Effect of Liraglutide on Diastolic Dysfunction on Cardiac MRI in Type 2 Diabetes Patients

Diabetes Mellitus Type 2 Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02655770
• Other study ID #: 2015-000410-22
• Secondary ID: 2015-000410-22
• Status: Completed
• Phase: Phase 4
• Start date: February 2016
• Est. completion date: December 2019

Study information

• Verified date: January 2021
• Source: Rigshospitalet, Denmark
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 40
• Est. completion date: December 2019
• Est. primary completion date: December 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

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.

Related Conditions & MeSH terms

• Cardiac MRI
• Diabetes Mellitus
• Diabetes Mellitus Type 2
• Diabetes Mellitus, Type 2
• Diastolic Dysfunction
• Myocardial Perfusion

Intervention

Drug:
• Liraglutide

• Placebo

Locations

Country	Name	City	State
Denmark	The department of cardiology, Rigshospitalet Denmark	Copenhagen Ø

Sponsors (3)

Lead Sponsor	Collaborator
Rigshospitalet, Denmark	Novo Nordisk A/S, Slagelse Hospital

Country where clinical trial is conducted

Denmark, 

References & Publications (10)

Bhashyam S, Fields AV, Patterson B, Testani JM, Chen L, Shen YT, Shannon RP. Glucagon-like peptide-1 increases myocardial glucose uptake via p38alpha MAP kinase-mediated, nitric oxide-dependent mechanisms in conscious dogs with dilated cardiomyopathy. Circ Heart Fail. 2010 Jul;3(4):512-21. doi: 10.1161/CIRCHEARTFAILURE.109.900282. Epub 2010 May 13. — View Citation

Factor SM, Okun EM, Minase T. Capillary microaneurysms in the human diabetic heart. N Engl J Med. 1980 Feb 14;302(7):384-8. — View Citation

From AM, Scott CG, Chen HH. The development of heart failure in patients with diabetes mellitus and pre-clinical diastolic dysfunction a population-based study. J Am Coll Cardiol. 2010 Jan 26;55(4):300-5. doi: 10.1016/j.jacc.2009.12.003. Erratum in: J Am Coll Cardiol. 2010 Nov 2;56(19):1612. — View Citation

Kannel WB, Hjortland M, Castelli WP. Role of diabetes in congestive heart failure: the Framingham study. Am J Cardiol. 1974 Jul;34(1):29-34. — View Citation

Nathanson D, Ullman B, Löfström U, Hedman A, Frick M, Sjöholm A, Nyström T. Effects of intravenous exenatide in type 2 diabetic patients with congestive heart failure: a double-blind, randomised controlled clinical trial of efficacy and safety. Diabetologia. 2012 Apr;55(4):926-35. doi: 10.1007/s00125-011-2440-x. Epub 2012 Jan 13. — View Citation

Nitenberg A, Paycha F, Ledoux S, Sachs R, Attali JR, Valensi P. Coronary artery responses to physiological stimuli are improved by deferoxamine but not by L-arginine in non-insulin-dependent diabetic patients with angiographically normal coronary arteries and no other risk factors. Circulation. 1998 Mar 3;97(8):736-43. — View Citation

Rodrigues B, McNeill JH. The diabetic heart: metabolic causes for the development of a cardiomyopathy. Cardiovasc Res. 1992 Oct;26(10):913-22. Review. — View Citation

Thrainsdottir I, Malmberg K, Olsson A, Gutniak M, Rydén L. Initial experience with GLP-1 treatment on metabolic control and myocardial function in patients with type 2 diabetes mellitus and heart failure. Diab Vasc Dis Res. 2004 May;1(1):40-3. — View Citation

van Heerebeek L, Hamdani N, Handoko ML, Falcao-Pires I, Musters RJ, Kupreishvili K, Ijsselmuiden AJ, Schalkwijk CG, Bronzwaer JG, Diamant M, Borbély A, van der Velden J, Stienen GJ, Laarman GJ, Niessen HW, Paulus WJ. Diastolic stiffness of the failing diabetic heart: importance of fibrosis, advanced glycation end products, and myocyte resting tension. Circulation. 2008 Jan 1;117(1):43-51. Epub 2007 Dec 10. — View Citation

Yancy CW, Lopatin M, Stevenson LW, De Marco T, Fonarow GC; ADHERE Scientific Advisory Committee and Investigators. Clinical presentation, management, and in-hospital outcomes of patients admitted with acute decompensated heart failure with preserved systolic function: a report from the Acute Decompensated Heart Failure National Registry (ADHERE) Database. J Am Coll Cardiol. 2006 Jan 3;47(1):76-84. Epub 2005 Dec 15. Erratum in: J Am Coll Cardiol. 2006 Apr 7;47(7):1502. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in diastolic properties as assessed by CMR.	LA passive emptying fraction (%) (before and after glycopyrolate)	Measured in week 18 and compared to baseline.
Primary	Change in diastolic properties as assessed by CMR.	LV peak filling rate (ml/s) (before and after glycopyrolate)	Measured in week 18 and compared to baseline.
Secondary	MRI indices of myocardial perfusion		Measured in week 18 and compared to baseline.
Secondary	Echocardiographic indices of diastolic dysfunction		Measured in week 18 and compared to baseline.