Effect of Liraglutide on Arterial Inflammation Assessed as [ ¹⁸ F]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 [ 18 F]-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 [ 18 F]-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 [ 18 F]-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 [ 18 F]-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.

Ceramides and phospholipids are downregulated with liraglutide treatment: results from the LiraFlame randomized controlled trial

“… Adapted from Ripa et al . 8 Data are n (%), mean (SD) or median [IQR]. Differences in baseline characteristics between the liraglutide and the placebo group were tested using unpaired t-test and the χ2 test.…”

“…Mean changes (95% CI) over the 26 weeks for the liraglutide-treated group compared with placebo in body weight were −3.7 (−4.8 to −2.6) vs −0.18 (−0.76 to 0.40) kg (p<0.0001); and HbA 1c −5.1 (−8.0 to −2.0) vs −0.08 (−1.9 to 1.7) mmol/mol (p=0.006). 8 Mean changes (95% CI) for the liraglutide-treated group compared with placebo for clinical lipid measurements were as follows: LDL-cholesterol 0.06 (−0.17 to 0.30) vs −0.08 (−0.29 to 0.13) mmol/L (p=0.37); 8 HDL-cholesterol 0.06 (0.004 to 0.12) vs 0.05 (−0.02 to 0.11) mmol/L (p=0.72); total cholesterol 0.08 (−0.18 to 0.35) vs −0.03 (−0.26 to 0.21) mmol/L (p=0.54); triglycerides −0.11 (−0.44 to 0.21) vs 0.01 (−0.19 to 0.21) mmol/L (p=0.52).…”

“…The primary end point of the LiraFlame trial, change in vascular inflammation assessed using ¹⁸F-fluorodeoxyglucose PET/CT, was unchanged. 8 …”

“…The primary end point of the trial was change in vascular inflammation assessed using ¹⁸F-fluorodeoxyglucose PET/CT, 8 and here we report results from the secondary end point of change from baseline to week 26 in the lipidome for the liraglutide-treated group compared with placebo. The protocol for this analysis was developed before the last participant was enrolled in the study.…”

“…Mean changes (95% CI) over the 26 weeks for the liraglutide-treated group compared with placebo in body weight were −3.7 (−4.8 to −2.6) vs −0.18 (−0.76 to 0.40) kg (p<0.0001); and HbA 1c −5.1 (−8.0 to −2.0) vs −0.08 (−1.9 to 1.7) mmol/mol (p=0.006). 8 Mean changes (95% CI) for the liraglutide-treated group compared with placebo for clinical lipid measurements were as follows: LDLcholesterol 0.06 (−0.17 to 0.30) vs −0.08 (−0.29 to 0.13) mmol/L (p=0.37); 8 Lipids reduced by liraglutide treatment compared with placebo In total, 260 lipids were identified (figure 1, online supplemental table S1) covering 11 lipid families including ceramides, diglycerides, hexocyl-ceramides, lactosyl ceramides, lysophosphatidylcholines, lysophosphatidylethanolamines, phosphatidylcholines, phosphatidylethanolamines, phosphatidylinositoles, sphingomyelins and triglycerides. Of the 260 lipids, 21 were significantly decreased after liraglutide treatment compared with placebo (figure 1, online supplemental table S1).…”