背景:降脂药和抗高血压药通常用于心血管疾病(CVD)。然而,联合用药与CVD的关系仍存在争议.我们旨在探讨降脂药和降压药的基因代理药物之间的关联,要么单独,要么两者兼而有之,有心血管疾病的风险,其他临床和安全性结果。
方法:我们通过降脂药物和降压药物的中位遗传评分,将英国生物银行的423,821名个体分为4组:降低低密度脂蛋白胆固醇(LDL-C)由他汀类药物或前蛋白转化酶枯草杆菌蛋白酶/kexin9型(PCSK9)抑制剂的靶标介导,通过β受体阻滞剂(BBs)或钙通道阻滞剂(CCB)的靶标介导的较低收缩压(SBP),结合基因降低的LDL-C和SBP,和参考(遗传较高的LDL-C和SBP)。在阶乘孟德尔随机化中,在每组中探索了与CVD风险和其他临床结局的关联。
结果:在心血管疾病(包括冠状动脉疾病,中风,和外周动脉疾病)和其他临床结果(缺血性卒中,出血性中风,心力衰竭,糖尿病,慢性肾病,和痴呆)(所有结局的交互作用P>0.05)。以PCSK9抑制剂和BBs对CVD的影响为例:与参考文献相比,PCSK9组患CVD的风险降低4%(比值比[OR],0.96;95CI,0.94-0.99),在BBs组中观察到3%的风险降低(OR,0.97;95CI,0.94-0.99),两者结合起来,风险降低6%(OR,0.94;95CI,0.92-0.97;相互作用P=0.87)。
结论:降脂和抗高血压联合用药的遗传代理药物对CVD具有独立和累加作用,其他临床和安全性结果,对CVD临床实践有影响,随后的试验以及息肉的药物开发。
BACKGROUND: Lipid-lowering drugs and antihypertensive drugs are commonly combined for cardiovascular disease (CVD). However, the relationship of combined medications with CVD remains controversial. We aimed to explore the associations of genetically proxied medications of lipid-lowering and antihypertensive drugs, either alone or both, with risk of CVD, other clinical and safety outcomes.
METHODS: We divided 423,821 individuals in the UK Biobank into 4 groups via median genetic scores for targets of lipid-lowering drugs and antihypertensive drugs: lower low-density lipoprotein cholesterol (LDL-C) mediated by targets of statins or proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, lower systolic blood pressure (SBP) mediated by targets of β-blockers (BBs) or calcium channel blockers (CCBs), combined genetically lower LDL-C and SBP, and reference (genetically both higher LDL-C and SBP). Associations with risk of CVD and other clinical outcomes were explored among each group in factorial Mendelian randomization.
RESULTS: Independent and additive effects were observed between genetically proxied medications of lipid-lowering and antihypertensive drugs with CVD (including coronary artery disease, stroke, and peripheral artery diseases) and other clinical outcomes (ischemic stroke, hemorrhagic stroke, heart failure, diabetes mellitus, chronic kidney disease, and dementia) (P > 0.05 for interaction in all outcomes). Take the effect of PCSK9 inhibitors and BBs on CVD for instance: compared with the reference, PCSK9 group had a 4% lower risk of CVD (odds ratio [OR], 0.96; 95%CI, 0.94-0.99), and a 3% lower risk was observed in BBs group (OR, 0.97; 95%CI, 0.94-0.99), while combined both were associated with a 6% additively lower risk (OR, 0.94; 95%CI, 0.92-0.97; P = 0.87 for interaction).
CONCLUSIONS: Genetically proxied medications of combined lipid-lowering and antihypertensive drugs have an independent and additive effects on CVD, other clinical and safety outcomes, with implications for CVD clinical practice, subsequent trials as well as drug development of polypills.