Leptin Infusion and Endothelial Vasomotor Response

NCT04374500 | Completed Early Phase 1 Results FDA Drug

• 1 other identifier: 05-150M
• Study Type: interventional
• Target: 103
• Locations: 2 countries
• Sites: 2

Brief Summary

Adipose tissue is an active endocrine organ producing several hormones with circulatory and metabolic effects. In 1994, the hormone leptin was discovered. The lack of this hormone explained extreme obesity in rare patients and parenteral substitution restored body weight and metabolic disturbances. It was however soon discovered that most humans had too high levels which were related to development of cardiovascular diseases and diabetes. It was hypothesised that leptin induced vessel dysfunction which could explain this association. In this study, we wanted to examine the association between leptin and vessel function by using the venous occlusion plethysmography method. We used three protocols to evaluate this association. First protocol. In ten healthy males, leptin was infused locally in the forearm and forearm blood flow (FBF) was measured. Second protocol. In ten healthy males, leptin or normal saline was infused locally in the forearm and FBF was measured. Concomitantly, four vasodilatators were infused locally in the forearm in a randomised order and the response (blood flow and fibrinolysis) was measured. Third protocol. In eighty-three patients with known coronary artery disease, three vasodilators were infused locally in the forearm in a random order and response (FBF and fibrinolysis) was measured. The response was related to endogenous leptin levels. The two first protocols were performed in Umeå, Sweden whereas the third was performed in Edinburgh, UK, all in 2006.

Conditions

Endothelial Dysfunction; Obesity; Vasodilation; Venous Occlusion Plethysmography

Outcome Measures

Primary Outcomes (1)

• Forearm Blood-flow (FBF)

  The primary outcome in all protocols were local blood-flow in the forearm (FBF). This was measured by venous occlusion plethysmography using mercury-in-silastic strain gauges and the unit is mL/100mL of tissue/min. In protocol 1, the FBF response to increasing levels of leptin was evaluated, In protocol 2, the FBF response to vasodilators on top of leptin or saline infusion was evaluated, and in protocol 3, FBF was measured after infusion of vasodilators and no leptin was given.

  18 minutes in protocol 1, 3 hours in protocol 2, non-applicable (NA) in protocol 3

Secondary Outcomes (4)

• Release of Fibrinolytic Variables (Tissue Plasminogen Activator [tPA] and Plasminogen Activator Inhibitor-1 [PAI-1])

  18 minutes in protocol 1, 3 hours in protocol 2, NA in protocol 3

• Leptin

  18 minutes in protocol 1, 3 hours in protocol 2, NA in protocol 3

• Systolic Blood Pressure

  18 minutes in protocol 1, 3 hours in protocol 2, NA in protocol 3

• Heart Rate

  18 minutes in protocol 1, 3 hours in protocol 2, NA in protocol 3

Study Arms (3)

Leptin infusion

EXPERIMENTAL

This applies to protocol 1 when 10 healthy men got leptin infused locally in the forearm and forearm blood flow (FBF) was measured. The other forearm was used as the control.

Drug: Leptin infusion in healthy men

Leptin infusion plus vasodilator infusion

EXPERIMENTAL

This applies to protocol 2 when 10 healthy men got either a background infusion of leptin or saline locally in the forearm when measuring vasoresponse (FBF) to four vasodilatators. Each participant had two examinations with either leptin or saline and the order was randomised. The other forearm was used as the control.

Drug: Leptin infusion plus vasodilators in healthy men

Vasodilator infusion in CAD patients

EXPERIMENTAL

This applies to protocol 3 when 83 men and women with known CAD (coronary artery disease) got three vasodilators locally infused in the forearm while measuring vasoresponse (FBF). The other forearm was used as the control.

