Effect of renal impairment on the pharmacokinetics and safety of dorzagliatin, a novel dual‐acting glucokinase activator

Miao, Jia; Fu, Ping; Ren, Shan; Hu, Chao; Wang, Ying; Jiao, Chengfeng; Li, Ping; Zhao, Yu; Tang, Cui; Qian, Yuli; Yang, Rong; Dong, Yanli; Jiang, Rong; Wang, Yaohui; Jin, Xiaowei; Sun, Yu; Chen, Li

doi:10.1111/cts.13174

Cited by 18 publications

(13 citation statements)

References 20 publications

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“…Dorzagliatin was also studied in a population with end-stage renal disease and a healthy control group to evaluate the effect of renal impairment on pharmacokinetics and safety. The results suggested that dorzagliatin can be safely used in patients with T2D at all stages of renal impairment without a need for dose adjustment 58 .…”

Section: Any Hypoglycemiamentioning

confidence: 93%

Dorzagliatin in drug-naïve patients with type 2 diabetes: a randomized, double-blind, placebo-controlled phase 3 trial

Zhu

Ma³

et al. 2022

Nat Med

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Improving glucose sensitivity remains an unmet medical need in treating type 2 diabetes (T2D). Dorzagliatin is a dual-acting, orally bioavailable glucokinase activator that enhances glucokinase activity in a glucose-dependent manner, improves glucose-stimulated insulin secretion and demonstrates effects on glycemic control in patients with T2D. We report the findings of a randomized, double-blind, placebo-controlled phase 3 clinical trial to evaluate the efficacy and safety of dorzagliatin in patients with T2D. Eligible drug-naïve patients with T2D (n = 463) were randomly assigned to the dorzagliatin or placebo group at a ratio of 2:1 for 24 weeks of double-blind treatment, followed by 28 weeks of open-label treatment with dorzagliatin for all patients. The primary efficacy endpoint was the change in glycated hemoglobin from baseline to week 24. Safety was assessed throughout the trial. At week 24, the least-squares mean change in glycated hemoglobin from baseline (95% confidence interval) was −1.07% (−1.19%, −0.95%) in the dorzagliatin group and −0.50% (−0.68%, −0.32%) in the placebo group (estimated treatment difference, −0.57%; 95% confidence interval: −0.79%, −0.36%; P < 0.001). The incidence of adverse events was similar between the two groups. There were no severe hypoglycemia events or drug-related serious adverse events in the dorzagliatin group. In summary, dorzagliatin improved glycemic control in drug-naïve patients with T2D and showed a good tolerability and safety profile.

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Section: Any Hypoglycemiamentioning

confidence: 93%

Dorzagliatin in drug-naïve patients with type 2 diabetes: a randomized, double-blind, placebo-controlled phase 3 trial

Zhu

Ma³

et al. 2022

Nat Med

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“…Whereas, this study confirmed that dorzagliatin triggered only 0.7 and 0.4% of drug-related hypoglycemia and hyperlipidemia, suggesting that dorzagliatin does not significantly increase the incidence of hypoglycemia and hyperlipidemia. In addition, meta-analysis confirmed that dorzagliatin does not increase serious AEs and related studies showed that dorzagliatin can be used in patients with T2DM at all stages of renal impairment (12,45), which implies that dorzagliatin has a good safety profile.…”

Section: Discussionmentioning

confidence: 81%

Efficacy and safety of dorzagliatin for type 2 diabetes mellitus: A meta-analysis and trial sequential analysis

Yang

Tong

et al. 2022

Front. Cardiovasc. Med.

