CETP and SGLT2 inhibitor combination therapy improves glycemic control.
CETP and SGLT2 inhibitor combination therapy improves glycemic control.
复制标题
CETP 和 SGLT2 抑制剂联合治疗可改善血糖控制。
DOI：
10.1101/2023.06.13.23291357
复制
发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Davidson,MichaelH
中科院分区：
文献类型：
--
作者：
Khomtchouk,BohdanB;Sun,Patrick;Ditmarsch,Marc;Kastelein,JohnJP;Davidson,MichaelH
重要性：在过去探索其治疗心血管疾病功效的临床试验中，胆固醇酯转移蛋白 (CETP) 抑制与降低新发糖尿病风险相关，并且有可能重新用于治疗代谢疾病。值得注意的是，作为一种口服药物，它可以在患者需要服用胰岛素等注射药物之前补充现有的口服药物，例如钠-葡萄糖协同转运蛋白 2 (SGLT2) 抑制剂。目的：确定 CETP 抑制剂是否可以作为 SGLT2 抑制的口服附加药物来改善血糖控制。设计、设置和参与者：对具有欧洲血统的英国生物银行参与者的一般人群进行 2×2 阶乘孟德尔随机化 (MR)。暴露：先前构建的 CETP 和 SGLT2 功能的遗传评分被组合在 2×2 因子框架中，以表征联合 CETP 和 SGLT2 抑制与单独抑制之间的关联。主要结果和指标：糖化血红蛋白和 2 型糖尿病发病率。结果：233,765 名英国生物银行参与者的数据表明，CETP 和 SGLT2 基因抑制的个体的糖化血红蛋白水平 (mmol/mol) 显着低于对照（效应大小：-0.136；95% CI：-0.190 至 -0.081；p 值：1.09E-06），单独抑制 SGLT2 （效应值：-0.082；95% CI：-0.140 至 -0.024；p 值：0.00558），以及单独使用 CETP 抑制（效应值：-0.08479；95% CI：-0.136 至 -0.033；p 值：0.00118）。此外，与对照相比，CETP和SGLT2联合抑制与糖尿病发病率降低（对数比值比）相关（效应值：-0.068；95% CI：-0.115至-0.021；p值：4.44E-03）和单独抑制SGLT2（效应值：-0.062；95% CI：-0.062；95% CI： -0.112至-0.012； p 值：0.0149）。结论和相关性：我们的结果表明，与单独使用 SGLT2 抑制剂相比，CETP 和 SGLT2 抑制剂治疗可以改善血糖控制。未来的临床试验可以探索 CETP 抑制剂是否可以重新用于治疗代谢性疾病，并在升级为胰岛素或胰高血糖素样肽 1 (GLP1) 受体激动剂等注射药物之前提供口服治疗选择，使高危患者受益。
Importance: Cholesteryl ester transfer protein (CETP) inhibition has been associated with decreased risk of new-onset diabetes in past clinical trials exploring their efficacy in cardiovascular disease and can potentially be repurposed to treat metabolic disease. Notably, as an oral drug it can potentially be used to supplement existing oral drugs such as sodium-glucose cotransporter 2 (SGLT2) inhibitors before patients are required to take injectable drugs such as insulin. Objective: To identify whether CETP inhibitors could be used as an oral add-on to SGLT2 inhibition to improve glycemic control. Design, Setting, and Participants: 2×2 factorial Mendelian Randomization (MR) is performed on the general population of UK Biobank participants with European ancestry. Exposures: Previously constructed genetic scores for CETP and SGLT2 function are combined in a 2×2 factorial framework to characterize the associations between joint CETP and SGLT2 inhibition compared to either alone. Main Outcomes and Measures: Glycated hemoglobin and type-2 diabetes incidence. Results: Data on 233,765 UK Biobank participants suggests that individuals with genetic inhibition of both CETP and SGLT2 have significantly lower glycated hemoglobin levels (mmol/mol) than control (Effect size: −0.136; 95% CI: −0.190 to −0.081; p-value: 1.09E-06), SGLT2 inhibition alone (Effect size: −0.082; 95% CI: −0.140 to −0.024; p-value: 0.00558), and CETP inhibition alone (Effect size: −0.08479; 95% CI: −0.136 to −0.033; p-value: 0.00118). Furthermore, joint CETP and SGLT2 inhibition is associated with decreased incidence of diabetes (log-odds ratio) compared to control (Effect size: −0.068; 95% CI: −0.115 to −0.021; p-value: 4.44E-03) and SGLT2 inhibition alone (Effect size: −0.062; 95% CI: −0.112 to −0.012; p-value: 0.0149). Conclusions and Relevance: Our results suggest that CETP and SGLT2 inhibitor therapy may improve glycemic control over SGLT2 inhibitors alone. Future clinical trials can explore whether CETP inhibitors can be repurposed to treat metabolic disease and provide an oral therapeutic option to benefit high-risk patients before escalation to injectable drugs such as insulin or glucagon-like peptide 1 (GLP1) receptor agonists.