Discussion
Though metformin can effectively inhibit the secretion of glycogen in
the liver and increase the sensitivity of peripheral tissue to insulin,
about 30% of patients of T2DM are still troubled by poor glycemic
control or adverse reactions. Here our analysis showed that (1) GKAs,
alone or combined with metformin, could effectively reduce FPG and
glycosylated hemoglobin compared with placebo; (2) GKAs, alone or
combined with metformin, did not affect the incidence of AE but
increased the incidence of hypoglycemic events compared with placebo.
Thus, our results suggest GKAs may help metformin to better regulate
blood glucose with good tolerance.
Some previous studies have shown that the effective duration of GKAs is
relatively short14,24. In this study, we included
short-term treatment (2 days) and mid-term treatment (4 months), and the
data showed that GKAs was effective in the treatment of T2DM compared
with the placebo-controlled group, and there was no significant
heterogeneity. Therefore, GKAs may reduce FPG and HbA1c in patients with
T2DM in short to mid-term. Moreover, our study shows that the
combination of GKAs may help patients, who still have poor glycemic
control after taking metformin, better control their blood glucose. Of
note, in the study of Zhang et al 2013, the combination of GKAs and
metformin could effectively reduce FPG and HbA1c in the patients with
poorly controlled blood glucose by metformin20,
suggesting that GKAs can effectively help metformin adjust blood glucose
by regulating GK. At the same time, earlier use of combination therapy
to prolong the duration of drug effect is also consistent with the
direction of ADA diabetes treatment guidelines25.
Regarding the safety, the main side effect of metformin is the
gastrointestinal reaction, which can cause nausea, vomiting, diarrhea,
and so on, which is related to the main effect of metformin on the
intestine. Our analysis showed that the combination of GKAs and
metformin did not significantly increase the risk of gastrointestinal
related AEs, such as nausea and diarrhea, but increased the risk of
hypoglycemia. Our subgroup analysis showed that dual-acting allosteric
glucokinase activator did increase the risk of hypoglycemia compared
with the control group, however liver-selective glucokinase activator
did not. A recent study in China, D.Zhu et al.2018, has shown that the
new liver selection of GKA (Dorzagliatin), which avoids the reduction of
GK targeting in the pancreas, has no risk of hypoglycemia23. Meanwhile, another study showed that the incidence
of hypoglycemia in GKAs can be effectively reduced by adjusting the
affinity between GK and substrate26. However, some
studies have shown that GKAs also bring the risk of hypoglycemia and
increasing triglycerides. Zhai at el. showed that piragliatin(GKA)
combined with other diabetes drugs increases the risk of
hypoglycemia27. And Wilding at el. showed that
triglycerides increased by 18–22% in randomized patients receiving
titrated AZD1656(GKA) 4 months in the main study
population19. Therefore, the safety of GKAs may need
further evaluation, especially for hypoglycemia and triglycerides.
Although we included high-quality trials, several limitations in our
meta-analysis remain to be noted as follows: (1)
The number of included studies is
limited, and only groups with higher dose and frequency of
administration are included in each study, which may lead to the risk of
selection bias; (2) There are other interference factors because of the
study design of each study is different, such as the type and dosage of
GKAs (MK-0941/AZD1656, etc.) and the time point or follow-up of FPG and
HbA1c evaluation; (3) The long-term efficacy and safety of GKAs are
still unclear.