ADA – New Dual PPAR Agonist Promising for Diabetes

The experimental compound significantly reduced baseline A1c in a dose-dependent manner by an absolute 0.36% to 1.35% more than placebo, Robert R. Henry, M.D., of the University of California San Diego, and colleagues found.

The phase II study results also revealed a reassuring safety profile, with less edema and weight gain than pioglitazone (Actos) at the lower doses, the group reported here at the American Diabetes Association meeting.

Bernard Charbonnel, M.D., of the University of Nantes in France, wrote in an accompanying editorial that more than 50 investigational PPAR drugs have failed over safety concerns since the approval of thiazolidinediones.

Two of these PPAR dual agonists — muraglitazar and tesaglitazar — reached phase III clinical trials before safety concerns derailed development.

Dual PPAR agonists aim to combine the lipid benefit of PPAR-alpha agonists, such as fibrates, with the glycemic advantages of the PPAR-gamma agonists, such as the thiazolidinediones.

Dr. Henry’s group studied aleglitazar in a multinational, dose-ranging phase II study that included 332 patients with Type 2 diabetes who were either drug-naive or had been treated with no more than two oral agents, (which were discontinued before the run-in period).

Participants were randomized to 16 weeks of double-blind treatment with placebo or aleglitazar (50, 150, 300, or 600 ?g once daily) or open-label treatment with pioglitazone (45 mg once daily) as a reference.

In addition to the primary endpoint benefits for hemoglobin A1c reduction over 16 weeks, aleglitazar showed a similar dose-response for fasting plasma glucose, with more than a 3% absolute reduction compared with placebo for the highest, 600-?g dose.

The trend of changes over time suggested the maximum effect of aleglitazar on hemoglobin A1c concentration had yet to be reached at 16 weeks, whereas the impact on fasting plasma glucose peaked after eight weeks.
As hoped, the experimental agent improved lipids as well. These findings included:

• a reduction in triglycerides compared with placebo at all doses of aleglitazar (P<0.001 for percentage changes);
• an increase in HDL cholesterol compared with placebo at all doses (P<0.05 for percentage changes);
• improvement in LDL cholesterol only at doses of 150 ?g or higher compared with placebo (P<0.05 for percentage changes);
• systolic blood pressure reductions of 3.1 to 7.4 mm Hg compared with 2.6 mm Hg with placebo;
• high-sensitivity C-reactive protein reductions of 0.14 to 1.73 mg/L.

Thomas W. Donner, M.D., of the University of Maryland’s Joslin Diabetes Center in Baltimore, who was not involved in the study, commented that the results, “suggest a cardiovascular benefit could be seen with long-term aleglitazar use, as has been shown with pioglitazone.” The researchers noted that aleglitazar at 150 ?g was comparable to pioglitazone for reductions in hemoglobin A1c and fasting plasma glucose. Aleglitazar at this dose also produced larger improvements in triglycerides, HDL cholesterol, and LDL cholesterol than did pioglitazone.

Henry RR, et al “Effect of the dual peroxisome proliferator-activated receptor-?/? agonist aleglitazar on risk of cardiovascular disease in patients with type 2 diabetes (SYNCHRONY): a phase II, randomised, dose-ranging study” Lancet 2009.