Effect of Liraglutide on Arterial Inflammation Assessed as [18F]FDG Uptake in Patients With Type 2 Diabetes: A Randomized, Double-Blind, Placebo-Controlled Trial

Abstract

Background: The mechanism behind the cardiovascular protection observed with human GLP-1 RA (glucagon-like peptide-1 receptor agonists) in type 2 diabetes is unknown. We hypothesized that treatment with the GLP-1 RA liraglutide had a positive effect on vascular inflammation.

Methods: LIRAFLAME (Effect of liraglutide on vascular inflammation in type-2 diabetes: A randomized, placebocontrolled, double-blind, parallel clinical PET/CT trial) was a double-blind, randomized controlled trial performed at a single university hospital clinic in Denmark. Patients with type 2 diabetes were via computer-generated randomization list assigned (1:1) liraglutide up to 1.8 mg or placebo once daily for 26 weeks. The primary end point was change in vascular inflammation over 26 weeks assessed by [¹⁸F]-fluorodeoxyglucose positron emission tomography/computed tomography. Analyses were based on intention-to-treat. Key secondary outcomes included change in other indices of atherosclerosis.

Results: Between October 26, 2017, and August 16, 2019, 147 patients were screened and 102 were randomly assigned to liraglutide (n=51) or placebo (n=51) and 99 (97%) completed the trial. Change in the [¹⁸F]-fluorodeoxyglucose positron emission tomography measure of vascular inflammation (active-segment target-to-background ratio) did not differ between treatment groups: change from baseline to 26 weeks was -0.04 (95% CI, -0.17 to 0.08) in the liraglutide group compared with -0.09 (-0.19 to 0.01) in the placebo group (mean difference, 0.05 [95% CI, -0.11 to 0.21], P=0.53). Secondary analyses restricted to [¹⁸F]-fluorodeoxyglucose positron emission tomography of the carotid arteries as well as other indices of atherosclerosis confirmed the primary result. We performed an explorative analysis of interaction between treatment group and history of cardiovascular disease (P=0.052).

Conclusions: In this low to moderate risk population with type 2 diabetes, liraglutide did not change vascular inflammation assessed as [¹⁸F]-fluorodeoxyglucose uptake compared with placebo. An explorative analysis indicated a possible effect in persons with history of cardiovascular disease, in line with current guidelines where liraglutide is recommended to patients with history of cardiovascular disease. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03449654.

Keywords: Type 2 Diabetes; atherosclerosis; cardiovascular diseases; carotid arteries; glucagon-like peptide 1; inflammation.

Figure 1.

[¹⁸F]fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) imaging approach. The abdominal aorta, the thoracic aorta, and the carotid arteries were identified and manually traced with free hand or ellipse regions of interest (ROI) on all axial CT images without use of the PET images. Afterwards the ROIs were copied onto the spatially aligned PET examination as shown in the figure. The FDG uptake was quantified in each ROI as the standardized uptake value (SUV) by measuring a maximum pixel activity value (SUVmax). Target-to-background ratio was finally calculated as a ratio of SUVmax and the average blood SUV estimated from venous blood in the superior cava vein or the jugular vein.

Figure 2.

Trial profile. eGFR indicates estimated glomerular filtration rate.

Figure 3.

Arterial inflammation evaluated with [¹⁸F]fluorodeoxyglucose (FDG)-positron emission tomography (PET) in the liraglutide and the placebo-treated group. A, Mean change from baseline to end-of-treatment in active segments target-to-background ratio for the liraglutide group and the placebo group (primary end point). Mean plots with SE. Unpaired t test for comparison. B, Representative [¹⁸F]FDG-PET/computed tomography images from a participant treated with liraglutide. The ascending thoracic aorta is outlined at baseline and follow-up examination.

Figure 4.

Arterial inflammation evaluated with [18F]fluorodeoxyglucose (FDG)-positron emission tomography (PET) in the subgroup of patients with and without cardiovascular disease. Mean change from baseline to end-of-treatment in most diseased segment target-to-background ratio for the liraglutide group and the placebo group in subgroups of patients with and without cardiovascular disease (CVD). Mean plots with SE. Unpaired t test for comparison of the change from baseline to end-of-treatment between the groups.