diet does not adequately regulate cholesterol levels in
individuals with dyslipidemia. A diet consisting of more moderate amounts of fats and
carbohydrates may be more beneficial for individuals with the dyslipidemia of the metabolic
syndrome. The purpose of this study is to compare the effects of a diet moderate in fat and
carbohydrate versus a low fat, high carbohydrate diet on the cholesterol levels, inflammatory
factors and vascular response in individuals with metabolic syndrome.

During the initial screening period, participants follow an American Heart Association (AHA)
Step 1 diet and cholesterol levels are tested for eligibility under the criteria of the
Metabolic Syndrome. Before being randomized, eligible participants have a frequently sampled
intravenous glucose tolerance test (FSIVGTT), an abdominal CT scan to measure fat content in
two locations and two brachial artery reactivity tests. The FSIVGTT provides information
about whether participants are insulin sensitive or insulin resistant. The CT scan measures
the fat content in the abdomen and the liver. The brachial artery reactivity tests measure
blood flow through the brachial artery in the arm.

This 7-month study consists of two 1-month feeding periods, a rest month between the two
feeding periods and a 4-month follow-up diet in a free-living setting. In Month 1,
participants are randomly assigned to follow either a moderate fat, moderate carbohydrate
diet or a low fat, high carbohydrate diet. Participants receive prepared food at study visits
twice a week. Weight and vital signs are measured at each study visit, and blood is collected
at baseline, and Weeks 3-1/2 and 4. A brachial artery reactivity test, using an ultrasound to
measure artery size and blood flow in the arm, is performed twice in Week 4. In the Month 2
rest period, participants follow an AHA Step 1 diet at home. In Month 3, participants switch
to the other diet and all study procedures and evaluations are repeated as in Month 1. During
the following Months 4 through 7, participants continue following the second assigned diet,
but are responsible for preparing their own food. They meet with a dietician once a week for
1 month to learn how to prepare meals at home. During this 4-month period, blood collection,
vital sign measurements, and review of medical history and diet continue at monthly visits.
At the end of Month 7, participants again undergo two brachial artery reactivity tests.

As of October, 2010, 148 were screened with 71 eligible to be randomized. Seven discontinued
prior to completion and 64 completed the 7 month study. The intervention is complete and
analyses are ongoing.

Inclusion Criteria:

- Metabolic Syndrome: individuals must have at least three of the following five
criteria:

1. Abdominal obesity greater than 90 cm in Asian men, greater than 102 cm in all
other men, greater than 80 cm in Asian women, and greater than 88 cm in all other
women

2. Triglycerides greater than or equal to 150 mg/dL at two screening visits
(Required for the purposes of this study, which focuses on the dyslipidemic
phenotype)

3. HDL cholesterol levels less than 40 mg/dL in men and less than 50 mg/dL in women

4. Blood pressure levels greater than 130/85 mmHg or taking an allowed blood
pressure medication at Visit 1 (see definition in exclusions below)

5. Fasting glucose greater than or equal to 100mg/dL at Visit 1

Exclusion Criteria:

- LDL greater than or equal to 190 mg/dL

- Triglycerides greater than 500mg/dL at Visit 1

- Blood pressure over a mean of 150/95 at the two first visits

- Body mass index greater than 40 kg/m²

- Currently taking any lipid lowering medication other than statins

- Currently taking high doses of thiazide diuretics (greater than 50mg/day), or any
other blood pressure medication in the past 4 weeks

- Use of plant sterols from sources such as Benecol or Take Control margarines in the
past 4 weeks

- Use of any fish oil supplements in the week prior to screening

- Blood glucose greater than 140 mg/dL or use of diabetes medications

- Hospitalization for coronary disease in the last 6 months

- Use of nitroglycerin or other nitrates

- Unstable liver, renal, gastrointestinal or pulmonary disease or mental disease, or
medically unstable for other reasons

- Alcohol intake greater than 2 drinks/day, any illegal drug use, smoking, chronic NSAID
use or NSAID use within 5 days before the BAR study

- Pregnancy intended within one year or one year prior or currently lactating

- In reproductive age women, an irregular menstrual cycle (must have consistent
menstrual cycle between 24 to 32 days)

- Use or expectation of use of oral or patch contraceptive

- Unable or unlikely to be able to comply with study requirements