Estimating the effect of lipid-lowering agents on novel subtypes of adult-onset diabetes

IF 4.6 2区医学 Q1 ENDOCRINOLOGY & METABOLISM

Diabetes/Metabolism Research and Reviews Pub Date : 2024-04-25 DOI:10.1002/dmrr.3793

Jianan Ye, Keyu Guo, Jiaqi Li, Xia Li, Zhiguang Zhou, Lin Yang

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Abstract

Aims

The aims of the present study were to assess the effects of lipid-lowering drugs [HMG-CoA reductase inhibitors, proprotein convertase subtilisin/kexin type 9 inhibitors, and Niemann–Pick C1-Like 1 (NPC1L1) inhibitors] on novel subtypes of adult-onset diabetes through a Mendelian randomisation study.

Materials and Methods

We first inferred causal associations between lipid-related traits [including high-density lipoprotein cholesterol, low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), apolipoproteins A-I, and apolipoproteins B] and novel subtypes of adult-onset diabetes. The expression quantitative trait loci of drug target genes for three classes of lipid-lowering drugs, as well as genetic variants within or nearby drug target genes associated with LDL-C, were then utilised as proxies for the exposure of lipid-lowering drugs. Mendelian randomisation analysis was performed using summary data from genome-wide association studies of LDL-C, severe autoimmune diabetes, severe insulin-deficient diabetes (SIDD), severe insulin-resistant diabetes (SIRD), mild obesity-related diabetes (MOD), and mild age-related diabetes.

Results

There was an association between HMGCR-mediated LDL-C and the risk of SIRD [odds ratio (OR) = 0.305, 95% confidence interval (CI) = 0.129–0.723; p = 0.007], and there was an association of PCSK9-mediated LDL-C with the risk of SIDD (OR = 0.253, 95% CI = 0.120–0.532; p < 0.001) and MOD (OR = 0.345, 95% CI = 0.171–0.696; p = 0.003). Moreover, NPC1L1-mediated LDL-C (OR = 0.109, 95% CI = 0.019–0.613; p = 0.012) and the increased expression of NPC1L1 gene in blood (OR = 0.727, 95% CI = 0.541–0.977; p = 0.034) both showed a significant association with SIRD. These results were further confirmed by sensitivity analyses.

Conclusions

In summary, the different lipid-lowering medications have a specific effect on the increased risk of different novel subtypes of adult-onset diabetes.

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估算降脂药对成人型糖尿病新亚型的影响

研究目的本研究旨在通过孟德尔随机研究评估降脂药物[HMG-CoA 还原酶抑制剂、蛋白转换酶枯草酶/kexin 9 型抑制剂和 Niemann-Pick C1-Like 1 (NPC1L1) 抑制剂]对成年型糖尿病新亚型的影响。材料与方法我们首先推断了血脂相关性状（包括高密度脂蛋白胆固醇、低密度脂蛋白胆固醇（LDL-C）、甘油三酯（TG）、载脂蛋白 A-I 和载脂蛋白 B）与成年型糖尿病新亚型之间的因果关系。然后利用三类降脂药物靶基因的表达定量性状位点，以及与低密度脂蛋白胆固醇相关的药物靶基因内或附近的遗传变异，作为降脂药物暴露的替代物。利用低密度脂蛋白胆固醇、严重自身免疫性糖尿病、严重胰岛素缺乏性糖尿病（SIDD）、严重胰岛素抵抗性糖尿病（SIRD）、轻度肥胖相关性糖尿病（MOD）和轻度年龄相关性糖尿病的全基因组关联研究的汇总数据进行了孟德尔随机分析。结果 HMGCR介导的低密度脂蛋白胆固醇（LDL-C）与 SIRD 风险之间存在关联[几率比（OR）= 0.305，95% 置信区间（CI）= 0.129-0.723; p = 0.007]，PCSK9介导的LDL-C与SIDD（OR = 0.253，95% CI = 0.120-0.532; p <0.001）和MOD（OR = 0.345，95% CI = 0.171-0.696; p = 0.003）的风险存在关联。此外，NPC1L1 介导的低密度脂蛋白胆固醇（OR = 0.109，95% CI = 0.019-0.613；p = 0.012）和血液中 NPC1L1 基因表达的增加（OR = 0.727，95% CI = 0.541-0.977；p = 0.034）均与 SIRD 有显著关联。敏感性分析进一步证实了这些结果。结论总之，不同的降脂药物对不同新型亚型成人型糖尿病风险的增加有特定的影响。

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/Metabolism Research and Reviews 医学-内分泌学与代谢

CiteScore

17.20

自引率

2.50%

发文量

审稿时长

4-8 weeks

期刊介绍： Diabetes/Metabolism Research and Reviews is a premier endocrinology and metabolism journal esteemed by clinicians and researchers alike. Encompassing a wide spectrum of topics including diabetes, endocrinology, metabolism, and obesity, the journal eagerly accepts submissions ranging from clinical studies to basic and translational research, as well as reviews exploring historical progress, controversial issues, and prominent opinions in the field. Join us in advancing knowledge and understanding in the realm of diabetes and metabolism.