Metabolic improvement during short-term treatment with a GLP-1 receptor agonist does not improve cardiac diastolic function in patients type 2 diabetes: a randomized double-blind placebo-controlled trial
Authors: Bojer A S , Soerensen M S , Bjerre J , Gaede P , Vejlstrup N , Madsen P L 
Published: October 2021

Abstract

Background/Introduction
The cardioprotective effect of glucagon-like peptide-1 (GLP-1) receptor agonists in patients with type 2 diabetes is still not well explained. In these patients, diastolic dysfunction is significant and linked to outcome, and the cardioprotective effect of GLP-1 receptor agonists may be by improving diastolic function.

Purpose
To investigate if short-term treatment of liraglutide a GLP-1 receptor agonist improves left ventricular diastolic function.

Methods
In an investigator-initiated double-blind randomized placebo-controlled trial the effect of 18 weeks of treatment with liraglutide on diastolic function was assessed in type 2 diabetes patients and echocardiographic signs of diastolic dysfunction (echo-Doppler determined E/e'≥9 or/and lateral e'≤10 cm/sec). Primary outcomes were improved left ventricle filling (the early peak filling rate, ePFR) and left atrium ease of emptying (the passive emptying fraction, LAPEF), assessed by cardiac magnetic resonance imaging at rest and during chronotropic stress (glycopyrrolate 4 mg/kg; a cholinergic receptor antagonist increasing heart rate, and thereby inducing chronotropic stress without also affecting contractility). Secondary outcomes included left ventricular and left atrial volumes and systolic function, measures of aortic stiffness, and echocardiographic diastolic parameters.

Results
Forty patients were randomized to liraglutide s.c. 1.8 mg/day (n=20) or placebo (n=20). Liraglutide reduced HbA1c (−0.47% 95% CI (−0.88 to −0.06)) and weight (−2.9kg 95% CI (−4.6 to −1.2)), both p&lt;0.03). Liraglutide did not change ePFR at rest −24±60 vs. −6±46 ml/sec, during stress 2±58 vs. −2±38 ml/sec, or the changes from rest and stress 12.9±72.5 vs. 4.7±104.0, all p&gt;0.05. LAPEF decreased with liraglutide during stress (median (Q1, Q3)) −3.1 (−9.0, 1.1) vs. 1.0 (−2.9, 6.1) %, p=0.049, but no changes were evident at rest −4.3 (−7.9, 1.9) vs. −0.6 (−3.1, 2.2) %, p=0.19, or for the changes from rest to stress −1.7±8.4 vs. 0.8±8.2, p=0.4. All secondary outcomes were unchanged by liraglutide.

Conclusions
Short-term treatment with liraglutide did not improve diastolic function in patients with type 2 diabetes and echocardiographic signs of diastolic dysfunction. This suggests that the cardioprotective effect seen in long-term studies of liraglutide is not related to the improvement of left ventricular diastolic function.

Funding Acknowledgement
Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): ASB has received funding from the Danish Heart Association [16-R107-A6790-22002, and 18-R125-A8444-22110]. Novo Nordisk supported the study by an unrestricted grant covering the costs of CMR scans and blood analyses. Novo Nordisk provided free study medication and matching placebo pens. None of the funding sources played any role in the process of conduction, interpretation of results or publishing the study Primary OutcomesSecondary Outcomes