Lee Moon-Kyu, Kim Sin Gon, Watkins Elaine, Moon Min Kyong, Rhee Sang Youl, Frias Juan P, Chung Choon Hee, Lee Seung-Hwan, Block Bradley, Cha Bong Soo, Park Hyeong Kyu, Kim Byung Joon, Greenway Frank
Sungkyunkwan University School of Medicine, Samsung Medical Center, (06351) 81 Irwon-ro, Irwon-dong, Gangnam-gu, Seoul, South Korea.
Korea University Anam Hospital, Goryeodae-ro Seongbuk-gu, Seoul 02841, Republic of Korea.
J Diabetes Complications. 2020 May;34(5):107555. doi: 10.1016/j.jdiacomp.2020.107555. Epub 2020 Feb 2.
MLR-1023, called Tolimidone when evaluated unsuccessfully by Pfizer for gastric ulcer disease, has been repurposed as a novel oral insulin sensitizer with its effects mediated by selective activation of Lyn kinase. We aimed to evaluate the optimal dose, efficacy and safety of MLR-1023 in patients with type 2 diabetes.
Type 2 diabetes patients (18-75 years) on diet/exercise therapy were randomized and double-blinded to receive MLR-1023 (100-mg or 200-mg, once-daily [qd] or twice-daily [bid]) or matching placebo for 28 days. The primary endpoint was postprandial glucose (PPG) area under the curve (AUC) in a mixed meal tolerance test (MMTT) at day 29. Secondary endpoints included changes in fasting plasma glucose (FPG), insulin, HbA1c, lipids and body weight and adverse events. ANCOVA model was used for efficacy analysis.
The placebo-corrected least-squares mean differences (ΔLSM) in MMTT PPG AUC0-3 h (mmol/L) were -5.96 and -5.6 (both p = 0.03) in the MLR-1023 100-mg qd and 100-mg bid groups, respectively. The placebo-corrected ΔLSM in FPG (mmol/L) was -2.34 (p = 0.003) in the MLR-1023 100-mg qd group. Triglycerides improved with MLR-1023 (ΔLSM, -0.56 mmol/L, p = 0.07 and -0.59 mmol/L, p = 0.05) in the 200mgqd and 200 mg bid groups, respectively. Reductions in fasting insulin, HbA1c and body weight were not statistically significant. Most common adverse events with MLR-1023 treatment were headache (4.2%) and somnolence (2.5%).
MLR-1023 100-mg once-daily for 4 weeks was the most effective dose with significant reduction in PPG AUC following a MMTT. MLR-1023 was safe and well-tolerated in patients with type 2 diabetes. Clinical Trials Registration Number: NCT02317796.
MLR-1023在辉瑞公司针对胃溃疡疾病评估未成功时被称为托利米酮，现被重新用作一种新型口服胰岛素增敏剂，其作用通过Lyn激酶的选择性激活介导。我们旨在评估MLR-1023在2型糖尿病患者中的最佳剂量、疗效和安全性。
接受饮食/运动治疗的2型糖尿病患者（18 - 75岁）被随机分为双盲组，接受MLR-1023（100毫克或200毫克，每日一次[qd]或每日两次[bid]）或匹配的安慰剂，为期28天。主要终点是第29天混合餐耐量试验（MMTT）中餐后血糖（PPG）曲线下面积（AUC）。次要终点包括空腹血糖（FPG）、胰岛素、糖化血红蛋白（HbA1c）、血脂和体重的变化以及不良事件。采用协方差分析模型进行疗效分析。
MLR-1023 100毫克qd组和100毫克bid组在MMTT中PPG AUC0 - 3小时（mmol/L）的安慰剂校正最小二乘均值差异（ΔLSM）分别为 -5.96和 -5.6（均p = 0.03）。MLR-1023 100毫克qd组FPG（mmol/L）的安慰剂校正ΔLSM为 -2.34（p = 0.003）。在200毫克qd组和200毫克bid组中，甘油三酯随MLR-1023改善（ΔLSM分别为 -0.56 mmol/L，p = 0.07和 -0.59 mmol/L，p = 0.05）。空腹胰岛素、HbA1c和体重的降低无统计学意义。MLR-1023治疗最常见的不良事件是头痛（4.2%）和嗜睡（2.5%）。
MLR-1023 100毫克每日一次，持续4周是最有效的剂量，MMTT后PPG AUC显著降低。MLR-1023在2型糖尿病患者中安全且耐受性良好。临床试验注册号：NCT02317796。
