Effectiveness and safety of dorzagliatin for type 2 diabetes: A combined analysis of clinical trials

Type 2 diabetes mellitus (T2DM) is a progressive chronic metabolic disease characterized by pancreatic ß-cells dysfunction and insulin resistance (1). Epidemiology has shown that about 537 million adults worldwide had diabetes in 2021, 90–95% of whom had T2DM, and the prevalence of T2DM is still increasing (2). T2DM can induce retinal, renal and cardiovascular complications (3, 4), and it is part of the leading causes of death and disability worldwide (5), which seriously affects the physical and mental health of diabetic patients (6). Currently, the treatment of T2DM relies on the combination of multiple hypoglycemic agents or insulin (7), but there are still a small number of patients with poor glycemic control and an increasingly prominent risk of adverse events (AEs). The onset of T2DM is associated with an increase of hepatic glucose output, and metformin is the only drug commonly used in clinical settings that can target a reduction in hepatic glucose output (8). However, metformin has a limited ability to lower glycemia and often needs to be combined with other hypoglycemic agents (9). Glucokinase (GK) acts as a glucose sensor with a role in regulating glucose-stimulated insulin secretion (10), and promotes hepatic glucose uptake as well as glycogen synthesis and storage (8), thereby maintaining glycemic homeostasis in patients. GK has become a popular target for hypoglycemic drug research, however, the development and research of previous glucokinase agonist (GKA) has not been smooth. GKA such as piragliatin and ARRY-403 were terminated due to the poor hypoglycemic effect and the risk of inducing hypoglycemia and increasing liver burden (11), while novel GKA are still in the development stage.

Dorzagliatin is a novel hypoglycemic agent for the treatment of T2DM with dual agonistic effects on GK in the pancreas and liver (12). It can promote the secretion of insulin and the synthesis of hepatic glycogen, improve the utilization of glucose by peripheral tissues (7), and also improve the function of β-cells in patients with T2DM (13). Dorzagliatin has been reported to significantly and consistently reduce glycated hemoglobin A1c (HbA1c) in patients with T2DM and is well-tolerated (14). Currently, no meta-analysis related to dorzagliatin is available, and the evidence-based evidence of dorzagliatin for T2DM remains to be elucidated. Therefore, this study was conducted to search for published randomized controlled trials of dorzagliatin for T2DM and to carry out meta-analysis and trial sequential analysis (TSA) in order to provide an evidence-based basis for the clinical use of dorzagliatin.

This study strictly followed the systematic review and meta-analysis methodology of the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) (15).

GKA is a new class of hypoglycemic agents that lower glycemia by activating pancreatic and hepatic GK, regulating glucose-stimulated insulin secretion (20) and promoting hepatic glycogen synthesis (8). Unfortunately, a series of GKA development and clinical trials have not yet been successful. Piragliatin was the first GKA to enter clinical studies (21) and rapidly lowered FPG and postprandial glucose in patients with T2DM in a dose-dependent manner (22), but was later found to increase the risk of potential lactic acidosis, fatty liver, and hypoglycemia (23–25). AZD-1656, another GKA, was effective in reducing HbA1c in patients with T2DM, but its hypoglycemic effect diminished over time, with no significant difference in HbA1c reduction from placebo at the fourth month (26). In addition, AZD-1656 has been reported to independently increase triglycerides by 4–22% (27), as well as induce hypoglycemia, and no further studies related to AZD-1656 have been published since 2014 to date (28). ARRY-403, a dual pancreatic and hepatic GK agonist, is effective in reducing FPG and postprandial glucose in patients with T2DM who are poorly controlled metformin (29). However, its hypoglycemic incidence was as high as 9.0% (29), thus limiting the clinical use of ARRY-403. The risk of hypoglycemia and elevated blood lipids are the main conflicts that exist in GKA and are the main reasons for GKA to discontinue clinical trials. GKA-related drug development and clinical trials are still ongoing, and researchers are continuing to explore a new type of hypoglycemic drug that combines efficacy and safety.

Dorzagliatin, the first GKA to enter phase III clinical trials (30), has dual agonistic effects on pancreatic and hepatic GK. It not only promotes insulin secretion from pancreatic β-cells, but also promotes glycogen synthesis and storage in the liver, thereby promoting peripheral glucose uptake and utilization and exerting hypoglycemic effects. Studies have shown that dorzagliatin has a good hypoglycemic effect and can effectively reduce HbA1c, FPG and 2h-PPG, which has potential value of application (31). However, given that GKA tends to increase the incidence of hypoglycemia and has a risk of elevated lipids in previous studies, its safety remains to be further evaluated. This meta-analysis and TSA included a total of three clinical studies and 1,332 sample sizes and is the first publication to date to examine dorzagliatin for T2DM, with the aim of assessing the specific benefits and potential risks of dorzagliatin for T2DM. TSA, harbord regression and quality of evidence evaluation gave a more comprehensive and credible result for this study.

