Glucokinase activator fails to improve glycemic control in diabetes
MedWire News: Addition of the glucokinase activator (GKA), MK-0941, to stable-dose insulin glargine does not improve glycemic control in patients with Type 2 diabetes on a long-term basis, report researchers.
The add-on regimen is also associated with an increased incidence of hypoglycemia, elevated triglycerides, and increased blood pressure, they say.
Barry Goldstein (Merck & Co., Rahway, New Jersey, USA) and colleagues say their trial represents the first published clinical assessment of efficacy and safety after prolonged treatment with a GKA.
The researchers randomly assigned 587 diabetes patients who were on stable-dose insulin glargine to receive either MK-0941 (10, 20, 30, or 40 mg, 3 times per day) or matching placebo over 14 weeks. This was followed by a 40-week continuation phase during which patients who were not already at the maximum dose of MK-0941 received doses uptitrated to a maximum of 40 mg.
As reported in the journal Diabetes Care, the addition of MK-0941 to insulin glargine resulted in significant reductions in HBA1c at week 14, with mean reductions from baseline ranging from -0.5% to -0.8% in a dose-dependent manner, compared with placebo.
Between weeks 14 and 30, the reductions in HbA1c seen in the MK-0941 patients deteriorated, with the largest and most rapid deterioration occurring in patients receiving the 40-mg dose.
MK-0941 also caused an increase from baseline in triglycerides of up to 19% and increases in body weight of up to 0.8 kg, compared with placebo.
"The efficacy of MK-0941 appeared to wane sooner in those treated with the highest dose, in which increases in triglycerides and body weight were observed. This higher dose exposure and activation of GK may have led to multiple metabolic perturbations that affected the glucose-lowering response," say the authors.
In addition, the number of hypoglycemic adverse events during week 14 was significantly higher in the MK-0941 20- and 40-mg groups, compared with placebo (61 and 63 vs 40).
At week 14 there was also a statistically significant difference in systolic blood pressure between the MK-0941 40 mg and placebo groups (2.5 vs -1.3 mmHg).
"It is unknown whether the efficacy and safety profiles observed with MK-0941 were compound-specific or mechanism based," write Goldstein and team.
"A better understanding of the GK mechanism and its downstream metabolic effects is needed to determine whether GK activation with other compounds may be a viable treatment target for Type 2 diabetes," they conclude.
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By Sally Robertson