Safety
Four included trials reported the AEs during the trial
phase14,15,19,23, and 307 out of a total of 605
patients had at least one AE. As shown in Figure 5 , GKAs did
not significantly increase the incidence of at least one AE compared
with placebo (RR 1.11, 95% CI: 0.95 to 1.3, P = 0.19). Of note, GKAs
increased the incidence of hypoglycemic events(RR 1.181, 95% CI: 1.35
to 2.42, P <0.0001), but they did not increase the relative
risk of headache(RR 1.3, 95% CI: 0.49 to 3.43, P = 0.60), diarrhea(RR
1.64, 95% CI: 0.69 to 3.87, P = 0.26), and nausea(RR 2.65,95%CI: 0.53
to 13.26,P=0.24).
Then, we did further subgroup meta-analysis according to the type of
GKAs. As shown in Figure 6 , we found that there was no
significant difference in the risk of hypoglycemia between
Liver-selective glucokinase activator and placebo (RR 1.59, 95% CI:
0.58 to 4.39, P = 0.37), but GKAs (pancreas liver double activator) did
increase the risk(RR 1.84, 95% CI: 1.36 to 2.49, P <0.0001).
And in GKAs (pancreas liver double activator) subgroup analysis, there
was heterogeneity (I2 > 50%). It seems that there are
significant differences in the effectiveness and incidence of
hypoglycemia among different types of GKAs.
Quality of Evidence
Most of the findings were supported by high certainty evidence.Table 2 shows the GRADE summary of findings for FPG, HbA1c,
Total AEs, Hypoglycemia, Headache, Diarrhea and Nausea.