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Treatment with rosiglitazone was not associated with an increased risk of major ischemic cardiovascular events in a large, international study of patients with type 2 diabetes and coronary artery disease.
"Our analyses did not detect any significant hazard of increased ischemic cardiovascular risk with rosiglitazone treatment despite its use in this particularly vulnerable, higher risk population," Dr. Richard Bach of Washington University, St. Louis, and the other authors concluded.
The study, an analysis of data from the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial, was published online July 15 (doi: 10.1161/CIRCULATIONAHA.112.000678).
The primary outcomes of the study were published in 2009 (N. Engl. J. Med. 2009; 360:2503-15).
The cardiac safety of rosiglitazone, a thiazolidinedione (TZD) marketed as Avandia by GlaxoSmithKline, has been mired in controversy for several years because of analyses of data showing that rosiglitazone may increase the risk of MI or death. The Food and Drug Administration issued an alert about the safety of the drug and limited its use in 2010. The agency also halted a long-term prospective cardiovascular safety study of rosiglitazone. In 2010, the Europeans Medicines Agency took rosiglitazone off the market in Europe, citing the same data.
In June 2013, at an FDA advisory panel meeting held to review the readjudicated results of a cardiovascular safety trial of rosiglitazone – which did not identify a greater rate of adverse cardiovascular outcomes among those on the drug – the majority of the panel recommended loosening or lifting the restrictions that had been placed on prescribing the drug in 2010. (The FDA has not yet acted on the panel’s recommendations.)
In the post hoc analysis of the BARI 2D data, the investigators compared the rates – between those on rosiglitazone and those not on a TZD – of mortality, MI, stroke, and other outcomes, and composite outcomes among nearly 2,400 patients with type 2 diabetes and coronary artery disease in the study. Over an average of 4.5 years, about 990 patients were on rosiglitazone at some point during the study (for up to 3,025 patient-years of exposure) and 485 were treated with rosiglitazone for at least 80% of the time. About 1,200 were not on a TZD.
After adjustment for differences in multiple baseline characteristics and other antidiabetes medications, the results were as follows:
• The incidence of all-cause death was similar among those on rosiglitazone, compared with those not on a TZD (hazard ratio, 0.83), a statistically nonsignificant difference.
• The composite of death, MI, and stroke was significantly lower among those on rosiglitazone (HR, 0.72).
• The incidence of stroke alone was significantly lower among those on rosiglitazone (HR, 0.36).
• The incidence of MI was lower among those on rosiglitazone (HR, 0.77) and the incidence of heart failure was higher (HR, 1.22), but these differences were not statistically significant.
When compared with those not on a TZD, the incidence of fractures was higher in those on a TZD (HR, 1.62), a risk that appeared to be more pronounced among women.
The investigators did not find a significant interaction between rosiglitazone and coadministration with other antidiabetes and cardiovascular medications (insulin, metformin, gemfibrozil, other fibrates, sulfonylureas, nitrates, or ACE inhibitors) on the composite rate of death, MI and stroke, or on individual rates of death, MI, stroke, or fractures. There was a significant interaction, however, with rosiglitazone and metformin on the risk of heart failure associated with rosiglitazone, with a relative risk of heart failure significantly greater among those patients on rosiglitazone but not on metformin, than on those who were on both.
These results "provide no evidence that use of rosiglitazone is associated with increased rates of major adverse ischemic cardiovascular events among patients with type 2 diabetes and established CAD," the authors concluded.
While the study had limitations, the researchers noted that a possible difference between this study and studies that found adverse cardiovascular effects associated with rosiglitazone was that in BARI 2D, patients received intensive medical therapy for ischemic heart disease, angina, and/or lowering cholesterol and blood pressure. Therefore, they concluded, the results "may imply that, in the context of intensive treatment of cardiovascular risk factors, rosiglitazone may provide benefit with retained safety, alone or in combination with other hypoglycemic medications, for high-risk patients with type 2 diabetes and established CAD."
