Insulin Resistance, Postmenopause
Conditions
Brief summary
The purpose of this research study is to determine if a relationship between insulin resistance (IR) and testosterone (T) exists in women who have already gone through menopause.
Detailed description
This study tests the central hypothesis that insulin resistance (IR) increases androgen (male sex hormone) production in postmenopausal women. Participation will include five visits, each lasting on average 2.5 hours, over a period of 13-20 weeks. At the screening visit, the participant's medical history, current use of medications and dietary supplements, and social habits will be recorded. This information will be reviewed on each subsequent visit; participants are asked to maintain their current diet and physical activity level throughout the study. A brief physical exam will be performed, and blood will be drawn. At the 2nd (baseline) visit, patients will undergo a euglycemic-hyperinsulinemic clamp (a procedure to measure insulin sensitivity by continuous intravenous infusion of insulin, and variable infusion of glucose). Blood samples will be drawn throughout the procedure. At completion, the insulin infusion will be stopped, participants will be fed, and the glucose infusion continued for at least 15 minutes to ensure stability of the blood glucose concentration. After the procedure, participants will be randomized to receive either metformin plus leuprolide placebo, leuprolide plus metformin placebo, or metformin placebo plus leuprolide placebo. The leuprolide or leuprolide placebo will be administered as an injection by a nurse. The metformin or metformin placebo will be dispensed to the participant in the form of pills, with instructions for titrating the dose. Participants will be contacted by telephone once weekly during the titration period to assess drug tolerability and adverse events (AEs). Participants will be maintained at their maximum tolerated dose for the duration of the study intervention period. Participants will return every 4 weeks for follow-up. Blood will be drawn, the nurse will administer the leuprolide or leuprolide placebo injection, and metformin or metformin placebo will be dispensed. At the final visit (week 12), participants will undergo a brief physical exam, and will then undergo a final euglycemic-hyperinsulinemic clamp.
Interventions
DRUGmetformin
Initiated on 500 mg daily and titrated up to 1000 mg twice a day during the first four weeks, remaining at that dose until 12 weeks
DRUGleuprolide injection
3.75 mg injection every 4 weeks (e.g. at baseline, 4, and 8 weeks)
DRUGplacebo pill
matching pill twice a day for 12 weeks
DRUGplacebo injection
matching injection every 4 weeks (e.g. baseline, 4, and 8 weeks)
Sponsors
National Institute on Aging (NIA)
The John A. Hartford Foundation
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
University of Pennsylvania Diabetes and Endocrinology Research Center (DERC)
TAP Pharmaceutical Products Inc.
University of Pennsylvania
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
50 Years to 79 Years
Healthy volunteers
Yes
Inclusion criteria
* Postmenopausal women aged 50-79 years with absence of menses for 12 months; for women 50-54 years, Follicle stimulating hormone\>30 U/mL to confirm postmenopausal status * At least one intact ovary * Free testosterone and fasting insulin levels within required study parameters * Willing to comply with all study-related procedures * Capable of giving informed consent
Exclusion criteria
* History of cancer requiring treatment within the past 5 years (exceptions may be made by investigator) * Hospitalization for treatment of vascular disease in the past 6 months * Uncontrolled hypertension * Hospitalization for chronic obstructive pulmonary disease or asthma in the past 3 months * Use of continuous oxygen at home * Surgery in the last 30 days * Positive for HIV * Abnormal blood tests (hemoglobin, fasting triglycerides, fasting glucose, creatinine, liver function) * History of diabetes mellitus or use of any anti-hyperglycemic medication in the past 3 months * Disease associated with disordered glucose metabolism (Cushing's disease, acromegaly, pheochromocytoma not surgically cured, chronic pancreatitis) * History of chronic renal insufficiency * Intravenous (IV) contrast studies with iodinated materials planned for the 12 week intervention period that cannot be postponed according to the participant's primary care provider * Acute or chronic metabolic acidosis * History of liver disease * Congestive heart failure * History of androgen-secreting tumors * Hormone replacement therapy or antiandrogen use in past 6 months * Use of dehydroepiandosterone (DHEA) or other androgen-containing products in past 6 months * Corticosteroid use, other than topical, ophthalmic, intraarticular, and inhaled preparations, in past 3 months * Undiagnosed current vaginal bleeding * Excessive alcohol intake, either acute or chronic; current illicit substance abuse * Participation in an investigational drug study within 6 weeks prior to screening visit * Serious or unstable medical or psychological conditions that, in the opinion of the investigator, would compromise the patient's safety or successful participation in the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change in Free Testosterone (T) | Baseline to 12 weeks | Percent change in free T by equilibrium dialysis between baseline and 12 weeks |
| Change in Insulin Sensitivity | baseline and 12 weeks | Change in insulin sensitivity (mg/kg/min) calculated from hyperinsulinemic euglycemic clamp |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change in Low Density Lipoprotein (LDL) | baseline and 12 weeks | — |
| Percent Change in Systolic Blood Pressure | baseline and 12 weeks | — |
| Percent Change in Luteinizing Hormone (LH) From Baseline | baseline and 12 weeks | — |
| Dehydroepiandrosterone Sulfate (DHEA-S) | baseline and 12 weeks | — |
| Body Mass Index (BMI) | baseline and 12 weeks | — |
| Free T and IR in Women in Whom Metabolic Syndrome is Present vs. Absent | baseline and 12 weeks | — |
| Percent Change in Homeostasis Model Assessment Index of Insulin Resistance (HOMA-IR) | baseline and 12 weeks | Insulin resistance calculated from homeostasis model assessment of insulin resistance (HOMA-IR) equation: fasting insulin x fasting glucose / 405. Higher values indicate more insulin resistance. |
Countries
United States
Participant flow
Recruitment details
The participants were recruited beginning 8/11/05 and continued until the last patient was consented on 4/8/08.