HbA1c is formed by glycosylation of hemoglobin and mainly reflects the glycemic status of patients with T2DM during the past 2–3 months (32). FPG has a moderate sensitivity to hyperglycemia (33) and 2h-PPG is an independent predictor of diabetes mellitus (34). Both are used to assess the current glycemia levels, the former being associated with basal insulin secretion from pancreatic β-cells and glucose production in the liver (34), and the latter reflecting postprandial insulin secretion (35). Meta-analysis showed that dorzagliatin significantly reduced HbA1c, FPG, and 2h-PPG compared with placebo, and TSA confirmed that these benefits were conclusive. This implies that dorzagliatin has a clear hypoglycemic effect, both in terms of short-term glycemic control and long-term glycemic modulation. Meta-analysis results also showed that dorzagliatin had an increase in HOMA2-β and a decrease in HOMA2-IR, and TSA confirmed the benefit of HOMA2-β. HOMA2-β and HOMA2-IR can assess alterations in pancreatic β-cells function and insulin resistance, respectively (36, 37). This evidence suggests that dorzagliatin modulates pancreatic β-cells function and reduces insulin resistance, a result consistent with the findings of Chow et al. (38) and Feng et al. (39), and islet β-cells dysfunction and insulin resistance are central links of T2DM (27). In addition, Zhu et al. (18) and Yang et al. (19) found that dorzagliatin still had significant reductions in HbA1c, FPG, and 2h-PPG at 52 weeks of continuous administration, suggesting that continued administration of dorzagliatin can achieve at least 52 weeks of hypoglycemic benefit without complete loss of efficacy over time, as was the case with AZD-1656. Zhu et al. (17) found that HOMA2-IR scores remained significantly lower at the 13th week after dorzagliatin was discontinued, and Zeng et al. (40) also found that patients with T2DM maintained stable glycemic control after discontinuation of dorzagliatin (7). This suggests that the effects of dorzagliatin in lowering glycemia and improving insulin resistance have long term effects, which implies that dorzagliatin may have a higher clinical value. Notably, the findings of Yang et al. (19) were based on the context of combined metformin rather than dorzagliatin alone. Fortunately, the study by Chen et al. (41) confirmed that there is no interaction between dorzagliatin and metformin, so there is no need to be concerned about the effect of metformin on the efficacy of dorzagliatin.

On blood pressure-related endpoints, meta-analysis showed no significant differences in SBP and DBP for dorzagliatin compared with placebo, suggesting that dorzagliatin does not have a risk of elevated blood pressure. On blood lipid-related endpoints, meta-analysis showed that dorzagliatin increased TG by 0.43 mmol/L and TC by 0.13 mmol/L compared with placebo, and TSA confirmed that the differences in TG and TC were conclusive. Notably, although dorzagliatin caused a mild increase in TG and TC, the increase was significantly lower than previous GKA (42) and did not increase the risk of hyperlipidemia. In addition, dorzagliatin does not cause an increase in LDL-C and a decrease in HDL-C, with LDL-C being precisely one of the main causes of increased major cardiovascular adverse events (43, 44). Overall, dorzagliatin has the advantage of not causing an increase in LDL-C and a decrease in HDL-C, and the disadvantage of having a potential risk of increasing TG and TC. Clinicians should remain aware of the potential risk of increased TG with dorzagliatin, as elevated TG is a typical manifestation of T2DM and increases the cardiovascular risk of patients. We look forward to more studies exploring the cardiovascular risk of dorzagliatin in the future.

On weight-related endpoints, dorzagliatin increased body weight by 0.38 kg and BMI by 0.14 kg/m² compared with placebo. TSA confirmed that these differences are conclusive, which seems to imply that dorzagliatin has an increased risk of body weight. Interestingly, both included studies reported a trend in reduction of body weight and BMI in dorzagliatin's own pre and post controls, although this reduction was not statistically different. The study by Yang et al. (19) showed that dorzagliatin treatment reduced patients' body weight by 0.19 kg and BMI by 0.07 kg/m², and the study by Zhu et al. (18) study found that dorzagliatin treatment reduced patients' weight by 0.14 kg and BMI by 0.05 kg/m². There are two possible reasons for this situation. Firstly, the effect of dorzagliatin on body weight gain was so weak, and the psychological effect of placebo exceeded that of dorzagliatin. Secondly, throughout the treatment period, the researchers could not fully control the patients' diet as well as their lifestyle habits, etc. These confounding factors may have contributed to the differences in the results. Therefore, it is not certain that dorzagliatin has a risk of increasing body weight and BMI. In addition, although both meta-analysis and TSA judged the body weight gain of dorzagliatin relative to placebo to be statistically different, it was not clinically significant enough, as the body weight gain of 0.38 kg over 24 weeks was extremely minimal. Therefore, we can tentatively conclude that the weak effect of dorzagliatin on body weight does not pose a significant potential risk.

