P2–397: Safety and tolerability of rosiglitazone (RSG) in patients with mild to moderate Alzheimer's disease (AD)

Abstract

Rosiglitazone (PPARγ agonist) approved for the treatment of type–2 diabetes is being tested in AD. Risner et al reported rosiglitazone was generally well–tolerated in a 24–week, double–blind, placebo–controlled monotherapy trial (N=511) in AD subjects (baseline MMSE 16–26). To report additional safety, tolerability, and biomarker results for RSG in AD patients. Subjects were randomized to receive placebo or an unmarketed formulation of RSG 2, 4, or 8 mg/day for 24 weeks. Safety and tolerability were assessed via patient–reported events, clinical chemistry, hematology, changes from baseline in fasting insulin and plasma glucose, homeostasis model assessment (HOMA) estimate of insulin resistance, and inflammatory markers. Adverse events (AEs) are summarized in Table below for overall safety population and by APOE ϵ4 carriage status. A small number of cases of edema were seen in RSG–treated subjects, and none were seen on placebo. One fatality owing to acute cardiac failure unrelated to study drug (RSG 8mg) was reported. With the exception of one report of atrial fibrillation and cardiac failure in a single subject (RSG 8 mg), other serious adverse events (SAEs) were not considered to be related to the study medication. No clinically significant trends were noted in the hematology, clinical chemistry, vital signs, or ECG parameters. Observed changes in insulin sensitivity and glycemic control parameters (fasting insulin, fasting plasma glucose, HbA1c, and HOMA IR) were within expected ranges and were typical of an older population who had a low level of insulin resistance and consistent with other recent AD studies. A significant linear trend in RSG dose response at Week 24 LOCF was noted for the expression of the CD40L protein marker, but the overall RSG treatment effect or individual RSG versus placebo treatment differences were not statistically significant. No major differences were observed between APOE ϵ4 negative and APOE ϵ4 positive subjects in the overall incidence of SAEs or AEs. The adverse events and tolerability profile observed in this AD population were comparable to the well established safety profile reported with rosiglitazone in type 2 diabetes.