The BANGALORE Study; Combination of Berberine, Lipoic Acid, and Picrorhiza

Though medical treatment has been effective in the treatment of cardiometabolic diseases
(including coronary atherosclerosis and diabetes mellitus), the incidence of these disorders
continues to be high. Many reasons are responsible, but lifestyle changes, including an
increased prevalence of obesity and the metabolic syndrome, are significant for this cause.
Recent reported guidelines by the JNC-VII and National Cholesterol Education Panel/ATP-III
suggest that blood pressure reduction is effective in improving the overall quality of life
and may be helpful in the prevention of cardiovascular disease.

Diagnosis and treatment of obese patients with hypertension requires that health care
providers address the issues of hypertension, glucose intolerance, body weight and
dyslipidemia. Strategies to promote therapeutic lifestyle change (TLC), specifically
increased physical activity and reduced dietary intake resulting in weight loss, are not as
well defined. A sedentary lifestyle and poor cardiorespiratory fitness are not only
associated with the (cardio) metabolic syndrome but could actually be considered features of
the metabolic syndrome. These issues are significant in the health of certain individuals,
who experience greater difficulty in treated BP control, experience increased hypertensive
and diabetic complications, and have higher levels of obesity.

In this study, the investigators will evaluate the efficacy of the nutritional supplements
berberine, alpha-lipoic acid, and picrorhiza (BLR) when consumed 30 minutes before meals, on
appetite suppression, body composition and weight control. Additionally, the investigators
will evaluate the effects of this combination of nutraceuticals on the mechanistic effects
of oxidation, inflammation, and vascular function in a high-risk population with the
metabolic syndrome.

The investigators will evaluate the initiation of BLR in patients which meet at least 3 of
the 5 criteria (ATP-III guidelines) for the cardiometabolic syndrome. The investigators
will determine whether the BLR combination as compared to placebo provides benefit in
appetite suppression, body composition and certain clinical endpoints, including effects on
endothelial function, lipid levels, and glucose control. This study will analyze the
effects of 12 week administration of BLR versus placebo on these parameters in a population
of patients (n=40) with the cardiometabolic syndrome. The study has a parallel design
consisting of 2 weeks of washout and then 12 weeks of treatment to either BLR or placebo.
The total study period is 14 weeks. Patients will be assigned to the BLR or placebo group
in a 3:1 ratio so that 30 patients will receive BLR and 10 patients will receive placebo.
See attached study design.

Primary Objective To assess the comparative effect of a combination (known as BLR) of
berberine (200 mg), alpha-lipoic acid (150 mg), and picrorhiza (100 mg) three times a day,
compared to placebo three times a day, on parameters relate to appetite suppression, weight
control and body composition in a high risk population with the metabolic syndrome.

Secondary Co-objectives

To evaluate the effects of BLR versus placebo on changes in:

- Endothelial function using noninvasive brachial artery reactivity (BAR) ultrasound

- Biomarkers including IL-6, HOMA-IR, HbA1C, hsCRP, adiponectin, plasma/urine
isoprostanes, PAI-1, TNFα-II, aldosterone, and glutathione redox ratio

- Urinary protein excretion

- Clinical chemistry including plasma glucose, blood urea nitrogen, creatinine, total
bilirubin, uric acid, transaminases (SGOT/AST, SGPT/ALT), alkaline phosphatase,
C-reactive protein, and lipoproteins

Inclusion Criteria:

- Male and female subjects ≥ 18 years and ≤ 80 years with (cardio)metabolic syndrome as
identified by investigators, OR

- Male and female subjects ≥ 18 years and ≤ 80 years with (cardio)metabolic syndrome
defined by ATP-III criteria:

Insulin resistance, identified by 1 of the following

- Type 2 diabetes with HgA1C < 8.0% or on medical therapy

- Impaired fasting glucose

- Impaired glucose tolerance

- Or for those with normal fasting glucose levels (<100 mg/dl), glucose uptake below
the lowest quartile for background population under investigation under
hyperinsulinemic, euglycemic conditions

Plus any 2 of the following:

- Plasma triglycerides ≥ 150 mg/dl (≥ 1.7 mmol/L)

- HDL cholesterol <35 mg/dl (<0.9 mmol/L) in men or <39 mg/dl) (1.0 mmol/L) in women

- BMI >30 kg/m2 and/or waist:hip ratio > 0.9 in men, >0.85 in women

- Urinary albumin excretion rate ≥ 20 µg/min or albumin:creatinine ratio ≥ 30 mg/g

Exclusion Criteria:

- • Females of childbearing potential who are pregnant, lactating or who do not employ
adequate birth control procedures.

- Presence of any serious disorder including, renal, pulmonary, hepatic,
gastrointestinal, endocrine/metabolic (with the exception of non-insulin
dependent type 2 diabetes), hematologic/oncologic, neurologic and psychiatric
diseases are exclusionary.

- History of heart failure.

- Stroke or heart attack within past 6 months.

- Use of insulin.

- Non-dominant upper arm circumference greater than 50 cm. (19.5 inches)

- Currently using any prescription or over-the-counter weight loss products

- Previous bariatric surgery or other weight reduction procedures

- Weight loss or gain of greater than 15 pounds in the last 3 months

- Past or current diagnosis of an eating disorder