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Cited by 137Diabetes Treatment and ManagementCardiovascular Function and Risk FactorsHeart Failure Treatment and Management

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Effect of liraglutide on cardiac function in patients with type 2 diabetes mellitus: randomized placebo-controlled trial

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Bizino, Maurice B., Jazet, Ingrid M., Westenberg, Jos J. M., van Eyk, Huub J., Paiman, Elisabeth H. M., Smit, Jan W. A., Lamb, Hildebrandus J.·2019·Cardiovascular Diabetology
DOI 10.1186/s12933-019-0857-6PMC PMC6492440
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Abstract

Abstract Background Liraglutide is an antidiabetic agent with cardioprotective effect. The purpose of this study is to test efficacy of liraglutide to improve diabetic cardiomyopathy in patients with diabetes mellitus type 2 (DM2) without cardiovascular disease. Methods Patients with DM2 were randomly assigned to receive liraglutide 1.8 mg/day or placebo in this double-blind trial of 26 weeks. Primary outcome measures were LV diastolic function (early (E) and late (A) transmitral peak flow rate, E/A ratio, early deceleration peak (Edec), early peak mitral annular septal tissue velocity (Ea) and estimated LV filling pressure (E/Ea), and systolic function (stroke volume, ejection fraction, cardiac output, cardiac index and peak ejection rate) assessed with CMR. Intention-to-treat analysis of between-group differences was performed using ANCOVA. Mean estimated treatment differences (95% confidence intervals) are reported. Results 23 patients were randomized to liraglutide and 26 to placebo. As compared with placebo, liraglutide significantly reduced E (− 56 mL/s (− 91 to − 21)), E/A ratio (− 0.17 (− 0.27 to − 0.06)), Edec (− 0.9 mL/s 2 * 10 −3 (− 1.3 to − 0.2)) and E/Ea (− 1.8 (− 3.0 to − 0.6)), without affecting A (3 mL/s (− 35 to 41)) and Ea (0.4 cm/s (− 0.9 to 1.4)). Liraglutide reduced stroke volume (− 9 mL (− 16 to − 2)) and ejection fraction (− 3% (− 6 to − 0.1)), but did not change cardiac output (− 0.4 L/min (− 0.9 to 0.2)), cardiac index (− 0.1 L/min/m 2 (− 0.4 to 0.1)) and peak ejection rate (− 46 mL/s (− 95 to 3)). Conclusions Liraglutide reduced early LV diastolic filling and LV filling pressure, thereby unloading the left ventricle. LV systolic function reduced and remained within normal range. Future studies are needed to investigate if liraglutide-induced left ventricular unloading slows progression of diabetic cardiomyopathy into symptomatic stages. Trial registration ClinicalTrials.gov: NCT01761318.

