Editor's note: In December 2023, the National Drug Catalogue for Basic Medical Insurance, Work-related Injury Insurance and Maternity Insurance (2023) was announced, and the world's first glucokinase activator (GKA) dolagliatin tablets (Huatangning ®) were officially included in the national medical insurance. On January 28, 2024, the National Medical Insurance Listing Conference of Dolagliatin was successfully held, and a number of big names in the field gathered in eight cities to focus on clinical practice to promote the wide application of this new drug. The highlights of the conference are now extracted for the benefit of readers.
Stable sugar new leather, prosperous and colorful
01. Focus on clinical needs and overcome all difficulties
Since glucokinase (GK) was first discovered in 1963, research on GK has been explored for more than 60 years. Based on the concept that GK plays a central role in the regulation of blood glucose homeostasis, the research team has always focused on the clinical needs of patients and adhered to a rigorous scientific attitude, and has carried out a total of 17 clinical studies from phase I., phase II to phase III in the past 10 years, many of which have been published in international core journals, and the research results have attracted global attention (Figure 1). From basic to clinical, from target to finished drug, dolagliatin leads the development of first-in-class hypoglycemic drugs in China to achieve an original breakthrough of "from 0 to 1", becoming the world's first and only GKA-class hypoglycemic drugs.
Figure 1. The development history of dolagliatin
02. From the approval of the listing to the access to medical insurance, good news followed
In September 2022, dolagliatin tablets were successfully approved for marketing in China. Since then, good news has followed. As the world's first and China's first launch, dolagliatin was selected as a major scientific and technological project of the Ministry of Science and Technology of the People's Republic of China in the 12th and 13th Five-Year Plans of the People's Republic of China, and has successively obtained clinical medication guidance from multiple domestic consensuses, such as the Clinical Expert Consensus on the Evaluation and Protection of Pancreatic Islet β Cell Function in Type 2 Diabetes Mellitus, the Expert Guidance on the Clinical Application of Dolagliatin, and the Pharmaceutical Expert Consensus on Glucokinase Activator Dolagliatin. In December 2023, dolagliatin tablets were successfully included in the new version of the National Medical Insurance Catalog.
A new mechanic to talk about homeostasis
01. Directly attack the first step of glucose metabolism and reshape blood sugar homeostasis
As the body's glucose sensor, GK is the core "element" of blood glucose homeostasis and the first key enzyme for intracellular glucose metabolism/utilization, playing a central role in the regulation of blood glucose homeostasis. GK has unique enzyme kinetic characteristics, which senses glucose levels in a concentration-dependent manner, and initiates the synergistic effect of the core organs of blood glucose regulation (pancreatic islets, liver, and intestines) in a timely manner to maintain blood glucose homeostasis. Basic studies have shown that patients with type 2 diabetes mellitus (T2DM) have impaired ability to regulate their own blood glucose and are in a state of blood glucose homeostasis [1-3].
Dolagliatin has a new mechanism of action that is different from other existing hypoglycemic drugs, and directly targets the first step of glucose metabolism by enhancing GK activity, and helps improve blood glucose homeostasis by binding GK in a glucose concentration-dependent manner. Dolagliatin is an ectopic allosteric GK total activator that acts on GK targets in glucose-storing and exporting organs such as pancreatic islets, liver, and intestinal endocrine cells, increasing the body's ability to perceive changes in blood glucose, improving impaired glucose-stimulated insulin and GLP-1 secretion and hepatic glycogen synthesis, and improving glycemic homeostasis in patients with T2DM (Figure 2) [4,5].
Figure 2. Mechanism of action of dolagliatin
02. Multiple benefits: lowering blood sugar while improving blood sugar fluctuations, and protecting β cell function
The unique mechanism of dolagliatin and its clinical benefits are supported by ample evidence. Animal studies have shown that dolagliatin significantly improves GK function in the pancreas, liver, and intestine [6,7]. Two phase III studies in Nature Medicine, a top international medical journal, demonstrated excellent glucose control efficacy in patients with T2DM, both alone and in combination with metformin (Figure 3), and was generally well tolerated [8,9].
Figure 3. Dolagliatin alone or in combination with metformin significantly reduces HbA1c
Fluctuations in blood glucose are an independent risk factor for cardiovascular disease. In addition to its good hypoglycemic efficacy and improved glycemic control attainment rate, clinical studies have shown that dolagliatin can also help improve blood glucose fluctuations, increasing the time within the glucose target range (TIR) from 59.9% to 83.7% [10].
A number of basic studies based on animal experiments have also found that dolagliatin has a β cell protective effect and helps to repair pancreatic islet function, which may be of great significance for delaying the progression of T2DM. Animal studies have demonstrated that dolagliatin significantly increases the number of β cells in diabetic rats to 75% and improves glucose-stimulated insulin secretion response (GSIS) even to normal levels [6,7,11]. In phase I studies, dolagliatin was shown to be effective in improving insulin secretion in patients with T2DM [12], and in phase II and III studies, dolagliatin significantly improved glucose disposition index (DI), HOMA2-β, and HOMA2-IR in patients with T2DM (Fig. 4) [8,9,13].
Figure 4. Dolagliatin significantly improved β cell function in patients with T2DM
In terms of liver safety, current basic research and clinical research data support that dolagliatin has a good liver safety. Basic studies have shown that dolagliatin increases hepatic GK expression to 80% of normal [11], suggesting that its effect is moderate and there is no overactivation. In phase III clinical studies, dolagliatin mildly increased triglycerides, liver enzymes, and uric acid levels, but the effect was mild [8,9], suggesting a favorable liver safety profile.
Message from the big coffee: The future can be expected, and we will go to the new prosperous era of China's stable sugar management
In the final summary of the meeting, Professor Mu Yiming of the PLA General Hospital pointed out that as the first original innovative drug with a new mechanism in the field of diabetes in recent years, dolagliatin is an important contribution to the management of diabetes diseases and the breakthrough of drug research and development in China. Dolagliatin aims to improve GK activity, and has a wide range of synergistic effects on important organs that regulate glucose and lipid metabolism such as the intestine, pancreas and liver. We look forward to more clinical studies to help us better unravel its mechanism of action and help people with diabetes benefit from treatment more precisely."
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