Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Clinical Trial
. 2024 Aug 6;84(6):540-557.
doi: 10.1016/j.jacc.2024.04.064.

Liraglutide Improves Myocardial Perfusion and Energetics and Exercise Tolerance in Patients With Type 2 Diabetes

Amrit Chowdhary  1 , Sharmaine Thirunavukarasu  1 , Tobin Joseph  1 , Nicholas Jex  1 , Sindhoora Kotha  1 , Marilena Giannoudi  1 , Henry Procter  1 , Lizette Cash  1 , Sevval Akkaya  1 , David Broadbent  1 , Hui Xue  2 , Peter Swoboda  1 , Ladislav Valkovič  3 , Peter Kellman  2 , Sven Plein  1 , Oliver J Rider  4 , Stefan Neubauer  4 , John P Greenwood  5 , Eylem Levelt  6
Affiliations
Clinical Trial

Liraglutide Improves Myocardial Perfusion and Energetics and Exercise Tolerance in Patients With Type 2 Diabetes

Amrit Chowdhary et al. J Am Coll Cardiol. .

Abstract

Background: Type 2 diabetes (T2D) is characterized by insulin resistance (IR) and dysregulated insulin secretion. Glucagon-like peptide-1 receptor agonist liraglutide promotes insulin secretion, whereas thiazolidinedione-pioglitazone decreases IR.

Objectives: This study aimed to compare the efficacies of increasing insulin secretion vs decreasing IR strategies for improving myocardial perfusion, energetics, and function in T2D via an open-label randomized crossover trial.

Methods: Forty-one patients with T2D (age 63 years [95% CI: 59-68 years], 27 [66%] male, body mass index 27.8 kg/m2) [95% CI: 26.1-29.5 kg/m2)]) without cardiovascular disease were randomized to liraglutide or pioglitazone for a 16-week treatment followed by an 8-week washout and a further 16-week treatment with the second trial drug. Participants underwent rest and dobutamine stress 31phosphorus magnetic resonance spectroscopy and cardiovascular magnetic resonance for measuring the myocardial energetics index phosphocreatine to adenosine triphosphate ratio, myocardial perfusion (rest, dobutamine stress myocardial blood flow, and myocardial perfusion reserve), left ventricular (LV) volumes, systolic and diastolic function (mitral in-flow E/A ratio), before and after treatment. The 6-minute walk-test was used for functional assessments.

Results: Pioglitazone treatment resulted in significant increases in LV mass (96 g [95% CI: 68-105 g] to 105 g [95% CI: 74-115 g]; P = 0.003) and mitral-inflow E/A ratio (1.04 [95% CI: 0.62-1.21] to 1.34 [95% CI: 0.70-1.54]; P = 0.008), and a significant reduction in LV concentricity index (0.79 mg/mL [95% CI: 0.61-0.85 mg/mL] to 0.73 mg/mL [95% CI: 0.56-0.79 mg/mL]; P = 0.04). Liraglutide treatment increased stress myocardial blood flow (1.62 mL/g/min [95% CI: 1.19-1.75 mL/g/min] to 2.08 mL/g/min [95% CI: 1.57-2.24 mL/g/min]; P = 0.01) and myocardial perfusion reserve (2.40 [95% CI: 1.55-2.68] to 2.90 [95% CI: 1.83-3.18]; P = 0.01). Liraglutide treatment also significantly increased the rest (1.47 [95% CI: 1.17-1.58] to 1.94 [95% CI: 1.52-2.08]; P =0.00002) and stress phosphocreatine to adenosine triphosphate ratio (1.32 [95% CI: 1.05-1.42] to 1.58 [95% CI: 1.19-1.71]; P = 0.004) and 6-minute walk distance (488 m [95% CI: 458-518 m] to 521 m [95% CI: 481-561 m]; P = 0.009).

Conclusions: Liraglutide treatment resulted in improved myocardial perfusion, energetics, and 6-minute walk distance in patients with T2D, whereas pioglitazone showed no effect on these parameters (Lean-DM [Targeting Beta-cell Failure in Lean Patients With Type 2 Diabetes]; NCT04657939).

Keywords: cardiovascular magnetic resonance imaging; glucagon like peptide 1 receptor agonists; liraglutide; magnetic resonance spectroscopy, pioglitazone; type 2 diabetes.

