Findings from the phase II SYNCHRONY study show that aleglitazar, a treatment for type 2 diabetes, could be safe and effective and thus will be entered into phase III trials. The data are published in an Article Online First and in an upcoming edition of the Lancet, and is being presented at the American Diabetes Association meeting in New Orleans, USA.
Aleglitazar is in a class of drugs called PPAR co-agonists, meaning it can affect both glucose and fat (lipid) control. It also shares functional similarities with the thiazolidinedione family of drugs, along with, for example, rosiglitazone and pioglitazone. Both rosiglitazone and pioglitazone are well documented as effective agents for blood glucose control in patients with type 2 diabetes; but both also have a number of safety concerns attached to their use, for example an increased risk of heart failure. A number of PPAR co-agonists developed so far have been discontinued owing to toxic effects. Professor Robert R Henry, University of California, San Diego, USA, and colleagues—authors of SYNCHRONY—were hopeful that aleglitazar could have a similar positive effect on glucose control, but without the accompanying safety issues.
In this phase II randomised study, patients with type 2 diabetes (either drug-naïve or treated with two or fewer oral agents) were enrolled from 47 sites in seven countries. Following a five-week run in period with all patients on placebo, 332 were randomised to 16 weeks’ treatment with aleglitazar at once-daily doses of 50, 150, 300, 600 µg, or matching placebo (55 in each group), or to pioglitazone 45 mg once daily (57 patients) as a reference. The primary endpoint was the change in glycosylated haemoglobin concentration (HbA1c)* from baseline to the end of treatment.
The researchers found that aleglitazar reduced baseline HbA1c versus placebo in a dose-dependent manner, from -0.36% with 50 µg to -1.35% at 600 µg. The trend of changes over time suggested that the maximum effect of aleglitazar on HbA1c concentration was not yet reached after 16 weeks of treatment. The side effects of oedema, haemodilution, and weight gain occurred in a dose-dependent manner. However, at aleglitazar doses less than 300 µg, no patients had congestive heart failure, frequency of oedema (two cases at 150 µg) was less than placebo (three cases) and also less than with pioglitazone (four cases). Furthermore, at a dose of 150 µg, bodyweight gain was less than half that with pioglitazone (0.52 kg vs 1.06 kg).
The authors say: “Importantly, aleglitazar seemed to be safe and well tolerated over the course of the 16-week study. The sample size of this study was too small to make definitive conclusions, but that no heart attack or stroke events occurred is reassuring. By contrast, excess cardiovascular events have been noted for patients given muraglitazar and rosiglitazone after a fairly short exposure to treatment.”
They conclude: “The favourable balance in the safety and efficacy profile of aleglitazar represents encouraging short-term clinical data for this agent and provides good evidence to enter phase III investigation.”
They add: “It will be particularly interesting to see whether the combined beneficial glucose and lipid effects will translate into a benefit on cardiovascular outcomes.”
In an accompanying Comment, Dr Bernard Charbonnel, Institut du Thorax, University of Nantes, France, says: “The balance of safety and efficacy in today’s paper is encouraging, but it is impossible to draw definitive clinical conclusions from such a phase II study. Experience with muraglitazar has shown that a good lipid and blood glucose profile is not sufficient to predict clinical outcomes. It is a strength that cardiovascular events, including heart failure, were adjudicated in SYNCHRONY (two cases of heart failure, no heart attacks), but the sample size and short duration of the study do not allow firm conclusions.”
He concludes: “Research in this difficult area must be encouraged, and the coming years will tell whether hopes raised by the SYNCHRONY study for aleglitazar are confirmed by appropriate long-term clinical trials.”
Date: June 8, 2009