Abbreviations
ADA: The American Diabetes Association
AE: Adverse event
BID: twice a day
CI: Confidence interval
FPG: Fasting plasma glucose
GKA: Glucokinase activator
GK: Glucokinase
HbA1c: Glycated hemoglobin
PD: Pharmacodynamics
PK: Pharmacokinetics
QD: Once a day
RR: Relative risk
T2DM: Type 2 diabetes mellitus
Introduction
Type 2 diabetes mellitus (T2DM) is characterized by a chronic hyperglycaemic state due to decreases in insulin secretion and sensitivity1. Complications caused by poor blood glucose control are the main hazards. Increasing studies show that high-risk diseases such as heart and cerebrovascular diseases are closely related to poor blood glucose control2-4. More than 400 million adults worldwide live with diabetes, which causes excess mortality, morbidity, and substantial economic cost. The global annual cost of diabetes is estimated at more than $800bn (£636bn; American Diabetes Association (ADA) “Standards of Medical Care in Diabetes (2018)”, metformin should be the first-line drug of choice for single drug treatment and the basic drug for combined treatment; if the blood glucose control is not up to standard, it is necessary to consider the combined treatment of two hypoglycemic drugs to minimize the risk of cardiovascular events and death in patients. Despite these therapies and several other available classes of agents, only 52.5% of patients achieve glycaemic control6. Therefore, novel mechanisms are needed to avoid or reduce adverse events associated with existing drug categories and to delay or avoid loss of efficacy associated with current therapies over time7.
Glucokinase (GK), one of the four hexokinases, catalyzes the phosphorylation of glucose to glucose-6-phosphate in the presence of ATP and Mg2+4,8,9. It mainly exists in islet alpha/beta-cells, hepatocytes, glucose-sensitive ventromedial hypothalamic neurons, gastrointestinal K/L-cells and pituitary gonadotropins, and functions as a key controller of glucose metabolism10,11. In the pancreas, GK serves as a ‘glucostat’ controlling the threshold for GSIS in beta-cells. In hepatocytes, GK stored in the nucleus as a GK-glucokinase regulatory protein (GKRP) complex 7, which plays an integral role in glucose homeostasis and offers a potential therapeutic target for the treatment of T2DM11. According to different organs activated by GK, glucokinase activators (GKAs) can be divided into two kinds: pancreas liver double activator and liver-selective activator. Since 2003, Grimsby et al. from Roche company found the first synthetic GKA12, more than 20 small molecule GKAs have participated in phase I and II clinical trials. Though many clinical trials have evaluated the ability of GKAs to regulate blood glucose, the efficacy and safety of GKAs remain unclear13. For example, Meininger et al. have shown that GKAs can significantly improve glycated hemoglobin (HbA1c) and 2-hour postprandial blood glucose, but has no significant effect on fasting plasma glucose (FPG), and GKAs have a significant relationship with the increased incidence of hypoglycemia, triglycerides and systolic blood pressure 14. However, Vella et al. found that GKAs had a good hypoglycemic effect without adverse effects such as hypoglycemia, dyslipidemia, and hypertension15;
In this study, we aimed to systematically assess the regulation of GKAs on blood glucose in patients with T2DM, including diabetes diagnostic indicators (FPG, HbA1c) and safety events, moreover, we also evaluated the impact of different types of GKAs on hypoglycemic events.