Liraglutide reduces cardiac adipose tissue in type 2 diabetes: A secondary analysis of the LIRAFLAME randomized placebo-controlled trial.

AIM: To test the hypothesis that treatment with liraglutide can reduce cardiac adipose tissue. MATERIALS AND METHODS: LIRAFLAME is a randomized placebo-controlled, double-blind, parallel clinical study. Participants with type 2 diabetes were randomized to treatment with liraglutide 1.8 mg/d or placebo for 26 weeks. Computed tomography was performed at baseline and at end of treatment to evaluate the cardiac adipose tissue volume, quantified automatically. We report the results of a secondary endpoint evaluating changes in cardiac adipose tissue. RESULTS: A total of 102 participants were randomly assigned to liraglutide (n = 51) or placebo (n = 51). At baseline, the mean (SD) cardiac adipose tissue volume was comparable between the liraglutide and the placebo group (232.6 [112.8] vs. 227.0 [103.2] mL; P = 0.80). The mean change in body weight was -3.7 (-4.8, -2.6) kg in the liraglutide and -0.18 (-0.76, 0.40) kg in the placebo group. From baseline to end of treatment the mean cardiac adipose tissue change was -11.5 (95% confidence interval -17.6, -5.4) mL in the liraglutide (P < 0.001) and -0.01 (-5.3, 5.3) mL in the placebo (P = 1.00) groups. The reduction in cardiac adipose tissue was significantly greater in the liraglutide compared to the placebo group (mean difference -11.4 [-19.4, -3.3] mL; P = 0.006), but significance was lost after adjustment for changes in body mass index (P = 0.46). CONCLUSION: Treatment with liraglutide for 26 weeks was associated with a reduction in cardiac adipose tissue compared to placebo. The reduction was not independent of weight loss, suggesting that this is not a drug-specific effect.

Ceramides as Risk Markers for Future Cardiovascular Events and All-Cause Mortality in Long-standing Type 1 Diabetes.

Ceramides are lipid molecules involved in inflammation-related signaling. Recent studies have shown that higher amounts of specific circulating ceramides and their ratios are associated with future development of cardiovascular (CV) disease (CVD). We examined the associations between serum ceramide levels with CVD, kidney failure, and all-cause mortality in individuals with long-standing type 1 diabetes (T1D). We included 662 participants with T1D and 6-year follow-up, with a mean age of 55 years and mean diabetes duration of 33 years. Baseline serum samples were analyzed using liquid chromatography-mass spectrometry. Six predefined ceramide levels were measured, and predefined ratios were calculated. Adjusted Cox regression analyses on ceramide levels in relation to future CV events (CVE), kidney failure, and all-cause mortality were performed, with and without adjustment for age, sex, BMI, LDL, triglycerides, systolic blood pressure, HbA1c, history of CVD, smoking status, statin use, estimated glomerular filtration rate (eGFR), and urinary albumin excretion rate (UAER). The ceramide ratio cer(d18:1/18:0)/cer(d18:1/24:0) was significantly associated with risk of CVE (hazard ratio [HR] = 1.33, P = 0.01) and all-cause mortality (HR = 1.48, P = 0.01) before and after adjustments. All five investigated ceramide ratios were associated with kidney failure, before adjusting for the kidney markers eGFR and UAER. In this study, we demonstrate specific ceramides and ratios associated with 6-year cardiovascular risk and all-cause mortality in a T1D cohort. This highlights the strength of ceramide association with vascular complications and presents a new potential tool for early risk assessment if validated in other cohorts. ARTICLE HIGHLIGHTS: Improved tools for assessing risk for diabetes complication before onset will help in complication prevention. We investigated a set of six predefined ceramides and their ratios versus 6-year outcomes of cardiovascular events, kidney failure, and all-cause mortality in people with long-standing type 1 diabetes, using Cox regression with and without adjustment for potential confounders. We found that several ceramides and ceramide ratios associated with cardiovascular events and all-cause mortality. The ratio of cer(d18:1/18:0)/cer(d18:1/24:0) was an especially robust marker. These finding show that ceramides can be biomarkers of cardiovascular disease and all-cause mortality in individuals with long-standing type 1 diabetes.

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

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.