Introduction Treatment with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) can reduce risk of cardiovascular disease (CVD) in persons living with type 2 diabetes, however the mechanisms explaining this cardiovascular benefit are still debated. We investigated changes in the plasma lipidome following treatment with the GLP-1 RA liraglutide. Research design and methods In a double-blind placebo-controlled trial, we randomized 102 persons with type 2 diabetes to liraglutide or placebo for 26 weeks. Fasting blood plasma was collected at baseline and at end-of-treatment. The lipidome was measured using liquid-chromatography-coupled mass-spectrometry as a secondary end point in the study. Treatment response of each lipid was tested with lipid-specific linear mixed-effect models comparing liraglutide with placebo. Bonferroni p<7.1e-03 was employed. The independence of the findings from clinical covariates was evaluated with adjustment for body mass index, HbA1c, fasting status, lipid-lowering treatment and change in lipid-lowering treatment during the trial. Results In total, 260 lipids were identified covering 11 lipid families. We observed significant decreases following liraglutide treatment compared with placebo in 21 lipids (p<7.1e-03) from the following lipid families: ceramides, hexocyl-ceramides, phosphatidylcholines, phosphatidylethanolamines and triglycerides. We confirmed these findings in adjusted models (p≤0.01). In the liraglutide-treated group, the individual lipids were reduced in the range of 14%–61% from baseline level, compared with 19% decrease to 27% increase from baseline level in the placebo group. Conclusions Compared with placebo, liraglutide treatment led to a significant downregulation in ceramides, phospholipids and triglycerides, which all are linked to higher risk of CVD. These findings were independent of relevant clinical covariates. Our findings are hypothesis generating and shed light on the biological mechanisms underlying the cardiovascular benefits observed with GLP-1 RAs in outcome studies, and further strengthen the evidence base for recommending GLP-1 RAs to prevent CVD in type 2 diabetes. Trial registration number [NCT03449654][1]. Data are available upon reasonable request. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT03449654&atom=%2Fbmjdrc%2F9%2F1%2Fe002395.atom

中文翻译：

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利拉鲁肽治疗下调神经酰胺和磷脂：来自 LiraFlame 随机对照试验的结果

引言 使用胰高血糖素样肽 1 受体激动剂 (GLP-1 RA) 进行治疗可以降低 2 型糖尿病患者患心血管疾病 (CVD) 的风险，但解释这种心血管益处的机制仍存在争议。我们研究了 GLP-1 RA 利拉鲁肽治疗后血浆脂质组的变化。研究设计和方法 在一项双盲安慰剂对照试验中，我们将 102 名 2 型糖尿病患者随机分配至利拉鲁肽组或安慰剂组，为期 26 周。在基线和治疗结束时收集空腹血浆。使用液相色谱-偶联质谱法作为研究的次要终点测量脂质组。使用脂质特异性线性混合效应模型测试每种脂质的治疗反应，比较利拉鲁肽与安慰剂。邦费罗尼 p<7。采用1e-03。通过调整体重指数、HbA1c、空腹状态、降脂治疗和试验期间降脂治疗的变化来评估结果与临床协变量的独立性。结果共鉴定出260种脂质，涵盖11个脂质家族。我们观察到，与安慰剂相比，利拉鲁肽治疗后在来自以下脂质家族的 21 种脂质 (p<7.1e-03) 中显着降低：神经酰胺、己基神经酰胺、磷脂酰胆碱、磷脂酰乙醇胺和甘油三酯。我们在调整后的模型中证实了这些发现（p≤0.01）。在利拉鲁肽治疗组中，个体血脂较基线水平降低 14%–61%，而安慰剂组较基线水平降低 19% 至 27%。结论 与安慰剂相比，利拉鲁肽治疗导致神经酰胺、磷脂和甘油三酯的显着下调，这些都与更高的心血管疾病风险有关。这些发现独立于相关的临床协变量。我们的发现是假设的产生，并阐明了在结果研究中观察到的 GLP-1 RA 心血管益处背后的生物学机制，并进一步加强了推荐 GLP-1 RA 预防 2 型糖尿病患者心血管疾病的证据基础。试验注册号 [NCT03449654][1]。可应合理要求提供数据。[1]：/lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT03449654&atom=%2Fbmjdrc%2F9%2F1%2Fe002395.atom 这些发现独立于相关的临床协变量。我们的发现是假设的产生并阐明了在结果研究中观察到的 GLP-1 RA 心血管益处的生物学机制，并进一步加强了推荐 GLP-1 RA 预防 2 型糖尿病患者心血管疾病的证据基础。试验注册号 [NCT03449654][1]。可应合理要求提供数据。[1]：/lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT03449654&atom=%2Fbmjdrc%2F9%2F1%2Fe002395.atom 这些发现独立于相关的临床协变量。我们的发现是假设的产生，并阐明了在结果研究中观察到的 GLP-1 RA 心血管益处背后的生物学机制，并进一步加强了推荐 GLP-1 RA 预防 2 型糖尿病患者心血管疾病的证据基础。试验注册号 [NCT03449654][1]。可应合理要求提供数据。[1]：/lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT03449654&atom=%2Fbmjdrc%2F9%2F1%2Fe002395.atom 试验注册号 [NCT03449654][1]。可应合理要求提供数据。[1]：/lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT03449654&atom=%2Fbmjdrc%2F9%2F1%2Fe002395.atom 试验注册号 [NCT03449654][1]。可应合理要求提供数据。[1]：/lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT03449654&atom=%2Fbmjdrc%2F9%2F1%2Fe002395.atom