PubMed Disclaimer

Conflict of interest statement

Funding Support and Author Disclosures The views expressed are those of the author(s) and not necessarily those of the Wellcome Trust, the NHS, the NIHR, or the Department of Health and Social Care. This independent research has been jointly funded by the Wellcome Trust (grant number: 221690/Z/20/Z) and Diabetes UK (grant number:18/0005870) and has been performed at the National Institute for Health and Care Research (NIHR) Leeds Biomedical Research Centre (BRC) (NIHR203331). Funding for open access charge is from Wellcome Trust (grant number: 221690/Z/20/Z). Dr Chowdhary has received grants from the British Heart Foundation (grant number: FS/CRTF/20/24003). Dr Valkovič has received grants from the Sir Henry Dale Fellowship supported jointly by the Wellcome Trust and the Royal Society (#221805/Z/20/Z), and Slovak Grant Agencies VEGA (#2/0004/23) and APVV (#21-0299). Dr Levelt acknowledges support from the Wellcome Trust Clinical Career Development Fellowship (grant number: 221690/Z/20/Z), Diabetes UK (grant number: UK 18/0005908) and the NIHR Leeds Biomedical Research Centre. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Figures

Figure 1:
Figure 1:. Cardiac 31phosphorus magnetic resonance spectroscopy (31P-MRS) protocol
After the completion of rest chemical shift imaging (CSI) acquisition, dobutamine was infused at incremental doses between 10 and 40μg/kg/min as necessary to achieve the target heart rate of 65% maximum (maximum heart rate calculated as 220 – age). The figure shows representative rest and dobutamine stress cardiac phosphorus spectra images. 2,3-DPG indicates 2,3-diphosphoglycerate; ATP, adenosine triphosphate; PCr, phosphocreatine; PDE, phosphodiesters.
Figure 2:
Figure 2:. Multiparametric scan protocol.
Magnetic resonance imaging (MRI) protocol consisted of thoracic and abdominal water/fat images using a non-breath-hold multi-echo gradient echo (GRE) sequence, followed by cardiac cine imaging, pre- and post-contrast T1 mapping, perfusion imaging, velocity-encoded mitral in-flow imaging, and late gadolinium enhancement (LGE) imaging. Cine images, perfusion imaging and velocity-encoded mitral in-flow imaging were repeated at target heart rate of 65% maximum (maximum heart rate calculated as 220 – age) using an identical dobutamine infusion protocol to that of the dobutamine stress cardiac 31phosphorus magnetic resonance spectroscopy (31P-MRS) acquisition. The figure shows representative images from indicated cardiac sequences. LV indicates left ventricular.
Figure 3:
Figure 3:. Consort flow diagram
Consort flow diagram showing the recruitment pathway with details of numbers of study patients with type 2 diabetes who were screened, assessed and randomised, followed allocated treatment and completed follow-up, and were included in data analysis.
Figure 4:
Figure 4:. Myocardial changes due to the study medications
Box and Whisker plots demonstrating changes in (A) dobutamine stress myocardial blood flow (MBF), (B) myocardial perfusion reserve index (MPRI), (C) rest phosphocreatine to ATP ratio (PCr/ATP) and D) dobutamine stress PCr/ATP in the two treatment arms of the study.
Central illustration:
Central illustration:. Changes in myocardial biomarkers due to treatment with liraglutide or pioglitazone.
Central illustration representing the study aims, design, findings and clinical implications. A significant increase in myocardial perfusion reserve index and myocardial energetics index as measured by PCr/ATP was seen after 16 weeks of liraglutide therapy for 16 weeks.
See this image and copyright information in PMC

References

    1. Rawshani A, Rawshani A, Franzén S et al. Risk Factors, Mortality, and Cardiovascular Outcomes in Patients with Type 2 Diabetes. New England Journal of Medicine 2018;379:633–644. - PubMed
    1. Marwick TH, Gimelli A, Plein S et al. Multimodality imaging approach to left ventricular dysfunction in diabetes: an expert consensus document from the European Association of Cardiovascular Imaging. European Heart Journal - Cardiovascular Imaging 2022;23:e62–e84. - PubMed
    1. Sattar N, Lee MMY, Kristensen SL et al. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of randomised trials. The Lancet Diabetes & Endocrinology 2021;9:653–662. - PubMed
    1. Dahl K, Brooks A, Almazedi F et al. Oral semaglutide improves postprandial glucose and lipid metabolism, and delays gastric emptying, in subjects with type 2 diabetes. Diabetes, Obesity and Metabolism 2021;23:1594–1603. - PMC - PubMed
    1. Helen S, Solomon C, Maila M et al. Pioglitazone and cause-specific risk of mortality in patients with type 2 diabetes: extended analysis from a European multidatabase cohort study. BMJ Open Diabetes Research & Care 2018;6:e000481. - PMC - PubMed

Publication types

MeSH terms

Associated data