13th August 2023, Dr Chee L Khoo
Over the last 2 decades we have seen a number of new classes of glucose-lowering agents in the management of patients with type 2 diabetes (T2D). It was quite a few years after the introduction of the thiazolidinediones (pio- and rosiglitazones) that the DPP4 inhibitors, the GLP1- RA and then SGLT2 inhibitors came along and now changed the way we manage T2D. We now have a “new” class. It’s not actually that new as many of the clinical trials were published 5-6 years now. Dorzagliatin is a glucose-kinase activator (GKA) and an increasing number of publications are emerging suggesting a role for the management of hyperglycaemia in patients with T2D. As always at GPVoice, we keep you abreast of what is coming up your way.
In the human body, glucose-kinase (GK) is mainly concentrated in pancreatic cells and liver cells, as well as the hypothalamus and gastrointestinal tract (1).
In the pancreatic beta cells, GK is the “glucose receptor”. Its main function is to control the release of insulin according to the concentration of glucose. When plasma glucose rise, GK phosphorylates glucose and produces a large amount of ATP through glucose metabolism. It also inactivates the K ATP channels on the surface of the islet cells causes Ca2+ influx which activate the islet cells to release insulin, leading to reduction of blood glucose levels.
In the hepatic cells, GK regulates glycogen content in the liver. GK catalyses the conversion of glucose to glucose-6-phosphate (G6P) which is further converted into glycogen. The availability of GK for glycogen synthesis is regulated by the binding of GK Regulatory Protein (GKRP). When glucose is high, the GK-GKRP complex is broken down and more GK is available for glycogen synthesis. Under hypoglycaemic conditions, GKRP binds to GK to prevent phosphorylation of glucose.
In the hypothalamus, GK is located in glucose-sensing neurons and prevents hypoglycaemic effects caused by overactivation of GK in the liver and pancreas through neuromodulation. Following overexcitation of GK in the hypothalamus, the hypothalamus induces the body to decrease the secretion of adrenaline, norepinephrine, and glucagon, thereby resulting in hypoglycaemia. GKA can be designed to reduce their blood brain barrier permeability and avoid overactivation of the GK and hence, reduce the risk of hypoglycaemia.
There are GK in the K and L cells in the intestines (the cells that produce the incretins, GLP1 and GIP) and their roles are not entirely clear.
GK and T2D
You can see what an important role GK plays in glucose homeostasis. In knock-out mice where liver specific GK is deleted, hyperglycaemia develops after 6 weeks of life. On the other hand, in mice where there is overexpression of GK, hypoglycaemia develops. However, these mice gain more weight and develop glucose intolerance and insulin resistance.
Glucose kinase agonists
GKA are a novel class of drugs for the treatment of diabetes, improving the sensitivity of the body to glucose through the joint action of the pancreas and liver. There are two major challenges in the development of GKA, namely overcoming the rapid development of drug resistance and reducing the occurrence of treatment-related adverse effects (e.g. hypoglycaemia and abnormal serum triglyceride levels).
At present, a number of small-molecule GKAs have been reported and quite a few have entered the clinical research stage. The most advanced of the candidate molecules is Dorzagliatin which has completed a number of Phase III trials.
Dorzagliatin
Dorzagliatin is an oral GKA that was developed for the treatment of T2D, type 1 diabetes mellitus and diabetic kidney disease. Dorzagliatin improves glycaemic control by activating pancreatic and hepatic glucokinase in a glucose-dependent manner.
In a randomised, double-blind, placebo-controlled phase III trial, 463 drug-naive patients with T2D 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 (2). At week 24, the least-squares mean change in HbA1c from baseline was −1.07% in the dorzagliatin group and −0.50% in the placebo group (p<0.001). The incidence of adverse events was similar between the two groups. There were no severe hypoglycaemia events or drug-related serious adverse events in the dorzagliatin group.
In another randomised, double-blind, placebo-controlled phase III trial, 767 patients were randomly assigned to receive dorzagliatin or placebo as an add-on to metformin (1,500 mg per day) for 24 weeks of double-blind treatment, followed by 28 weeks of open-label treatment with dorzagliatin for all patients (3). At week 24, the least-squares mean change from baseline in HbA1c was −1.02% in the dorzagliatin group and −0.36% in the placebo group (p < 0.0001). The incidence of adverse events was similar between groups.
In summary, GKAs are another new class of glucose lowering agents. Dorzagliatin is the first kid off the block. It was developed by Hua Medicine (China). The above two RCTs have shown efficacy (HbA1c reduction of 1%) and safety (no significant adverse events) although the sample size is small and the duration of the trials were just shy of 6 months. Although it was approved for use in the management in hyperglycaemia in China last year, nothing is coming up in US, Europe or Australia.
There are at least a dozen potential candidates in the GK space with a number of prominent big guns involved including Astra-Zeneca, Pfizer, MSD, Bristol-Myers Squibb and Elli Lilly. Not all have gone according to plan as a number of candidates have been dropped due to the lack of efficacy and significant side effects. The space is busy and there will be more candidates coming up. GKAs, when they approved by our regulatory authorities will complement our existing armamentarium in glucose lowering as it works on a different mechanism of action.
References:
Ren Y, Li L, Wan L, Huang Y, Cao S. Glucokinase as an emerging anti-diabetes target and recent progress in the development of its agonists. J Enzyme Inhib Med Chem. 2022 Dec;37(1):606-615. doi: 10.1080/14756366.2021.2025362.
Zhu D, Li X, Ma J, et al. Dorzagliatin in drug-naïve patients with type 2 diabetes: a randomized, double-blind, placebo-controlled phase 3 trial. Nat Med. 2022 May;28(5):965-973. doi: 10.1038/s41591-022-01802-6.
Yang W, Zhu D, Gan S, et al. Dorzagliatin add-on therapy to metformin in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled phase 3 trial. Nat Med. 2022 May;28(5):974-981. doi: 10.1038/s41591-022-01803-5. Epub 2022 May 12. PMID: 35551292; PMCID: PMC9117147.