Leadership Sinai Centre for Diabetes, Mount Sinai Hospital, Toronto, Canada.
Division of Endocrinology, University of Toronto, Toronto, Canada.
Nat Commun. 2022 Oct 16;13(1):6109. doi: 10.1038/s41467-022-33867-9.
Combining a glucagon-like peptide-1 receptor agonist (GLP1-RA) with basal insulin is an emerging option when initiating injectable therapy in longstanding type 2 diabetes (T2DM). Recognizing that short-term insulin therapy can improve beta-cell function and induce glycemic remission in early T2DM, we hypothesized that adding the short-acting GLP1-RA exenatide to basal insulin in early T2DM may enhance the achievability of these outcomes. In this completed, 20-week, open-label, parallel-arm trial at an academic hospital, 103 individuals aged 30-80 years with <7 years duration of T2DM were randomized (by computer-generated sequence) to 8-weeks treatment with (i) insulin glargine (Glar; n = 33), (ii) glargine + thrice-daily lispro (Glar/Lispro; n = 35), or (iii) glargine + twice-daily exenatide (Glar/Exenatide; n = 35), followed by 12-weeks washout. The analyzed population of 102 participants (median 3.5 years of T2DM, A1c 6.6% ±0.7%) consisted of 33 on Glar, 35 on Glar/Lispro and 34 on Glar/Exenatide. Oral glucose tolerance tests at baseline, 4-weeks, 8-weeks and 20-weeks enabled assessment of beta-cell function (Insulin Secretion-Sensitivity Index-2 (ISSI-2)) and glycemic control. Mean ISSI-2 over the 8-week intervention (primary outcome) did not differ across the groups (Glar/Exenatide 237 ± 11; Glar/Lispro 208 ± 11; Glar 223 ± 11; p = 0.19). Baseline-adjusted A1c at 8-weeks (secondary outcome) was lowest in Glar/Exenatide followed by Glar/Lispro and Glar (mean 5.9% vs 6.0% vs 6.2%; p = 0.0007). After 12-weeks washout, however, neither baseline-adjusted A1c nor baseline-adjusted ISSI-2 (secondary outcomes) differed between the groups, nor did (additional outcome) rates of remission (Glar/Exenatide 26.7%, Glar/Lispro 43.8%, Glar 32.1%; p = 0.35). There were no severe hypoglycemia episodes. In conclusion, adding exenatide to basal insulin in early T2DM does not further enhance underlying beta-cell function or the capacity to achieve diabetes remission, despite yielding on-treatment glycemic benefit.
在长期 2 型糖尿病（T2DM）患者中启动注射治疗时，将胰高血糖素样肽-1 受体激动剂（GLP1-RA）与基础胰岛素联合使用是一种新兴选择。鉴于短期胰岛素治疗可以改善β细胞功能并诱导早期 T2DM 的血糖缓解，我们假设在早期 T2DM 中，将短效 GLP1-RA 艾塞那肽添加到基础胰岛素中可能会增强这些结果的可实现性。在这项在学术医院进行的完成的、20 周、开放性、平行臂试验中，103 名年龄在 30-80 岁、T2DM 病程<7 年的患者按计算机生成的序列随机（分组）接受 8 周的治疗，方案如下：（i）甘精胰岛素（Glar；n=33）；（ii）甘精胰岛素+每日三次赖脯胰岛素（Glar/Lispro；n=35）；或（iii）甘精胰岛素+每日两次艾塞那肽（Glar/Exenatide；n=35），随后进行 12 周洗脱期。102 名参与者（中位 T2DM 病程 3.5 年，A1c 6.6%±0.7%）的分析人群包括接受甘精胰岛素治疗的 33 名、接受甘精胰岛素/赖脯胰岛素治疗的 35 名和接受甘精胰岛素/艾塞那肽治疗的 34 名。基线、4 周、8 周和 20 周时进行口服葡萄糖耐量试验，以评估β细胞功能（胰岛素分泌敏感性指数-2（ISSI-2））和血糖控制情况。8 周干预期间（主要结局）的平均 ISSI-2 各组间无差异（Glar/Exenatide 237±11；Glar/Lispro 208±11；Glar 223±11；p=0.19）。8 周时（次要结局）校正基线的 A1c 最低的是甘精胰岛素/艾塞那肽组，其次是甘精胰岛素/赖脯胰岛素组和甘精胰岛素组（均值 5.9% vs 6.0% vs 6.2%；p=0.0007）。然而，洗脱 12 周后，各组间校正基线的 A1c 和校正基线的 ISSI-2（次要结局）均无差异，缓解率（Glar/Exenatide 26.7%，Glar/Lispro 43.8%，Glar 32.1%；p=0.35）也无差异。没有发生严重低血糖事件。总之，在早期 T2DM 中，将艾塞那肽添加到基础胰岛素中并不能进一步增强潜在的β细胞功能或实现糖尿病缓解的能力，尽管治疗期间血糖有获益。
