*For medical professionals only
This drug is expected to become a treatment for patients with type 2 diabetes the “breaker”.
Recently, a novel drug that regulates blood sugar with a new mechanism—glucokinase activator(GKA)< /span> class of innovative drugs Two Phase III clinical studies of dopagliflozin – SEED(seeding study) span>[1]and DAWN(Dawn Research)< strong>[2]The results were also published in the top international medical journals Nature Medicine(IF=53.44)Heavy release. This is also the first time that the results of the Phase III study of GKA drugs have been published in a top international medical journal. Among them, the SEED study was led by Professor Zhu Dalong, director of the Department of Endocrinology and Director of the Department of Internal Medicine, Drum Tower Hospital Affiliated to Nanjing University School of Medicine; the DAWN study was led by Professor Yang Wenying from the China-Japan Friendship Hospital. Nature Medicineis an academic journal of Nature focusing on the field of biomedicine, focusing on “displaying the mechanism of novel disease processes. , Physiologically Relevant Findings with Direct Evidence” original paper. In recent years, he has begun to focus on publishing large-scale clinical research papers. The impact factor of Nature Medicine has continued to rise, with an impact factor of 53.44 in the past two years. Lancet, the Journal of the American Medical Association JAMA, and the British Medical Journal BMJ are among the top five international medical journals. As a joint research and development of Chinese innovative drug companies and Chinese researchers, the world’s first blood glucose sensor-glucokinase （GK）, remodeling As a new drug for the treatment of diabetes with the goal of blood glucose homeostasis, the phase III study of dopagliflozin, whether as a single drug or in combination with metformin, is of epoch-making significancefor Diabetes treatment opens a new chapter. As a finished drug, GKA is favored by top journalsIt has always been effective in controlling blood sugar levels and improving insulin sensitivity in type 2 diabetes(T2DM)< /span>The problems that cannot be solved well in the management of patients with diabetes[3]. Despite clinical attempts to control blood sugar through a variety of interventions, the blood sugar control of diabetic patients in my country is still not ideal[4]. Over the years, scholars have been constantly seeking new breakthroughs. Until 1964, people discovered the existence of GK, and were pleasantly surprised to find that as the first key enzyme of glucose metabolism, it could sense changes in glucose concentration and It transmits glucose signals to various target organs for glucose regulation[5], and achieves blood glucose homeostasis by regulating the secretion of glucose-controlling hormones. These concepts and studies have aroused strong research and development enthusiasm among scientists, resulting in the new drug GKA for the treatment of T2DM. However, the research of new drugs is never easy. Scholars from various countries have made numerous attempts to study GKA drugs, and they have also experienced numerous failures. In the end, the Chinese innovative drug company Hua Medicine< /strong>Doggliatin stands out. So far, dopagliflozin has completed 17 clinical studies in China and the United States. Now, the results of the Phase III clinical trial led by Chinese researchers have been published, which has become a major breakthrough in the field of diabetes treatment. It is worth noting that, in addition to the international influence of the drug, Dopagliflozin is the first first-in-class developed by Chinese companies and researchers to submit to NMPA for approval< span>(FIC)Diabetes drugs, These results have a milestone breakthrough significance for the clinical application of dopagliflozin in the future. Unique effect, GKA provides a new solution for blood sugar controlNature Medicine Of the two studies of dopagliflozin recently published on , the SEED study was a monotherapy study designed to evaluate its efficacy in a 24-week, double-blind, placebo-controlled study in patients with newly diagnosed drug-naïve T2DM and safety, as well as assessing the safety profile in a follow-up 28-week open-label treatmentsign. The 52-week study found that during treatment with dopagliflozin, the drug demonstrated rapid onset of action, sustained and effective reductions in glycated hemoglobin(HbA1c), and its effect on pancreatic beta cells The function of improving the function, and can also significantly reduce the 2-hour postprandial blood glucose(p<0.001). In terms of safety, during the trial period, the incidence of adverse reactions of dopagliflozin was not significantly higher than that of the placebo group(Figure 1)[1] .