Participants by arm
| Arm | Count |
|---|---|
| Metformin metformin plus leuprolide placebo (LP) injection | 12 |
| Leuprolide leuprolide plus metformin placebo (MP) pill | 12 |
| Placebo MP placebo pill plus LP placebo injection | 11 |
| Total | 35 |
Baseline characteristics
| Characteristic | Metformin | Leuprolide | Placebo | Total |
|---|---|---|---|---|
| Age, Continuous | 56 years STANDARD_DEVIATION 4 | 58 years STANDARD_DEVIATION 7 | 62 years STANDARD_DEVIATION 7 | 58 years STANDARD_DEVIATION 7 |
| Sex/Gender, Customized Female | 12 participants | 12 participants | 11 participants | 35 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 12 | 0 / 12 | 0 / 11 |
| other Total, other adverse events | 0 / 12 | 0 / 12 | 0 / 11 |
| serious Total, serious adverse events | 0 / 12 | 0 / 12 | 0 / 11 |
Outcome results
Primary
Change in Insulin Sensitivity
Change in insulin sensitivity (mg/kg/min) calculated from hyperinsulinemic euglycemic clamp
Time frame: baseline and 12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Metformin | Change in Insulin Sensitivity | 0.44 mg/kg/min | Standard Deviation 0.8 |
| Leuprolide | Change in Insulin Sensitivity | 0.04 mg/kg/min | Standard Deviation 0.81 |
| Placebo | Change in Insulin Sensitivity | -0.08 mg/kg/min | Standard Deviation 0.73 |
Primary
Percent Change in Free Testosterone (T)
Percent change in free T by equilibrium dialysis between baseline and 12 weeks
Time frame: Baseline to 12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Metformin | Percent Change in Free Testosterone (T) | -6.9 percent change | Standard Deviation 22.8 |
| Leuprolide | Percent Change in Free Testosterone (T) | -35.8 percent change | Standard Deviation 31.8 |
| Placebo | Percent Change in Free Testosterone (T) | 12.1 percent change | Standard Deviation 17.8 |
Secondary
Body Mass Index (BMI)
Time frame: baseline and 12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Metformin | Body Mass Index (BMI) | -1.3 percent change | Standard Deviation 3.2 |
| Leuprolide | Body Mass Index (BMI) | 0.1 percent change | Standard Deviation 1.5 |
| Placebo | Body Mass Index (BMI) | 0.3 percent change | Standard Deviation 1.1 |
Secondary
Dehydroepiandrosterone Sulfate (DHEA-S)
Time frame: baseline and 12 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Metformin | Dehydroepiandrosterone Sulfate (DHEA-S) | 2.6 percent change |
| Leuprolide | Dehydroepiandrosterone Sulfate (DHEA-S) | 0.9 percent change |
| Placebo | Dehydroepiandrosterone Sulfate (DHEA-S) | -2.9 percent change |
Secondary
Free T and IR in Women in Whom Metabolic Syndrome is Present vs. Absent
Time frame: baseline and 12 weeks
Population: Data were not collected and the outcome will never be analyzed.
Secondary
Percent Change in Homeostasis Model Assessment Index of Insulin Resistance (HOMA-IR)
Insulin resistance calculated from homeostasis model assessment of insulin resistance (HOMA-IR) equation: fasting insulin x fasting glucose / 405. Higher values indicate more insulin resistance.
Time frame: baseline and 12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Metformin | Percent Change in Homeostasis Model Assessment Index of Insulin Resistance (HOMA-IR) | -31.0 percent change | Standard Deviation 24.39 |
| Leuprolide | Percent Change in Homeostasis Model Assessment Index of Insulin Resistance (HOMA-IR) | -8.18 percent change | Standard Deviation 35.3 |
| Placebo | Percent Change in Homeostasis Model Assessment Index of Insulin Resistance (HOMA-IR) | 4.67 percent change | Standard Deviation 38.16 |
Secondary
Percent Change in Low Density Lipoprotein (LDL)
Time frame: baseline and 12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Metformin | Percent Change in Low Density Lipoprotein (LDL) | -10.8 percent change | Standard Deviation 22.2 |
| Leuprolide | Percent Change in Low Density Lipoprotein (LDL) | 5.3 percent change | Standard Deviation 19.3 |
| Placebo | Percent Change in Low Density Lipoprotein (LDL) | 25.3 percent change | Standard Deviation 50.8 |
Secondary
Percent Change in Luteinizing Hormone (LH) From Baseline
Time frame: baseline and 12 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Metformin | Percent Change in Luteinizing Hormone (LH) From Baseline | 4.6 percent change |
| Leuprolide | Percent Change in Luteinizing Hormone (LH) From Baseline | -96.5 percent change |
| Placebo | Percent Change in Luteinizing Hormone (LH) From Baseline | -1.2 percent change |
Secondary
Percent Change in Systolic Blood Pressure
Time frame: baseline and 12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Metformin | Percent Change in Systolic Blood Pressure | -4.2 percent change | Standard Deviation 8.6 |
| Leuprolide | Percent Change in Systolic Blood Pressure | 4.0 percent change | Standard Deviation 13.6 |
| Placebo | Percent Change in Systolic Blood Pressure | -0.3 percent change | Standard Deviation 8.6 |