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.