Diabetes, Endocrine Disease
Conditions
Keywords
Metabolism, Cortisol, Hypercortisolism, Glucose Intolerance
Brief summary
Background: * Metabolic syndrome is a name given to a group of factors that tend to occur together. These risk factors include central obesity (extra weight around the middle of the body) and high blood pressure and blood sugar levels. They also include low levels of HDL (good cholesterol) and high triglyceride levels. A person is said to have metabolic syndrome if they have three or more of the above risk factors. People with metabolic syndrome are at increased risk for type 2 diabetes, stroke, and heart disease. * Cortisol, a hormone produced by the adrenal glands, is an important regulator of metabolism. People with central obesity and metabolic syndrome may have higher than normal cortisol levels that the body cannot regulate properly. Abnormal cortisol levels may play an important role in metabolic syndrome. Mifepristone is a drug that blocks cortisol. Researchers are interested in studying its effects on metabolic syndrome. Objectives: \- To study the effects of short-term mifepristone treatment for metabolic syndrome. Eligibility: \- Men and Women between 35 and 70 years of age are overweight or obese, and have abnormal glucose and triglyceride levels. Design: * Participants will be screened with a physical exam and medical history. They will also have blood and urine tests. * Participants will be admitted to the metabolic unit at the National Institutes of Health Clinical Center for the first 3 days of the study: * Day 1: Body measurements (height, weight, waist, hip, and neck) and blood pressure tests. Also, 24 hours of regular blood draws and 24-hour urine collection to monitor regular daily cortisol levels. * Day 2: Glucose/insulin infusion test to measure blood sugar levels. * Day 3: Infusion of cortisol-like compounds and then regular blood draws for about 3 hours to evaluate how cortisol is metabolized. * At the end of Day 3, participants will receive mifepristone or a look-alike capsule to take for 7 days at home. * After 7 days, participants will return to the metabolic unit to repeat the Day 1 and Day 2 study procedures. They will continue to take mifepristone. * One week after the second set of study tests, participants will return for a brief physical exam and blood tests. * The study procedures will be repeated after 6 to 8 weeks, with the other study drug.
Detailed description
The hormone cortisol is a key regulator of metabolism that influences the use of glucose (sugar) and fat as fuels. Persistently increased cortisol levels, as in Cushing s syndrome, lead to obesity, type 2 diabetes mellitus and lipid abnormalities including elevated triglyceride levels and low high-density lipoprotein (HDL) levels. These same disorders are also present in patients without Cushing s syndrome, suggesting that cortisol may be involved in their pathogenesis. Mifepristone is a cortisol-like drug that blocks cortisol action in the body. It can reverse lipid abnormalities, diabetes and obesity in Cushing s syndrome patients but its effects on these conditions have not been tested in patients without the syndrome. The long-term aim of this clinical trial is to evaluate the ability of mifepristone to reverse or improve glucose intolerance, dyslipidemia, hypertension and weight gain. An initial 7-day prospective, randomized, placebo-controlled, crossover study is proposed here to look at the effect of short-term administration of oral mifepristone or placebo on glucose intolerance. Given that there are no human data available on the effect of mifepristone on insulin sensitivity, this will be a pilot study of 15 subjects. Data from this study will then be used to design a larger trial to evaluate long-term effects on blood pressure and weight, as well as glucose and triglyceride control. Overweight or obese subjects with abnormal glucose tolerance will undergo each of the two treatments in a randomized order, including mifepristone by mouth and a look-alike inert tablet by mouth. Each treatment study will include two or three days of baseline tests that will be repeated after seven days of treatment. Treatments will be separated by at least six and no more than eight weeks. The tests will include blood drawing, urine collection, administration of glucose and insulin by vein, and a cortisol-like material to evaluate the metabolism of cortisol and a related hormone, corticosterone.
Interventions
DRUGMifepristone
Mifepristone 50mg tablet by mouth every six hours for nine days.
DRUGPlacebo
Placebo (matching mifepristone 50mg tablet) by mouth every six hours for nine days.
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
35 Years to 70 Years
Healthy volunteers
Yes
Inclusion criteria
* INCLUSION CRITERIA: 1. Men and women 35 - 70 years of age 2. Subjects will be overweight or obese, with body mass index (BMI) ranging from 25 - 37 kg/m2. 3. Subjects will have either impaired fasting glucose (greater than or equal to 100 mg/dL) or a 2-hour glucose value greater than or equal to 140 mg/dl during an oral glucose tolerance test (OGTT). OR Mild diabetes defined as patients with a Hemoglobin A1C (HbA1C) less than or equal to 7% on no medications (diet-controlled) or on a stable dose of metformin and no other hypoglycemic agents for greater than or equal to 3 months before study entry. 4. Willing and able to comply with study requirements.
