Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, 211166, China.
Department of Epidemiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, China.
BMC Med. 2024 May 20;22(1):201. doi: 10.1186/s12916-024-03407-x.
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.
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.
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).
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.
降脂药和降压药通常联合用于心血管疾病（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药物遗传学指标单独或联合与 CVD 风险以及其他临床和安全性结局的相关性。
我们通过他汀类药物或前蛋白转化酶枯草溶菌素/糜蛋白酶 9（PCSK9）抑制剂靶点降低 LDL-C、β受体阻滞剂（BB）或钙通道阻滞剂（CCB）靶点降低收缩压（SBP）、联合降低 LDL-C 和 SBP 的遗传指标以及参考（遗传上 LDL-C 和 SBP 均较高）的降血脂和降压药物的中位数遗传评分，将英国生物库中的 423821 个人分为 4 组。在每个组中，通过因子 Mendelian 随机化探讨与 CVD 及其他临床结局的相关性。
降脂药和降压药的遗传药物之间存在独立和累加的作用与 CVD（包括冠状动脉疾病、中风和外周动脉疾病）和其他临床结局（缺血性中风、出血性中风、心力衰竭、糖尿病、慢性肾脏病和痴呆）之间存在独立和累加的作用（所有结局的交互作用 P 值均>0.05）。以 PCSK9 抑制剂和 BB 对 CVD 的作用为例：与参考组相比，PCSK9 组 CVD 风险降低 4%（比值比 [OR]，0.96；95%置信区间 [CI]，0.94-0.99），BB 组风险降低 3%（OR，0.97；95%CI，0.94-0.99），而联合使用则与风险降低 6%相关（OR，0.94；95%CI，0.92-0.97；交互作用 P 值=0.87）。
降脂和降压联合用药的药物遗传学指标对 CVD、其他临床和安全性结局具有独立和累加的作用，对 CVD 临床实践、后续试验以及复方药的药物开发具有重要意义。
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