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Effect of Intact GLP-1 (7-36) and GLP-1 Metabolite (9-36) on Coronary and Peripheral Vascular Function in Adults

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ClinicalTrials.gov Identifier: NCT02333591
Recruitment Status : Completed
First Posted : January 7, 2015
Last Update Posted : March 11, 2019
Sponsor:
Collaborator:
Hvidovre University Hospital
Information provided by (Responsible Party):
Mette Zander, Bispebjerg Hospital

Brief Summary:

GLP-1 is an agent for treatment of type 2 diabetes and may have protective effects on the cardiovascular system. The mechanism is complex and there seems to be a dual function with intact GLP-1 (7-36), acting through the GLP-1 receptor, and the GLP-1 (9-36) metabolite acting independently of the GLP-1 receptor.

Coronary flow reserve (CFR) is the ratio of flow through the coronary arteries during stress to during rest and it reflects coronary microcirculation. Impaired CFR is a strong predictor of poor prognosis of cardiovascular disease.

The aim of the study is to investigate the acute effects of GLP-1 on coronary microcirculation and endothelial function in adults with obesity.


Condition or disease Intervention/treatment Phase
Coronary Microvascular Dysfunction Drug: GlucagonLikePeptide-1 (7-36) Drug: GlucagonLikePeptide-1 (9-36) Drug: Saline Phase 4

Detailed Description:

Several studies have shown beneficial effects of glucagon-like-peptide-1 (GLP-1) on the cardiovascular system. Native GLP-1 is secreted from L-cells in the intestine as GLP-1(7-36) 1 but is rapidly metabolised by the ubiquitous enzyme dipeptidyl-peptidase-4 (DPP4) to the metabolite GLP-1(9-36). However, the physiological effect of GLP-1 on the cardiovascular system is complex and there seems to be a dual function with intact GLP-1 (7-36), acting through the GLP-1 receptor, and the GLP-1 (9-36) metabolite acting independently of the GLP-1 receptor.

The aim of the study is to investigate the acute effects of intact GLP-1 and GLP-1 metabolite on coronary microcirculation and endothelial function in adults.

Method 20 adults with obesity are recruited to a double-blind randomized cross-over study.

The first 10 included adults will receive 2½ hours infusion of intact GLP-1 (7-36) together with a DPP-IV inhibitor and 2½ hours infusion of saline, on two separate occasions. The infusions will be given in randomized order with a minimum of 24 hours washout period.

The next 10 included adults will receive 2½ hours infusion of GLP-1 (9-36) metabolite and 2½ hours infusion of saline. These will also be given in randomized order with a minimum of 24 hours washout period. Endothelial function and CFR will be measured before and after one, respectively two, hours of infusion.

The effect of GLP-1 infusions on microvascular function is evaluated by coronary flow reserve (CFR), the ratio between echocardiographic measured coronary flow velocity in LAD during adenosine induced myocardial hyperaemia and rest. The effect on endothelial function is assessed by flow mediated dilation (FMD).

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 25 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double (Participant, Outcomes Assessor)
Primary Purpose: Basic Science
Official Title: Effect of Intact GLP-1 (7-36) and GLP-1 Metabolite (9-36) on Coronary and Peripheral Vascular Function in Adults
Study Start Date : July 2016
Actual Primary Completion Date : June 2018
Actual Study Completion Date : June 2018

Arm Intervention/treatment
Active Comparator: GlucagonLikePeptide-1 (7-36)

GLP-1 (7-36) is diluted in saline and human serum albumin. Plasma levels of GLP-1 (7-36) are rapidly raised and then maintained stable with 5,91 pmol/kg/min (0-2 min) reduced to 2,53 pmol/kg/min (2-4 min) reduced to 2,34 pmol/kg/min (4-6 min) reduced to 2,2 pmol/kg/min (6-8 min) reduced to 2,02 pmol/kg/min (8-10 min) and then maintained stable for 2½ hours with 1.5 pmol/kg/min.