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Fig. 1 Trial profile. Patients were randomized with stratification according to sex and insulin use. One patient in liraglutide group withdrew consent before he ever received study drug. This patient was therefore not included in intention-to-treat analysis. In another patient assigned to liraglutide, withdrawal had taken place upon repeated hypoglycaemic events (on further examination this patient had positive anti-glutamic acid decarboxylase autoantibody titer and undetectable c-peptide levels consistent with type 1 diabetes mellitus). In the placebo group, one patient was lost to follow-up because he was in detention. All other patients reached end of study. ITT intention-to-treat
Fig. 1 Trial profile. Patients were randomized with stratification according to sex and insulin use. One patient in liraglutide group withdrew consent before he ever received study drug. This patient was therefore not included in intention-to-treat analysis. In another patient assigned to liraglutide, withdrawal had taken place upon repeated hypoglycaemic events (on further examination this patient had positive anti-glutamic acid decarboxylase autoantibody titer and undetectable c-peptide levels consistent with type 1 diabetes mellitus). In the placebo group, one patient was lost to follow-up because he was in detention. All other patients reached end of study. ITT intention-to-treatCC BY · PubMed Central
Fig. 2 LV diastolic function. Bar graphs of MR-derived indices of LV diastolic function. Blue bars indicate baseline measurement and red bars follow-up. Ea reflects the early peak longitudinal annular motion that is dependent on LV myocardial relaxation. E/Ea is the MR estimate of LV filling pressure. NS not significant
Fig. 2 LV diastolic function. Bar graphs of MR-derived indices of LV diastolic function. Blue bars indicate baseline measurement and red bars follow-up. Ea reflects the early peak longitudinal annular motion that is dependent on LV myocardial relaxation. E/Ea is the MR estimate of LV filling pressure. NS not significantCC BY · PubMed Central
Fig. 3 LV systolic function. Bar graphs of MRI-derived indices of systolic function. Blue bars indicate baseline measurement and red bars follow-up. In the liraglutide group stroke volume decreased, whereas cardiac index remained unchanged because of the increased heart rate. Bpm beats per minute
Fig. 3 LV systolic function. Bar graphs of MRI-derived indices of systolic function. Blue bars indicate baseline measurement and red bars follow-up. In the liraglutide group stroke volume decreased, whereas cardiac index remained unchanged because of the increased heart rate. Bpm beats per minuteCC BY · PubMed Central
Fig. 4 Pressure-volume relation. The LV filling pressure estimate E/Ea plotted against LV end-diastolic pressure (LVEDV). Liraglutide treatment (squares; blue = baseline, red = follow-up) results in a lower E/Ea and LVEDV, whereas placebo treated patients (circles; blue = baseline, red = follow-up) have higher E/Ea and LVEDV at follow-up then at baseline. Note that the shift in pressure volume curve is in opposite directions for liraglutide versus placebo. There was a tendency towards improved compliance in the liraglutide group
Fig. 4 Pressure-volume relation. The LV filling pressure estimate E/Ea plotted against LV end-diastolic pressure (LVEDV). Liraglutide treatment (squares; blue = baseline, red = follow-up) results in a lower E/Ea and LVEDV, whereas placebo treated patients (circles; blue = baseline, red = follow-up) have higher E/Ea and LVEDV at follow-up then at baseline. Note that the shift in pressure volume curve is in opposite directions for liraglutide versus placebo. There was a tendency towards improved compliance in the liraglutide groupCC BY · PubMed Central

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Authors
Bizino, M. B., Jazet, I. M., Westenberg, J. J. M., van Eyk, H. J., Paiman, E. H. M., Smit, J. W. A., & Lamb, H. J.
Affiliations
Leiden University Medical Center (NL)
Corresponding author
Bizino, Maurice B.
ORCID
Venue
Cardiovascular Diabetology
Publisher
Springer Science and Business Media LLC
Published
2019-04-30
Volume
18
Issue
1
Pages
55-55
ISSN
1475-2840 (ISSN-L)
DOI
10.1186/s12933-019-0857-6
PMC
PMC6492440
OpenAlex
W2946264273
Cited by
137
References
42
Citations by year
2026: 8 · 2025: 12 · 2024: 21 · 2023: 20 · 2022: 26 · 2021: 18 · 2020: 25 · 2019: 7
FWCI
15.41
Type
journal article
Language
en
Update notices
correction (2019-08-09)
Open access
Licence
Locations
  • Cardiovascular Diabetology (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Radboud Repository (Radboud University) (submittedVersion, other-oa)
  • Data Archiving and Networked Services (DANS) (submittedVersion)
  • Leiden Repository (Leiden University) (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Radboud Repository (Radboud University) (submittedVersion)
Funders
Novo Nordisk (NA)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Function and Risk Factors
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Failure Treatment and Management
Keywords
liraglutide, type 2 diabetes, diabetic cardiomyopathy, left ventricular diastolic function, left ventricular filling pressure, left ventricular systolic function, cardiac magnetic resonance, GLP-1 receptor agonists, cardioprotection, stroke volume, ejection fraction, cardiac unloading, cardiovascular risk reduction
MeSH terms
Liraglutide, Adolescent, Adult, Aged, Blood Glucose, Diabetes Mellitus, Type 2, Double-Blind Method, Female, Humans, Hypoglycemic Agents, Magnetic Resonance Imaging, Male, Middle Aged, Netherlands, Stroke Volume, Time Factors, Biomarkers, Ventricular Function, Left, Treatment Outcome, Ventricular Pressure, Ventricular Dysfunction, Left, Recovery of Function, Young Adult, Diabetic Cardiomyopathies

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