• 原研：微芯生物
• 原研商品名：双洛平 | Bilessglu
• 分类：PPAR受体激动剂
• FDA批准日期：——

结构：

介绍：

西格列他（Chiglitazar，又名Carfloglitazar，商品名：双洛平/Bilessglu）是微芯生物（Chipscreen Biosciences）开发的PPAR全受体激动剂。完全激动PPAR的3个亚型，PPARα、PPARδ和PPARγα受体。激动PPARα和PPARδ受体能够促进脂肪酸β氧化，激动PPARγ能够增强脂肪组织对于胰岛素敏感性，提高葡萄糖的利用效率，促进脂肪组织内脂肪酸合成及氧化。西格列他对PPARγ的亲和力高于PPARα和PPARδ（B K He., 2012）。

Compound	PPARα		PPARγ		PPARδ
	EC50 (μM)	% Max	EC50 (μM)	% Max	EC50 (μM)	% Max
SMMC-7721
Chiglitazar	1.1 ± 0.3	142	0.09 ± 0.02	105	1.7 ± 0.4	123
rosiglitazone	8.4 ± 1.5	11	0.04 ± 0.02	100	9.3 ± 2.3	42
pioglitazone	2.2 ± 0.5	130	0.17 ± 0.05	103	4.8 ± 1.2	77
U2OS
Chiglitazar	1.2 ± 0.3	147	0.08 ± 0.02	117	1.5 ± 0.2	244
rosiglitazone	7.3 ± 1.9	16	0.04 ± 0.02	100	13.3 ± 3.5	42
Pioglitazone	3.2 ± 0.7	152	0.18 ± 0.06	91	4.8 ± 1.3	74

动物实验显示西格列他能够显著降低糖尿病模型鼠的血糖和胰岛素水平（B K He., 2012）。

In vivo effects on blood glucose control and insulin sensitization of chiglitazar. Male db/db (a, c and d) and male KKAy mice (b) were treated with vehicle (Ctrl), rosiglitazone (Ros), or chiglitazar (Chi) at the indicated doses for various days. Plasma glucose (a and b) and insulin (c) levels were measured at the indicated time points. Glucose tolerance (d) was evaluated and the results are presented as the area under curves (AUC) generated from 0, 30, 60, and 120 min after the glucose load. ∗P < 0.05, and ∗∗P < 0.01 compared with Ctrl; #P < 0.05 and ##P < 0.01 compared with day 0. n = 10 per group for db/db mice, and n = 8 per group for KKAy mice. Data are expressed as mean ± SE.

西格列他对于KKAy糖尿病模型鼠的体重未产生显著影响，尽管能够增加db/db糖尿病模型鼠的体重，但未显著增加腹部脂肪垫的重量。

Influence in body and abdominal fat pad weights of chiglitazar. (a) Male KKAy mice were orally administered daily with vehicle (Ctrl), rosiglitazone (Ros) of 5 mg kg−1, or chiglitazar (Chi) of 5 and 20 mg kg−1 for 12 days, and changes in body weight were evaluated at the indicated days. (b) and (c) Male db/db mice were orally administered daily with vehicle (Ctrl), rosiglitazone (Ros) of 5 mg kg−1, or chiglitazar (Chi) of 5, 10, and 20 mg kg−1 for 14 days. Changes in body weight were evaluated at the indicated days (b), and the fat pads were weighed from the scarified animals at day 15 (c). #P < 0.05 compared with day 0, and ∗P < 0.05 compared with Ctrl. n = 8 per group for KKAy, and n = 10 per group for db/db. Data are expressed as mean ± SE.

2021年，Linong Ji等人发表西格列他治疗2 型糖尿病3期临床试验CMAP的研究结果。CMAP（NCT02121717）为随机、双盲、安慰剂对照3期临床试验。共纳入535名饮食和运动干预仍不能有效控制血糖的成人2型煻尿病患者。患者按1：1：1比例随机接受西格列他32、48mg或安慰剂一天一次进行治疗。至第24周，西格列他 32和48 mg与安慰剂相比糖化血红蛋白（HbA1c）相对降低0.87%（95% CI: -1.10至-0.65; P < 0.0001）和 1.05%（95% CI: -1.29至-0.81; P < 0.0001）。此外西格列他组血糖控制、胰岛素敏感性和甘油三酯得到显著改善，高密度胆固醇脂蛋白和和低密度胆固醇脂蛋白增加。各组之间总不良事件的发生率相似。在西格列他32、48mg剂量组中，分别有4.2%和3.6%的患者报告发生轻度水肿，0%和1.2%的患者报告发生中度水肿。此外，西格列他32、48mg剂量组的体重平均增加1.1和1.9kg，腰围平均增加0.2和1.5cm略有增加（Linong Ji., 2021）。