Drug: Vasodilators in CAD patients

Interventions

Leptin infusion plus vasodilators in healthy men DRUG

This applies only to protocol 2 with two arms (leptin or saline) where four vasodilatators (bradykinin, acetylcholine, sodium nitroprusside and verapamil) were infused concomitantly

Also known as: Four vasodilators (bradykinin, acetylcholine, sodium nitroprusside and verapamil) on top of leptin or saline infusion

Leptin infusion plus vasodilator infusion

Leptin infusion in healthy men DRUG

This applies only to protocol 1 when only leptin was given

Also known as: Leptin infusion only and blood flow measured

Leptin infusion

Vasodilators in CAD patients DRUG

This applies only to protocol 3

Also known as: Three vasodilators (acetylcholine, sodium nitroprusside, substance P) only, related to endogenous leptin levels

Vasodilator infusion in CAD patients

Eligibility Criteria

• Gender Eligibility Details: Only males chosen for protocol 1 and 2. The reason is that men are more easily cannulated in the forearm artery with less risk for vasospasm.
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Healthy male
• No regular medication
• Non-smoking
• Abstain from alcohol for 24 hours and from food, tobacco and caffeine-containing drinks for at least 4 hours before each study visit
• Established coronary artery disease
• Stable angina pectoris
• Documented ≥ 50% stenosis of at least one major epicardial coronary vessel

You may not qualify if:

• Coronary revascularisation within three months
• Diabetes mellitus
• Cardiac failure (ejection fraction \<35% or New York Heart Association (NYHA) ≥2)
• Renal impairment (creatinine ≥200 µmol/L)
• Systolic blood pressure \<100 or \>190 mmHg

Sponsors & Collaborators

• Stefan Soderberg: lead
• University of Edinburgh: collaborator

Study Sites (2)

Umeå University Hopsital

Umeå, 90185, Sweden

Location

British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh

Edinburgh, United Kingdom

Location

Related Publications (1)

• Gonzalez M, Robinson S, Mills NL, Eriksson M, Sandstrom T, Newby DE, Olsson T, Blomberg A, Soderberg S. Vasomotor and fibrinolytic effects of leptin in man. Scand Cardiovasc J. 2025 Dec;59(1):2478867. doi: 10.1080/14017431.2025.2478867. Epub 2025 Mar 19.

  PMID: 40066842 DERIVED

MeSH Terms

Conditions

Obesity; Aneurysm

Interventions

Vasodilator Agents; Bradykinin; Acetylcholine; Nitroprusside; Verapamil; Substance P; Single Person

Condition Hierarchy (Ancestors)

Overweight; Overnutrition; Nutrition Disorders; Nutritional and Metabolic Diseases; Body Weight; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Vascular Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Cardiovascular Agents; Therapeutic Uses; Pharmacologic Actions; Chemical Actions and Uses; Kinins; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Neuropeptides; Oligopeptides; Proteins; Nerve Tissue Proteins; Autacoids; Inflammation Mediators; Biological Factors; Biogenic Amines; Amines; Organic Chemicals; Ferricyanides; Cyanides; Anions; Ions; Electrolytes; Inorganic Chemicals; Ferric Compounds; Iron Compounds; Hydrogen Cyanide; Nitrogen Compounds; Phenethylamines; Ethylamines; Tachykinins; Marital Status; Family Characteristics; Demography; Population Characteristics; Socioeconomic Factors

Limitations and Caveats

Sympathetic activity should have been measured simultaneously, but was not done.

Results Point of Contact

• Title: Stefan Söderberg
• Organization: Umeå University, Umeå, Sweden

stefan.soderberg@umu.se

+46 70 319 38 03

Study Officials

• Stefan Söderberg, MD, PhD

  Umeå University, Umeå Sweden

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor

Model Details: In protocol 1, each participant was examined once. Leptin was given intraarterially in the forearm in increasing doses and forearm blood flow (FBF) was measured. No masking, no randomisation. In protocol 2, each participant was examined twice and they got either leptin or saline intraarterially in the forearm at least 2 weeks apart, and the order was randomised. Concomitantly, they got four vasodilatators (bradykinin, acetylcholine, sodium nitroprusside and verapamil) intraarterially in a randomised order. In protocol 3, each participant was examined once and the three vasodilatators (substance P, acetylcholine, and sodium nitroprusside) were given intraarterially in the forearm in a randomised order.

Study Record Dates

• First Submitted: May 1, 2020
• First Posted: May 5, 2020
• Study Start: January 1, 2006
• Primary Completion: October 27, 2006
• Study Completion: December 20, 2006
• Last Updated: May 9, 2023
• Results First Posted: July 17, 2020

Record last verified: 2022-07

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, ICF
• Time Frame: On reasonable request
• Access Criteria: Contact with principal investigator (email)

Locations

GB (1); SE (1)