Resetting the glucose sensor: dorzagliatin and the evolution of glucokinase activation in diabetes therapy

The progressive decline in functional β-cell mass represents a fundamental, unmet challenge in type 2 diabetes (T2DM) management. Dorzagliatin (HMS5552), a fourth-generation, dual-acting, and glucose-dependent glucokinase activator (GKA), offers a distinct mechanistic approach that aims to move beyond symptomatic glycemic control toward potential glucose sensor modulation. This review critically synthesizes the development of dorzagliatin, designed to overcome the hypoglycemia and tachyphylaxis of earlier GKAs. While its unique allosteric mechanism enables synchronized restoration of insulin secretion and hepatic glucose metabolism, we critically evaluate its clinical positioning. Observational data from the DREAM study suggest sustained drug-free glycemic maintenance; however, we emphasize that these findings do not yet meet the rigorous 2021 American Diabetes Association/European Association for the Study of Diabetes consensus definition of "diabetes remission" and require validation through randomized withdrawal trials. Furthermore, we address the critical absence of long-term cardiovascular outcomes trials (CVOTs) and the theoretical concerns regarding hepatic de novo lipogenesis. We also propose a synergistic framework for combining dorzagliatin with sodium-glucose cotransporter-2 inhibitors to counteract compensatory endogenous glucose production, positioning it as a precision-driven component in the evolving T2DM therapeutic landscape. Should future CVOTs demonstrate safety and efficacy, GKAs like dorzagliatin could potentially be integrated into treatment guidelines, possibly as a "sensor-calibrator" for a subset of patients identified through metabolic and genetic phenotyping. However, it must be emphasized that no CVOT data are currently available for dorzagliatin.