There are several lessons to be drawn from these results, "some generalizable and others very specific to this study," Dr. Daniel Einhorn, president of the American Association of Clinical Endocrinologists and medical director of the Scripps Whittier Diabetes Institute, said in an interview. First, "it takes time to digest data generated by large clinical trials," he said, noting that "nuances" of the population and concomitant treatments, subgroup analyses, and other factors "routinely refine our understanding of the findings of large studies."
BARI 2D reflects real-life situations for people with access to good care, since intensive treatment of CV risk factors is the goal of appropriate therapy in the United States, he noted. As with pioglitazone (the other TZD marketed in the United States), "there are plausible and extensively researched mechanisms whereby rosiglitazone would be expected to confer cardiovascular benefit" given its mechanism(s) of action, he said.
Finally, the previous FDA panel meetings on rosiglitazone were characterized by a "politicized and media grandstanding climate ... which is not conducive to the best science," while the recent panel meeting in June "appeared more dispassionate," he added.
But even with generic formulations available, neither TZD is likely to be used extensively "because of years of safety concerns, including those regarding bone and cancer, the effect of TZDs to cause weight gain and fluid retention, patient/family concerns raised by ads from lawyers, and the advent of newer agents with a seemingly less concerning safety profile."
Dr. Einhorn has been an adviser to Halozyme Therapeutics, MannKind, and Freedom Meditech, and a consultant to Eli Lilly, Novo Nordisk, Sanofi-Aventis, Bristol-Myers Squibb/AstraZeneca and Novartis.
The study was funded by the National Heart, Lung, and Blood Institute and the National Institute of Diabetes and Digestive and Kidney Diseases, with funding from companies that included rosiglitazone manufacturer GlaxoSmithKline. The lead author, Dr. Bach, disclosed ties to several pharmaceutical companies, but not GSK; one author disclosed having received honoraria from GSK.
The results of the post hoc analysis of the BARI 2D data were first reported at the American Diabetes Association meeting in 2009.
Rosiglitazone therapy in BARI 2D demonstrates rather reassuring efficacy and safety data. This supports the recommendation of a recent FDA advisory panel to modify rosiglitazone restrictions based on the RECORD results. It is critical to evaluate efficacy and safety removed from media hype and the vocal decrees of small numbers of individuals. Once a negative spin via the media is placed on a form of therapy, subsequent analysis, valid and reassuring as it may be, cannot undue the damage.
The issue of pancreatic disease and incretin based therapy is in front of us right now. Let’s get this one right the first time!
Dr. Paul Jellinger is an endocrinologist in Hollywood, Fla. He is on the speakers bureau for several manufacturers of diabetes drugs, but not GSK.
Rosiglitazone therapy in BARI 2D demonstrates rather reassuring efficacy and safety data. This supports the recommendation of a recent FDA advisory panel to modify rosiglitazone restrictions based on the RECORD results. It is critical to evaluate efficacy and safety removed from media hype and the vocal decrees of small numbers of individuals. Once a negative spin via the media is placed on a form of therapy, subsequent analysis, valid and reassuring as it may be, cannot undue the damage.
The issue of pancreatic disease and incretin based therapy is in front of us right now. Let’s get this one right the first time!
Dr. Paul Jellinger is an endocrinologist in Hollywood, Fla. He is on the speakers bureau for several manufacturers of diabetes drugs, but not GSK.
Rosiglitazone therapy in BARI 2D demonstrates rather reassuring efficacy and safety data. This supports the recommendation of a recent FDA advisory panel to modify rosiglitazone restrictions based on the RECORD results. It is critical to evaluate efficacy and safety removed from media hype and the vocal decrees of small numbers of individuals. Once a negative spin via the media is placed on a form of therapy, subsequent analysis, valid and reassuring as it may be, cannot undue the damage.
The issue of pancreatic disease and incretin based therapy is in front of us right now. Let’s get this one right the first time!
Dr. Paul Jellinger is an endocrinologist in Hollywood, Fla. He is on the speakers bureau for several manufacturers of diabetes drugs, but not GSK.
