The oral, highly potent, and selective free fatty acid receptor 1 agonist TAK-875 significantly improved glycemic control in patients with type 2 diabetes without increasing treatment-emergent hypoglycemic events in a phase II, randomized, controlled trial comparing TAK-875, glimepiride, and placebo.

Activation of free fatty acid receptor 1 (FFAR1), which is also known as G-protein–coupled receptor 40, has been shown in preclinical studies to stimulate glucose-dependent beta-cell insulin secretion. The current findings show that it is a potential therapeutic target in the treatment of type 2 diabetes, Dr. Charles F. Burant of the University of Michigan, Ann Arbor and his colleagues reported online in the Feb. 27 issue of the Lancet.

At weeks 4, 8, and 12 of treatment, all of the 303 patients who were randomized to receive treatment with TAK-875 at doses ranging from 6.25 to 200 mg once daily, as well as all of the 62 patients randomized to receive treatment with 4-mg glimepiride (a sulphonylurea that acts as an insulin secretagogue) once daily, achieved significant least-squares mean reductions from baseline in hemoglobin A_1c, compared with the 61 patients randomized to a placebo group. At 12 weeks, mean reductions in the TAK-875 group ranged from 0.65 percentage points with the 6.25-mg dose to roughly 1.0 percentage points with the 50-mg and higher doses; in the glimepiride group, the mean reduction was 1.05 percentage points, compared with 0.13 in the placebo group, the investigators said (Lancet 2012 Feb. 27 [doi:10.1016/S0140-6736(11)61879-5]).

Only the decrease in the 6.25-mg TAK-875 group was significantly smaller than that in the glimepiride group, they noted.

Additionally, the percentage of patients reaching the American Diabetes Association target of HbA_1c less than 7.0% by 12 weeks was generally similar in the 25- to 200-mg TAK-875 and glimepiride groups, and changes, relative to the placebo group, were significant, they said.

About 2% and 3% of the TAK-875 patients and the placebo patients, respectively, experienced treatment-emergent hypoglycemic events during treatment, compared with 19% of the glimepiride patients, and the events were mild to moderate in intensity in all groups. This finding suggests a therapeutic advantage of agents targeting FFAR1, compared with sulphonylureas, which are associated with frequent occurrence of hypoglycemia.

The incidence of other treatment-related adverse events was also similar in the TAK-875 and placebo patients (occurring in 49% and 48%, respectively), compared with 61% in the glimepiride patients, and these also were typically mild or moderate in nature, with no noted dose relationship.

The percentage of patients with treatment-emergent adverse events that were determined by the investigators to be related to the study drug was lowest in the TAK-875 patients (7%, compared with 11% in the placebo group and 23% in the glimepiride group).

Participants in this double-blind study were outpatient adults, aged 18-80 years, with type 2 diabetes who had not responded to either an 8-week diet and exercise plan or to metformin treatment, and who were enrolled during November 2009–September 2010 in 95 sites in the United States, Mexico, and Guatemala. Baseline characteristics were similar in all groups.

After a 2-week, single-blind, placebo run-in period, the patients were treated for 12 weeks, followed by a 2-week follow-up period.

The fact that a significant change in HbA_1c, as compared with placebo, was apparent at 4 weeks after treatment initiation with all doses of TAK-875 suggests a rapid onset of action.

"By comparison with placebo, the improvement in HbA_1c on TAK-875 is associated with both a reduction in fasting and post-challenge glucose and a decrease in AUC [area under the curve] for glucose during [oral glucose tolerance testing]. The improvement in glucose homeostasis is probably driven by glucose-dependent insulin secretion as the insulinogenic index, a measure of beta-cell function, was increased," the investigators wrote, adding that the mechanism of increased insulin secretion is "probably a direct effect of TAK-875 on beta-cell FFAR1, increasing the levels of intracellular secondary messengers that augment insulin secretion."

The promising results in this study are limited by a fairly short study period and small sample size, the investigators noted.

Additional studies of longer duration are needed to assess true efficacy, durability of clinical efficacy, and safety of TAK-875, and to "establish the appropriate placement of FFAR1 agonists in the treatment framework for type 2 diabetes," they said.

Additional therapeutic agents for type 2 diabetes are needed, particularly given the expected increase in the number of cases in the next few decades, and the insufficient effects and/or unacceptable side effects of currently available treatments. It appears, based on this and other studies, that activation FFAR1 receptors can be beneficial in the treatment of type 2 diabetes, the researchers concluded.

This study was sponsored by Takeda Global Research and Development, for which Dr. Burant serves as an unpaid consultant and advisor. All other study authors are employed by the company.

Novel FFAR1 Agonist Shows Promise for Type 2 Diabetes