Background—Thiazolidinediones (TZDs), which have actions that involve both peroxisome proliferator–activated receptor (PPAR)-–dependent and –independent effects, improve insulin sensitivity in type II diabetes and inhibit early atherogenesis in mice. However, the effects of TZDs on advanced lesion progression are unknown.

Methods and Results—Pioglitazone and rosiglitazone enhanced macrophage apoptosis by a number of stimuli, including those thought to be important in advanced atherosclerosis. Macrophage death was not enhanced by non-TZD PPAR activators, and TZD-induced apoptosis was still observed in PPAR-deficient macrophages. In wild-type macrophages, death enhancement was associated with reduced activation of the cell-survival mediator nuclear factor-B. TZDs also increased the ability of macrophages to phagocytically clear apoptotic cells, which is proposed to protect against plaque necrosis in advanced lesions. The mechanism of this effect was complex, involving both PPAR-dependent and -independent mechanisms. To explore the net effect on advanced atherosclerosis in vivo, Ldlr^-/- mice were fed a nondiabetogenic cholesterol-enriched diet to promote midstage lesions. Then, pioglitazone was administered with the diet for an additional 10 weeks. Aortic root lesions from the pioglitazone-treated mice showed a substantial increase in apoptotic cells and plaque necrosis compared with lesions from non–drug-treated mice.

Conclusions—The potential atheroprotective effects of TZDs conferred by insulin sensitization may be partially offset by adverse effects on advanced atherosclerosis. Because the mechanisms of the beneficial and proposed adverse effects may differ, these findings have potentially important implications for drug optimization.