Genetic Evidence for the Benefits and Risks of Glucose-Lowering Drugs on Cardiovascular-Kidney-Metabolic Syndrome: A Drug-Target Mendelian Randomization Study.

IF 3.7 3区医学 Q1 MEDICINE, GENERAL & INTERNAL

International Journal of Medical Sciences Pub Date : 2026-05-11 eCollection Date: 2026-01-01 DOI:10.7150/ijms.133077

Jian Lu, Shuaigang Sun, Xinru Shang, Shimin Jiang, Zekai Deng, Shunwei Wang, Chenping Wei, Jiaqi Hu, Wenge Li

{"title":"Genetic Evidence for the Benefits and Risks of Glucose-Lowering Drugs on Cardiovascular-Kidney-Metabolic Syndrome: A Drug-Target Mendelian Randomization Study.","authors":"Jian Lu, Shuaigang Sun, Xinru Shang, Shimin Jiang, Zekai Deng, Shunwei Wang, Chenping Wei, Jiaqi Hu, Wenge Li","doi":"10.7150/ijms.133077","DOIUrl":null,"url":null,"abstract":"Background: To explore the potential benefits and risks of glucose-lowering drugs on cardiovascular-kidney-metabolic (CKM) syndrome outcomes using drug-target Mendelian randomization (MR).Methods: Genetic instruments for eight glucose-lowering drugs were identified from variants associated with glycated hemoglobin (HbA1c) and drug target gene expression. We employed two-sample MR and meta-analysis to estimate associations with nine CKM syndrome-related diseases, including coronary artery disease (CAD), myocardial infarction (MI), stroke, heart failure (HF), atrial fibrillation (AF), venous thromboembolism (VTE), peripheral artery disease (PAD), chronic kidney disease (CKD), and metabolic syndrome (MetS), using data from UK Biobank, FinnGen, and other large GWAS consortia. Supplementary analyses included summary-data-based MR (SMR) and colocalization.Results: Genetic proxies for sodium-glucose cotransporter 2 inhibitors (SGLT2i) were associated with reduced risks of CAD (OR 0.85, 95% CI 0.73-0.98), HF (OR 0.66, 95% CI 0.44-0.98), and MetS (OR 0.64, 95% CI 0.50-0.82). GLP-1 receptor agonists (GLP-1RA) were linked to lower risks of CAD (OR 0.90, 95% CI 0.84-0.96), HF (OR 0.92, 95% CI 0.86-0.99), and CKD (OR 0.87, 95% CI 0.79-0.95). Metformin showed protective association with CAD (OR 0.51, 95% CI 0.40-0.66) and PAD (OR 0.99, 95% CI 0.99-1.00). Sulfonylureas showed a modest association with reduced CAD (OR 0.98, 95% CI 0.96-1.00). Conversely, insulin was associated with a higher risk of MetS (OR 1.07, 95% CI 1.02-1.13), and thiazolidinediones (TZDs) with an increased risk of HF (OR 1.12, 95% CI 1.05-1.20). SMR provided additional evidence for protective roles of GLP1R and VEGFA for CAD, KCNJ11 for HF, ABCC8 for HF and AF, and PRKAB1 for multiple cardiovascular outcomes. The detrimental effects of INSR on MetS and SERPINE1 on CKD and MetS were also verified.Conclusions: This study provides genetic evidence revealing the potential benefits and risks of certain glucose-lowering drugs in the management of CKM syndrome. These findings may inform target validation, drug repurposing, and personalized therapies for CKM syndrome.","PeriodicalId":14031,"journal":{"name":"International Journal of Medical Sciences","volume":"23 7","pages":"2197-2208"},"PeriodicalIF":3.7000,"publicationDate":"2026-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13280743/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"International Journal of Medical Sciences","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.7150/ijms.133077","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2026/1/1 0:00:00","PubModel":"eCollection","JCR":"Q1","JCRName":"MEDICINE, GENERAL & INTERNAL","Score":null,"Total":0}

引用次数: 0

Abstract

Background: To explore the potential benefits and risks of glucose-lowering drugs on cardiovascular-kidney-metabolic (CKM) syndrome outcomes using drug-target Mendelian randomization (MR).

Methods: Genetic instruments for eight glucose-lowering drugs were identified from variants associated with glycated hemoglobin (HbA1c) and drug target gene expression. We employed two-sample MR and meta-analysis to estimate associations with nine CKM syndrome-related diseases, including coronary artery disease (CAD), myocardial infarction (MI), stroke, heart failure (HF), atrial fibrillation (AF), venous thromboembolism (VTE), peripheral artery disease (PAD), chronic kidney disease (CKD), and metabolic syndrome (MetS), using data from UK Biobank, FinnGen, and other large GWAS consortia. Supplementary analyses included summary-data-based MR (SMR) and colocalization.

