Pioglitazone reduces restenosis post-PCI
Pioglitazone reduces restenosis post-PCI
Orlando, FL - Results of a randomized trial suggest that treatment with the oral antidiabetic agent pioglitazone (Actos®, Takeda Pharma) reduced restenosis after PCI compared with placebo in nondiabetic patients, without significant metabolic effects. The results were presented during a late-breaking clinical-trial session here at the American College of Cardiology 2005 Scientific Sessions.
"We are excited about these data because they suggest that these agents, in addition to their metabolic effects, may exhibit protective effects in the vessel wall," Dr Nikolaus Marx (University of Ulm, Germany) told a press conference here. "Based on our data, larger clinical trials should show whether these favorable effects on neointima formation translate into clinical benefitfor example, in reduction of the need for revascularization and reintervention."
A local effect?
Several studies in patients with type 2 diabetes have shown that oral antidiabetic agents such as rosiglitazone and pioglitazone reduce restenosis, Marx said. What has not been clear is whether these effects result from better control of metabolic factors with these drugs in type 2 diabetes or whether they may have some direct effect in the vessel wall. Marx's group and others have shown in basic studies that glitazones affect a receptor in the vessel wall called peroxisome proliferator-activated receptor-gamma (PPAR-) and that this inhibits the migration and proliferation of smooth-muscle cells and reduces inflammation, critical for the development of restenosis.
To try to clarify the role of metabolic vs vessel-wall effects with these agents, the researchers randomized 50 nondiabetic patients with CAD undergoing PCI in de novo lesions to receive either 30 mg/day of pioglitazone or placebo in addition to standard treatment for six months. The primary end point was the extent of neointimal formation by intravascular ultrasound (IVUS) at the end of that period.
Nondiabetic patients treated with pioglitazone showed no significant effects on metabolic factors such as fasting blood glucose, insulin, or lipid profiles compared with placebo, and there were no significant changes from baseline in these parameters in either group.
However, there was a significant reduction in neointima volume vs placebo in those receiving pioglitazone, and this translated into a significant reduction in mean diameter stenosis in the stented area, he said. "So I think it's really of relevance, but as I said before, I think this study should initiate larger clinical trials," Marx told heartwire .
Primary end point: Neointima volume by intravascular ultrasound at six months
The reduction in mean diameter stenosis led to a significant reduction in binary restenosis, but this difference was not paralleled by a significant effect on minimal lumen diameter (MLD) or late-loss index (LLI), Marx noted. There was a trend to higher MLD and smaller LLI in the pioglitazone group, he said, "but this was not the primary end point of this study."
No serious drug-related side effects were seen with pioglitazone treatment.
Moderator for the session was Dr Lloyd Klein (Rush University Medical Center, Chicago, IL). "There really aren't any drugs out there that have been shown over and over to prevent restenosis, and this is a very, very promising study," Klein commented during the press conference here.
The study was sponsored by Takeda Pharma, makers of pioglitazone.
"A good start"
Invited discussant for the trial was Dr Jeffrey J Popma (Brigham and Women's Hospital, Harvard Medical School, Boston, MA). Popma congratulated Marx and colleagues on their study but questioned what the role would be for this intervention in the era of drug-eluting stents.
"I have to say that, with all the drug-eluting-stent data we've seen over the past couple of days, the reduction in neointima volume that was demonstrated was not as dramatic as we've seen with drug-eluting-stent programs," he said. However, he pointed out that other areas of research have shown that even smaller degrees of hyperplasia reduction can have beneficial effects, and, importantly in this trial, there were no safety concerns identified.
Popma mused on whether the effects of oral antidiabetic agents should be explored further. "Absolutely we should in diabetic patients," he said. "We probably should," he added, in patients without diabetes who have high risk for restenosis because of small vessels and diffuse disease or contraindications to long-term dual antiplatelet therapy. However, in those without diabetes and with focal disease and larger vessels, there are already effective therapies, and this approach would probably not be appropriate in this group, he said.
"So what conclusions can be drawn about the current study by Dr Marx and his colleagues?" Popma said. "It's certainly a good start."
