Type II diabetes occurs when a person’s sensitivity to insulin reduces, so although the pancreas continues to make it – albeit, potentially, in lower amounts – the body does not respond adequately to the hormone. It is usually treated with drugs such as sulfonylureas, but these damage the beta cells leading to Type I diabetes a few years down the line.
Various alternatives have been introduced that act via several different mechanisms, but there have been concerns about side-effects, and some, including drugs like rosiglitazone, have been removed from the market as a result.
New mechanisms are thus required, and one of these is the free fatty acid receptor 1, or GPR40, which is largely expressed in the pancreas, and potentiates glucose-stimulated insulin secretion. Takeda is investigating TAK-875 as a potential agonist of this receptor, and several clinical trials have already been carried out.1 In one Phase IIa randomised, placebo-controlled, double blind, parallel group study, a total of 65 patients with Type II diabetes were given 100 or 400mg of the drug once a day for two weeks, or placebo.2 Plasma glucose levels were significantly lower in the treatment groups than the placebo group after the patients were given 75g oral glucose, and a significantly larger effect was seen in the higher dose group. There were no serious adverse events, and those that did occur were mild and not dose-dependent. There were no hypoglycaemic events during the study.
In another randomised, double blind, placebo and glimepiride comparator controlled, parallel group Phase II trial, a total of 426 subjects with Type II diabetes were given doses ranging between 6.25 to 200mg once a day over 12 weeks, or placebo or glimepiride.3 Every dose of the drug gave significantly greater reductions in glycosylated haemoglobin than placebo, and at week 12 all doses of at least 50mg gave comparable reductions to glimepiride.
The incidence of hypoglycaemia was 2.3% across TAK-875 groups, which was not significantly different from placebo (3.3%), and significantly lower than the 16% seen with glimepiride. Side-effects were greater with glimepiride, and discontinuations because of adverse events were low across all groups. The drug is now in Phase III trials.
references
1. N. Negoro et al. ACS Med. Chem. Lett. 2010, 1 290
2. T. Araki et al. 71st Sci. Sess. Amer. Diabet. Assn, 2011 (24–28 Jun, San Diego), Abst. 312-OR
3. P. Viswanathan et al. 47th Ann. Meet. Eur. Assoc. Study Diabetes 2011 (12–16 Sep, Lisbon), Abst. 187