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ObjectiveTo evaluate the efficacy and safety of dorzagliatin in the treatment of type 2 diabetes mellitus (T2DM) by using meta-analysis and trial sequential analysis (TSA).MethodSearch for clinical trials of dorzagliatin for T2DM in eight databases, with a time limit of build to July 2022. The included studies that met the requirements were carried out for meta-analysis and TSA.ResultsIn terms of efficacy endpoints, meta-analysis showed that dorzagliatin decreased glycated hemoglobin A1c(HbA1c) [mean difference (MD) −0.65%, 95% confidence interval (CI) −0.76 ~ −0.54, P < 0.00001], fasting plasma glucose (FPG) (MD −9.22 mg/dL, 95% CI −9.99 ~ −8.44, P < 0.00001), 2 h postprandial glucose (2h-PPG) (MD −48.70 mg/dL, 95% CI −55.45 ~ −41.96, P < 0.00001), homeostasis model assessment 2 of insulin resistance (HOMA2-IR) (MD −0.07, 95% CI −0.14 ~ −0.01, P = 0.03) and increased homeostasis model assessment 2 of ß-cells function (HOMA2-β) (MD 2.69, 95% CI 1.06 ~ 4.31, P = 0.001) compared with placebo. And TSA revealed that the benefits observed for the current information set were conclusive, except for HOMA2-IR. In comparison with placebo, dorzagliatin increased triglyceride(TG) (MD 0.43 mmol/L, 95% CI 0.30 ~ 0.56, P < 0.00001), total cholesterol (TC) (MD 0.13 mmol/L, 95% CI 0.05 ~ 0.21, P = 0.001), body weight (MD 0.38 kg, 95% CI 0.12–0.63, P = 0.004) and body mass index (BMI) (MD 0.14 kg/m2, 95% CI 0.05–0.24, P = 0.003), while low density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), systolic blood pressure (SBP) and diastolic blood pressure (DBP) were comparable. And TSA demonstrated that TG, TC, body weight, and BMI were conclusive. In terms of safety endpoints, dorzagliatin increased total adverse events (AEs) [risk ratio (RR) 1.56, 95% CI 1.06 ~ 2.30, P = 0.03], while serious AEs, hyperlipidemia, and hypoglycaemia were all comparable. And TSA indicated that the results need to be confirmed by additional studies. Harbord regression showed no publication bias.ConclusionDorzagliatin was effective in lowering glycemia, reducing insulin resistance and improving islet ß-cells function without affecting blood pressure, LDL-C, and HDL-C. Although dorzagliatin caused a mild increase in TG and TC, it did not increase the incidence of hyperlipidemia, and the small increases in body weight and BMI were not clinically significant enough. In terms of safety, the total AEs caused by dorzagliatin may be a cumulative effect of single AEs, with no drug-related adverse event being reported at a higher incidence than placebo alone. Dorzagliatin's serious AEs, hyperlipidemia, and hypoglycemia are comparable to that of placebo, and dorzagliatin has a good safety profile.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?RecordID=371802 identifier: CRD42022371802.

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“…The recommended dosage of dorzagliatin is one 75 mg oral tablet twice daily, 1 h before breakfast and dinner. No dosage modification is necessary for patients with T2D and chronic kidney disease 48,49 …”

Section: Clinical Exploration On Gk Targetmentioning

confidence: 99%

Clinical investigation of glucokinase activators for the restoration of glucose homeostasis in diabetes

Li,

Zhu

2024

Journal of Diabetes

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As a sensor, glucokinase (GK) controls glucose homeostasis, which progressively declines in patients with diabetes. GK maintains the equilibrium of glucose levels and regulates the homeostatic system set points. Endocrine and hepatic cells can both respond to glucose cooperatively when GK is activated. GK has been under study as a therapeutic target for decades due to the possibility that cellular GK expression and function can be recovered, hence restoring glucose homeostasis in patients with type 2 diabetes. Five therapeutic compounds targeting GK are being investigated globally at the moment. They all have distinctive molecular structures and have been clinically shown to have strong antihyperglycemia effects. The mechanics, classification, and clinical development of GK activators are illustrated in this review. With the recent approval and marketing of the first GK activator (GKA), dorzagliatin, GKA's critical role in treating glucose homeostasis disorder and its long‐term benefits in diabetes will eventually become clear.image

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Effect of renal impairment on the pharmacokinetics and safety of dorzagliatin, a novel dual‐acting glucokinase activator

Cited by 18 publications

References 20 publications

Dorzagliatin in drug-naïve patients with type 2 diabetes: a randomized, double-blind, placebo-controlled phase 3 trial

Dorzagliatin in drug-naïve patients with type 2 diabetes: a randomized, double-blind, placebo-controlled phase 3 trial

Efficacy and safety of dorzagliatin for type 2 diabetes mellitus: A meta-analysis and trial sequential analysis

Clinical investigation of glucokinase activators for the restoration of glucose homeostasis in diabetes

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