Efficacy and safety of glucokinase activators for type 2 diabetes mellitus: A systematic review

Glucokinase activators (GKAs) are newly drug class proposed for diabetes treatment. This systematic review aimed to assess the efficacy and safety of GKAs in type 2 diabetes mellitus (T2DM) compared to placebo for their readiness in clinical practice and future development. Systematic review on online databases including CINAHL, the Cochrane Library, EMBASE, MEDLINE, Scopus, Web of Science, and ClinicalTrials. gov was conducted with inception until December 2018. Randomized-controlled trials (RCTs) reported in English were assessed in terms of study quality, placebo-corrected efficacy on glycemic control, and list of safety issues. Thirteen studies were included comprising of eight candidates for GKAs namely AMG 151 (ARRY-403), AZD1656, dorzagliatin, MK-0941, PF-04937319, PF-04991532, RO4389620 (piragliatin), and TTP399. Of the promising GKAs, efficacy on glycemic control was demonstrated on HbA1c reduction more than fasting plasma glucose (FPG) and 2-hours post prandial glucose (2h PPG). Compared to placebo, GKAs contributed to significant HbA1c decrease up to 0.7-0.8%. Direct GKAs revealed great potency, but more selective GKAs offered certain moderation. This was due to some raised concerns such as hypoglycemia, triglyceride alteration, and adverse events leading to discontinuation. Regardless of limited data, some factors might influence the effects of GKAs in T2DM, for example, structure-molecular aspect, varied trial settings, and diversity in participants' background. These findings shed light in diabetes management. However, mechanisms towards the unmet benefits of GKAs in T2DM should be tackled. Large clinical trials with longer duration are also still needed.