Reductions in cardiovascular (CV) outcomes in recently reported trials, along with the recent approval by the U.S. Food and Drug Administration of an additional indication for empagliflozin to reduce the risk of CV death in type 2 diabetes patients with evidence of CV disease, have renewed interest in CV outcome trials (CVOTs) of glucose-lowering drugs. Composite end points are a pragmatic necessity in CVOTs to ensure that sample size and duration of follow-up remain reasonable. Combining clinical outcomes into a composite end point increases the numbers of events ascertained and thus statistical power and precision. Historically, composite CV end points in diabetes trials have included a larger number of components, while more recent CVOTs almost exclusively use a composite of CV death, nonfatal myocardial infarction (MI), and nonfatal stroke—the so-called three-point major adverse CV event (3P-MACE) composite—or add hospitalization for unstable angina (HUA) to these three outcomes (4P-MACE). The inclusion of HUA increases the number of events for analysis, but noteworthy disadvantages include clinical subjectivity in ascertainment of HUA and its lower prognostic relevance compared with CV death, MI, or stroke. Furthermore, results from recent CVOTs indicate that glucose-lowering agents seem to have minimal impact on HUA. Its inclusion therefore potentially favors a shift of the hazard ratio (HR) toward the null, which is especially problematic in trials designed to demonstrate noninferiority. The primary outcome of 3P-MACE may offer a better balance than 4P-MACE between statistical efficiency, operational complexity, the likelihood of diagnostic precision (and therefore clinical relevance) for each of the component outcomes, clinical importance, and the aim to adequately capture any potential treatment effect of the intervention. Nevertheless, as individual medications may mechanistically differ in their impact on CV outcomes, no particular individual or composite end point can be seen as a “gold standard” for CVOTs of all glucose-lowering drugs.

在最近报道的试验中，心血管（CV）结果的降低以及美国食品和药物管理局最近批准了依帕列净的另一种适应症，以减少有CV疾病迹象的2型糖尿病患者的CV死亡风险。对降糖药物的CV结果试验（CVOT）感兴趣。复合终点是CVOT中务实的必要条件，以确保样本量和随访时间保持合理。将临床结果结合到一个复合终点中，可以增加确定的事件数量，从而提高统计功效和准确性。从历史上看，糖尿病试验中的复合CV终点包括大量成分，而最近的CVOT几乎仅使用CV死亡，非致命性心肌梗塞（MI），非致命性中风-所谓的三点主要不良CV事件（3P-MACE）综合症-或在这三个结局（4P-MACE）中增加因不稳定型心绞痛（HUA）的住院治疗。包含HUA会增加分析事件的数量，但值得注意的缺点包括在确定HUA方面具有临床主观性，并且与CV死亡，MI或中风相比，其预后相关性较低。此外，最新CVOT的结果表明，降糖药似乎对HUA的影响最小。因此，将其包括在内可能有助于使危险比（HR）向无效状态转变，这在旨在证明非劣效性的试验中尤其成问题。3P-MACE的主要结果可能会比4P-MACE在统计效率，操作复杂性，每个成分结局的诊断准确性（以及因此具有临床相关性）的可能性，临床重要性以及充分捕获干预措施的任何潜在治疗效果的目标。然而，由于个别药物对CV结局的影响可能在机械上有所不同，因此没有任何特定的个体或复合终点可被视为所有降糖药物CVOT的“黄金标准”。