Diabetes Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy.
The Belgian Diabetes Registry, Academic Hospital and Diabetes Research Centre, Vrije Universiteit Brussel, Brussels, Belgium.
Front Endocrinol (Lausanne). 2023 Jun 20;14:1175640. doi: 10.3389/fendo.2023.1175640. eCollection 2023.
In a recent randomized, multicenter trial (NCT02814838) a short-term anti-inflammatory treatment with ladarixin (LDX; an inhibitor of the CXCR1/2 chemokine receptors) did not show benefit on preserving residual beta cell function in new-onset type 1 diabetes. We present a analysis of trial patients in the predefined subgroup analysis developed according to baseline daily insulin requirement (DIR) tertiles.
A double-blind, randomized (2:1), placebo-controlled study was conducted in 45 men and 31 women (aged 18-46 years) within 100 days of the first insulin administration. Patients received LDX (400 mg twice daily) for three cycles of 14 days on/14 days off, or placebo. The primary endpoint was the area under the curve for C-peptide [AUC (0-120 min)] in response to a 2-h mixed meal tolerance test (MMTT) at week 13 ± 1. Seventy-five patients completed the week 13 MMTT and were divided into three groups according to the DIR tertiles: lower, ≤ 0.23U/kg/die (n = 25); middle, 0.24-0.40 U/kg/die (n = 24); upper, ≥ 0.41 U/kg/die (n = 26).
When considering the patients in the upper tertile (HIGH-DIR), C-peptide AUC (0-120 min) at 13 weeks was higher in the LDX group (n = 16) than in the placebo (n = 10) group [difference: 0.72 nmol/L (95% CI 0.9-1.34), p = 0.027]. This difference reduced over time (0.71 nmol/L at 26 weeks, p = 0.04; 0.42 nmol/L at 52 weeks, p = 0.29), while it has never been significant at any time in patients in the lower and/or middle tertile (LOW-DIR). We characterized at baseline the HIGH-DIR and found that endo-metabolic (HOMA-B, adiponectin, and glucagon-to-C-peptide ratio) and immunologic (chemokine (C-C motif) ligand 2 (CCL2)/monocyte chemoattractant protein 1 (MCP1) and Vascular Endothelial Growth Factor (VEGF)) features distinguished this group from LOW-DIR.
While LDX did not prevent the progressive loss of beta-cell function in the majority of treated subjects, the analysis suggests that it could work in subjects with HIGH-DIR at baseline. As we found differences in endo-metabolic and immunologic parameters within this subgroup, this generates the hypothesis that the interactions between host factors and drug action can contribute to its efficacy. Further research is needed to evaluate this hypothesis.
在最近一项随机、多中心试验（NCT02814838）中，使用 ladarixin（LDX；CXCR1/2 趋化因子受体抑制剂）进行短期抗炎治疗并未显示出对新诊断 1 型糖尿病患者保留残余β细胞功能有益。我们根据基线每日胰岛素需求（DIR）三分位组进行了预先指定的亚组分析。
在首次胰岛素给药后 100 天内，对 45 名男性和 31 名女性（年龄 18-46 岁）进行了一项双盲、随机（2:1）、安慰剂对照研究。患者接受 LDX（400mg 每日两次）治疗，为期 14 天/14 天停药，共 3 个周期，或安慰剂。主要终点是第 13 周±1 时 C 肽[0-120 分钟时的曲线下面积（AUC（0-120 min））]对 2 小时混合餐耐量试验（MMTT）的反应。75 名患者完成了第 13 周的 MMTT，并根据 DIR 三分位组分为三组：低，≤0.23U/kg/d（n=25）；中，0.24-0.40 U/kg/d（n=24）；高，≥0.41 U/kg/d（n=26）。
当考虑高 DIR 患者（n=16）时，LDX 组（n=16）的 C 肽 AUC（0-120min）在第 13 周时高于安慰剂组（n=10）[差值：0.72 nmol/L（95%CI 0.9-1.34），p=0.027]。这种差异随时间而减少（26 周时为 0.71 nmol/L，p=0.04；52 周时为 0.42 nmol/L，p=0.29），而在低和/或中 DIR 患者的任何时间均未达到显著水平。我们在基线时对高 DIR 患者进行了特征描述，发现其代谢（HOMA-B、脂联素和胰高血糖素与 C 肽的比值）和免疫（趋化因子（C-C 基序）配体 2（CCL2）/单核细胞趋化蛋白 1（MCP1）和血管内皮生长因子（VEGF））特征将其与低 DIR 患者区分开来。
虽然 LDX 未能预防大多数治疗患者β细胞功能的进行性丧失，但分析表明，它可能对基线时高 DIR 患者有效。由于我们在该亚组中发现了代谢和免疫参数的差异，这就产生了一个假设，即宿主因素与药物作用的相互作用可能有助于其疗效。需要进一步研究来评估这一假设。