Orlando, FL - Results of a randomized trial suggest that treatment with the oral antidiabetic agent pioglitazone (Actos®, Takeda Pharma) reduced restenosis after PCI compared with placebo in nondiabetic patients, without significant metabolic effects. The results were presented during a late-breaking clinical-trial session here at the American College of Cardiology 2005 Scientific Sessions.
"We are excited about these data because they suggest that these agents, in addition to their metabolic effects, may exhibit protective effects in the vessel wall," Dr Nikolaus Marx (University of Ulm, Germany) told a press conference here. "Based on our data, larger clinical trials should show whether these favorable effects on neointima formation translate into clinical benefitfor example, in reduction of the need for revascularization and reintervention."
A local effect?
Several studies in patients with type 2 diabetes have shown that oral antidiabetic agents such as rosiglitazone and pioglitazone reduce restenosis, Marx said. What has not been clear is whether these effects result from better control of metabolic factors with these drugs in type 2 diabetes or whether they may have some direct effect in the vessel wall. Marx's group and others have shown in basic studies that glitazones affect a receptor in the vessel wall called peroxisome proliferator-activated receptor-gamma (PPAR-) and that this inhibits the migration and proliferation of smooth-muscle cells and reduces inflammation, critical for the development of restenosis.
To try to clarify the role of metabolic vs vessel-wall effects with these agents, the researchers randomized 50 nondiabetic patients with CAD undergoing PCI in de novo lesions to receive either 30 mg/day of pioglitazone or placebo in addition to standard treatment for six months. The primary end point was the extent of neointimal formation by intravascular ultrasound (IVUS) at the end of that period.
Nondiabetic patients treated with pioglitazone showed no significant effects on metabolic factors such as fasting blood glucose, insulin, or lipid profiles compared with placebo, and there were no significant changes from baseline in these parameters in either group.
However, there was a significant reduction in neointima volume vs placebo in those receiving pioglitazone, and this translated into a significant reduction in mean diameter stenosis in the stented area, he said. "So I think it's really of relevance, but as I said before, I think this study should initiate larger clinical trials," Marx told heartwire .
Primary end point: Neointima volume by intravascular ultrasound at six months
| End point | Pioglitazone | Placebo | p |
| Neointimal volume, mm | 2.3+1.1 | 3.1+1.6 | <0.05 |
The reduction in mean diameter stenosis led to a significant reduction in binary restenosis, but this difference was not paralleled by a significant effect on minimal lumen diameter (MLD) or late-loss index (LLI), Marx noted. There was a trend to higher MLD and smaller LLI in the pioglitazone group, he said, "but this was not the primary end point of this study."
No serious drug-related side effects were seen with pioglitazone treatment.
Moderator for the session was Dr Lloyd Klein (Rush University Medical Center, Chicago, IL). "There really aren't any drugs out there that have been shown over and over to prevent restenosis, and this is a very, very promising study," Klein commented during the press conference here.
The study was sponsored by Takeda Pharma, makers of pioglitazone.
"A good start"
Invited discussant for the trial was Dr Jeffrey J Popma (Brigham and Women's Hospital, Harvard Medical School, Boston, MA). Popma congratulated Marx and colleagues on their study but questioned what the role would be for this intervention in the era of drug-eluting stents.
"I have to say that, with all the drug-eluting-stent data we've seen over the past couple of days, the reduction in neointima volume that was demonstrated was not as dramatic as we've seen with drug-eluting-stent programs," he said. However, he pointed out that other areas of research have shown that even smaller degrees of hyperplasia reduction can have beneficial effects, and, importantly in this trial, there were no safety concerns identified.
Popma mused on whether the effects of oral antidiabetic agents should be explored further. "Absolutely we should in diabetic patients," he said. "We probably should," he added, in patients without diabetes who have high risk for restenosis because of small vessels and diffuse disease or contraindications to long-term dual antiplatelet therapy. However, in those without diabetes and with focal disease and larger vessels, there are already effective therapies, and this approach would probably not be appropriate in this group, he said.
"So what conclusions can be drawn about the current study by Dr Marx and his colleagues?" Popma said. "It's certainly a good start."
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