Change from baseline to week 24 in HbA1c (a), fasting plasma glucose (b), and 2-h postprandial plasma glucose (c); change in HbA1c at week 24 in subgroups with baseline HbA1c <8.5% and ≥ 8.5% (d), proportions of patients who reached HbA1c <7.0% at week 24 (e), and proportions of patients who achieved HbA1c lowering over 0.5% at week 24 (f). ****P < 0.0001 vs. placebo by ANCOVA (a–d) or Cochran-Mantel-Haenszel test (e, f). Error bar shows standard error of the mean (SEM).

Change from baseline to week 24 in fasting insulin (a), HOMA-IR (b), HOMA-B (c), triglycerides (d), free fatty acid (e), HDL-cholesterol (f), LDL-cholesterol (g), and total cholesterol (h), with values presented as the least squares mean. * P < 0.05, ** P < 0.01, *** P < 0.001, and **** P < 0.0001 vs. placebo by ANCOVA. Error bar shows standard error of the mean (SEM).

同年，Weiping Jia等人发表西格列他治疗2 型糖尿病3期临床试验CMAS的研究结果。CMAS（NCT02173457）为随机、双盲3期临床试验。共纳入 740名饮食和运动干预仍不能有效控制血糖的成人2型煻尿病患者。患者按1：1：1比例随机接受西格列他32、48mg或西格列汀（Sitagliptin）100mg一天一次进行治疗。至第24周，西格列他 32和48 mg与西格列汀相比糖化血红蛋白（HbA1c）降低幅度基本相似（1.40%、1.47%和1.39%）。与西格列汀相比西格列他48 mg组空腹和餐后2小时血糖和空腹胰岛素显著降低，高密度胆固醇脂蛋白和和低密度胆固醇脂蛋白增加。各组之间总不良事件的发生率相似。在西格列他32、48mg剂量组中，分别有0%和2.4%的患者报告发生轻度水肿，0.4%和0.4%的患者报告发生中度水肿。此外，西格列他32、48mg剂量组的体重分别平均增加 0.80和 1.14kg和腰围分别减少0.1cm和增加0.4cm（Weiping Jia., 2021）。

Glycemic control parameters of the chiglitazar and sitagliptin groups: mean HbA1c over treatment time (a), mean fasting plasma glucose over treatment time (b), mean 2-h postprandial plasma glucose over treatment time (c), change in mean HbA1c at week 24 in subgroups with baseline HbA1c <8.5% and  8.5% (d), and proportions of patients who reached HbA1c <7.0% (e), or achieved HbA1c lowering  0.5% at week 24 (f). Values represented as the least squares mean change (a–c) or mean change (d) from baseline or observed proportions (e, f). * P < 0.05, ** P < 0.01, and *** P < 0.001 vs. sitagliptin 100 mg by ANCOVA (a–c). Error bar shows standard error of the mean (SEM).

Change from baseline to week 24 in fasting insulin (a), HOMA-IR (b), HOMA-B (c), triglycerides (d), free fatty acid (e), HDL-cholesterol (f), LDL-cholesterol (g), and total cholesterol (h), with values presented as the least squares mean. * P < 0.05, ** P < 0.01, *** P < 0.001, and **** P < 0.0001 vs. sitagliptin 100 mg by ANCOVA. Error bar shows standard error of the mean (SEM).

2021年10月国家药品监督管理局批准西格列他单药用于配合饮食控制和运动，改善成人2型糖尿病患省的血稳控制。

2024年，微芯生物宣布国家药品监督管理局批准西格列他联合二甲双胍治疗经二甲双胍单药治疗后血糖控制不佳的2型糖尿病（微芯生物., 2024）。

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