Abstract：
OBJECTIVE: To perform a participant-level post hoc meta-analysis of Phase 3a trials in type 2 diabetes (T2D) to characterize the hypoglycaemia safety and glycaemic efficacy of once-weekly insulin icodec (icodec).
METHODS: All ONWARDS 1-5 randomized participants were pooled as overall T2D, insulin-naive, an insulin-experienced subgroups, and by once-daily trial comparator (degludec or glargine U100). The main outcomes included incidence and rates of clinically significant and severe hypoglycaemia. Additional endpoints included change in glycated haemoglobin (HbA1c) from baseline and HbA1c target achievement without clinically significant or severe hypoglycaemia.
RESULTS: The meta-analysis comprised 3765 participants (1882 icodec vs. 1883 comparators). In the overall T2D pool, clinically significant hypoglycaemia incidence was similar in the icodec group versus the comparator group (17.9% vs. 16.2%, odds ratio [OR] 1.14, 95% confidence interval [CI] 0.94, 1.38); however, rates were low but significantly higher in the icodec group (1.15 vs. 1.00 episodes/participant-year of exposure, estimated rate ratio 1.51 [95% CI 1.24, 1.85]). Fewer severe hypoglycaemic episodes occurred with icodec than with comparators (8 vs. 18). A greater reduction in HbA1c occurred with icodec versus comparators, irrespective of subgroup (estimated treatment difference range [-0.10 to -0.29%]; all p < 0.05). Across subgroups, except for the insulin-experienced subgroup, the odds of achieving HbA1c <53 mmol/mol (7.0%) without clinically significant or severe hypoglycaemia were greater with icodec than with comparators (OR range 1.30-1.55; all p < 0.05).
CONCLUSIONS: Icodec was associated with a similar incidence but higher rates of clinically significant hypoglycaemia (equating to one additional hypoglycaemic episode every 6 years) and fewer severe hypoglycaemic episodes versus comparators. Our findings also confirmed the greater efficacy of icodec that was demonstrated in the ONWARDS trial programme.
METHODS: All ONWARDS 1-5 randomized participants were pooled as overall T2D, insulin-naive, an insulin-experienced subgroups, and by once-daily trial comparator (degludec or glargine U100). The main outcomes included incidence and rates of clinically significant and severe hypoglycaemia. Additional endpoints included change in glycated haemoglobin (HbA1c) from baseline and HbA1c target achievement without clinically significant or severe hypoglycaemia.
RESULTS: The meta-analysis comprised 3765 participants (1882 icodec vs. 1883 comparators). In the overall T2D pool, clinically significant hypoglycaemia incidence was similar in the icodec group versus the comparator group (17.9% vs. 16.2%, odds ratio [OR] 1.14, 95% confidence interval [CI] 0.94, 1.38); however, rates were low but significantly higher in the icodec group (1.15 vs. 1.00 episodes/participant-year of exposure, estimated rate ratio 1.51 [95% CI 1.24, 1.85]). Fewer severe hypoglycaemic episodes occurred with icodec than with comparators (8 vs. 18). A greater reduction in HbA1c occurred with icodec versus comparators, irrespective of subgroup (estimated treatment difference range [-0.10 to -0.29%]; all p < 0.05). Across subgroups, except for the insulin-experienced subgroup, the odds of achieving HbA1c <53 mmol/mol (7.0%) without clinically significant or severe hypoglycaemia were greater with icodec than with comparators (OR range 1.30-1.55; all p < 0.05).
CONCLUSIONS: Icodec was associated with a similar incidence but higher rates of clinically significant hypoglycaemia (equating to one additional hypoglycaemic episode every 6 years) and fewer severe hypoglycaemic episodes versus comparators. Our findings also confirmed the greater efficacy of icodec that was demonstrated in the ONWARDS trial programme.
摘要：
目的：对2型糖尿病（T2D）3a期试验进行参与者水平的事后荟萃分析，以表征每周一次的icodec胰岛素（icodec）的低血糖安全性和血糖疗效。
方法：将所有ONWARDS1-5名随机参与者汇总为整体T2D，初治胰岛素，经历过胰岛素的亚组，并通过每日一次的试验比较器(degludec或glargineU100)。主要结果包括具有临床意义和严重低血糖的发生率和发生率。其他终点包括糖化血红蛋白（HbA1c）相对于基线的变化和HbA1c目标的实现，而没有临床显着或严重的低血糖。
结果：荟萃分析包括3765名参与者（1882例icodec与1883年比较器)。在整个T2D池中，icodec组与比较组的临床显着低血糖发生率相似（17.9％vs.16.2%,优势比[OR]1.14，95%置信区间[CI]0.94，1.38)；然而，icodec组的发病率较低，但明显较高(1.15vs.1.00发作/参与者暴露年，估计比率1.51[95%CI1.24，1.85])。icodec比比较者发生的严重低血糖发作少（8vs.18).与比较物相比，icodec的HbA1c降低幅度更大，与亚组无关（估计治疗差异范围[-0.10至-0.29%]；所有p<0.05）。跨分组，除了有胰岛素经验的亚组，在无临床显著或严重低血糖的情况下,icodec达到HbA1c<53mmol/mol(7.0%)的几率高于对照者(OR范围为1.30~1.55;所有p<0.05).
结论：Icodec与相似的发病率相关，但临床上显著的低血糖发生率较高（相当于每6年又一次低血糖发作），与比较者相比，严重的低血糖发作较少。我们的发现还证实了在ONWARDS试验计划中证明的icodec的更高疗效。
方法：将所有ONWARDS1-5名随机参与者汇总为整体T2D，初治胰岛素，经历过胰岛素的亚组，并通过每日一次的试验比较器(degludec或glargineU100)。主要结果包括具有临床意义和严重低血糖的发生率和发生率。其他终点包括糖化血红蛋白（HbA1c）相对于基线的变化和HbA1c目标的实现，而没有临床显着或严重的低血糖。
结果：荟萃分析包括3765名参与者（1882例icodec与1883年比较器)。在整个T2D池中，icodec组与比较组的临床显着低血糖发生率相似（17.9％vs.16.2%,优势比[OR]1.14，95%置信区间[CI]0.94，1.38)；然而，icodec组的发病率较低，但明显较高(1.15vs.1.00发作/参与者暴露年，估计比率1.51[95%CI1.24，1.85])。icodec比比较者发生的严重低血糖发作少（8vs.18).与比较物相比，icodec的HbA1c降低幅度更大，与亚组无关（估计治疗差异范围[-0.10至-0.29%]；所有p<0.05）。跨分组，除了有胰岛素经验的亚组，在无临床显著或严重低血糖的情况下,icodec达到HbA1c<53mmol/mol(7.0%)的几率高于对照者(OR范围为1.30~1.55;所有p<0.05).
结论：Icodec与相似的发病率相关，但临床上显著的低血糖发生率较高（相当于每6年又一次低血糖发作），与比较者相比，严重的低血糖发作较少。我们的发现还证实了在ONWARDS试验计划中证明的icodec的更高疗效。