Figure 1: Study on the effect of dopagliflozin monotherapyHOMA2-β: Pancreatic beta cell homeostasis model Assessment[2], an indicator of pancreatic β-cell function using a new homeostatic modelETD (95% CI): estimated treatment differences and corresponding 95% confidence intervals BID: twice a day; HbA1c: Glycated hemoglobinEffective and long-lasting: < span>
- 24 weeks HbA1c was 1.07% lower than baseline, a significant improvement In the placebo group(p<0.001)
- attainment rate of HbA1cat 24 weeks was 42.5%, significantly higher than the placebo group(p<0.001)
- significantly improved β-cell function, HOMA2-β and placebo at 24 weeks Compared with the placebo group, the 2-hour postprandial blood glucose level increased by 3.28
- 24 weeks compared with the placebo group, which was significantly decreased by 2.33mmol/L
- < span>24-week fasting blood glucose value was significantly lower than the placebo group by 0.33mmol/L
- 52-week HbA1c still Remaining stable
Well tolerated and safe:
Hypoglycemia within 24 weeks(<3mmol/L)incidence<1%, no severe hypoglycemia events
hypoglycemia within 52 weeks(<3mmol/L) span>incidence<1%, no severe hypoglycemia events
no drug-related events within 52 weeks
Another DAWN study was the synergistic control of blood sugar with dopagliflozin in T2DM patients who failed adequate metformin treatment. Metformin is the first-line treatment for T2DM, and it needs to be combined with other hypoglycemic drugs after failure of glycemic control. So far, despite the combination of various antidiabetic drugs, the persistent decline of β-cell function is still an urgent problem for T2DM patients. The results of this test show that the combination of the two drugs can further significantly reduce HbA1c and two-hour postprandial blood glucose, and significantly improve β-cell function and insulin sensitivity[2 ]. (Picture 2)Figure 2: Dopagliflozin combined with metformin effect study >Significant and long-lasting effect:
- 24 weeksHbA1c 1.02% lower than baseline, significantly better than placebo(p<0.0001)
- 24 weeksHbA span>1c compliance rate was 44.4%, which was significantly higher than that of the placebo group 10.7%（p<0.0001）
- significantly Compared with the placebo group, HOMA2-β at 24 weeks increased by 2.43
- 2-hour postprandial blood glucose level at 24 weeks was significantly lower than that in the placebo group by 2.48mmol/ L
- 24-week fasting blood glucose was significantly lower than the placebo group by 0.38mmol/L
- 52-weekHbA 1c remains stable
Well tolerated and safe:
- Low blood sugar within 24 weeks(<3mmol/L) Incidence <1%, no severe hypoglycemia events
- 52 Weekly hypoglycemia(<3mmol/L)incidence<1%, no serious hypoglycemia event
- 52 weeks of no drug-related serious adverse events
Nature MedicineThe data from these two studies demonstrate that < strong>Dopagliflozin has a significant effect of controlling blood sugar and improving the function of pancreatic islet β cells. It can also restore the early phase secretion of insulin and effectively reduce insulin resistance. At the same time, it also showed good safety and tolerance during use. Therefore, we believe that the fruitful results of GKA research and translation will also benefit 140 million Chinese diabetic patients, and radiate the world with this as the center, guiding a new direction for the treatment of diabetic patients. Salute to the father of GK with ingenuityThe success of Doggliatin has brought together many Chinese and foreign experts and scholars common wisdom. In 1968, Professor Franz Matschinsky, the father of glucokinase, discovered the central role of GK in glucose-stimulated insulin secretion, and proposed that glucokinase was a glucose sensor, and actively promoted the drug research and development of glucokinase activators. and fail. Finally, after 10 years of arduous efforts by the R&D team of Hua Medicine, Chinese clinical experts overcame difficulties and made it into Phase III clinical trials and successfully completed. As the core scientific advisor of Hua Medicine, Professor Matschinsky has devoted his whole life to the research of GKA drugs, and has made outstanding contributions to the success of dopagliflozin. For this reason, Professor Matschinsky won the world championship in 2020. The “Nobel Prize” in the field of endocrinology and metabolism – Rolf Luft Award. Professor Matschinsky sowed a seed for GKA research and cultivated it carefully. However, it is a pity that he did not have time to witness the day when it actually bears fruit. But we believe that the success of Douglietin will definitely become a monument in the history of overcoming diabetes, and Professor Matschinsky’s contribution will always be engraved on this monument. (Dedicated to Prof. Franz M Matschingsky, a pioneer in glucokinase research)Summary:The research on GKA drugs has gone through half a century from the generation to the development to the comprehensive verification of the efficacy of innovative drugs. investment and dedication. Looking back on the 100-year history of diabetes research, the discovery of insulin has saved the lives of countless diabetic patients, and now, the research results of dopagliflozin have been published in Nature Medicine, allowing We believe that the first innovative drug for diabetes with a new mechanism will lay a solid foundation for improving the quality of treatment for diabetic patients. ▎Hua Ling and Bayer join hands to innovate, share a vision, and benefit Chinese diabetic patientsIn March 2021, Hua Medicine submitted dopagliflozin for the treatment of T2DM to the National Medical Products Administration(NMPA) The new drug marketing application was accepted in April. Currently, dopagliflozin is in the review sprint stage, and Hua Medicine is actively cooperating with the NMPA, striving to obtain the drug’s new drug marketing approval as soon as possible. Once dopagliflozin is approved in China, it will be fully promoted by Bayer Pharma, a leader in the field of diabetes. As the promotion service provider, Bayer will be responsible for the marketing, promotion and medical education activities of the product in China. The collaboration was facilitated by the Bayer Prescription Drug China Cooperative Innovation Center. As a global leader in the field of medicine, Bayer is committed to working with external partners to jointly promote breakthrough innovations, bring positive changes to patient health, and achieve the goal of “cooperative innovation, joint cure”. References:[1]Zhu,D.,et al.Dorzagliatin in drug-naïve patients with type 2 diabetes:a randomized,double -blind, placebo-controlled phase 3 trial. Nat Med(2022).[2] Yang, W., 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).[3]RISE Consortium.Lack of Durable Improvements in β-Cell Function Following Withdrawal of Pharmacological Interventions in Adults With Impaired Glucose Tolerance or Recently Diagnosed Type 2 Diabetes. Diabetes Care. 2019 Sep;42(9):1742-1751.[4]Li Y,et al.Prevalence of diabetes recorded in mainland China using 2018 diagnostic criteria from the American Diabetes Association:national cross sectional study.BMJ.2020 Apr 28;369:m997.[5]Matschinsky FM,et al.Research and development of glucokinase activators for diabetes therapy:theoretical and practical aspects. Handb Exp Pharmacol. 2011;(203) :357-401.*The copyright of this article belongs to the original author, if you need to reprint, please contact the original author for authorization600″ height=”300″ layout=”responsive” sizes=”(min-width: 320px) 320px, 100vw” src=”https://mmbiz.qpic.cn/mmbiz_gif/1M5YTmIPqarF1jibp0KibLJolerYLrXERDtqKgcgmSMMO07P0piacqdnYxHSyEcibibyVsOwBDcwRibxibHAGlpOAiajiaw/640″ width=”600″>