Hepatic glucokinase activation may improve glycemic control in type 2 diabetes
medwireNews: The hepatoselective glucokinase (GK) activator TTP399 reduces glycated hemoglobin (HbA1c) levels without increasing the risk for hypoglycemia among patients with type 2 diabetes, suggest findings from the phase IIb AGATA trial.
“Although multiple small-molecule activators of GK have been in clinical development, their initial therapeutic promise has been hampered by the occurrence of hypoglycemia, increased triglyceride concentrations, and loss of efficacy over time,” say the researchers, noting that these adverse events that are related to ongoing beta-cell activation.
They explain that hepatoselective GK activators – agents that activate the enzyme in hepatocytes but not in pancreatic beta cells – “would be less likely to cause these [adverse events],” and note that “[a]nimal studies have demonstrated that TTP399 does not activate GK in pancreatic β-cells, does not alter insulin secretion, and does not result in hypoglycemia.”
As reported in Science Translational Medicine, Carmen Valcarce (vTv Therapeutics Inc, High Point, North Carolina, USA) and co-researchers demonstrated that TTP399 improved glycemic control, reduced insulin resistance, and decreased bodyweight without changing insulin levels or hepatic lipids in animal models including diabetic Umeå ob/ob mice and Gottingen minipigs.
They then carried out a randomized controlled trial in which 190 patients with type 2 diabetes from 21 US centers were randomly assigned to receive oral TTP399 at a dose of 400 or 800 mg/day, sitagliptin 100 mg/day, or placebo, all given alongside continued metformin treatment.
The 42 patients given the 800 mg dose of TTP399 experienced a significantly greater least squares mean reduction in HbA1c levels from baseline to the 6-month follow-up compared with the 48 patients given placebo, with a difference between the groups of 0.9%.
Placebo-subtracted reductions in HbA1c levels were 0.2% for the 50 patients given the 400 mg dose, and 1.0% for the 49 patients given the positive control sitagliptin.
Average reductions in HbA1c levels were also greater among the 49 patients given sitagliptin compared with those in the placebo group, with a placebo-subtracted difference of 1.0%.
Although TTP399 treatment was not associated with a significant reduction in bodyweight in the whole trial population (average bodyweight at baseline=91.6–95.9 kg), treatment with the 800 mg dose resulted in a significant 3.4 kg greater least squares mean reduction relative to placebo when the analysis was restricted to patients who weighed 100 kg or more at baseline.
Patients given the 800 mg dose, but not the 400 mg dose or sitagliptin, also experienced a significant increase in high-density lipoprotein cholesterol levels compared with those given placebo, but there were no significant differences in the levels of triglycerides, or low-density lipoprotein or total cholesterol among the groups.
The AGATA (Add Glucokinase Activator to Target A1c) investigators say that rates of treatment-emergent adverse events were “generally similar among groups,” ranging from 50.0% to 61.2%. No serious adverse events occurred, and no cases of severe hypoglycemia or confirmed asymptomatic hypoglycemia were reported.
Taken together with evidence from preclinical studies, these trial findings “indicate that TTP399 may have a superior profile compared to other GK [activators],” and therefore “may be a therapeutically viable member of this class,” write Valcarce and team.
And they conclude: “Additional research on the effects of TTP399 in a larger clinical trial is needed to confirm these promising results.”
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