NCT01425580

Brief Summary

Glucagon-like peptide-1 (GLP-1) is a naturally occurring incretin with insulinotropic properties. Apart from the glycemic actions, cardiovascular effects by GLP-1 have recently been reviewed. Receptors for GLP-1 are expressed in the rodent and human heart and acute activation of GLP-1 signalling has been shown to influence e.g. heart rate and blood pressure. In a knock-out mouse model, GLP-1R-/- mice exhibited a defective cardiovascular contractile response together with left ventricular hypertrophy. GLP-1 improves severe left ventricular heart failure in humans suffering from a myocardial infarction. Hence, it has been demonstrated that GLP-1 exerts direct functional effects through both GLP-1 receptor dependent and independent pathways in the heart. Native GLP-1 is an extremely short acting peptide, with a half-time breakdown of 1-2 minutes, a feature that makes it unsuitable as a drug treatment for type 2 diabetes. To this end, several long-acting GLP-1 analogues, drugs for treating type 2 diabetes, have been tested for this purpose. The analogue liraglutide exerts its effects via the native GLP-1 receptor, localized not only on the pancreatic β-cells, but also in the human heart. Interestingly, liraglutide has been demonstrated to have beneficial effect on heart function in mice. Taken together, recent data shows that GLP-1 and its stable analogue liraglutide exert beneficial cardiovascular effects. The purpose of this study is to determine whether the glucagon-like peptide-1 (GLP-1) analogue liraglutide improves heart function (measured as left ventricle longitudinal function and/or functional reserve during rest and/or after exercise) after 18 weeks of liraglutide + metformin, compared with glimepiride + metformin, using tissue Doppler echocardiography.

Trial Health

87
On Track

Trial Health Score

Automated assessment based on enrollment pace, timeline, and geographic reach

Enrollment
62

participants targeted

Target at P50-P75 for phase_2

Timeline
Completed

Started Jan 2012

Typical duration for phase_2

Geographic Reach
1 country

2 active sites

Status
completed

Health score is calculated from publicly available data and should be used for screening purposes only.

Trial Relationships

Click on a node to explore related trials.

Study Timeline

Key milestones and dates

First Submitted

Initial submission to the registry

August 26, 2011

Completed
4 days until next milestone

First Posted

Study publicly available on registry

August 30, 2011

Completed
4 months until next milestone

Study Start

First participant enrolled

January 1, 2012

Completed
4.6 years until next milestone

Primary Completion

Last participant's last visit for primary outcome

August 1, 2016

Completed
Same day until next milestone

Study Completion

Last participant's last visit for all outcomes

August 1, 2016

Completed
Last Updated

September 1, 2016

Status Verified

August 1, 2016

Enrollment Period

4.6 years

First QC Date

August 26, 2011

Last Update Submit

August 31, 2016

Conditions

Congestive Heart FailureType 2 Diabetes Mellitus

Keywords

Congestive Heart FailureType 2 Diabetes MellitusGLP-1Liraglutide

Outcome Measures

Primary Outcomes (1)

  • Left ventricle longitudinal function and/or functional reserve during rest and/or after exercise using tissue Doppler echocardiography

    18 weeks

Secondary Outcomes (13)

  • 24-hour blood pressure

    18 weeks

  • Energy delivering from the carotid artery

    18 weeks

  • N-terminal pro b-type natriuretic peptide (NT-proBNP) levels in serum over time and symptoms of dyspnea or fatigue as assessed by patient and clinician using established scoring systems

    18 weeks

  • Gene and protein expression (Affymetrix/proteomics)

    18 weeks

  • Plasma markers of inflammation i.e. hsCRP, IL-6, TNF-α and PAI-1

    18 weeks

  • +8 more secondary outcomes

Study Arms (2)

liraglutide

EXPERIMENTAL

The present trial is a two centre, open, assessor-blinded and active-controlled, parallel-group trial, in combination with metformin. The trial will compare the treatment with liraglutide 1.8 mg (s.c) QD + metformin up to 1 g BID, with that of glimepiride 4 mg QD (comparator) + metformin up to 1 g BID, on LV function in subjects with type 2 diabetes.

Drug: liraglutideDrug: glimepirideDrug: Metformin

glimepiride

ACTIVE COMPARATOR

4 mg p.o. (QD)

Drug: liraglutideDrug: glimepirideDrug: Metformin

Interventions

liraglutideDRUG

1.8 mg s.c. (QD)

glimepirideliraglutide
glimepirideDRUG

4 mg p.o. (QD)

glimepirideliraglutide
MetforminDRUG

500 mg p.o. (BID)

glimepirideliraglutide

Eligibility Criteria

Age18 Years - 80 Years
Sexall
Healthy VolunteersNo
Age GroupsAdult (18-64), Older Adult (65+)

You may qualify if:

