Metabolic Syndrome X, Obesity
Conditions
Keywords
Obesity, Metabolic Syndrome X, Hypertension, Dyslipidemia, Impaired glucose tolerance
Brief summary
Obesity is common (\>30% of US adults), contributes to substantial morbidity and mortality, but is difficult to treat. Partly this is due to the transient, arduous and modest nature of lifestyle interventions. Partly it is due to the limited efficacy and safety problems of existing pharmacotherapy. Only one drug, orlistat, is approved for long-term use in obesity; but its effects on weight are relatively small. There are drugs that have been approved for other diseases but which also reduce weight. One promising approach to treating obesity is combination therapy with orlistat and one or more of these other agents. The investigators propose an innovative approach to developing new therapies for obesity coupling the use of combination therapy with rigorous assessment of cardiovascular safety. Vascular function is a quantitative surrogate clinical endpoint that has been strongly and independently linked to future cardiovascular events. Our hypothesis is that combination pharmacotherapy will reduce weight and improve vascular function in obese human subjects. The co-primary endpoints will be weight and vascular function.
Interventions
DRUGOrlistat
DRUGTopiramate
DRUGPlacebo
Placebo pills and capsules for metformin, orlistat and topiramate
DRUGMetformin
Sponsors
University of Iowa
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
40 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Age 40 to 75 years * Male or postmenopausal female * BMI ≥ 30 kg/m2 * One or more major cardiovascular (CV) risk factors (hypertension, dyslipidemia, impaired glucose tolerance OR metabolic syndrome)
Exclusion criteria
* Congestive heart failure * Renal impairment * History of bariatric surgery (i.e. lap-band, Roux-en-Y or biliopancreatic diversion) * Type I diabetes mellitus * Weight loss \> 10% in the past 6 months * Recurrent nephrolithiasis * Current treatment for seizure disorder * Hepatic cirrhosis * Current use of study medications * Current use of oral estrogen * History of smoking cessation in the past three months * Current cholestasis or malabsorption syndrome * Planned use of any herbal or over-the-counter supplements for weight loss * History of allergic reactions to metformin, topiramate, orlistat or any of ingredients * Medical conditions requiring continuous use of phosphodiesterase inhibitors and/or the inability to withhold phosphodiesterase inhibitors for 48 hours * Participation in another clinical drug study within four weeks prior to this investigation. * Participation in any other weight loss or rigorous exercise program. * Any disease or condition that in the opinion of the investigator may interfere with completion of the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Weight (Percent Change From Baseline) | Baseline and 6 months | Weight obtained in the fasting state on a gowned subject. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Office Systolic Blood Pressure (mmHg Change From Baseline) | Baseline and 6 months | Automated sphygmomanometry while sitting |
| Centimeter Change in Waist Circumference | Baseline and 6 months | Waist circumference for central adiposity |
| Carotid-femoral Pulse Wave Velocity (PWV)(Change After 6 Months From Baseline) | Baseline and 6 months | Change in carotid-femoral pulse wave velocity in meters/second (Sphygmocor). |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORGary L Pierce, PhD
University of Iowa
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Metformin Metformin only | 22 |
| Metformin + Orlistat Metformin
Orlistat | 20 |
| Metformin + Topiramate Metformin
Topiramate | 21 |
| Topiramate Topiramate only | 21 |
| Metformin + Topiramate + Orlistat Metformin
Orlistat
Topiramate | 21 |
| Placebo Placebo: Placebo pills and capsules for metformin, orlistat and topiramate | 23 |
| Total | 128 |
Baseline characteristics
| Characteristic | Metformin | Total | Placebo | Metformin + Topiramate + Orlistat | Topiramate | Metformin + Topiramate | Metformin + Orlistat |
|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 3 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 21 Participants | 125 Participants | 23 Participants | 19 Participants | 21 Participants | 21 Participants | 20 Participants |
| Age, Continuous | 55.04 years STANDARD_DEVIATION 7.14 | 55.13 years STANDARD_DEVIATION 7.75 | 55.78 years STANDARD_DEVIATION 7.89 | 56.14 years STANDARD_DEVIATION 9.05 | 54.3 years STANDARD_DEVIATION 9.05 | 54.19 years STANDARD_DEVIATION 6.06 | 55.09 years STANDARD_DEVIATION 7.46 |
| Region of Enrollment United States | 22 participants | 128 participants | 23 participants | 21 participants | 21 participants | 21 participants | 20 participants |
| Sex: Female, Male Female | 14 Participants | 83 Participants | 16 Participants | 13 Participants | 13 Participants | 14 Participants | 13 Participants |
| Sex: Female, Male Male | 8 Participants | 45 Participants | 7 Participants | 8 Participants | 8 Participants | 7 Participants | 7 Participants |
| Weight | 22 Participants | 128 Participants | 23 Participants | 21 Participants | 21 Participants | 21 Participants | 20 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| other Total, other adverse events | 0 / 22 | 0 / 20 | 0 / 21 | 0 / 21 | 0 / 21 | 0 / 23 |
| serious Total, serious adverse events | 0 / 22 | 0 / 20 | 0 / 21 | 0 / 21 | 0 / 21 | 0 / 23 |
Outcome results
Primary
Weight (% Change From Baseline)
Weight obtained in the fasting state on a gowned subject.
