Abstract：
Despite advances in the management of type 2 diabetes mellitus (T2DM), one-third of patients with diabetes do not achieve the desired glycemic goal. Considering this inadequacy, many agents that activate glucokinase have been investigated over the last two decades but were withdrawn before submission for marketing permission. Dorzagliatin is the first glucokinase activator that has been granted approval for T2DM, only in China. As overstimulation of glucokinase is linked with pathophysiological disturbances such as fatty liver and cardiovascular issues and a loss of therapeutic efficacy with time. This review aims to highlight the benefits of glucokinase activators vis-à-vis the risks associated with chronic enzymatic activation. We discuss the multisystem disturbances expected with chronic activation of the enzyme, the lessons learned with glucokinase activators of the past, the major efficacy and safety findings with dorzagliatin and its pharmacological properties, and the status of other glucokinase activators in the pipeline. The approval of dorzagliatin in China was based on the SEED and the DAWN trials, the major pivotal phase III trials that enrolled patients with T2DM with a mean glycosylated hemoglobin of 8.3-8.4%, and a mean age of 53-54.5 years from multiple sites in China. Patients with uncontrolled diabetes, cardiac diseases, organ dysfunction, and a history of severe hypoglycemia were excluded. Both trials had a randomized double-blind placebo-controlled phase of 24 weeks followed by an open-label phase of 28 weeks with dorzagliatin. Drug-naïve patients with T2DM with a disease duration of 11.7 months were enrolled in the SEED trial while the DAWN trial involved patients with T2DM with a mean duration of 71.5 months and receiving background metformin therapy. Compared with placebo, the decline in glycosylated hemoglobin at 24 weeks was more with dorzagliatin with an estimated treatment difference of - 0.57% in the SEED trial and - 0.66% in the DAWN trial. The desired glycosylated hemoglobin (< 7%) was also attained at more than two times higher rates with dorzagliatin. The glycemic improvement was sustained in the SEED trial but decreased over 52 weeks in the DAWN trial. Hyperlipidemia was observed in 12-14% of patients taking dorzagliatin versus 9-11% of patients receiving a placebo. Additional adverse effects noticed over 52 weeks with dorzagliatin included an elevation in liver enzymes, hyperuricemia, hyperlacticacidemia, renal dysfunction, and cardiovascular disturbances. Considering the statistically significant improvement in glycosylated hemoglobin with dorzagliatin in patients with T2DM, the drug may be given a chance in treatment-naïve patients with a shorter disease history. However, with the waning therapeutic efficacy witnessed in patients with long-standing diabetes, which was also one of the potential concerns with previously tested molecules, extended studies involving patients with chronic and uncontrolled diabetes are needed to comment upon the long-term therapeutic performance of dorzagliatin. Likewise, evidence needs to be generated from other countries, patients with organ dysfunction, a history of severe hypoglycemia, cardiac diseases, and elderly patients before extending the use of dorzagliatin. Apart from monitoring lipid profiles, long-term safety studies of dorzagliatin should involve the assessment of serum uric acid, lactate, renal function, liver function, and cardiovascular parameters.
摘要：
尽管在2型糖尿病（T2DM）的管理方面取得了进展，三分之一的糖尿病患者没有达到预期的血糖目标.考虑到这种不足，在过去的20年中,许多激活葡萄糖激酶的药物已被研究,但在提交上市许可前被撤回.Dorzagliatin是第一个被批准用于T2DM的葡萄糖激酶激活剂。只有在中国。由于葡萄糖激酶的过度刺激与病理生理紊乱如脂肪肝和心血管问题以及随着时间的推移失去治疗功效有关。这篇综述旨在强调葡萄糖激酶激活剂相对于与慢性酶活化相关的风险的益处。我们讨论了酶的慢性激活所预期的多系统干扰，从过去的葡萄糖激酶激活剂中学到的教训，Dorzagliatin的主要疗效和安全性及其药理特性，以及管道中其他葡萄糖激酶激活剂的状态。dorzagliatin在中国的批准是基于SEED和DAWN试验，主要的关键III期试验纳入了平均糖化血红蛋白为8.3-8.4%的T2DM患者,来自中国多个地点的平均年龄为53-54.5岁。不受控制的糖尿病患者，心脏病,器官功能障碍,并排除严重低血糖病史.两项试验的随机双盲安慰剂对照期为24周，随后是dorzagliatin的28周开放标签期。SEED试验纳入了病程为11.7个月的药物初治T2DM患者，而DAWN试验纳入了平均病程为71.5个月且接受二甲双胍背景治疗的T2DM患者。与安慰剂相比，Dorzagliatin在24周时的糖化血红蛋白下降更多,在SEED试验和DAWN试验中的估计治疗差异为-0.57%.用dorzagliatin也以两倍以上的比率获得所需的糖基化血红蛋白(<7%)。在SEED试验中血糖改善持续，但在DAWN试验中下降超过52周。在12-14％的服用dorzagliatin的患者中观察到高脂血症，而在接受安慰剂的患者中观察到9-11％。dorzagliatin在52周内发现的其他不良反应包括肝酶升高，高尿酸血症,高乳酸血症,肾功能不全,和心血管疾病。考虑到2型糖尿病患者使用多扎利他对糖化血红蛋白的改善具有统计学意义,该药物可能会在病史较短的未治疗患者中获得治疗机会。然而,随着长期糖尿病患者治疗效果的下降，这也是先前测试的分子的潜在问题之一，需要涉及慢性和未受控制的糖尿病患者的扩展研究来评价多扎利他的长期治疗效果.同样，需要从其他国家获得证据，器官功能障碍患者，有严重低血糖史,心脏病,和老年患者在延长使用多扎他汀之前。除了监测血脂谱,dorzagliatin的长期安全性研究应包括血清尿酸的评估，乳酸，肾功能,肝功能,和心血管参数。
