New Diabetes Drug Cuts Glycemic Risk

A novel agent that activates a free fatty acid receptor successfully increased insulin secretion without raising the risk of hypoglycemia in patients with type 2 diabetes, a randomized study found.

The mean reduction in glycated hemoglobin (HbA1c) among patients taking 50 mg/day of TAK-875 was −1.12% at week 12, compared with −1.05% in patients on 4 mg of the sulfonylurea glimepiride daily and −0.13% in those on placebo, according to Charles F. Burant, MD, of the University of Michigan in Ann Arbor, and colleagues.

However, hypoglycemia developed in only 2% of patients receiving the experimental agent compared with 19% of those given glimepiride (P-value range 0.010 to 0.002 versus all TAK-875 groups), the researchers reported online in the Lancet.

TAK-875 is an activator of free fatty acid receptor 1 (FFAR1), a cell-surface receptor expressed in pancreatic beta cells.

Its activation raises insulin secretion, but unlike many other anti-diabetic agents, does so only when glucose levels are elevated.

Animal studies and small human trials have suggested that this agent could be a safe alternative to other insulin-stimulating agents.

Burant and colleagues enrolled 426 patients whose blood sugar was inadequately controlled by diet or metformin, and assigned them to various doses of the FFAR1 agonist or to the control groups.

The patients' mean age was 52, and slightly more than half were women.

Significant reductions in HbA1c were seen in patients on all doses of FFAR1, which ranged from 6.2 mg per day to 200 mg per day.

These reductions were similar to those seen in patients receiving glimepiride, with the exception of the lowest dose of TAK-875.

Onset of effect was rapid, with significant HbA1c changes evident after one month.

The percentage of patients who achieved the HbA1c target established by the American Diabetes Association of less than 7% ranged from 33% to 48% in the 25 mg to 200 mg dose groups.

Significant decreases were observed in the area under the curve for the two-hour glucose tolerance test for the 25 mg through 200 mg doses, with P-values at week 12 ranging from 0.031 to <0.0001 compared with placebo, the researchers reported.

In addition, the area under the curve for the glucose tolerance test did not differ for doses of TAK-875 up to 100 mg, compared with sulfonylurea.

A significant difference was seen on this measure, however, for the 200 mg dose in comparison with glimepiride (P=0.001).

Fasting at postprandial glucose levels showed similar reductions in the higher dose TAK-875 and glimepiride groups.

To assess the effect of treatment on beta-cell insulin secretion, Burant's group measured the C-peptide-to-glucose ratio during the first half hour of the glucose tolerance test, and found significant insulin increases in patients receiving 25 mg, 100 mg, or 200 mg doses.