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.
Effects on weight varied, with patients on placebo showing unexplained weight loss, and those on lower doses of TAK-875 and glimepiride experiencing weight gains.
Further studies are needed to more fully explore the effects of TAK-875 on weight, according to the investigators.
Overall rates of adverse events were similar in the TAK-875 and placebo groups, but were higher in the glimepiride group (61% versus 49%).
Treatment was discontinued in three patients taking TAK-875 because of events such as renal failure and myocardial infarction, and in two patients on glimepiride because of angina and hyperglycemia.
No changes were reported in blood pressure, cholesterol, or liver enzymes.
"The mechanism of increased insulin secretion is probably a direct effect of TAK-875 on activation of beta-cell FFAR1, increasing the levels of intracellular secondary messengers that augment insulin secretion," the investigators explained.
The researchers acknowledged that their study was short in duration and included a fairly small sample size, and called for further trials.
In a comment accompanying the study, Clifford J. Bailey, PhD, of Aston University in Birmingham, England, noted that "the question of durability" remains a challenge for therapies that increase the release of insulin.
Sulfonylureas, for example, often lose their effect, either because patients lose their sensitivity to these agents or beta-cell loss continues.
"On the journey to approval of a new class of treatment for type 2 diabetes, many questions will be asked of the FFAR1 agonists. Can they unlock the secretion-shy beta cells, provide durable efficacy, and avoid off-target safety issues? We travel hopefully," Bailey wrote.
The study was funded by Takeda Global Research and Development.
The lead author is an unpaid consultant and adviser to Takeda; all co-investigators are employees of the company.
The lead author is an unpaid consultant and adviser to Takeda; all co-investigators are employees of the company.
Primary source: The Lancet
Source reference:
Burant C, et al "TAK-875 versus placebo or glimepiride in type 2 diabetes mellitus: a phase 2, randomized, double-blind, placebo-controlled trial" Lancet 2012; DOI:10.1016/S0140-6736(11)61879-5.
Additional source: The Lancet
Source reference:
Bailey C "Could FFAR1 assist insulin secretion in type 2 diabetes?" Lancet 2012; DOI:10.1016/S0140-6736(12)60165-2.
Source reference:
Burant C, et al "TAK-875 versus placebo or glimepiride in type 2 diabetes mellitus: a phase 2, randomized, double-blind, placebo-controlled trial" Lancet 2012; DOI:10.1016/S0140-6736(11)61879-5.
Additional source: The Lancet
Source reference:
Bailey C "Could FFAR1 assist insulin secretion in type 2 diabetes?" Lancet 2012; DOI:10.1016/S0140-6736(12)60165-2.
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