Thiazolidinedione Safety Profile Good in Pilot Alzheimer's Study

Pioglitazone, a thiazolidinedione used to reduce insulin resistance in patients with type 2 diabetes, was well tolerated in a pilot study of nondiabetic patients with probable Alzheimer’s disease, providing support for continuing studies of this class of drugs in early stages of Alzheimer’s, according to a report published online on Sept. 13 in the Archives of Neurology.

Safety was the primary objective of the study, and while no effects of treatment on clinical efficacy, a secondary outcome, were observed, the authors concluded that “disappointing results of treatment trials based on the amyloid hypothesis, and the reasonable degree of safety identified in this trial, suggest that exploratory studies of thiazolidinediones remain warranted.” The lead author was Dr. David Geldmacher, of the University of Virginia, Charlottesville, one of the two study sites.

In the double-blind, placebo-controlled study, 29 patients who met the criteria for probable Alzheimer’s disease (AD) were randomized to receive pioglitazone, titrated to 45 mg/day, or placebo, plus 100 IU vitamin E daily, for 18 months, between 2001 and 2004. They continued treatment with cholinesterase inhibitors; 20%-27% of the patients also received memantine, once it became available.

Pioglitazone, marketed as Actos as a treatment for type 2 diabetes, is a potent inhibitor of peroxisome proliferator–activated receptor gamma (PPARg), a nuclear receptor that that regulates glucose and lipid metabolism, which are abnormal in AD. This is a “potential therapeutic target for the treatment of AD,” because PPARg activation “robustly suppresses inflammation as well as expression of cytokines and other inflammatory mediators associated with activated microglia,” they said, noting that that, “a local microglia-mediated inflammatory response centers on the amyloid plaques in the AD brain.”

They referred to some evidence that rosiglitazone, another thiazolidinedione, had “limited efficacy,” in patients with early AD, but the results were mixed. This was the first study of pioglitazone in patients with AD, they said.

In the study, almost 29% of those on pioglitazone developed peripheral edema, a known adverse effect associated with pioglitazone, compared with none of the patients on placebo. But otherwise, there were no serious adverse events, and the drug was well tolerated, with “no pattern of effect on blood glucose levels, hemoglobin A1c levels, or other blood chemistry or hematologic measures,” they said (Arch. Neurol. 2010 Sept. 13 [doi:10.1001/archneurol.2010.229]).

As expected, because of the small size of the study, “no significant effect of treatment was observed on any clinical outcome measures,” which included measures of cognition and activities of daily living, the authors said.

The authors recommended that future studies of these agents should focus on earlier stages of disease and “be augmented by biomarkers, such as nuclear imaging techniques, to measure changes in microglial activation associated with treatment.” They noted that these studies will need to closely monitor patients for peripheral edema and other cardiovascular morbidities.

The study was supported by the National Institute of Aging. Pioglitazone manufacturer Takeda Pharmaceuticals North America provided the pioglitazone and placebo tablets free of charge but had no other role in the conduct or analysis of the study. Two of the four authors have received consulting fees from Takeda and consulting fees and research support from GlaxoSmithKline. One of the study sites, Case Western Reserve University, Cleveland, has a patent for the use of pioglitazone in the treatment of AD and other CNS disorders.

Pioglitazone, a thiazolidinedione used to reduce insulin resistance in patients with type 2 diabetes, was well tolerated in a pilot study of nondiabetic patients with probable Alzheimer’s disease, providing support for continuing studies of this class of drugs in early stages of Alzheimer’s, according to a report published online on Sept. 13 in the Archives of Neurology.

Safety was the primary objective of the study, and while no effects of treatment on clinical efficacy, a secondary outcome, were observed, the authors concluded that “disappointing results of treatment trials based on the amyloid hypothesis, and the reasonable degree of safety identified in this trial, suggest that exploratory studies of thiazolidinediones remain warranted.” The lead author was Dr. David Geldmacher, of the University of Virginia, Charlottesville, one of the two study sites.

In the double-blind, placebo-controlled study, 29 patients who met the criteria for probable Alzheimer’s disease (AD) were randomized to receive pioglitazone, titrated to 45 mg/day, or placebo, plus 100 IU vitamin E daily, for 18 months, between 2001 and 2004. They continued treatment with cholinesterase inhibitors; 20%-27% of the patients also received memantine, once it became available.

Pioglitazone, marketed as Actos as a treatment for type 2 diabetes, is a potent inhibitor of peroxisome proliferator–activated receptor gamma (PPARg), a nuclear receptor that that regulates glucose and lipid metabolism, which are abnormal in AD. This is a “potential therapeutic target for the treatment of AD,” because PPARg activation “robustly suppresses inflammation as well as expression of cytokines and other inflammatory mediators associated with activated microglia,” they said, noting that that, “a local microglia-mediated inflammatory response centers on the amyloid plaques in the AD brain.”