A DPP-IV inhibitor - Januvia 100 mg is given the evening before and ½ an hour before the infusion is started.

Drug: Saline
Infused intravenously for 2,5 hours.
Other Name: NaCl, Placebo

Active Comparator: GlucagonLikePeptide-1 (9-36)
GLP-1 (9-36) is diluted in saline and human serum albumin. Plasma levels of GLP-1 (9-36) are rapidly raised and then maintained stable with 5,91 pmol/kg/min (0-2 min) reduced to 2,53 pmol/kg/min (2-4 min) reduced to 2,34 pmol/kg/min (4-6 min) reduced to 2,2 pmol/kg/min (6-8 min) reduced to 2,02 pmol/kg/min (8-10 min) and then maintained stable for 2½ hours with 1.5 pmol/kg/min
Drug: Saline
Infused intravenously for 2,5 hours.
Other Name: NaCl, Placebo

Placebo Comparator: NaCl
Saline is infused with a flow rate of 240 ml/h for 10 min and then reduced to 86 ml/h for 2½ hours.
Drug: GlucagonLikePeptide-1 (7-36)
Diluted in saline and human serum albumin, then infused intravenously for 2,5 hours.

Drug: GlucagonLikePeptide-1 (9-36)
Diluted in saline and human serum albumin, then infused intravenously for 2,5 hours.




Primary Outcome Measures :
  1. Coronary Flow Reserve [ Time Frame: At baseline and after 2 hours of infusion ]

    Coronary flow reserve (CFR) reflects microvessel coronary function and is the ratio between echocardiographic measured coronary flow velocity in LAD during adenosine induced myocardial hyperaemia and rest.

    The outcome is measured at every infusion/intervention (4 times).



Secondary Outcome Measures :
  1. Endothelial function (Assessed by Flow Mediated Dilation) [ Time Frame: At baseline and after 1 hour of infusion ]
    Assessed by Flow Mediated Dilation (FMD) The outcome is measured at every infusion/intervention (4 times).



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Ages Eligible for Study:   35 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Age 35-70 years
  • BMI > 25 kg/m2.
  • Central obesity (measured by waist circumference, defined as ≥ 94cm for men and ≥ 80 cm for women)
  • Non smokers (6 months abstinent is required)
  • Normal creatinine
  • For fertile women; negative pregnancy test and use of safe anticonception.
  • Speak and understand Danish or English
  • Mental ability to follow and understand the study

Exclusion Criteria:

  • Known Diabetes
  • Known hypertension (untreated hypertension ≤ 160/100 at inclusion is accepted)
  • Haemoglobin < 6.5 mmol/l
  • Allergy towards Januvia or Exenatide, Adenosin or Glycerylnitrate
  • Documented significant stenosis of the left anterior descending artery (LAD) at coronary angiography or CT-angiography or regional dysfunction documented during dipyridamol stress-echocardiography. If stress test at baseline shows significant stenosis the patient will be excluded from the study.
  • Pregnancy
  • Severe asthma
  • Active cancer, severe co-morbidity with limited life-expectancy, severe hepatic co-morbidity, chronic alcohol abuse, atrial fibrillation, chronic or previous acute pancreatitis, inflammatory bowel disease.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02333591


Locations
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Denmark
Department of Research in Endocrinology, Bispebjerg University Hospital
Copenhagen, Denmark, 2400
Sponsors and Collaborators
Mette Zander
Hvidovre University Hospital
Investigators
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Principal Investigator: Mette Zander, PhD, MD Department of Endocrinology, Bispebjerg University Hospital
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Responsible Party: Mette Zander, MD, PhD, Bispebjerg Hospital
ClinicalTrials.gov Identifier: NCT02333591    
Other Study ID Numbers: MZ02
2013-001240-64 ( EudraCT Number )
First Posted: January 7, 2015    Key Record Dates
Last Update Posted: March 11, 2019
Last Verified: March 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided