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Congestive Heart FailurePhase 2NCT01425580

Liraglutide and Heart Failure in Type 2 Diabetes

A Phase 2 study testing liraglutide, glimepiride and Metformin in people with Congestive Heart Failure and Type 2 Diabetes Mellitus, run by Thomas Nystrom at 2 sites in Sweden.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 to 80 years
What is being tested?
liraglutide, glimepiride and Metformin
Could I receive a placebo?
No, everyone receives an active treatment
How many people
62 participants
Where
2 sitesSweden
Study dates
Jan 2012to Aug 2016
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 80 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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.
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  • 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.

Who cannot join

  • 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.
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  • 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)
  • Treatment with another investigational agent within 30 days before study entry, judged by the investigator.
  • Severe gastrointestinal disease, including gastroparesis. As judged by the investigator.
  • Body mass index (BMI) > 40 kg/m2.
  • Malignant neoplasm requiring chemotherapy, surgery, radiation or palliative therapy in the previous 5 years. Patients with intraepithelial squamous cell carcinoma of the skin treated with topical 5FU and subjects with basal cell skin cancer are allowed to enter the trial.
  • Females of child bearing potential who are pregnant, breast-feeding or intend to become pregnant or are not using adequate contraceptive methods (adequate contraceptive measures as required by local law or practice).
  • Current drug and alcohol abuse.
  • History of acute or chronic pancreatitis
  • Subjects considered by the investigator to be unsuitable for the study.
  • -

Trial locations and contacts

2 sites in 1 country.

Sweden2 sites

  • Karolinska Institutet, Department of Clinical Science and Education, Södersjukhuset

    Stockholm, 118 83

  • Karolinska Institutet, Division of Internal Medicine Södersjukhuset AB

    Stockholm, 118 83

Other trials in Sweden

About this study

Official title: Effects on Subclinical Heart Failure in Type 2 Diabetic Subjects on Liraglutide Treatment Versus Glimepiride Both in Combination With Metformin

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.

Read the detailed description

The subjects will attend a screening visit (Visit 1) in order to assess their eligibility. If found eligible, the subjects will return at Visit 2 within approximately 4 weeks, after Visit 1, with an up-titration with metformin 1 g BID or the maximal tolerated dosage of metformin (Run-in period).

At Visit 2 patients will be tested for;

  • Heart function at rest and during an exercise ECG Stress Test with tissue Doppler echocardiography
  • 24-hour blood pressure
  • Anthropometric assessment
  • Symptoms of dyspnea or fatigue (scoring system, classified as NYHA).
  • Quality of life (SF 36)
  • Blood test (venipuncture)

Subsequently thereafter, subjects will during visit 2 be randomized to receive either liraglutide 1.8 mg s.c. (initial dose of 0.6 mg with an up-titration of 0.6 mg every week, final dose 1.8 mg QD) or glimepiride 4 mg p.o (initial dose of 2 mg, with an up-titration of 1 mg every week, final dose 4 mg QD).

At Visit 2, subjects will be supplied with a glucose meter (Abbot Contour) and instruction on use of the device including regular calibration according to the manufacturer's instruction. Subjects will be instructed on how to record the results of the self measured plasma glucose (SMPG) values in the meter. Subjects will then ask to monitor a 7 point profile glucose curve consecutively in three days before visit 3, at visit 4 and at the end of treatment (visit 5). SMBG values will be transferred via a computerized system (Diasend®).

Visit 3. Telephone visit. Self-reporting glucose measurements.

Visit 4. Telephone visit. Self-reporting glucose measurements.

At week 18 (Visit 5), subjects will be re-tested for:

  • Heart function at rest and during an exercise ECG Stress Test with tissue Doppler echocardiography
  • 24-hour blood pressure
  • Anthropometric assessment
  • Symptoms of dyspnea or fatigue (scoring system, classified as NYHA).
  • Quality of life (SF 36)
  • Blood test (venipuncture)
Being tested
liraglutide, glimepiride, Metformin
Keywords
Congestive Heart Failure, Type 2 Diabetes Mellitus, GLP-1, Liraglutide
Medical subject headings
Heart Failure, Diabetes Mellitus, Type 2

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

Study groups in NCT01425580
Study groupRoleWhat they receive
liraglutideExperimentalThe 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.
Receives: Drug: liraglutide; Drug: glimepiride; Drug: Metformin
glimepirideActive comparator4 mg p.o. (QD)
Receives: Drug: liraglutide; Drug: glimepiride; Drug: Metformin

What is being measured

The primary outcome is the main question the study is designed to answer.

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

    Measured: 18 weeks

Secondary outcomes (13)

  1. 24-hour blood pressure

    Measured: 18 weeks

  2. Energy delivering from the carotid artery

    Measured: 18 weeks

  3. 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

    Measured: 18 weeks

  4. Gene and protein expression (Affymetrix/proteomics)

    Measured: 18 weeks

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

    Measured: 18 weeks

  6. Plasma markers of endothelial activation i.e. E-selectin, VCAM-1, ICAM-1 and plasma levels of nitrate/nitrite

    Measured: 18 weeks

  7. Lipids

    Measured: 18 weeks

  8. A1c

    Measured: 18 week

  9. Body weight

    Measured: 18 weeks

  10. Adverse events in terms of hypoglycaemia

    Measured: 18 weeks

  11. Quality of life (SF 36)

    Measured: 18 weeks

  12. Exercise ECG, including working capacity

    Measured: 18 weeks

  13. Global LV function (echocardiography) expressed as ejection fraction (EF)

    Measured: 18 weeks

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted30 Aug 2011 (estimated)
  2. Study startJan 2012
  3. Primary completionAug 2016
  4. Study completionAug 2016

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
62 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01425580
Sponsor's protocol ID
EU-nr 2010-022695-31
Other IDs
2010-022695-31
Status last verified
Aug 2016
First submitted
26 Aug 2011
Last updated
1 Sep 2016
Results posted
No
Data monitoring committee
No

Publications

  • 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.

    PubMed 37349083

  • 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.

    PubMed 34920733

  • 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.

    PubMed 29548934

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing liraglutide, glimepiride and Metformin in people with Congestive Heart Failure and Type 2 Diabetes Mellitus, run by Thomas Nystrom at 2 sites in Sweden.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 9 inclusion and 24 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 1 Sep 2016. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 sites in Sweden. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Left ventricle longitudinal function and/or functional reserve during rest and/or after exercise using tissue Doppler echocardiography (time frame: 18 weeks). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01425580, which also lists 3 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 1 Sep 2016.

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