Obesity Clinical Trial
Official title:
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)
The goal of the study is to identify and treat women with midlife weight gain who have
normal blood sugars, but increased insulin levels (hyperinsulinemia) following the
performance of a glucose tolerance test. The study will evaluate effects of a unique
carbohydrate modified diet alone and in combination with metformin(MF) and Avandamet® (MF
plus rosiglitazone (RSG)) on insulin levels in a wide range of ethnically diverse women
(aged 35-55) at three academic medical centers. The primary study hypothesis is that insulin
sensitizing medications, in combination with alterations in carbohydrate intake, will reduce
insulin levels and improve established risk factors for the metabolic syndrome.
The alarming prevalence of obesity, diabetes, and related comorbidities and the paucity of
easily adopted, cost-effective preventive strategies for high risk populations, suggest that
pharmaco-therapies and dietary regimens targeted to reducing insulin resistance could have
important clinical and public health implications.
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
;
Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment
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