Efficacy and safety of novel dual glucokinase activator dorzagliatin in type-2 diabetes A meta-analysis

Abstract

Background & aims: Glucokinase has a critical role in regulating glucose homeostasis in humans, and has been a target for diabetes drug development since 1990s. Dorzagliatin is a novel allosteric dual glucokinase activator targeting both pancreatic and hepatic glucokinase. No meta-analysis has analysed the efficacy and safety of dorzagliatin in type-2 diabetes (T2DM). We undertook this meta-analysis to address this knowledge-gap.

Methods: Electronic databases were searched for RCTs involving T2DM patients receiving dorzagliatin in intervention arm, and placebo/active comparator in control arm. Primary outcome was to evaluate changes in HbA1c. Secondary outcomes were to evaluate alterations in blood glucose parameters, lipids, insulin-resistance and adverse events.

Results: From initially screened 17 articles, data from 3 RCTs (1333 patients) was analysed. Over 12-24 weeks use, dorzagliatin had significantly higher lowering of HbA1c [MD -0.66% (95%CI: -0.74 to -0.59); P < 0.01; I² = 99%], fasting glucose [MD -32.03 mg/dl (95%CI: 45.12 to -18.94); P < 0.01; I² = 100%], 2-h post-prandial glucose [MD -43.49 mg/dl (95%CI: -46.26 to -40.72); P < 0.01; I² = 90%] along with greater number of patients achieving HbA1c<7% [OR 6.01 (95% CI: 2.50-14.46); P < 0.01; I² = 83%], as compared to placebo. Dorzagliatin was associated with significant elevation of triglycerides [MD 0.43 mmol/L (95%CI:0.30-0.56); P < 0.01; I² = 0%], greater occurrence of hyperlipidaemia [RR 1.52 (95% CI:1.05-2.18); P = 0.03; I² = 0%], and increase in body-weight [MD 0.40 kg (95%CI:0.06-0.75); P = 0.03; I² = 0%], compared to placebo. The occurrence of total-adverse-events [RR 1.43 (95%CI:1.11-1.83); P < 0.01; I² = 0%] but not severe adverse-events [RR 0.92 (95%CI:0.54-1.57); P = 0.76; I² = 0%] was significantly higher with dorzagliatin.

Conclusion: Dorzagliatin has good glycaemic efficacy and well tolerated over 6-months use. Mild increase in body-weight, serum triglycerides and overall adverse events remain issues of concern warranting further evaluation in longer clinical trials with active controls.

Keywords: Dorzagliatin; Dyslipidemia; Meta-analysis; Safety; Type-2 diabetes.