On safety endpoints, total AEs were significantly higher for dorzagliatin than for placebo, while serious AEs, hyperlipidemia, and hypoglycaemia were comparable to placebo, and TSA showed none of these results to be conclusive. Although the study results showed significantly higher total AEs for dorzagliatin than for placebo, none of the drug-related AEs in the included studies was reported separately at a higher rate than that of placebo, and the difference in total AEs may be the result of the accumulation of multiple indicators. In previous drug studies, hypoglycemia as well as elevated triglyceride levels were the major AEs in GKA. Whereas, this study confirmed that dorzagliatin triggered only 0.7 and 0.4% of drug-related hypoglycemia and hyperlipidemia, suggesting that dorzagliatin does not significantly increase the incidence of hypoglycemia and hyperlipidemia. In addition, meta-analysis confirmed that dorzagliatin does not increase serious AEs and related studies showed that dorzagliatin can be used in patients with T2DM at all stages of renal impairment (12, 45), which implies that dorzagliatin has a good safety profile.

Although this study strictly followed the PRISMA guidelines for systematic reviews and meta-analysis methods, the study still had some limitations (as follows). (1) A total of 3 clinical trials and a sample size of 1,332 were included in this study, with a small study base and total sample size, which may lead to reduced precision. (2) Narrow inclusion criteria may limit the generalizability of the results. All studies excluded patients with abnormal liver and kidney function, which means that the results of meta-analysis are not applicable to patients with hepatic impairment or renal insufficiency. Moreover, Zhu et al. (18) subjectively excluded patients with a history of T2DM for more than 3 years, and Yang et al. (19) excluded patients with TG >5.7 mmol/L, and these factors can lead to a decrease in generalizability of the results. (3) All of the three included studies were conducted in China and the study population was predominantly of Chinese descent. This implies that the benefit of dorzagliatin may only apply to Chinese or Asians, and it is unclear how dorzagliatin works in European-Americans and Africans. (4) The efficacy endpoints of the included studies were all at 24 weeks, meaning that the results of the studies only reflect the short-term or medium-term efficacy of dorzagliatin. Of concern is that while dorzagliatin is beneficial in the early stages after meal ingestion and absorption, it is more important to further utilize glucose for energy production and fatty acid synthesis and to incorporate it into fat acid storage tissues. Overweight or obesity, a prominent feature of T2DM, may limit the insulin secretory mechanisms of glycemic control, meaning that the long-term efficacy of dorzagliatin is unclear and requires continued exploration by more new studies.

In view of the limitations of the existing studies, we expect that future studies will be continuously improved. Firstly, continue to conduct similar randomized controlled double-blind trials. This could increase the samples and clinical data available for inclusion in evidence-based medicine, which could further improve the precision of study results. Secondly, a stratified study can be conducted controlling for relevant variables. The effect of dorzagliatin on patients with T2DM of different ages, disease duration, gender, and basal weight can be explored in a stratified manner in order to assess the full range of drug action characteristics on different baseline populations. Thirdly, to establish research centers in European-American and African countries. It is possible to further understand the effects of dorzagliatin in European-Americans and Africans, as well as to comprehensively assess the benefits and potential risks of dorzagliatin use in different races in combination with published studies. Fourthly, the value of dorzagliatin in combination medication can be studied in depth. As T2DM progresses, most patients need to achieve stable glycemic control with combination medications, and even eventually need to be treated with insulin (46). Fifthly, although theoretically the effect of dorzagliatin in raising TG and TC may pose a potential cardiovascular risk, there are no studies exploring major cardiovascular adverse events with dorzagliatin. We look forward to future studies that continue to explore the potential effects of dorzagliatin on cardiovascular events. Therefore, it is essential to actively conduct clinical trials of dorzagliatin in combination with other hypoglycemic agents or insulin, and a comprehensive assessment of the benefits and risks of dorzagliatin in combination is a prerequisite for rational clinical use. We expect dorzagliatin-related clinical trials to be further optimized and look forward to the benefits of dorzagliatin for patients with T2DM.

In terms of efficacy, dorzagliatin is effective in lowering glycemia, reducing insulin resistance and improving pancreatic β-cells function, with good glycemic control, without affecting blood pressure, LDL-C, and HDL-C. Although dorzagliatin caused a mild increase in TG and TC, it did not increase the incidence of hyperlipidemia, and the small increases in body weight and BMI were not clinically significant enough. In terms of safety, the total AEs caused by dorzagliatin may be a cumulative effect of single AEs, with no drug-related adverse event being reported at a higher incidence than that of placebo alone. Dorzagliatin's serious AEs, hyperlipidemia, and hypoglycemia are comparable to those of placebo, with a good safety profile. Current clinical trials have been conducted with dorzagliatin alone or in combination with metformin, and the role of dorzagliatin in other combinations needs to be further explored.

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.

YY conceived and designed the study. KT and XY participated in data processing and statistical analysis. YY, GH, and SY drafted the manuscript. FZ, PJ, MZ, and WJ contributed to data analysis and interpretation. YY, XY, KT, and WJ supervised the review of the study. All authors seriously revised and approved the final manuscript.

This study was funded by the National Natural Science Foundation of China (81973753).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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