Cardiometabolic Disease and Pulmonary Hypertension

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.

Study Overview

• Status: Terminated
• Conditions: Obesity
• Intervention / Treatment: Drug: Metformin; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 21
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 30 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Metformin; Metformin: 500mg twice daily for 1 week, followed by 1g twice daily for a total of 3 months.	Drug: Metformin; 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
Placebo Comparator: Placebo; Placebo: 500 mgh twice daily for 1 week, followed by 1g twice daily for a total of 3 months.	Drug: Placebo; 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pulmonary Vascular Hemodynamics (Rest)	The metformin and placebo groups will be compared with respect to resting mean pulmonary artery pressure (mmHg)	Baseline and 3 months
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)	Baseline and 3 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	baseline and 3 months

Collaborators and Investigators

• Sponsor: Massachusetts General Hospital
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: Jennifer E Ho, MD, Massachusetts General Hospital

Study record dates

Study Major Dates

• Study Start (Actual): November 27, 2017
• Primary Completion (Actual): December 22, 2020
• Study Completion (Actual): December 22, 2020

Study Registration Dates

• First Submitted: June 6, 2017
• First Submitted That Met QC Criteria: November 20, 2017
• First Posted (Actual): November 22, 2017

Study Record Updates

• Last Update Posted (Actual): January 21, 2022
• Last Update Submitted That Met QC Criteria: December 21, 2021
• Last Verified: December 1, 2021

More Information

Terms related to this study

• Keywords: Pulmonary Hypertension; Echocardiography; BMI; 6-minute walk test; CPET; Cardio Metabolic disease
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Hypertension; Hypertension, Pulmonary; Hypoglycemic Agents; Physiological Effects of Drugs; Metformin
• Other Study ID Numbers: 2017P001020; 1R01HL134893-01A1 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No