Decreases in circulating ANGPTL3/8 concentrations following retatrutide treatment parallel reductions in serum lipids

IF 5.7 2区医学 Q1 ENDOCRINOLOGY & METABOLISM

Diabetes, Obesity & Metabolism Pub Date : 2025-07-29 DOI:10.1111/dom.16661

Yi Wen PhD, Deven Lemen BS, Yanzhu Lin PhD, Yan Q. Chen MD, Ajit Regmi BS, William C. Roell PhD, Melissa K. Thomas MD, Mark L. Hartman MD, Tamer Coskun MD, Zvonko Milicevic MD, Axel Haupt MD, Giacomo Ruotolo MD, Robert J. Konrad MD

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Abstract

Aims

The aim of this study was to determine if retatrutide, a triple agonist of glucose-dependent insulinotropic polypeptide (GIP) receptor, glucagon-like peptide 1 (GLP-1) receptor and glucagon (GCG) receptor, may lower serum triglyceride (TG) and low-density lipoprotein cholesterol (LDL-C) levels in part by decreasing circulating concentrations of the angiopoietin-like protein 3/8 complex (ANGPTL3/8).

Materials and Methods

In post-hoc analyses of two phase 2 retatrutide trials, concentrations of ANGPTL3/8, ANGPTL4/8 complex (ANGPTL4/8), ANGPTL3 and ANGPTL4 were measured using dedicated immunoassays to determine percent changes from baseline. Correlations of ANGPTL protein and complex levels with lipid and metabolic parameters at baseline were analysed. Correlations of the changes in ANGPTL protein and complex levels versus the changes in lipid and metabolic parameters at study endpoints were also analysed. Direct effects of retatrutide itself, GIP, GLP-1, GCG and a GCG receptor (GCGR) antagonist antibody on ANGPTL3/8 secretion were studied in vitro using primary human hepatocytes.

Results

ANGPTL3/8 reductions were observed with 8 and 12 mg retatrutide doses in participants with type 2 diabetes, and with 1, 4, 8 and 12 mg retatrutide doses in participants with obesity or overweight but without diabetes. In both cases, ANGPTL3/8 decreases paralleled retatrutide-induced reductions in TG and LDL-C. In primary human hepatocytes, both glucagon and retatrutide decreased ANGPTL3/8 secretion, and these reductions were blocked with the GCGR antagonist antibody.

Conclusions

Together, these results suggest that the GCGR agonism of retatrutide could lead to reduced circulating ANGPTL3/8 concentrations, which may then contribute to decreases in TG and LDL-C levels.

Abstract Image

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利特鲁肽治疗后循环ANGPTL3/8浓度的降低与血脂的平行降低。

目的：本研究的目的是确定利特鲁肽（一种葡萄糖依赖性胰岛素性多肽（GIP）受体、胰高血糖素样肽1 （GLP-1）受体和胰高血糖素（GCG）受体的三重激动剂）是否可能通过降低血管生成素样蛋白3/8复合物（ANGPTL3/8）的循环浓度来降低血清甘油三酯（TG）和低密度脂蛋白胆固醇（LDL-C）水平。材料和方法：在两项利特鲁肽2期试验的事后分析中，使用专用免疫分析法测量ANGPTL3/8、ANGPTL4/8复合物（ANGPTL4/8）、ANGPTL3和ANGPTL4的浓度，以确定与基线相比的百分比变化。分析ANGPTL蛋白和复合物水平与基线时脂质和代谢参数的相关性。还分析了研究终点ANGPTL蛋白和复合物水平变化与脂质和代谢参数变化的相关性。采用体外原代人肝细胞，研究利特鲁肽自身、GIP、GLP-1、GCG及GCG受体（GCGR）拮抗剂抗体对ANGPTL3/8分泌的直接影响。结果：在2型糖尿病患者中，8和12 mg的利特鲁肽剂量可以降低ANGPTL3/8，在肥胖或超重但没有糖尿病的患者中，1、4、8和12 mg的利特鲁肽剂量可以降低ANGPTL3/8。在这两种情况下，ANGPTL3/8的降低与利特鲁肽诱导的TG和LDL-C的降低平行。在原代人肝细胞中，胰高血糖素和利特鲁肽均可降低ANGPTL3/8的分泌，这种降低可被GCGR拮抗剂抗体阻断。结论：综上所述，这些结果表明利特鲁肽的GCGR激动作用可能导致循环ANGPTL3/8浓度降低，从而可能导致TG和LDL-C水平降低。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Diabetes, Obesity & Metabolism 医学-内分泌学与代谢

CiteScore

10.90

自引率

6.90%

发文量

319

审稿时长

3-8 weeks

期刊介绍： Diabetes, Obesity and Metabolism is primarily a journal of clinical and experimental pharmacology and therapeutics covering the interrelated areas of diabetes, obesity and metabolism. The journal prioritises high-quality original research that reports on the effects of new or existing therapies, including dietary, exercise and lifestyle (non-pharmacological) interventions, in any aspect of metabolic and endocrine disease, either in humans or animal and cellular systems. ‘Metabolism’ may relate to lipids, bone and drug metabolism, or broader aspects of endocrine dysfunction. Preclinical pharmacology, pharmacokinetic studies, meta-analyses and those addressing drug safety and tolerability are also highly suitable for publication in this journal. Original research may be published as a main paper or as a research letter.