Pinckney Ashley, Rigby Mark R, Keyes-Elstein Lynette, Soppe Carol L, Nepom Gerald T, Ehlers Mario R
Federal Systems Division, Rho Inc, Chapel Hill, North Carolina.
Section of Pediatric Endocrinology and Diabetology, Department of Pediatrics, Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, Indiana.
Clin Ther. 2016 Jun;38(6):1327-1339. doi: 10.1016/j.clinthera.2016.04.032. Epub 2016 May 18.
In natural history studies, maintenance of higher levels of C-peptide secretion (a measure of endogenous insulin production) correlates with a lower incidence of major hypoglycemic events in patients with type 1 diabetes mellitus (T1D), but it is unclear whether this is also true for drug-induced C-peptide preservation.
We analyzed hypoglycemic events and glycemic control data from the T1DAL (Inducing Remission in New-Onset T1D with Alefacept) study, a trial of alefacept in new-onset T1D, which found significant C-peptide preservation at 1 and 2 years. We performed a post hoc analysis using mixed models of the association between the meal-stimulated 4-hour C-peptide AUC (4-hour AUC) and rates of major hypoglycemia, measures of glycemic control (glycosylated hemoglobin [HbA1c]; mean glucometer readings), and variability (glucometer SDs; highest and lowest readings), and an index of partial remission (insulin dose-adjusted HbA1c[ IDAA1c]).
Data from 49 participants (33 in the alefacept group and 16 in the placebo group) were analyzed at baseline and 12 and 24 months. We found that the 4-hour AUC at baseline and at 1 year was a significant predictor of the number of hypoglycemic events during the ensuing 12-month interval (p = 0.030). There was a strong association between the 4-hour AUC and glucometer SDs (P < 0.001), highest readings (p < 0.001), and lowest readings (p = 0.03), all measures of glycemic variability. There was a strong inverse correlation between the 4-hour AUC and 2 measures of glycemic control: HbA1c and mean glucometer readings (both p < 0.001). There was also a strong inverse correlation between the 4-hour AUC and IDAA1c values (p < 0.001), as well as a strong correlation between IDAA1c values and glucometer SDs (p < 0.001), suggesting that reduced glycemic variability is associated with a trend toward partial remission. None of these analyses found a significant difference between the alefacept and placebo groups.
Measures of glycemic variability and control, including rates of hypoglycemia, are significantly correlated with preservation of C-peptide regardless of whether this is achieved by immune intervention with alefacept or natural variability in patients with new-onset T1D. Thus, preservation of endogenous insulin production by an immunomodulatory drug may confer clinical benefits similar to those seen in patients with higher C-peptide secretion due to slow disease progression.
在自然病史研究中，1型糖尿病（T1D）患者维持较高水平的C肽分泌（内源性胰岛素产生的一种衡量指标）与严重低血糖事件的较低发生率相关，但尚不清楚药物诱导的C肽保存情况是否也是如此。
我们分析了T1DAL（用阿法赛特诱导新发T1D缓解）研究中的低血糖事件和血糖控制数据，该研究是一项针对新发T1D患者的阿法赛特试验，发现1年和2年时C肽有显著保存。我们使用混合模型进行事后分析，以研究进餐刺激的4小时C肽AUC（4小时AUC）与严重低血糖发生率、血糖控制指标（糖化血红蛋白[HbA1c]；血糖仪平均读数）、变异性（血糖仪标准差；最高和最低读数）以及部分缓解指数（胰岛素剂量调整后的HbA1c[IDAA1c]）之间的关联。
对49名参与者（阿法赛特组33名，安慰剂组16名）在基线、12个月和24个月时的数据进行了分析。我们发现基线和1年时的4小时AUC是随后12个月期间低血糖事件数量的显著预测指标（p = 0.030）。4小时AUC与血糖仪标准差（P < 0.001）、最高读数（p < 0.001）和最低读数（p = 0.03）之间存在很强的关联，这些都是血糖变异性的指标。4小时AUC与两项血糖控制指标：HbA1c和血糖仪平均读数之间存在很强的负相关（均p < 0.001）。4小时AUC与IDAA1c值之间也存在很强的负相关（p < 0.001），以及IDAA1c值与血糖仪标准差之间存在很强的相关性（p < 0.001），这表明血糖变异性降低与部分缓解趋势相关。这些分析均未发现阿法赛特组和安慰剂组之间存在显著差异。
血糖变异性和控制指标，包括低血糖发生率，与C肽的保存显著相关，无论这是通过阿法赛特的免疫干预还是新发T1D患者的自然变异性实现的。因此，免疫调节药物对内源性胰岛素产生的保存可能带来与疾病进展缓慢导致C肽分泌较高的患者类似的临床益处。
