2 型糖尿病的精准医疗：胰岛素抵抗的临床标志物与 DPP-4 抑制剂治疗的短期和长期血糖反应改变相关。
Precision Medicine in Type 2 Diabetes: Clinical Markers of Insulin Resistance Are Associated With Altered Short- and Long-term Glycemic Response to DPP-4 Inhibitor Therapy.
机构信息
Health Statistics Group, University of Exeter Medical School, Exeter, U.K.
National Institute for Health Research Exeter Clinical Research Facility, University of Exeter Medical School, Exeter, U.K.
出版信息
Diabetes Care. 2018 Apr;41(4):705-712. doi: 10.2337/dc17-1827. Epub 2018 Jan 31.
OBJECTIVE
A precision approach to type 2 diabetes therapy would aim to target treatment according to patient characteristics. We examined if measures of insulin resistance and secretion were associated with glycemic response to dipeptidyl peptidase 4 (DPP-4) inhibitor therapy.
RESEARCH DESIGN AND METHODS
We evaluated whether markers of insulin resistance and insulin secretion were associated with 6-month glycemic response in a prospective study of noninsulin-treated participants starting DPP-4 inhibitor therapy (Predicting Response to Incretin Based Agents [PRIBA] study; = 254), with replication for routinely available markers in U.K. electronic health care records (Clinical Practice Research Datalink [CPRD]; = 23,001). In CPRD, we evaluated associations between baseline markers and 3-year durability of response. To test the specificity of findings, we repeated analyses for glucagon-like peptide 1 (GLP-1) receptor agonists (PRIBA, = 339; CPRD, = 4,464).
RESULTS
In PRIBA, markers of higher insulin resistance (higher fasting C-peptide [ = 0.03], HOMA2 insulin resistance [ = 0.01], and triglycerides [ < 0.01]) were associated with reduced 6-month HbA response to DPP-4 inhibitors. In CPRD, higher triglycerides and BMI were associated with reduced HbA response (both < 0.01). A subgroup defined by obesity (BMI ≥30 kg/m) and high triglycerides (≥2.3 mmol/L) had reduced 6-month response in both data sets (PRIBA HbA reduction 5.3 [95% CI 1.8, 8.6] mmol/mol [0.5%] [obese and high triglycerides] vs. 11.3 [8.4, 14.1] mmol/mol [1.0%] [nonobese and normal triglycerides]; = 0.01). In CPRD, the obese, high- triglycerides subgroup also had less durable response (hazard ratio 1.28 [1.16, 1.41]; < 0.001). There was no association between markers of insulin resistance and response to GLP-1 receptor agonists.
CONCLUSIONS
Markers of higher insulin resistance are consistently associated with reduced glycemic response to DPP-4 inhibitors. This finding provides a starting point for the application of a precision diabetes approach to DPP-4 inhibitor therapy.
目的
针对 2 型糖尿病的精准治疗方法旨在根据患者特征进行靶向治疗。我们研究了胰岛素抵抗和胰岛素分泌的指标是否与二肽基肽酶 4（DPP-4）抑制剂治疗的血糖反应有关。
研究设计和方法
我们在一项非胰岛素治疗参与者开始 DPP-4 抑制剂治疗的前瞻性研究（预测基于肠降血糖素的药物反应研究 [PRIBA]；n=254）中评估了胰岛素抵抗和胰岛素分泌标志物与 6 个月血糖反应的关系，并在英国电子健康记录（临床实践研究数据链接 [CPRD]；n=23001）中对常规可用标志物进行了复制。在 CPRD 中，我们评估了基线标志物与 3 年反应持久性之间的关联。为了测试发现的特异性，我们还对胰高血糖素样肽 1（GLP-1）受体激动剂（PRIBA，n=339；CPRD，n=4464）进行了重复分析。
结果
在 PRIBA 中，较高的胰岛素抵抗标志物（较高的空腹 C 肽 [=0.03]、HOMA2 胰岛素抵抗 [=0.01] 和甘油三酯 [<0.01]）与 DPP-4 抑制剂治疗 6 个月后的 HbA 反应降低有关。在 CPRD 中，较高的甘油三酯和 BMI 与 HbA 反应降低有关（均 <0.01）。在两个数据集（PRIBA HbA 降低 5.3 [95%CI 1.8, 8.6] mmol/mol [0.5%] [肥胖和高甘油三酯] vs. 11.3 [8.4, 14.1] mmol/mol [1.0%] [非肥胖和正常甘油三酯]；=0.01）中，肥胖（BMI≥30kg/m）和高甘油三酯（≥2.3mmol/L）定义的亚组在 6 个月时的反应均降低。在 CPRD 中，肥胖、高甘油三酯亚组的反应持久性也较低（风险比 1.28 [1.16, 1.41]；<0.001）。胰岛素抵抗标志物与 GLP-1 受体激动剂的反应之间没有关联。
结论
较高的胰岛素抵抗标志物与 DPP-4 抑制剂治疗的血糖反应降低有关。这一发现为应用精准糖尿病方法治疗 DPP-4 抑制剂提供了一个起点。
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