Exclusion criteria
1. Pregnancy and lactation 2. Diabetes requiring pharmacologic treatment. Diagnosis of diabetes will be based on the 2011 American Diabetes Association guidelines: HbA1C greater than or equal to 6.5%, fasting plasma glucose greater than or equal to 126 mg/dl, 2-hour glucose greater than or equal to 200 mg/dl during an OGTT, or a random blood glucose greater than or equal to 200 mg/dl along with classic symptoms of hyperglycemia (34) 3. Uncontrolled hypertension (blood pressure greater than or equal to 180/110 mmHg) 4. Current unstable medical conditions including clinically significant impaired cardiac function (Stage III and IV Cardiac failure), cardiac ischemia, severe respiratory insufficiency requiring oxygen therapy as assessed on history and/or physical exam 5. Liver function tests (alanine aminotransferase (ALT), aspartate aminotransferase (AST) more than 3-times the upper normal limit 6. Severe renal impairment (creatinine clearance \< 30 ml/min) 7. Evidence of human immunodeficiency virus (HIV) based on history and physical examination and/or known positive HIV antibodies 8. Evidence of hepatitis C based on history and physical examination and/or known positive hepatitis C (HCV) antibody 9. History of hemorrhagic disorders or on anticoagulants 10. History of endometrial cancer, endometrial hyperplasia, unexplained vaginal bleeding, or endometrial thickness greater than 6 mm 11. Change in dose of lipid-lowering medications (including 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMG Co-A) inhibitors , fibrates, niacin, ezetimibe, and over-the-counter fish oil supplements) within one month of study entry and during the study period 12. Current administration of medications known to be strong CYP3A4 inhibitors including ketoconazole, itraconazole, and erythromycin 13. Use of herbal supplements or grapefruit juice within 14 days of study drug initiation 14. Use of medications or dietary supplements that inhibit or induce CYP3A4 activity within 14 days of study drug initiation 15. Use of oral, injectable, or inhaled glucocorticoids or megestrol in the past six months 16. Use of estrogen-containing hormone therapy 17. Potential pseudocushing's states: depression or intake of \> 2 alcoholic drinks a day. Subjects will be screened for depression using the well-validated physician health questionnaire-9 (PHQ-9) with a score cut-off of greater than or equal to 10 for moderate depression (35). 18. Subjects who are actively dieting or are in a weight loss program 19. Midnight salivary cortisol \> 100 ng/dl on two separate occasions 20. Untreated thyroid dysfunction (thyroid stimulating hormone and Free thyroxine (FT4) not within normal range). If abnormal on screening labs, they will be repeated to confirm that not due to lab error or non-thyroidal illness. 21. Moderate to severe anemia (hemoglobin \< 10 g/dl) 22. Blood donation of more than 500 ml within one month prior to study enrollment 23. Subjects with a prolonged corrected Q-T interval (QTc) on electrocardiogram 24. Unable to give informed consent
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Insulin Sensitivity Index | Nine days | insulin sensitivity index based on the effect of insulin on glucose during frequently sampled intravenous glucose tolerance test (FSIVGTT) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Fasting Plasma Glucose | Nine days | fasting plasma glucose after study agent compared to baseline |
| Change in Fasting Insulin Levels | 9 days | Fasting insulin after study agent administration compared to baseline |
| Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) | 9 days | HOMA-IR is an index of insulin resistance, measured as glucose in mmol/L x insulin in mIU/mL)/22.5. HOMA-IR \> 2.5 indicates insulin resistance. |
| Adipose-tissue Insulin Resistance Index (Adipo-IR) | 9 days | The adipose tissue insulin resistance index (Adipo-IR), a surrogate measure for fasting adipose-tissue insulin resistance, was calculated as the product of fasting insulin and fasting free fatty acids (FFA) |
| Adipose-tissue Insulin Sensitivity Index (Adipo-SI) | 9 days | The Adipo-SI was calculated as ratio of the slope of the linear decrease in natural log transformed FFA \[Ln (FFA) slope\] during the first 90 minutes of the FSIVGTT and the area under the curve (AUC) of insulin during that 90-minute period (AUC Insulin 0-90 min). |
Countries
United States
Participant flow
Recruitment details
Subjects were recruited to the study by advertisements and fliers. Sixty-three adults were evaluated at the single study site (the NIH Clinical Center) after providing informed consent. The first subject consented on November 11, 2011 and the final subject consented on April 16, 2015.