Time frame: 6 months
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Metformin | Weight (% Change From Baseline) | -10.9 percentage of weight change |
| Metformin + Orlistat | Weight (% Change From Baseline) | -10.5 percentage of weight change |
| Metformin + Topiramate | Weight (% Change From Baseline) | -14.0 percentage of weight change |
| Topiramate | Weight (% Change From Baseline) | -12.2 percentage of weight change |
| Metformin + Topiramate + Orlistat | Weight (% Change From Baseline) | -16.7 percentage of weight change |
| Placebo | Weight (% Change From Baseline) | -6.7 percentage of weight change |
Secondary
Carotid-femoral Pulse Wave Velocity (PWV)(Change After 6 Months From Baseline)
Change in carotid-femoral pulse wave velocity (Sphygmocor).
Time frame: 6 months
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Metformin | Carotid-femoral Pulse Wave Velocity (PWV)(Change After 6 Months From Baseline) | -1.09 meters/sec |
| Metformin + Orlistat | Carotid-femoral Pulse Wave Velocity (PWV)(Change After 6 Months From Baseline) | -1.56 meters/sec |
| Metformin + Topiramate | Carotid-femoral Pulse Wave Velocity (PWV)(Change After 6 Months From Baseline) | -1.29 meters/sec |
| Topiramate | Carotid-femoral Pulse Wave Velocity (PWV)(Change After 6 Months From Baseline) | -0.24 meters/sec |
| Metformin + Topiramate + Orlistat | Carotid-femoral Pulse Wave Velocity (PWV)(Change After 6 Months From Baseline) | -0.46 meters/sec |
| Placebo | Carotid-femoral Pulse Wave Velocity (PWV)(Change After 6 Months From Baseline) | -0.74 meters/sec |
Secondary
Office Systolic Blood Pressure (mmHg Change From Baseline)
Automated sphygmomanometry while sitting
Time frame: 6 months
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Metformin | Office Systolic Blood Pressure (mmHg Change From Baseline) | -11.42 mmHg |
| Metformin + Orlistat | Office Systolic Blood Pressure (mmHg Change From Baseline) | -11.41 mmHg |
| Metformin + Topiramate | Office Systolic Blood Pressure (mmHg Change From Baseline) | -10.33 mmHg |
| Topiramate | Office Systolic Blood Pressure (mmHg Change From Baseline) | -8.55 mmHg |
| Metformin + Topiramate + Orlistat | Office Systolic Blood Pressure (mmHg Change From Baseline) | -14.47 mmHg |
| Placebo | Office Systolic Blood Pressure (mmHg Change From Baseline) | -13.26 mmHg |
Secondary
Waist (cm Change After 6 Months From Baseline)
Body fat distribution measured using anthropometry (waist, neck and hip circumferences)
Time frame: 6 months
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Metformin | Waist (cm Change After 6 Months From Baseline) | -10.62 cm change |
| Metformin + Orlistat | Waist (cm Change After 6 Months From Baseline) | -9.04 cm change |
| Metformin + Topiramate | Waist (cm Change After 6 Months From Baseline) | -11.65 cm change |
| Topiramate | Waist (cm Change After 6 Months From Baseline) | -16.63 cm change |
| Metformin + Topiramate + Orlistat | Waist (cm Change After 6 Months From Baseline) | -15.76 cm change |
| Placebo | Waist (cm Change After 6 Months From Baseline) | -10.78 cm change |