Results of a Phase II randomized trial published Online First in The Lancet, reveal that a new treatment for type 2 diabetes called TAK-875, enhances glycemic (blood sugar) control and is just as effective as the common drug treatment – sulphonylurea glimepiride. In addition, TAK-875 has less adverse effects and a considerably lower risk of hypoglycemia (low blood sugar).

Type 2 diabetes is the most prevalent form of diabetes. At present, type 2 diabetes is responsible for 90% of the 285 million individuals with the disease worldwide. The disease is primarily caused by lack of response to insulin, as a result blood sugar is unable to penetrate into fat, liver and muscle cells to be stored for energy, leading to high levels of blood sugar and a variety of chronic conditions.

Free fatty acid receptor 1 (FFA1), also known as G protein-coupled receptor 40 (GRP40), plays a crucial role in activating and controlling insulin production. FFA1 works by encouraging insulin to be released from pancreatic β-cells when glucose and fatty acids increase in the blood, such as after eating. This release of insulin causes blood sugar levels to drop. Medications that trigger the FFA1 receptor have the potential to help individuals who are diabetic to release more insulin and improve control of blood sugar levels.

TAK-875 is an innovative oral drug that improves the release of insulin in a glucose-dependent manner, meaning it has no effect on the release of insulin when blood sugar levels are normal. Therefore, TAK-875 has the potential to improve the control of blood glucose levels without the risk of hypoglycemia.

The study, led by Charles Burant from the University of Michigan Medical School, Michigan, USA, and his team, enrolled 426 individuals with type 2 diabetes who were not reaching sufficient blood sugar control through physical activity, diet or metformin treatment. The researchers randomly assigned 303 participants to receive 1 of 5 doses of TAK-875, 62 participants to receive glimepiride, and 61 participants to receive placebo.

The primary outcome the team measured was change in glycosylated haemoglobin (HbA1c) from baseline.

The researchers found that at 12 weeks, all 5 doses of TAK-875 lead to considerable reductions in HbA1c, compared with placebo. The team also found a similar reduction in participants receiving glimepiride.

Within 12 weeks, approximately two times more participants (33-48%) receiving a TAK-875 dose of 25 mg or higher, achieved the American Diabetics Association target of HbA1c less than 7%, than participants receiving placebo (19%) and was similar to glyburide (40%).

Among participants TAK-875 was generally well-tolerated. The team found that the incidence of hypoglycemia was considerably lower for all doses of TAK-875 (2%) and placebo (2%), compared with glimepiride (19%). In addition, the overall incidence of treatment-related adverse effects was comparable for all doses of TAK-875 (49%) and those receiving placebo (48%), although higher in participants who received glimepiride (61%) as a result of the increased risk of hypoglycemia.

The researchers explain:

“In view of the frequent hypoglycemia after treatment with sulfonylureas, the low risk of hypoglycemia after treatment with TAK-875 suggests that there may be therapeutic advantage of targeting FFAR1 in treating people with type 2 diabetes.”

They conclude:

“We are truly excited about the potential of TAK-875 and are eager to conduct larger trials to find out how well this drug works, how safe it is and what its place is in the treatment of diabetes.”

Clifford Bailey from Aston University Birmingham, UK, writes in an accompanying comment:

“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 β cells, provide durable efficacy, and avoid off-target safety issues?”

Written by Grace Rattue