CCR2 antagonism in patients with type 2 diabetes mellitus: a randomized, placebo-controlled study
CCR2 antagonism in patients with type 2 diabetes mellitus: a randomized, placebo-controlled study
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DOI：
10.1111/dom.12309
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发表时间：
2014-11-01
影响因子：
5.8
通讯作者：
Rothenberg, P.
中科院分区：
文献类型：
--
作者：
Di Prospero, N. A.;Artis, E.;Rothenberg, P.
目的：巨噬细胞通过C-C基序趋化因子受体-2（CCR 2）募集到脂肪组织中被认为在胰岛素抵抗和2型糖尿病（T2 DM）的发展中起作用。这项II期概念验证研究的目的是评价JNJ-41443532（一种口服生物利用度CCR 2拮抗剂）在T2 DM患者中的安全性、耐受性、药代动力学和药效学。方法：这是一项为期4周、双盲、安慰剂对照、随机化、多中心研究。共有89例患者随机接受250或1000 mg JNJ-41443532每日2次、30 mg吡格列酮每日1次（参考组）或安慰剂治疗。主要终点是23小时加权平均血糖（WMG）较基线的变化;次要终点包括空腹血糖（FPG）、胰岛素抵抗（IR）较基线的变化。（稳态模型评估[HOMA-IR]），胰岛素分泌（HOMA-% B）和体重。JNJ-41443532吸收进入体循环的中位t（max）为2 h，两种剂量的平均t（1/2）约为8 h;血浆全身暴露量的增加略高于剂量比例。4周后，与安慰剂组相比，所有治疗组均观察到23小时WMG和FPG降低，250 mg JNJ-41443532和吡格列酮组显著降低。所有治疗组的HOMA-IR均较低，但仅吡格列酮显著较低。相反，所有组的HOMA-% B均升高，但仅JNJ-41443532 250 mg组显著升高。所有组，包括安慰剂组，体重均随时间推移而降低。在常规安全性评估期间没有临床显著的发现，所有组治疗后出现的不良事件的发生率相似。结论：与安慰剂相比，JNJ-41443532给药可适度改善血药参数，T2 DM患者的耐受性通常良好。
Aims: Macrophage recruitment through C-C motif chemokine receptor-2 (CCR2) into adipose tissue is believed to play a role in the development of insulin resistance and type 2 diabetes mellitus (T2DM). The objective of this Phase 2 proof-of-concept study was to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of JNJ-41443532, an orally bioavailable CCR2 antagonist, in patients with T2DM.Methods: This was a 4-week, double-blind, placebo-controlled, randomized, multicenter study. A total of 89 patients were randomized to receive either 250-or 1000-mg of JNJ-41443532 twice daily, 30-mg of pioglitazone once daily (reference arm), or placebo. The primary endpoint was change from baseline in 23-h weighted mean glucose (WMG); secondary endpoints included change from baseline in fasting plasma glucose (FPG), insulin resistance (Homeostatic Model Assessment [HOMA-IR]), insulin secretion (HOMA-% B) and body weight.Results: Absorption of JNJ-41443532 into the systemic circulation occurred at a median t(max) of 2 h, and the mean t(1/2) was approximately 8 h for both doses; plasma systemic exposures increased slightly more than dose-proportionally. After 4 weeks, reductions in 23-h WMG and FPG were observed in all treatment groups compared with placebo and were significantly lower for 250-mg JNJ-41443532 and pioglitazone. HOMA-IR was lower for all treatment groups, but significantly lower only for pioglitazone. Conversely, HOMA-% B was increased for all groups, but significantly increased only for 250-mg JNJ-41443532. All groups, including placebo, had decreased body weight over time. There were no clinically significant findings during routine safety assessments and the incidence of treatment-emergent adverse events was similar across all groups.Conclusions: Administration of JNJ-41443532 resulted in modest improvement in glycaemic parameters compared with placebo, and was generally well tolerated in patients with T2DM.