EMPOWIR: Enhance the Metabolic Profile of Women With Insulin Resistance: Carbohydrate Modified Diet Alone and in Combination With Metformin or Metformin Plus Avandia in Non-Diabetic Women With Midlife Weight Gain and Documented Insulin Elevations (Syndrome W)

Progressive weight gain that starts in the fourth and fifth decades is commonly reported by
women from all ethnic and socio-economic groups. Our previous data suggest that, in large
and diverse subpopulations of healthy-appearing women this midlife weight gain may represent
the earliest clinical manifestation of insulin resistance - demarcated by increased insulin
response curves in the presence of completely normal glucose tolerance tests. We termed the
disorder Syndrome W to highlight its defining triad of weight gain, waist gain and
white-coat hypertension in women and its role as an alphabetic and chronologic antecedent to
the better known Syndrome X. As in other disorders of insulin action in younger women,
including Polycystic Ovarian Syndrome (PCOS), early adrenarche, and precocious puberty,
Syndrome W is, presumably, a harbinger of The Metabolic Syndrome and Type 2 diabetes at an
early and optimal period for intervention.

Preliminary data from our first pilot study suggested that metformin, in combination with a
hypocaloric, low-fat, carbohydrate modified dietary program produced significant and
sustainable weight loss in women with Syndrome W, with notable reductions in fasting insulin
levels. These findings supported hypotheses that insulin elevation might be an antecedent,
as well as a consequence, of weight gain, accounting for a progressive and intractable
weight spiral as women transition from their forties to their sixties. Additional two to
four year follow-up in an intention-to-treat analysis of consecutive women who lost ≥10% of
their body weight after one year of the treatment regimen further suggests that this
composite intervention prevents weight regain and the onset of overt glucose impairment. The
protocol evolved from evaluation and treatment of several hundred patients seen in The
Endocrine Faculty Practice over a ten year period and has been highly successful in a broad
ethnic range of normo-glycemic, hyperinsulinemic subjects. These include midlife women with
weight gain and overweight men with upper body obesity - populations which have not been
comparably treated in prior studies which focus predominantly on subjects with discernible
glycemic abnormalities. The magnitude and duration of the treatment effect suggest that
more rigorous study should be undertaken with a randomized clinical trial.

PPAR agonists including thiazolidinediones (TZD's) are a newer category of insulin
sensitizers with increasingly wide and well-studied positive attributes, including
redistribution of fat depots, increased adiponectin secretion, and reduction of inflammatory
and proinflammatory markers.

The combination of metformin and rosiglitazone (Avandamet®) is FDA-approved for the
treatment of hyperglycemia in patients with Type 2 diabetes. Previous clinical research and
recent laboratory data suggest that the two categories of insulin sensitizers have
independent and additive mechanisms of action that could target and, ultimately, modulate
the underlying pathogenesis of insulin resistance.

Comparison studies suggest that TZD's may have a greater insulin sensitizing action and
provide greater reduction in hyperinsulinemia than metformin. However, due to increased
adipocyte expression (and possible other mechanisms), weight gain is a common and
undesirable side effect of TZD treatment. The addition of metformin to rosiglitazone, along
with dietary strategies that reduce endogenous insulin production could prove an ideal
therapeutic option to attenuate insulin resistance and preserve ß-cell function in high risk
individuals. Early initiation of this dual regimen in normoglycemic subjects with documented
hyperinsulinemia could have profound implications for Syndrome W women and for an additional
25% of the adult US population estimated to have other manifestations of The Metabolic
Syndrome.

The primary study question addressed is whether dual treatment regimens which modulate
insulin action can reduce hyperinsulinemia and insulin resistance in high risk, but
healthy-appearing normoglycemic, hyperinsulinemic subjects identified because of
progressive, intractable, midlife weight gain

Inclusion Criteria:

1. Healthy, non-diabetic women with "≥20 pound weight gain since their twenties"

2. Age: 35-55

3. Peri-menopausal or postmenopausal status

4. Body Mass Index (BMI) 25-35 kg/m2

5. Either:

1. a single blood pressure recording ≥135/85 or the use of blood pressure
medication OR

2. HDL≤50mg/dl or triglycerides ≥150 mg/dl or the use of lipid modifying medication

6. Area-under-the-curve (AUC-)insulin level>100mcgU/ml along with normal fasting (≤100
mg/dl) & postprandial ((≤200 mg/dl) glucose determinations following a 75-gram
standard oral glucose tolerance test.

-

Exclusion Criteria:

1. known diabetes, fasting blood sugar ≥100 mg/dl or HbA-1-C≥6.0%

2. known hepatic disease or ALT>40

3. known renal disease or creatinine ≥ 1.4

4. known severe pulmonary disease

5. chronic acidosis of any etiology

6. Congestive heart failure (NYS Category 1), treated or untreated

7. Cancer - active within 5 years

8. current alcoholism or other substance abuse

9. co-morbid psychiatric disorder, which in the opinion of the screening physician would
require concomitant psychotherapy as part of obesity management

10. currently untreated thyroid abnormality (TSH≤0.2 or ≥4mIU/L)

11. pregnancy or contemplation of pregnancy

12. use of TZD or metformin within the past year

13. allergy to TZD or biguanide

14. use of FDA approved or alternate obesity agent within 6 months of the study

15. history of pseudotumor cerebri

16. other impairment, such as a history of medication noncompliance, which in the
judgment of the screening clinician, would preclude active study participation.

17. history of known or suspected heart disease