Two randomized genetic studies revealed that PCSK9 variants were associated with an increased risk of type 2 diabetes (T2D) and protective effects on the risk of cardiovascular diseases. The first study found that variants in PCSK9 (the target of PCSK9 inhibitors) and HMGCR (the target of statins) were associated with nearly identical protective effects on the risk of cardiovascular events per decrease of 10 mg per deciliter (0.26 mmol per liter) in the LDL cholesterol level: odds ratio (OR) for cardiovascular events 0.81 for both PCSK9 and HMGCR. Variants in these two genes were also associated with very similar effects on the risk of diabetes: OR for each 10 mg per deciliter decrease in LDL cholesterol, 1.11 for PCSK9 and 1.13 for HMGCR. The increased risk of diabetes was limited to persons with impaired fasting glucose levels for both genes and was lower in magnitude than the protective effect against cardiovascular events. When present together, PCSK9 and HMGCR variants had additive effects on the risk of both cardiovascular events and diabetes. The second study found that combined analyses of four independent PCSK9 variants scaled to 1 mmol/L lower LDL cholesterol showed associations with increased fasting glucose (0·09 mmol/L), bodyweight (1·03 kg), waist-to-hip ratio (0·006), and an OR for T2D of 1·29. These findings suggest an inverse biologic link between LDL and T2D and suggest that PCSK9 inhibitors will likely have a clinical profile similar to statins. Source: http://www.nejm.org/; http://www.thelancet.com/
两项随机遗传研究显示，PCSK9变异与2型糖尿病风险增加和对心血管病风险的保护作用相关。第一项研究发现，PCSK9（PCSK9抑制剂的靶点）和HMGCR（他汀类药物的靶点）的变异，与低密度脂蛋白胆固醇水平每降低10毫克/分升（0.26毫摩尔/升）对心血管事件风险几乎相同的保护作用相关：PCSK9和HMGCR对心血管事件的风险比均为0.81。这两个基因的变异对糖尿病风险亦具有非常相似的效果：低密度脂蛋白胆固醇每降低10毫克/分升，PCSK9的风险比为1.11，HMGCR的风险比为1.13。该两个基因糖尿病风险的增加仅限于空腹血糖水平异常者，并且在程度上低于对心血管事件的保护作用。当共同存在时，PCSK9和HMGCR变异对心血管事件和糖尿病风险具有叠加效应。第二项研究发现，四种独立的PCSK9变异综合分析，低密度脂蛋白胆固醇水平每降低1毫摩尔/升，与增加空腹血糖（0·09毫摩尔/升），体重（1·03公斤），腰臀比（0·006）相关，2型糖尿病风险比为1·29。这些研究结果提示低密度脂蛋白和2型糖尿病之间的反相生物学联系，并提示PCSK9抑制剂的临床效果可能类似于他汀。来源：http://www.nejm.org/; http://www.thelancet.com/