They referred to some evidence that rosiglitazone, another thiazolidinedione, had “limited efficacy,” in patients with early AD, but the results were mixed. This was the first study of pioglitazone in patients with AD, they said.

In the study, almost 29% of those on pioglitazone developed peripheral edema, a known adverse effect associated with pioglitazone, compared with none of the patients on placebo. But otherwise, there were no serious adverse events, and the drug was well tolerated, with “no pattern of effect on blood glucose levels, hemoglobin A1c levels, or other blood chemistry or hematologic measures,” they said (Arch. Neurol. 2010 Sept. 13 [doi:10.1001/archneurol.2010.229]).

As expected, because of the small size of the study, “no significant effect of treatment was observed on any clinical outcome measures,” which included measures of cognition and activities of daily living, the authors said.

The authors recommended that future studies of these agents should focus on earlier stages of disease and “be augmented by biomarkers, such as nuclear imaging techniques, to measure changes in microglial activation associated with treatment.” They noted that these studies will need to closely monitor patients for peripheral edema and other cardiovascular morbidities.

The study was supported by the National Institute of Aging. Pioglitazone manufacturer Takeda Pharmaceuticals North America provided the pioglitazone and placebo tablets free of charge but had no other role in the conduct or analysis of the study. Two of the four authors have received consulting fees from Takeda and consulting fees and research support from GlaxoSmithKline. One of the study sites, Case Western Reserve University, Cleveland, has a patent for the use of pioglitazone in the treatment of AD and other CNS disorders.

Pioglitazone, a thiazolidinedione used to reduce insulin resistance in patients with type 2 diabetes, was well tolerated in a pilot study of nondiabetic patients with probable Alzheimer’s disease, providing support for continuing studies of this class of drugs in early stages of Alzheimer’s, according to a report published online on Sept. 13 in the Archives of Neurology.

Safety was the primary objective of the study, and while no effects of treatment on clinical efficacy, a secondary outcome, were observed, the authors concluded that “disappointing results of treatment trials based on the amyloid hypothesis, and the reasonable degree of safety identified in this trial, suggest that exploratory studies of thiazolidinediones remain warranted.” The lead author was Dr. David Geldmacher, of the University of Virginia, Charlottesville, one of the two study sites.

In the double-blind, placebo-controlled study, 29 patients who met the criteria for probable Alzheimer’s disease (AD) were randomized to receive pioglitazone, titrated to 45 mg/day, or placebo, plus 100 IU vitamin E daily, for 18 months, between 2001 and 2004. They continued treatment with cholinesterase inhibitors; 20%-27% of the patients also received memantine, once it became available.

Pioglitazone, marketed as Actos as a treatment for type 2 diabetes, is a potent inhibitor of peroxisome proliferator–activated receptor gamma (PPARg), a nuclear receptor that that regulates glucose and lipid metabolism, which are abnormal in AD. This is a “potential therapeutic target for the treatment of AD,” because PPARg activation “robustly suppresses inflammation as well as expression of cytokines and other inflammatory mediators associated with activated microglia,” they said, noting that that, “a local microglia-mediated inflammatory response centers on the amyloid plaques in the AD brain.”

They referred to some evidence that rosiglitazone, another thiazolidinedione, had “limited efficacy,” in patients with early AD, but the results were mixed. This was the first study of pioglitazone in patients with AD, they said.

In the study, almost 29% of those on pioglitazone developed peripheral edema, a known adverse effect associated with pioglitazone, compared with none of the patients on placebo. But otherwise, there were no serious adverse events, and the drug was well tolerated, with “no pattern of effect on blood glucose levels, hemoglobin A1c levels, or other blood chemistry or hematologic measures,” they said (Arch. Neurol. 2010 Sept. 13 [doi:10.1001/archneurol.2010.229]).

As expected, because of the small size of the study, “no significant effect of treatment was observed on any clinical outcome measures,” which included measures of cognition and activities of daily living, the authors said.

The authors recommended that future studies of these agents should focus on earlier stages of disease and “be augmented by biomarkers, such as nuclear imaging techniques, to measure changes in microglial activation associated with treatment.” They noted that these studies will need to closely monitor patients for peripheral edema and other cardiovascular morbidities.

The study was supported by the National Institute of Aging. Pioglitazone manufacturer Takeda Pharmaceuticals North America provided the pioglitazone and placebo tablets free of charge but had no other role in the conduct or analysis of the study. Two of the four authors have received consulting fees from Takeda and consulting fees and research support from GlaxoSmithKline. One of the study sites, Case Western Reserve University, Cleveland, has a patent for the use of pioglitazone in the treatment of AD and other CNS disorders.