Clinical trial NCT02655770: Effect of Liraglutide on Diastolic Dysfunction on Cardiac MRI in Type 2 Diabetes Patients
Official title: Influence of Liraglutide on Diastolic Cardiac Function and Myocardial Perfusion as Determined by Magnetic Resonance Imaging in Patients With Type 2 Diabetes: a Double-blind Randomized Parallel-group Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Diabetes Mellitus Type 2
Diastolic Dysfunction
Cardiac MRI
Myocardial Perfusion
Lead sponsor: Rigshospitalet, Denmark
Sponsor class: OTHER
Collaborators: name: Slagelse Hospital
name: Novo Nordisk A/S
First posted: 2016-01-14
Enrollment: 40
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to determine whether liraglutide a GLP-1 analogue are effective in the treatment of diastolic dysfunction in type 2 diabetes patients analyzed by cardiac MRI. Secondary if the treatment has any effect on the perfusion of the heart on a cardiac-MRI.

Detailed description: Aim: To test if treatment with liraglutide a GLP-1 analogue in 18 weeks improves diastolic performance in type 2 diabetes (DM2) patients with diastolic dysfunction, compared to placebo. Furthermore, analyzing cardiac MRI indices of fibrosis and the effect on myocardial perfusion.

The investigators find that especially diastolic dysfunction is of interest, because it is highly overrepresented in DM2 patients and no treatment exists. Glucagon-like peptide 1 analogue could be a possible treatment agent, by increasing the energy level in the myocardium. No previous study has tested the effect of treatment with a glucagon-like peptide 1 analogue on diastolic dysfunction.

Design: A randomised double-blinded placebo-controlled clinical trial. Sample size: 40 patients, 20 in each group. The superior inter-study reproducibility results in considerably lower calculated sample sizes (reductions of 55% to 93%) required by cardiac MR compared with echocardiography to show clinically relevant changes. Power calculations show that only 30 patients are needed form our primary outcome, to allow for dropouts the investigators have chosen to include 40 patients.

Intervention: After randomization, patients will be treated with placebo or liraglutide (up to 1.8 mg s.c. once daily). Total treatment period will be 18 weeks. A cardiac MRI scan and an echocardiography will be preformed at baseline and after 18 weeks.

Eligibility criteria: Inclusion Criteria:

* Male or female patient fully capable of informed consent
* Informed consent
* Age 18-80 years (both years inclusive)
* T2DM diagnosed at least 3 months prior to visit 0
* NYHA class I-III at visit 0
* E/e\* ≥ 9 or e\* (lateral) ≤10 cm/sec, or both
* LVEF \> 50%
* LVEDV/BSA \< 97 ml/m2
* Stable on heart medication for 6 weeks prior to randomisation
* Stable on antidiabetic treatment for 30 days prior to randomisation
* T2DM must be either treated with one or more oral anti-diabetic drugs or treated with human NPH-insulin or long-acting insulin analogue, alone or in combination with oral drugs

Exclusion Criteria:

* Lack of consent.
* NYHA class IV
* Type 1 diabetes mellitus
* Incretin-based therapy (GLP-1 receptor agonists; exenatide, liraglutide or other and DPP-IV inhibitors) within 30 days prior to randomisation (visit 1)
* Glitazon therapy within 30 days prior to randomisation (visit 1)
* Hypertension with inadequate blood pressure control: Systolic blood pressure \> 140 mmHg and/or diastolic blood pressure \>85 mmHg\*
* Supine systolic blood pressure \<85 mmHg measured at visit 0
* Significant valvular heart disease
* Hypertrophic cardiomyopathy, ARVC/D, non-compaction or amyloidosis
* Myocardial infarction, unstable angina, angina on exertion (≥CCS class 2) or coronary revascularization within 3 months prior to randomisation (visit 1)
* Hospitalisation due to incompensated heart disease within 30 days to randomisation (visit 1)
* HbA1c \>10% at visit 0
* eGFR\< 60 ml/min/1,73 m2 at visit 0
* Liver disease with aspartate aminotransferase/alanine aminotransferase \>3 times upper limit of normal measured at visit 0\*\*
* Hypokalaemia (P-potassium \<3.5 mmol/L) or hyperkalaemia (P-potassium \>5.5 mmol/L) measured at visit 0\*\*
* Anaemia (haemoglobin \<6.5 mmol/L) measured at visit 0\*\*
* Conditions that may be associated with changes in markers of fibroses or collagen turnover (eg. on-going or active rheumatological disease requiring anti-inflammatory agents, immunosuppression, pulmonary fibrosis, active cancer)
* Prolonged use (\> 2 weeks) of glucocorticoids or NSAIDs within 2 weeks prior to visit 0
* Women of childbearing potential who are not on acceptable contraception. See below.
* Pregnant or breastfeeding women
* Cancer (except basal cell skin cancer or squamous cell skin cancer) unless complete remission for ≥ 5 years
* Alcohol/drug abuse
* Chronic or previous acute pancreatitis
* History of thyroid adenoma or carcinoma
* Inflammatory bowel disease
* Clinical signs of diabetic gastroparesis
* ICD/pacemaker or other contraindications to MRI scan
* Severe claustrophobia
* Atrial fibrillation
* Contraindications to glycopyrrolate: closed-angle glaucoma, prostate hyperplasia, tachycardia, bladder atony, cardia insufficiency, non-congenital pylorus stenosis and gastroparesis
* Known or suspected hypersensitivity to trial product or related products
* Current participation in any other clinical intervention trial
* Receipt of an investigational drug with 30 days prior to visit 0
* Other concominant disease or treatment that according to investigator's assessment makes the patient unsuitable for participation in the study

  * Measured twice at visit 0. In case of elevation, an ambulatory (24-hour) blood pressure will be performed, and the result of this will be conclusive

    * Measured at visit 0 with the possibility of one repeat analysis within a week, and the last measured value will be conclusive.

Primary outcomes:
measure: Change in diastolic properties as assessed by CMR.
timeFrame: Measured in week 18 and compared to baseline.
measure: Change in diastolic properties as assessed by CMR.
timeFrame: Measured in week 18 and compared to baseline.
Secondary outcomes:
measure: MRI indices of myocardial perfusion
timeFrame: Measured in week 18 and compared to baseline.
measure: Echocardiographic indices of diastolic dysfunction
timeFrame: Measured in week 18 and compared to baseline.
Other outcomes:
Locations:
city: Copenhagen Ø
country: Denmark
facility: The department of cardiology, Rigshospitalet Denmark
Study officials:
affiliation: Rigshospitalet, Denmark
name: Niels Vejlstrup, MD, Med.Sc.D
role: STUDY_DIRECTOR
References:
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