Pre-assignment details
Forty-four subjects were excluded; 31 had a normal oral glucose tolerance test and fasting glucose level, 2 exceeded BMI criterion, 2 exceeded HbA1C criterion, 2 had depression, and seven subjects had one of the following exclusion criteria: required insulin, \<35 years old, memory problems/compliance, abnormal thyroid function, drop out after screening, abnormal late night salivary cortisol, failure to complete screening. The remaining 19 subjects were randomized.
Participants by arm
| Arm | Count |
|---|---|
| Mifepristone, Then Placebo Participants first received Mifepristone 50mg tablet every six hours for nine days. After a washout period of no fewer than 6 but no more than 8 weeks, they then received Placebo tablet (matching mifepristone 50 mg) every six hours for nine days.
Mifepristone: Mifepristone 50mg tablet by mouth every six hours for nine days.
Placebo: Placebo (matching mifepristone 50mg tablet) by mouth every six hours for nine days. | 8 |
| Placebo, Then Mifepristone Participants first received Placebo tablet (matching mifepristone 50 mg) every six hours for nine days. After a washout period of no fewer than 6 but no more than 8 weeks, they then received Mifepristone 50 mg tablet every six hours for nine days.
Mifepristone: Mifepristone 50mg tablet by mouth every six hours for nine days.
Placebo: Placebo (matching mifepristone 50mg tablet) by mouth every six hours for nine days. | 8 |
| Total | 16 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | could not maintain iv line | 1 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Placebo, Then Mifepristone | Mifepristone, Then Placebo | Total |
|---|---|---|---|
| A1C | 6.3 percent STANDARD_DEVIATION 0.49 | 5.9 percent STANDARD_DEVIATION 0.35 | 6.1 percent STANDARD_DEVIATION 0.45 |
| Age, Continuous | 52.8 years STANDARD_DEVIATION 8.9 | 56.6 years STANDARD_DEVIATION 6.5 | 54.7 years STANDARD_DEVIATION 7.8 |
| Body mass index | 34.0 kg/M^2 STANDARD_DEVIATION 2.37 | 30.8 kg/M^2 STANDARD_DEVIATION 4.12 | 32.4 kg/M^2 STANDARD_DEVIATION 4.12 |
| diastolic blood pressure | 76.9 mmHg STANDARD_DEVIATION 9.9 | 77.6 mmHg STANDARD_DEVIATION 4.7 | 77.3 mmHg STANDARD_DEVIATION 7.5 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 8 Participants | 7 Participants | 15 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| fasting glucose | 108.1 mg/dL STANDARD_DEVIATION 20.6 | 101.0 mg/dL STANDARD_DEVIATION 5.8 | 104.6 mg/dL STANDARD_DEVIATION 15 |
| fasting insulin | 143.1 pmol/L STANDARD_DEVIATION 43.3 | 75.7 pmol/L STANDARD_DEVIATION 35.4 | 109 pmol/L STANDARD_DEVIATION 51.8 |
| free fatty acids | 0.54 mg/dL STANDARD_DEVIATION 0.23 | 0.62 mg/dL STANDARD_DEVIATION 0.18 | 0.60 mg/dL STANDARD_DEVIATION 0.19 |
| HDL cholesterol | 40.0 mg/dL STANDARD_DEVIATION 8.6 | 51.1 mg/dL STANDARD_DEVIATION 7.5 | 45.6 mg/dL STANDARD_DEVIATION 9.7 |
| LDL cholesterol | 108.3 mg/dL STANDARD_DEVIATION 41 | 104.9 mg/dL STANDARD_DEVIATION 41.3 | 106.6 mg/dL STANDARD_DEVIATION 40.1 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 3 Participants | 7 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 3 Participants | 4 Participants | 7 Participants |
| Region of Enrollment United States | 8 participants | 8 participants | 16 participants |
| Sex: Female, Male Female | 3 Participants | 4 Participants | 7 Participants |
| Sex: Female, Male Male | 5 Participants | 4 Participants | 9 Participants |
| systolic blood pressure | 133 mmHg STANDARD_DEVIATION 10.5 | 124 mmHg STANDARD_DEVIATION 16.1 | 128 mmHg STANDARD_DEVIATION 13.9 |
| total cholesterol | 184.3 mg/dL STANDARD_DEVIATION 53.8 | 177.9 mg/dL STANDARD_DEVIATION 59 | 181.1 mg/dL STANDARD_DEVIATION 54.6 |