  • Type 2 diabetes.
  • Heart Failure, visualized with echocardiography, one of the following (2.1, 2.2 or 2.3).
  • Ejection Fraction ≤ 50%.
  • Decreased systolic velocity (four chamber view) where two, out of four segments (Septum, Lateral, Inferior and Anterior Wall) has a relative decrease in velocity of 20% compared to a normal population.
  • Evidence of diastolic dysfunction as shown by abnormal left ventricular relaxation, filling, diastolic distensibility or stiffness. An E/E' ratio (ratio of early diastolic velocities of mitral inflow derived Doppler imaging and myocardial movement derived by tissue Doppler imaging) \>15 is considered diagnostic of diastolic dysfunction and an E/E' ratio \< 8 as diagnostic of the absence of diastolic heart failure. An increased left atrial size (\>49 ml/ m2) and an increased left ventricular mass (\>122 g/m2 in women and \>149 g/m2 in men) are considered sufficient evidence of diastolic dysfunction when the E/E' ratio is inconclusive.
  • HbA1c (accordingly to IFCC) 47 mmol/mol - 95 mmol/mol.
  • If antihypertensive treatment, the medication has to be stable, no change, for the last 1 month.
  • Male and female subjects, 18-80 years of age.
  • Signed informed consent form.

You may not qualify if:

  • Type 1 diabetes (autoantibody positive).
  • Any history of receiving GLP-1 analogues or dipeptidyl peptidase inhibitors (DPP-IV inhibitor) or glimeperide.
  • Previous treatment with glitazones within 6 months.
  • Previous treatment with other sulphonylurea within 3 months.
  • Previous treatment with insulin (any regimen) within 1 month.
  • Known severe heart failure, classified as NYHA 3-4.
  • Significant ischemic heart disease (defined as angina-limited exercise or unstable angina); documented acute myocardial infarction (MI) within the previous 8 weeks.
  • Active myocarditis; malfunctioning artificial heart valve.
  • Atria fibrillation or flutter
  • History of ventricular tachycardia within 3 months before study entry; second- or third-degree atrioventricular block.
  • Implanted pacemaker.
  • Supine systolic blood pressure \<85 mm Hg or \>200 mm Hg.
  • Primary renal impairment (creatinine clearance \< 30 ml/min), or creatinine clearance \< 60 ml/min if treated with metformin.
  • Uncorrected hypokalemia or hyperkalemia (potassium \<3.5 mmol/l or \>5.5 mmol/l).
  • Significant anemia (Hb \< 90 g/l)
  • +8 more criteria

Contact the study team to confirm eligibility.

Sponsors & Collaborators

Study Sites (2)

Karolinska Institutet, Department of Clinical Science and Education, Södersjukhuset

Stockholm, 118 83, Sweden

Location

Karolinska Institutet, Division of Internal Medicine Södersjukhuset AB

Stockholm, 118 83, Sweden

Location

Related Publications (3)

  • Scherbak NN, Kruse R, Nystrom T, Jendle J. Glimepiride Compared to Liraglutide Increases Plasma Levels of miR-206, miR-182-5p, and miR-766-3p in Type 2 Diabetes Mellitus: A Randomized Controlled Trial. Diabetes Metab J. 2023 Sep;47(5):668-681. doi: 10.4093/dmj.2022.0342. Epub 2023 Jun 22.

    PMID: 37349083DERIVED

  • Jendle J, Hyotylainen T, Oresic M, Nystrom T. Pharmacometabolomic profiles in type 2 diabetic subjects treated with liraglutide or glimepiride. Cardiovasc Diabetol. 2021 Dec 17;20(1):237. doi: 10.1186/s12933-021-01431-2.

    PMID: 34920733DERIVED

  • Jendle J, Fang X, Cao Y, Bojo L, Nilsson BK, Hedberg F, Santos-Pardo I, Nystrom T. Effects on repetitive 24-hour ambulatory blood pressure in subjects with type II diabetes randomized to liraglutide or glimepiride treatment both in combination with metformin: a randomized open parallel-group study. J Am Soc Hypertens. 2018 May;12(5):346-355. doi: 10.1016/j.jash.2018.02.003. Epub 2018 Feb 16.

    PMID: 29548934DERIVED

MeSH Terms

Conditions

Heart FailureDiabetes Mellitus, Type 2

Interventions

LiraglutideglimepirideMetformin

Condition Hierarchy (Ancestors)

Heart DiseasesCardiovascular DiseasesDiabetes MellitusGlucose Metabolism DisordersMetabolic DiseasesNutritional and Metabolic DiseasesEndocrine System Diseases

Intervention Hierarchy (Ancestors)

Glucagon-Like Peptide 1Glucagon-Like PeptidesProglucagonGastrointestinal HormonesHormonesHormones, Hormone Substitutes, and Hormone AntagonistsBiguanidesGuanidinesAmidinesOrganic Chemicals

Study Officials

  • Johan Jendle, MD, PhD

    University of Örebro

    PRINCIPAL INVESTIGATOR

Study Design

Study Type
interventional
Phase
phase 2
Allocation
RANDOMIZED
Masking
NONE
Purpose
TREATMENT
Intervention Model
PARALLEL
Sponsor Type
OTHER
Responsible Party
SPONSOR INVESTIGATOR
PI Title
MD, PhD

Study Record Dates

First Submitted

August 26, 2011

First Posted

August 30, 2011

Study Start

January 1, 2012

Primary Completion

August 1, 2016

Study Completion

August 1, 2016

Last Updated

September 1, 2016

Record last verified: 2016-08

Locations

SE(2)