Background

Evidence shows a positive association between the use of statins and new-onset diabetes. There is, however, contradictory evidence as to whether a similar association exists for the use of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors.

Objective

The aim of this study was to investigate the safety of PCSK9 monoclonal antibodies (PCSK9-mAbs) in regard to incident diabetes.

Methods and Results

Randomized controlled trials that reported data on the incidence of new-onset diabetes mellitus or the worsening of pre-existing diabetes were searched, and risk ratios (RRs) and 95% confidence intervals (CIs) were calculated to compare the endpoints. Twenty-three studies including 65,957 participants were identified. Compared with controls, PCSK9-mAb treatment was not associated with the adverse event of diabetes (RR 0.97, 95% CI 0.91–1.02; p = 0.22). When we analysed the trials in terms of PCSK9-mAb type, alirocumab was associated with a significant reduction in the risk of diabetes (RR 0.91, 95% CI 0.85–0.98; p = 0.01), whereas no significant reduction was observed in participants receiving evolocumab or bococizumab. Interestingly, compared with ezetimibe, which was actively used as lipid-modifying therapy in the control group, PCSK9-mAbs seem to have a lower risk of incident diabetes (RR 0.60, 95% CI 0.37–0.99; p = 0.04). This meta-analysis also revealed a noticeable increase in the risk of incident diabetes in the evolocumab and alirocumab pool (RR 2.14, 95% CI 1.12–4.07; p = 0.02) when the use of statins was equivalent between the experimental and active comparator arms.

Conclusion

Compared with placebo or any other comparator, PCSK9-mAb treatment was not associated with the adverse event of diabetes. However, evolocumab and alirocumab show high risk of incident diabetes when there is no interference from unbalanced use of statins. The imbalance in background lipid modifying therapy or different comparators used in the control arms of the studies might have masked the effect of PCSK9-mAb therapy on diabetes.

中文翻译：

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关于糖尿病的原蛋白转化酶枯草杆菌蛋白酶/ Kexin 9型单克隆抗体的安全性：随机对照试验的系统评价和荟萃分析。

背景

有证据表明，他汀类药物的使用与新发糖尿病之间存在正相关。但是，关于使用前蛋白转化酶枯草杆菌蛋白酶/ kexin 9型（PCSK9）抑制剂是否存在相似的关联，存在相反的证据。

目的

这项研究的目的是研究PCSK9单克隆抗体（PCSK9-mAbs）对于糖尿病的安全性。

方法与结果

检索报告新发糖尿病或已有糖尿病恶化情况的数据的随机对照试验，并计算风险比（RRs）和95％置信区间（CIs）以比较终点。确定了包括65,957名参与者在内的23项研究。与对照组相比，PCSK9-mAb治疗与糖尿病的不良事件无关（RR 0.97，95％CI 0.91-1.02；p  = 0.22）。当我们根据PCSK9-mAb类型分析试验时，alirocumab与糖尿病风险显着降低相关（RR 0.91，95％CI 0.85-0.98；p = 0.01），而接受evolocumab或bococizumab的参与者未见明显减少。有趣的是，与在对照组中积极用作脂质修饰疗法的依泽替米贝相比，PCSK9-mAb似乎具有降低患糖尿病的风险（RR 0.60，95％CI 0.37-0.99；p  = 0.04）。这项荟萃分析还显示，当实验组和活性比较组之间使用他汀类药物等效时，evolocumab和alirocumab库中发生糖尿病的风险显着增加（RR 2.14，95％CI 1.12–4.07；p  = 0.02）。 。

结论

与安慰剂或任何其他比较剂相比，PCSK9-mAb治疗与糖尿病的不良事件无关。但是，当不因他汀类药物不平衡使用而产生干扰时，evolocumab和alirocumab表现出发生糖尿病的高风险。研究的对照组中背景脂质修饰疗法或不同比较剂的不平衡可能掩盖了PCSK9-mAb疗法对糖尿病的影响。