The effects and safety of activators of glucokinase <i>versus</i> placebo in patients with type 2 diabetes mellitus: a systematic review and meta-analysis

Abstract

We undertook a systematic review and meta-analysis to assess the effects and safety of activators of glucokinase (GKAs) in patients with type 2 diabetes mellitus (T2DM). 11 RCTs, including 2,429 participants, are enrolled in our study. According to different doses, we divided the studies into 3 groups: low-dose group, medium-dose group and high-dose group for subgroup analysis. There were decreases of HbA1c in all dose group (WMD =-0.27, 95%CI (-0.51~-0.03), Z = 2.17, p = 0.03; WMD =-0.37, 95%CI (-0.58~-0.16), Z = 3.41, p = 0.0006; WMD =-0.60, 95%CI (-0.86~-0.33), Z = 4.43, p < 0.00001). Though the total risk of hypoglycemia is absolutely low, in the high-dose group higher hypoglycemia than the placebo can be observed (RR = 0.03, 95%CI (0.00~0.06), Z = 2.27, p = 0.02). In addition, the study found that the drug was less likely to have adverse reactions such as diarrhea, headache and dizziness, nasopharyngitis and upper respiratory tract infection (RR = 0.76, 95%CI (0.36~1.60), Z = 0.73, p = 0.47; RR = 1.26, 95%CI (0.73~2.17), Z = 0.83, p = 0.41; RR = 0.71, 95%CI (0.41~1.22), Z = 1.25, p = 0.21; RR = 1.61, 95%CI (0.77~3.36), Z = 1.26, p = 0.21). It concludes that GKAs are relatively effective and safe in the treatment of patients with T2DM, but in consideration of the potential risk of hypoglycemia in the high-dose group, the low-dose and medium-dose group, in the clinical practice, can be an excellent choice.

Safety, tolerability, pharmacokinetics, and pharmacodynamics of the glucokinase activator PB-201 and its effects on the glucose excursion profile in drug-naïve Chinese patients with type 2 diabetes: a randomised controlled, crossover, single-centre phase 1 trial

“…Mean glucose was 10¢680 mmol/L (SD 1¢990) with placebo and 10¢820 mmol/L (2¢670), 10¢020 mmol/L (2¢010), and 8¢700 mmol/L (2¢140) with three dose levels of PB-201. TIR increased as the dose of PB-201 increased, and TIRs in those given 100+50 and 100+100 mg were higher than that with placebo (mean TIR, 49¢380% [SD 27], 49¢210% [27], 56¢130% [25], and 63¢330% [20] with placebo and the three dose levels of PB-201, respectively; figure 3B). Only 0¢310%, 0, 0¢070%, and 4¢600% of time on average respectively were found to be TBR (<3¢9 mmol/L), indicating low frequencies of hypoglycaemia with both placebo and PB-201; the corresponding percentage of TBR (<3¢0 mmol/L) was 0 with all four regimens.…”

“…In two phase 2 clinical trials comparing PB-201, placebo, and active comparators as an add-on to metformin in patients with type 2 diabetes, hypoglycaemia occurred in 3¢0% (12/405) of patients with PB-201, 34¢4% (21/61) with glimepiride, 1¢8% (1/55) with sitagliptin, and 2¢5% (3/118) with placebo; all resolved with oral carbohydrates [10]. In comparison, hypoglycaemia was reported at an incidence rate ranging from 0¢6% (1/169) to 33¢8% (68/201) with other GKAs [27]. In a phase 2 trial in Chinese patients with type 2 diabetes, hypoglycaemia was reported in 5¢4% (11/205) of patients with dorzagliatin [8].…”

“…PB-201 showed a dose-proportional pharmacokinetic profile without apparent accumulation in the body and induced dosedependent lowering of blood glucose. PB-201 at 50+50, 100+50, and 100+100 mg increased mean time in range (49¢210% [standard deviation 27], 56¢130% [25], and 63¢330% [20] with three doses, respectively) versus placebo (49¢380% [27]) and reduced estimated glycated haemoglobin from baseline (À0¢5445% [1¢654], À1¢063% [1¢236], and À1¢888% [1¢381] vs À0¢581% [1¢200]). Fifteen patients (93¢8%) had treatment-emergent adverse events, which were mild.…”