EMPOWIR:Enhance the Metabolic Profile of Women With Insulin Resistance

Study Overview
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Brief Summary
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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
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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

Official Title
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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)

Conditions
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Hyperinsulinemia, Insulin Resistance, Obesity

Intervention / Treatment
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* Drug: metformin and rosiglitazone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy, non-diabetic women with ≥20 pound weight gain since their twenties Age: 35-55 Peri-menopausal or postmenopausal status Body Mass Index (BMI) 25-35 kg/m2 Either: a single blood pressure recording ≥135/85 or the use of blood pressure medication OR HDL≤50mg/dl or triglycerides ≥150 mg/dl or the use of lipid modifying medication 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: known diabetes, fasting blood sugar ≥100 mg/dl or HbA-1-C≥6.0% known hepatic disease or ALT>40 known renal disease or creatinine ≥ 1.4 known severe pulmonary disease chronic acidosis of any etiology Congestive heart failure (NYS Category 1), treated or untreated Cancer - active within 5 years current alcoholism or other substance abuse co-morbid psychiatric disorder, which in the opinion of the screening physician would require concomitant psychotherapy as part of obesity management currently untreated thyroid abnormality (TSH≤0.2 or ≥4mIU/L) pregnancy or contemplation of pregnancy use of TZD or metformin within the past year allergy to TZD or biguanide use of FDA approved or alternate obesity agent within 6 months of the study history of pseudotumor cerebri other impairment, such as a history of medication noncompliance, which in the judgment of the screening clinician, would preclude active study participation. history of known or suspected heart disease

Ages Eligible for Study
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Minimum Age: 35 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: A: Study diet<br>EMPOWIR dietary intervention food exchange program; 40-45% carbohydrates, 35-40% protein, and 20% fat AND 4 week dosage escalation of placebo metformin, 500 mg/day to a total dose of 2000mg/day; starting dose of placebo rosiglitazone 2mg/day added at weeks 3 and weeks 4 to a total dose of 4 mg/day. | Drug: metformin and rosiglitazone<br>* 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<br>* Other names: avandamet;|
| Active Comparator: B: Study diet plus Metformin<br>Metformin and Rosiglitazone Placebo EMPOWIR dietary intervention food exchange program; 40-45% carbohydrates, 35-40% protein, and 20% fat AND 4 week dosage escalation of metformin, 500 mg/day to a total dose of 2000mg/day; starting dose of placebo rosiglitazone 2mg/day added at weeks 3 and weeks 4 to a total dose of 4 mg/day. | Drug: metformin and rosiglitazone<br>* 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<br>* Other names: avandamet;|
| Active Comparator: C: Study diet plus metformin and avandia<br>Metformin and Rosiglitazone EMPOWIR dietary intervention food exchange program; 40-45% carbohydrates, 35-40% protein, and 20% fat AND 4 week dosage escalation of metformin, 500 mg/day to a total dose of 2000mg/day; starting dose of rosiglitazone 2mg/day added at weeks 3 and weeks 4 to a total dose of 4 mg/day. | Drug: metformin and rosiglitazone<br>* 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<br>* Other names: avandamet;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Fasting Insulin | Insulin was determined with a Siemens Immulite assay with respective intra-and inter-CV's 5.7 and 5.9%, and no cross reactivity to pro-insulin. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Body Weight | Body weight measurement was performed three times and averaged by a single study coordinator. | 6 months | 
| HOMA-IR | HOMA-IR was calculated by the formula: fasting insulin (uU/mL) times fasting glucose (mg/L) divided by 22.5. | 6 months | 
| Waist Circumference |  | 6 months | 
| Systolic BP | Blood pressure was assessed using NCEP guidelines. | 6 months | 
| Diastolic BP | Blood pressure was assessed using NCEP guidelines. | 6 months | 
| HDL | HDL was measured using two reagents homogeneous systems with selective detergents to homogenize the lipoprotein of interest. | 6 months | 
| Triglycerides | Triglycerides were measured by enzymatic immunoassay on an AU400 chemistry auto-analyzer with commercially available enzymatic reagents. | 6 months | 
| Adiponectin | Total adiponectin was measured with a commercial ELISA kit (Millipore/Linco Research, St. Charles, MO) in the laboratory of Dr. Philipp Scherer. | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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hyperinsulinemia, insulin resistance, perimenopause, obesity, overweight, women