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Liraglutide and Heart Failure in Type 2 Diabetes

Primary Purpose

Congestive Heart Failure, Type 2 Diabetes Mellitus

Status

Completed

Phase

Phase 2

Locations

Sweden

Study Type

Interventional

Intervention

liraglutide

glimepiride

Metformin

About this trial

This is an interventional treatment trial for Congestive Heart Failure focused on measuring Congestive Heart Failure, Type 2 Diabetes Mellitus, GLP-1, Liraglutide

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

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.

Exclusion Criteria:

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)
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.
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Sites / Locations

Karolinska Institutet, Department of Clinical Science and Education, Södersjukhuset
Karolinska Institutet, Division of Internal Medicine Södersjukhuset AB

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

liraglutide

glimepiride

Arm Description

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.

4 mg p.o. (QD)

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

24-hour blood pressure

Energy delivering from the carotid artery

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

Gene and protein expression (Affymetrix/proteomics)

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

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

Lipids

A1c

Body weight

Adverse events in terms of hypoglycaemia

Quality of life (SF 36)

Exercise ECG, including working capacity

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

Full Information

NCT ID

NCT01425580

First Posted

August 26, 2011

Last Updated

August 31, 2016

Sponsor

Thomas Nystrom

Collaborators

Örebro University, Sweden

1. Study Identification

Unique Protocol Identification Number

NCT01425580

Brief Title

Liraglutide and Heart Failure in Type 2 Diabetes

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

August 2016

Overall Recruitment Status

Completed

Study Start Date

January 2012 (undefined)

Primary Completion Date

August 2016 (Actual)

Study Completion Date

August 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor-Investigator

Name of the Sponsor

Thomas Nystrom

Collaborators

Örebro University, Sweden

4. Oversight

Data Monitoring Committee

5. Study Description

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.

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)

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Congestive Heart Failure, Type 2 Diabetes Mellitus

Keywords

Congestive Heart Failure, Type 2 Diabetes Mellitus, GLP-1, Liraglutide

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

62 (Actual)

8. Arms, Groups, and Interventions

Arm Title

liraglutide

Arm Type

Experimental

Arm Description

Arm Title

glimepiride

Arm Type

Active Comparator

Arm Description

4 mg p.o. (QD)

Intervention Type

Drug

Intervention Name(s)

liraglutide

Intervention Description

1.8 mg s.c. (QD)

Intervention Type

Drug

Intervention Name(s)

glimepiride

Intervention Description

4 mg p.o. (QD)

Intervention Type

Drug

Intervention Name(s)

Metformin

Intervention Description

500 mg p.o. (BID)

Primary Outcome Measure Information:

Title

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

Time Frame

18 weeks

Secondary Outcome Measure Information:

Title

24-hour blood pressure

Time Frame

18 weeks

Title

Energy delivering from the carotid artery

Time Frame

18 weeks

Title

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

Time Frame

18 weeks

Title

Gene and protein expression (Affymetrix/proteomics)

Time Frame

18 weeks

Title

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

Time Frame

18 weeks

Title

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

Time Frame

18 weeks

Title

Lipids

Time Frame

18 weeks

Title

A1c

Time Frame

18 week

Title

Body weight

Time Frame

18 weeks

Title

Adverse events in terms of hypoglycaemia

Time Frame

18 weeks

Title

Quality of life (SF 36)

Time Frame

18 weeks

Title

Exercise ECG, including working capacity

Time Frame

18 weeks

Title

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

Time Frame

18 weeks

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

80 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: 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. Exclusion Criteria: 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) 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. -

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Johan Jendle, MD, PhD

Organizational Affiliation

University of Örebro

Official's Role

Principal Investigator

Facility Information:

Facility Name

Karolinska Institutet, Department of Clinical Science and Education, Södersjukhuset

City

Stockholm

ZIP/Postal Code

118 83

Country

Sweden

Facility Name

Karolinska Institutet, Division of Internal Medicine Södersjukhuset AB

City

Stockholm

ZIP/Postal Code

118 83

Country

Sweden

12. IPD Sharing Statement

Citations:

PubMed Identifier

34920733

Citation

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.

Results Reference

derived

PubMed Identifier

29548934

Citation

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.

Results Reference

derived

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Liraglutide and Heart Failure in Type 2 Diabetes

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