Physicians' Academy for Cardiovascular Education

Novel agent targeting enzyme glucokinase as add-on to metformin in type 2 diabetes

Literature - Amin NB et al., Diabetes Obes Metab. 2015

Two Dose-Ranging Studies with PF-04937319, a systemic partial activator of glucokinase, as add-on therapy to Metformin in Adults with type 2 diabetes

Amin NB, Aggarwal N, Pall D, et al.,
Diabetes Obes Metab. 2015 Apr 16. doi: 10.1111/dom.12474. [Epub ahead of print]


Despite the availability of second-line therapies including sulphonylurea (SU) or dipeptidyl peptidase-4 inhibitor (DPP4i), in addition to metformin, only 52.5% of type 2 diabetes (T2DM) patients achieve glycaemic control [1]. Thus novel approaches are needed.
Genetic mutations in the gene encoding for the glucose phosphorylating enzyme glucokinase (GK) that increase its activity have been linked to increased insulin secretion and hyperinsulinaemic hypoglycaemia of infancy, and decreased GK activity is associated with lower insulin secretion and maturity-onset diabetes of the young type 2 [2]. Since GK activation increases glucose-stimulated insulin secretion in pancreatic β-cells and hepatocytes and hepatic glucose uptake and decreases hepatic glucose output [3], it has been proposed as a therapeutic target.
PF-04937319 is a partial GK activator (GKA) which has been designed [4] to maintain glucose lowering efficacy, while mitigating the risk of hypoglycaemia, as seen with other GKAs. In phase I studies, oral doses of PF-04937319 were safe and tolerated in T2DM or healthy subjects. A once-daily 14-day dosing of PF-04937319 in patients with T2DM was associated with a change from baseline in weighted-mean daily glucose of up to -2.72 (SD: 1.51) mmol/L.
This is a report of two parallel-group, randomised, double-blind placebo-controlled phase 2a studies to assess the efficacy and safety of a range of doses of PF-04937319 as add-on therapy in patients with T2DM inadequately controlled on metformin. The first study (testing 3-100 mg) included patients 18-70 years old, with titrated glimepiride as active comparator, and the second study (testing 10-100 mg) included patients ages 18-55 years, with maximum 5 years since diagnosis, with sitagliptin as active comparator.  

Main results

  • The highest dose of PF-04937319, 100 mg, gave an average HbA1c of -6.7 mmol/mol (-0.61%) from baseline in the first study, and -9.0 mmol/mol (-0.82%) in the second.
  • At week 12, except 3 mg, all doses yielded a decline in placebo-adjusted change in HbA1c in the first study. In the second, only 100 mg PF-04937319 gave a placebo-adjusted change in HbA1c, which closely tracked the effect of sitagliptin over time.
  • A clinically significant linear change from baseline response of HbA1c to PF-04937319 was seen across the evaluated dose-range.
  • A dose-responsive decrease in fasting plasma glucose (FPG) was seen with doses up to 50 mg. At 100 mg, the studies gave an inconsistent result, with the first study showing placebo-adjusted FPG change of +0.50 vs -0.83 mmol/L in the second study.
  • PF-04937319 and sitagliptin did not affect fasting insulin over time, while a sustained increase was seen with titrated glimepiride from week 2 to 12.
  • In the two studies, 18 serious adverse events (SAEs), including 2 deaths, were reported (in 12 patients). 7 SAEs, of which 1 death, occurred prior to randomisation. None of the SAEs were assessed to be treatment-related.
    Overall, hypoglycaemia was the most frequent AE, mostly reported with titrated glimepiride.
  • No dose-dependent effect on fasting serum triglycerides, nor in total, LLD or HDL cholesterol levels and liver function tests, with either treatment.
  • A marginal (<1 kg) placebo-adjusted increase in body weight was seen with PF-04937319, and 2.7 kg increase with glimepride at week 12, while sitagliptin had no effect on body weight. 


These first dose-ranging phase 2 studies of PF-04937319 show that out of 5 tested doses, 50 mg once-daily is the minimally efficacious dose, while 100 mg once-daily gave similar safety and efficacy to a DPP4i. The effect of 100 mg PF-04937319 on HbA1c was, however, lower than that observed with titrated glimepiride. This partial glucokinase activator was well-tolerated.
Studies with higher dosing or different dosing regimens of PF-04937319 are needed to investigate its therapeutic potential, also considering the divergent observations of the effect on FPG in the two studies, which needs elucidation. The data suggest that at doses higher than 100 mg once-daily PF-04937319 has the potential to improve glycaemic control with an acceptable risk/benefit profile, in patients with T2DM inadequately managed on metformin. It is hoped that PF-04937319 can offer efficacy similar to SU while offering a fixed-dose regimen that yields more glucose-dependent insulin secretion and hence a lower risk of hypoglycaemia.
Find this article online at Diabetes, Obesity and Metabolism


1. Casagrande SS, Fradkin JE, Saydah SH, Rust KF, Cowie CC. The prevalence of meeting HbA1c, blood pressure, and LDL goals among people with diabetes, 1988-2010. Diabetes Care 2013;62(12):3963-7.
2. Matschinsky FM, Magnuson MA, Zelent D, et al. The network of glucokinase-expressing cells in glucose homeostasis and the potential of glucokinase activators for diabetes therapy. Diabetes 2006;55:1–12
3.Matschinsky FM. GKAs for diabetes therapy: why no clinically useful drug after two decades of trying? Trends Pharmacol Sci 2013; 34(2):90-9.
4. Pfefferkorn JA, Guzman-Perez A, Oates PJ, et al. Designing glucokinase activators with reduced hypoglycemia risk: discovery of N,N-dimethyl-5-(2-methyl-6-((5-methylpyrazin-2-yl)-carbamoyl)benzofuran-4-yloxy)pyrimidine-2-carboxamide as a clinical candidate for the treatment of type 2 diabetes mellitus. Med. Chem. Commun. 2011;2(9):828-39.

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