Results: Genetic proxies for sodium-glucose cotransporter 2 inhibitors (SGLT2i) were associated with reduced risks of CAD (OR 0.85, 95% CI 0.73-0.98), HF (OR 0.66, 95% CI 0.44-0.98), and MetS (OR 0.64, 95% CI 0.50-0.82). GLP-1 receptor agonists (GLP-1RA) were linked to lower risks of CAD (OR 0.90, 95% CI 0.84-0.96), HF (OR 0.92, 95% CI 0.86-0.99), and CKD (OR 0.87, 95% CI 0.79-0.95). Metformin showed protective association with CAD (OR 0.51, 95% CI 0.40-0.66) and PAD (OR 0.99, 95% CI 0.99-1.00). Sulfonylureas showed a modest association with reduced CAD (OR 0.98, 95% CI 0.96-1.00). Conversely, insulin was associated with a higher risk of MetS (OR 1.07, 95% CI 1.02-1.13), and thiazolidinediones (TZDs) with an increased risk of HF (OR 1.12, 95% CI 1.05-1.20). SMR provided additional evidence for protective roles of GLP1R and VEGFA for CAD, KCNJ11 for HF, ABCC8 for HF and AF, and PRKAB1 for multiple cardiovascular outcomes. The detrimental effects of INSR on MetS and SERPINE1 on CKD and MetS were also verified.

Conclusions: This study provides genetic evidence revealing the potential benefits and risks of certain glucose-lowering drugs in the management of CKM syndrome. These findings may inform target validation, drug repurposing, and personalized therapies for CKM syndrome.

查看原文本刊更多论文

降血糖药物对心血管-肾-代谢综合征的益处和风险的遗传证据：一项药物靶向孟德尔随机研究。

背景：采用药物靶孟德尔随机化（MR）方法探讨降糖药物对心血管肾代谢综合征（CKM）结局的潜在益处和风险。方法：从与糖化血红蛋白（HbA1c）和药物靶基因表达相关的变异中鉴定出8种降糖药物的遗传仪器。我们采用双样本MR和荟萃分析来估计与九种CKM综合征相关疾病的相关性，包括冠状动脉疾病（CAD）、心肌梗死（MI）、中风、心力衰竭（HF）、心房颤动（AF）、静脉血栓栓塞（VTE）、外周动脉疾病（PAD）、慢性肾脏疾病（CKD）和代谢综合征（MetS），使用的数据来自UK Biobank、FinnGen和其他大型GWAS联盟。补充分析包括基于汇总数据的MR （SMR）和共定位。结果：钠-葡萄糖共转运蛋白2抑制剂（sgltti）的遗传代理与CAD （OR 0.85, 95% CI 0.73-0.98）、HF （OR 0.66, 95% CI 0.44-0.98）和MetS （OR 0.64, 95% CI 0.50-0.82）的风险降低相关。GLP-1受体激动剂（GLP-1RA）与CAD （OR 0.90, 95% CI 0.84-0.96）、HF （OR 0.92, 95% CI 0.86-0.99）和CKD （OR 0.87, 95% CI 0.79-0.95）的风险降低相关。二甲双胍与CAD （OR 0.51, 95% CI 0.40-0.66）和PAD （OR 0.99, 95% CI 0.99-1.00）具有保护作用。磺脲类药物与降低CAD有一定的相关性（OR 0.98, 95% CI 0.96-1.00）。相反，胰岛素与较高的MetS风险相关（OR 1.07, 95% CI 1.02-1.13），噻唑烷二酮类（TZDs）与HF风险增加相关（OR 1.12, 95% CI 1.05-1.20）。SMR为GLP1R和VEGFA对CAD、KCNJ11对HF、ABCC8对HF和AF、PRKAB1对多种心血管结局的保护作用提供了额外的证据。INSR对MetS的有害影响和SERPINE1对CKD和MetS的有害影响也得到证实。结论：本研究提供了遗传学证据，揭示了某些降糖药物在CKM综合征治疗中的潜在益处和风险。这些发现可能为CKM综合征的靶点验证、药物再利用和个性化治疗提供信息。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

International Journal of Medical Sciences MEDICINE, GENERAL & INTERNAL-

CiteScore

7.20

自引率

0.00%

发文量

185

审稿时长

2.7 months

期刊介绍： Original research papers, reviews, and short research communications in any medical related area can be submitted to the Journal on the understanding that the work has not been published previously in whole or part and is not under consideration for publication elsewhere. Manuscripts in basic science and clinical medicine are both considered. There is no restriction on the length of research papers and reviews, although authors are encouraged to be concise. Short research communication is limited to be under 2500 words.