EMPOWIR:Enhance the Metabolic Profile of Women With Insulin Resistance
Condition: Hyperinsulinemia; Insulin Resistance; Obesity
MeSH terms: Insulin Resistance; Hyperinsulinism
Study type: Interventional
Phase: Phase 2

Summary: 
      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.
    

Detailed description: 
      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
    

Intervention name(s): metformin and rosiglitazone
Intervention type(s): Drug
Intervention description(s): 4 week dosage escalation of metformin, 500 mg/day (or placebo) to a total dose of 2000mg/day; starting dose of rosiglitazone 2mg/day(or placebo) added at weeks 3 and weeks 4 to a a total dose of 4 mg/day
Other intervention name(s): glucophage; avandia; avandamet
Intervention MeSH terms: Metformin; Rosiglitazone
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: hyperinsulinemia; insulin resistance; perimenopause; obesity; overweight; women