A Phase III study showed Muraglitazar ( Pargluva ) 5 mg reduced A1C levels significantly more than Pioglitazone ( Actos ) 30 mg in patients with type 2 diabetes.
Both treatment groups were taking Metformin.
Significant effects were also seen on triglycerides and high-density lipoprotein cholesterol ( HDL-C ) levels.
Pargluva is the first agent in a new class of investigational compounds called glitazars, a dual alpha/gamma PPAR ( peroxisome proliferator-activated receptor ) activator.
Phase III study: Muraglitazar versus Pioglitazone
This Phase III, double-blind, randomized, active-controlled trial was conducted in 1,159 patients with type 2 diabetes who had inadequate glycemic control on Metformin alone.
Patients were assigned to either a once-daily dose of Pargluva 5 mg ( n=587 ) or Pioglitazone 30 mg ( n=572 ) for 24 weeks while continuing mean daily metformin doses of 1,854 mg and 1,851 mg in the Pargluva and Pioglitazone groups, respectively.
Starting at week 12, statin therapy could be initiated or adjusted as needed.
All analyses on mean change from baseline were adjusted for baseline level and used the last observation carried forward ( LOCF ) methodology. The mean baseline A1C value ( 8.1% ) and other disease characteristics were comparable between the two groups.
At week 24, the addition of Pargluva 5 mg reduced mean A1C values from baseline by 1.14% compared with the addition of Pioglitazone 30 mg, which resulted in a reduction of 0.85% ( p < 0.0001 between treatment groups ).
Sixty percent of patients taking Pargluva 5 mg attained the ADA recommended A1C goal ( < 7% ), compared to 45 percent of patients taking Pioglitazone 30 mg ( p < 0.0001 between treatment groups ).
Pargluva 5 mg also reduced fasting plasma glucose, a secondary endpoint, more than Pioglitazone 30 mg [ -44 mg/dL from baseline versus -33 mg/dL from baseline, respectively ( p < 0.0001 between treatment groups ) ].
At week 12, triglyceride levels decreased 28% and 14% versus baseline in patients treated with Pargluva 5 mg and Pioglitazone 30 mg, respectively ( p = 0.0001 between treatment groups ).
In patients with a triglyceride level above 150 mg/dL at baseline, the reduction was 35% and 19% for Pargluva 5 mg and Pioglitazone 30 mg, respectively ( p < 0.001 between treatment groups ).
HDL-C levels increased 19% in the Pargluva 5 mg group and 14% in the Pioglitazone 30 mg group ( p = 0.0001 between treatment groups ).
In addition, non-HDL-C levels decreased 6%, apoB levels decreased 12%, and free fatty acids decreased 30% in the Pargluva 5 mg group compared to decreases of 1%, 6% and 21%, respectively, in the Pioglitazone 30 mg group ( all p-values less than or equal to 0.0001 between groups ).
There were no significant effects on LDL-C in either group.
At week 24, Pargluva 5 mg reduced fasting plasma insulin more than Pioglitazone 30 mg [ -5.0 microunits/mL from baseline versus -3.6 microunits/mL from baseline, respectively ( p < 0.0001 between treatment groups ) ].
Treatment with Pargluva 5 mg also increased insulin sensitivity more than Pioglitazone 30 mg as measured by a decrease in homeostasis model assessment of insulin resistance ( HOMA-IR ) (p < 0.0001 between treatment groups ).
Other secondary endpoints showed that CRP ( C reactive protein ) decreased 30% and PAI-1 decreased 30% in the Pargluva 5 mg group versus decreases of 24% and 22%, respectively, in the Pioglitazone 30 mg group ( p = 0.04 for the CRP comparison and p = 0.0002 for the PAI-1 comparison ).
Discontinuation rates due to adverse events were 3% for Pargluva 5 mg and 2% for Pioglitazone 30 mg.
The incidence of serious adverse events was 4% for Pargluva and 3% for Pioglitazone.
Three deaths occurred during the 24 weeks of this study: two deaths in the Pargluva group ( stroke and sudden cardiac death ) and one death in the Pioglitazone group ( perforated ulcer ).
Investigators reported these cases not to be drug-related.
The rates of edema-related events for Pargluva versus Pioglitazone were 9.2% and 7.2%, respectively, and weight gain was 1.4 kg vs. 0.6 kg, respectively.
Investigator physicians reported that four patients developed events related to heart failure: three in the Pargluva group and one in the Pioglitazone group, all of whom recovered with diuretic therapy and/or withdrawal of study drug.
Confirmed hypoglycemia occurred in three patients taking Pargluva and one patient taking Pioglitazone.
There were no hypoglycemia-related serious adverse events or withdrawals.
The Phase III Pioglitazone comparative study continued with a 26-week extension, and preliminary analyses indicate that glycemic and lipid efficacy differences between Pargluva 5 mg and Pioglitazone 30 mg increased or were maintained after 50 weeks.
In the preliminary analyses, the overall profile of adverse events in the long-term phase was similar to that seen in the short-term phase.
Four additional deaths were reported for patients on Pargluva ( stroke, myocardial infarction, sudden cardiac death, and previously diagnosed pancreatic cancer ), which the investigators reported were not drug-related.
There were an additional two cases of heart failure on Pargluva and one on Pioglitazone. There were no deaths due to heart failure.
Source: American Diabetes Association ( ADA ) 65th Annual Scientific Sessions, 2005