Obesity
Conditions
Keywords
Pulmonary Hypertension, BMI, Echocardiography, CPET, 6-minute walk test, Cardio Metabolic disease
Brief summary
This study will investigate if metformin can help people with obesity and high pressures inside their lung blood vessels. Metformin is approved by the U.S. Food and Drug Administration (FDA) to treat diabetes, but metformin is not approved by the FDA to treat pulmonary hypertension. This study will examine whether Metformin will improve the high pressure inside lung blood vessels in people who are obese. The study will help understand the effect of metformin on pressures inside lung blood vessels.
Detailed description
Obesity can predispose people to develop high pressures inside their lung blood vessels, a condition called pulmonary hypertension, Pulmonary hypertension in turn, can lead to shortness of breath and other health complications such as heart failure. In this study, we seek to identify individuals at risk for the development of high pressures inside lung vessels based on BMI and dyspnea grade 1. Participants will be screened by echocardiography to estimate pulmonary pressures. Potential participants will undergo invasive cardiopulmonary exercise testing with hemodynamic monitoring, in order to identify individuals with abnormal pulmonary vascular function either at rest or during exercise. Patients who have undergone clinically-indicated cardiopulmonary exercise testing and meet inclusion/exclusion criteria will also be recruited. Those with abnormal pulmonary vascular function will be randomized to receive Metformin or placebo for a total of 3 months under an IND exemption. The primary outcomes include the effect on pulmonary vascular function at rest and during exercise. Secondary outcomes include change in pulmonary artery endothelial cell phenotypes.
Interventions
DRUGMetformin
One capsule by mouth twice a day, followed by an increase to two capsules by mouth twice a day for a total of 3 months
DRUGPlacebo
One capsule by mouth twice a day, followed by an increase to two capsules by mouth twice a day for a total of 3 months
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Massachusetts General Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
30 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Age 30-80 years * History of obesity and current BMI ≥ 25 kg/ m2 for study volunteers or BMI ≥ 25 kg/ m2 for those with clinically indicated CPET or known HFpEF * History of Dyspnea (Grade 1 or more) * Able to provide informed consent and willing to comply with study
Exclusion criteria
* History of diabetes mellitus * History of primary pulmonary arterial hypertension * History of moderate to severe COPD * History of severe Obstructive Sleep apnea * History of renal disease (eGFR\< 45 mL/min/1.732) * History of severe liver disease * History of cardiovascular disease (recent heart attack or stroke) except known HFpEF * History of blood clot in lung * History of Splenectomy * History of Active Cancer * Platelets count of \< 75,000 * International normalized ration (INR) of \> 1.5 * History of recent anemia (HB \< 9g/dL) * Current use of Metformin * Prior LVEF \< 50% on echocardiogram * Indication of severe valvular disease on echo * Pregnant or planning to become pregnant in next 4 months * History of HIV infection
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pulmonary Vascular Hemodynamics (Rest) | Baseline and 3 months | The metformin and placebo groups will be compared with respect to resting mean pulmonary artery pressure (mmHg) |
| Pulmonary Vascular Hemodynamics (Exercise) | Baseline and 3 months | The metformin and placebo groups will be compared with respect to augmentation of mean pulmonary artery pressure divided by augmentation of cardiac output during cardiopulmonary exercise testing (change in mean PAP divided by change in cardiac output from rest to peak exercise) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Effect on Pulmonary Artery Endothelial Cell Phenotypes | baseline and 3 months | We will compare the metformin and placebo groups. Specifically we will examine the following pulmonary artery endothelial cell phenotypes: (1) activation of phospho-eNOS as detected by immunofluorescence staining |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Metformin Metformin: 500mg tablet orally twice daily for 1 week, followed by two 500mg tablets orally twice daily for a total of 3 months. | 8 |
| Placebo Placebo: 500 mg tablet orally twice daily for 1 week, followed by two 500 mg tablets orally twice daily for a total of 3 months. | 7 |
| Total | 15 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | No primary outcome measurements | 0 | 1 |
| Overall Study | Side Effects | 1 | 2 |
| Overall Study | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | Metformin | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 65 years STANDARD_DEVIATION 10 | 60 years STANDARD_DEVIATION 10 | 63 years STANDARD_DEVIATION 10 |
| Body Mass Index (BMI) | 35.3 kg/m^2 STANDARD_DEVIATION 6 | 34.4 kg/m^2 STANDARD_DEVIATION 4.6 | 34.9 kg/m^2 STANDARD_DEVIATION 5.2 |
| Diastolic Blood Pressure (DBP) | 80 mmHg STANDARD_DEVIATION 8 | 86 mmHg STANDARD_DEVIATION 11 | 83 mmHg STANDARD_DEVIATION 9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 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 |
| Heart Rate (HR) | 70 beats per minute (bpm) STANDARD_DEVIATION 13 | 70 beats per minute (bpm) STANDARD_DEVIATION 15 | 70 beats per minute (bpm) STANDARD_DEVIATION 14 |
| Height | 65.1 inches STANDARD_DEVIATION 2.9 | 67.7 inches STANDARD_DEVIATION 4.2 | 66.3 inches STANDARD_DEVIATION 3.7 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 1 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 | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 7 Participants | 7 Participants | 14 Participants |
| Sex: Female, Male Female | 5 Participants | 4 Participants | 9 Participants |
| Sex: Female, Male Male | 3 Participants | 3 Participants | 6 Participants |
| Systolic Blood Pressure (SBP) | 133 mmHg STANDARD_DEVIATION 18 | 142 mmHg STANDARD_DEVIATION 14 | 137 mmHg STANDARD_DEVIATION 17 |
| Weight | 212.9 pounds STANDARD_DEVIATION 44.1 | 224.0 pounds STANDARD_DEVIATION 32.9 | 218.1 pounds STANDARD_DEVIATION 38.3 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 11 |
| other Total, other adverse events | 8 / 10 | 8 / 11 |
| serious Total, serious adverse events | 0 / 10 | 1 / 11 |
Outcome results
Primary
Pulmonary Vascular Hemodynamics (Exercise)
The metformin and placebo groups will be compared with respect to augmentation of mean pulmonary artery pressure divided by augmentation of cardiac output during cardiopulmonary exercise testing (change in mean PAP divided by change in cardiac output from rest to peak exercise)
Time frame: Baseline and 3 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Metformin | Pulmonary Vascular Hemodynamics (Exercise) | -0.29 mmHg/L/min | Standard Deviation 0.83 |
| Placebo | Pulmonary Vascular Hemodynamics (Exercise) | -1.42 mmHg/L/min | Standard Deviation 3 |
p-value: 0.3795% CI: [-1.65, 3.92]t-test, 2 sided
Primary
Pulmonary Vascular Hemodynamics (Rest)
The metformin and placebo groups will be compared with respect to resting mean pulmonary artery pressure (mmHg)
Time frame: Baseline and 3 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Metformin | Pulmonary Vascular Hemodynamics (Rest) | -3.00 mmHg | Standard Deviation 5.35 |
| Placebo | Pulmonary Vascular Hemodynamics (Rest) | -0.43 mmHg | Standard Deviation 4.89 |
p-value: 0.3595% CI: [-8.32, 3.18]t-test, 2 sided
Secondary
Effect on Pulmonary Artery Endothelial Cell Phenotypes
We will compare the metformin and placebo groups. Specifically we will examine the following pulmonary artery endothelial cell phenotypes: (1) activation of phospho-eNOS as detected by immunofluorescence staining
Time frame: baseline and 3 months