| triglycerides | 180.0 mg/dL STANDARD_DEVIATION 92.3 | 108.8 mg/dL STANDARD_DEVIATION 88.3 | 144.4 mg/dL STANDARD_DEVIATION 94.7 |
| Urine free cortisol | 18.1 ug/dl STANDARD_DEVIATION 7.2 | 27.8 ug/dl STANDARD_DEVIATION 23 | 22.9 ug/dl STANDARD_DEVIATION 17.2 |
| Weight | 102 kg STANDARD_DEVIATION 15.9 | 92.8 kg STANDARD_DEVIATION 15.8 | 97.2 kg STANDARD_DEVIATION 16 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 16 | 0 / 16 |
| other Total, other adverse events | 0 / 16 | 2 / 16 |
| serious Total, serious adverse events | 0 / 16 | 0 / 16 |
Outcome results
Primary
Change in Insulin Sensitivity Index
insulin sensitivity index based on the effect of insulin on glucose during frequently sampled intravenous glucose tolerance test (FSIVGTT)
Time frame: Nine days
Population: 2 subjects in each group missing data due to iv line problems
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Post-mifepristone | Change in Insulin Sensitivity Index | 1.49 min-1·μU·ml-1 | Standard Deviation 1.17 |
| Post-placebo | Change in Insulin Sensitivity Index | 1.41 min-1·μU·ml-1 | Standard Deviation 0.87 |
p-value: 0.6ANOVA
Secondary
Adipose-tissue Insulin Resistance Index (Adipo-IR)
The adipose tissue insulin resistance index (Adipo-IR), a surrogate measure for fasting adipose-tissue insulin resistance, was calculated as the product of fasting insulin and fasting free fatty acids (FFA)
Time frame: 9 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Post-mifepristone | Adipose-tissue Insulin Resistance Index (Adipo-IR) | 49.9 mmol/l·μU/l | Standard Deviation 45.9 |
| Post-placebo | Adipose-tissue Insulin Resistance Index (Adipo-IR) | 65.5 mmol/l·μU/l | Standard Deviation 43.8 |
p-value: 0.004ANOVA
Secondary
Adipose-tissue Insulin Sensitivity Index (Adipo-SI)
The Adipo-SI was calculated as ratio of the slope of the linear decrease in natural log transformed FFA \[Ln (FFA) slope\] during the first 90 minutes of the FSIVGTT and the area under the curve (AUC) of insulin during that 90-minute period (AUC Insulin 0-90 min).
Time frame: 9 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Post-mifepristone | Adipose-tissue Insulin Sensitivity Index (Adipo-SI) | 61.7 ln(mmol /uU/mL*min)*10^8 | Standard Deviation 32.9 |
| Post-placebo | Adipose-tissue Insulin Sensitivity Index (Adipo-SI) | 42.8 ln(mmol /uU/mL*min)*10^8 | Standard Deviation 23.9 |
p-value: 0.002ANOVA
Secondary
Change in Fasting Insulin Levels
Fasting insulin after study agent administration compared to baseline
Time frame: 9 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Post-mifepristone | Change in Fasting Insulin Levels | 95.6 pmol/L | Standard Deviation 76.1 |
| Post-placebo | Change in Fasting Insulin Levels | 142.8 pmol/L | Standard Deviation 102.2 |
p-value: <0.001ANOVA
Secondary
Change in Fasting Plasma Glucose
fasting plasma glucose after study agent compared to baseline
Time frame: Nine days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Post-mifepristone | Change in Fasting Plasma Glucose | 100.4 mg/dL | Standard Error 5.3 |
| Post-placebo | Change in Fasting Plasma Glucose | 107.8 mg/dL | Standard Error 15.7 |
p-value: <0.001ANOVA
Secondary
Homeostatic Model Assessment of Insulin Resistance (HOMA-IR)
HOMA-IR is an index of insulin resistance, measured as glucose in mmol/L x insulin in mIU/mL)/22.5. HOMA-IR \> 2.5 indicates insulin resistance.
Time frame: 9 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Post-mifepristone | Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) | 3.58 units on a scale | Standard Deviation 3.27 |
| Post-placebo | Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) | 5.78 units on a scale | Standard Deviation 4.92 |
p-value: <0.001ANOVA