National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China.
Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia Health System, Charlottesville, VA, USA.
Signal Transduct Target Ther. 2023 Apr 20;8(1):158. doi: 10.1038/s41392-023-01369-9.
Disease modifying therapies aiming to preserve β-cell function in patients with adult-onset autoimmune type 1 diabetes are lacking. Here, we conducted a multi-centre, randomized, controlled trial to assess the β-cell preservation effects of saxagliptin alone and saxagliptin combined with vitamin D as adjunctive therapies in adult-onset autoimmune type 1 diabetes. In this 3-arm trial, 301 participants were randomly assigned to a 24-month course of the conventional therapy (metformin with or without insulin) or adjunctive saxagliptin or adjunctive saxagliptin plus vitamin D to the conventional therapy. The primary endpoint was the change from baseline to 24 months in the fasting C-peptide. The secondary endpoints included the area under the concentration-time curve (AUC) for C-peptide level in a 2-h mixed-meal tolerance test, glycemic control, total daily insulin use and safety, respectively. The primary endpoint was not achieved in saxagliptin plus vitamin D group (P = 0.18) and saxagliptin group (P = 0.26). However, compared with the conventional therapy, 2-h C-peptide AUC from 24 months to baseline decreased less with saxagliptin plus vitamin D (-276 pmol/L vs. -419 pmol/L; P = 0.01), and not to the same degree with saxagliptin alone (-314 pmol/L; P = 0.14). Notably, for participants with higher glutamic acid decarboxylase antibody (GADA) levels, the decline of β-cell function was much lower in saxagliptin plus vitamin D group than in the conventional therapy group (P = 0.001). Insulin dose was significantly reduced in both active treatment groups than in the conventional therapy group despite all groups having similar glycemic control. In conclusion, the combination of saxagliptin and vitamin D preserves pancreatic β-cell function in adult-onset autoimmune type 1 diabetes, an effect especially efficacious in individuals with higher GADA levels. Our results provide evidence for a novel adjunct to insulin and metformin as potential initial treatment for adult-onset type 1 diabetes. (ClinicalTrials.gov identifier: NCT02407899).
目前缺乏用于保护成人发病自身免疫性 1 型糖尿病患者胰岛β细胞功能的疾病修正治疗方法。在此，我们开展了一项多中心、随机、对照临床试验，旨在评估在成人发病自身免疫性 1 型糖尿病中，西格列汀单药治疗以及联合维生素 D 作为辅助治疗对胰岛β细胞的保护作用。在这项三臂试验中，301 名参与者被随机分配至接受为期 24 个月的常规治疗（二甲双胍联合或不联合胰岛素）或接受辅助性西格列汀或联合西格列汀和维生素 D 的常规治疗。主要终点为从基线至 24 个月时空腹 C 肽的变化。次要终点分别为 2 小时混合餐耐量试验中 C 肽水平的浓度-时间曲线下面积（AUC）、血糖控制、总日胰岛素用量和安全性。西格列汀联合维生素 D 组（P=0.18）和西格列汀组（P=0.26）均未达到主要终点。然而，与常规治疗相比，西格列汀联合维生素 D 治疗组 24 个月至基线的 2 小时 C 肽 AUC 下降较少（-276 pmol/L 比-419 pmol/L；P=0.01），而西格列汀单药治疗组下降程度较小（-314 pmol/L；P=0.14）。值得注意的是，对于谷氨酸脱羧酶抗体（GADA）水平较高的参与者，西格列汀联合维生素 D 组的胰岛β细胞功能下降程度明显低于常规治疗组（P=0.001）。尽管所有组的血糖控制相似，但在这两个活性治疗组中胰岛素剂量均显著减少。综上，西格列汀联合维生素 D 可保护成人发病自身免疫性 1 型糖尿病患者的胰岛β细胞功能，在 GADA 水平较高的个体中效果更为显著。我们的研究结果为胰岛素和二甲双胍联合治疗提供了新的证据，为成人发病 1 型糖尿病的潜在初始治疗提供了新的选择。（临床试验注册编号：NCT02407899）
