A new treatment for type 2 diabetes using aleglitazar could be safe and effective and thus will be entered into phase III trials, according to the phase II SYNCHRONY study published June 8 in Lancet, and simultaneously presented at the American Diabetes Association (ADA) meeting in New Orleans.
Aleglitazar is in a class of drugs called PPAR co-agonists, affecting both glucose and fat control, which shares functional similarities with the thiazolidinedione (TZD) drug class. However, the authors noted that TZDs, such as rosiglitazone (Avandia from GlaxoSmithKline) and pioglitazone (Actos from Takeda), are well documented as effective agents for blood glucose control in patients with type 2 diabetes; but 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.
Robert R. Henry, MD, from the University of California, San Diego, and co-authors of SYNCHRONY trial are seeking to asses whether aleglitazar could have a similar positive effect on glucose control, but without the accompanying safety issues.
In the phase II randomized study, patients with type 2 diabetes were enrolled from 47 sites in seven countries. Following a five-week run in period with all patients on placebo, 332 were randomized 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 hemoglobin 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 percent with 50 µg to -1.35 percent 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 edema, hemodilution 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 edema (two cases at 150 µg) was less than placebo (three cases) and also less than with pioglitazone (four cases), according to the authors. Furthermore, at a dose of 150 µg, bodyweight gain was less than half that with pioglitazone (0.52 kg vs 1.06 kg).
"Importantly, aleglitazar seemed to be safe and well tolerated over the course of the 16-week study," Henry and colleagues wrote. "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."
"The favorable 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 wrote.
"It will be particularly interesting to see whether the combined beneficial glucose and lipid effects will translate into a benefit on cardiovascular outcomes," they added.
In an accompanying commentary, Bernard Charbonnel, MD, from the Institut du Thorax, University of Nantes in France, wrote that 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."
Charbonnel concluded: "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."