Treatment with rosiglitazone was not associated with an increased risk of major ischemic cardiovascular events in a large, international study of patients with type 2 diabetes and coronary artery disease.
"Our analyses did not detect any significant hazard of increased ischemic cardiovascular risk with rosiglitazone treatment despite its use in this particularly vulnerable, higher risk population," Dr. Richard Bach of Washington University, St. Louis, and the other authors concluded.
The study, an analysis of data from the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial, was published online July 15 (doi: 10.1161/CIRCULATIONAHA.112.000678).
The primary outcomes of the study were published in 2009 (N. Engl. J. Med. 2009; 360:2503-15).
The cardiac safety of rosiglitazone, a thiazolidinedione (TZD) marketed as Avandia by GlaxoSmithKline, has been mired in controversy for several years because of analyses of data showing that rosiglitazone may increase the risk of MI or death. The Food and Drug Administration issued an alert about the safety of the drug and limited its use in 2010. The agency also halted a long-term prospective cardiovascular safety study of rosiglitazone. In 2010, the Europeans Medicines Agency took rosiglitazone off the market in Europe, citing the same data.
In June 2013, at an FDA advisory panel meeting held to review the readjudicated results of a cardiovascular safety trial of rosiglitazone – which did not identify a greater rate of adverse cardiovascular outcomes among those on the drug – the majority of the panel recommended loosening or lifting the restrictions that had been placed on prescribing the drug in 2010. (The FDA has not yet acted on the panel’s recommendations.)
In the post hoc analysis of the BARI 2D data, the investigators compared the rates – between those on rosiglitazone and those not on a TZD – of mortality, MI, stroke, and other outcomes, and composite outcomes among nearly 2,400 patients with type 2 diabetes and coronary artery disease in the study. Over an average of 4.5 years, about 990 patients were on rosiglitazone at some point during the study (for up to 3,025 patient-years of exposure) and 485 were treated with rosiglitazone for at least 80% of the time. About 1,200 were not on a TZD.
After adjustment for differences in multiple baseline characteristics and other antidiabetes medications, the results were as follows:
• The incidence of all-cause death was similar among those on rosiglitazone, compared with those not on a TZD (hazard ratio, 0.83), a statistically nonsignificant difference.
• The composite of death, MI, and stroke was significantly lower among those on rosiglitazone (HR, 0.72).
• The incidence of stroke alone was significantly lower among those on rosiglitazone (HR, 0.36).
• The incidence of MI was lower among those on rosiglitazone (HR, 0.77) and the incidence of heart failure was higher (HR, 1.22), but these differences were not statistically significant.
When compared with those not on a TZD, the incidence of fractures was higher in those on a TZD (HR, 1.62), a risk that appeared to be more pronounced among women.
The investigators did not find a significant interaction between rosiglitazone and coadministration with other antidiabetes and cardiovascular medications (insulin, metformin, gemfibrozil, other fibrates, sulfonylureas, nitrates, or ACE inhibitors) on the composite rate of death, MI and stroke, or on individual rates of death, MI, stroke, or fractures. There was a significant interaction, however, with rosiglitazone and metformin on the risk of heart failure associated with rosiglitazone, with a relative risk of heart failure significantly greater among those patients on rosiglitazone but not on metformin, than on those who were on both.
These results "provide no evidence that use of rosiglitazone is associated with increased rates of major adverse ischemic cardiovascular events among patients with type 2 diabetes and established CAD," the authors concluded.
While the study had limitations, the researchers noted that a possible difference between this study and studies that found adverse cardiovascular effects associated with rosiglitazone was that in BARI 2D, patients received intensive medical therapy for ischemic heart disease, angina, and/or lowering cholesterol and blood pressure. Therefore, they concluded, the results "may imply that, in the context of intensive treatment of cardiovascular risk factors, rosiglitazone may provide benefit with retained safety, alone or in combination with other hypoglycemic medications, for high-risk patients with type 2 diabetes and established CAD."
There are several lessons to be drawn from these results, "some generalizable and others very specific to this study," Dr. Daniel Einhorn, president of the American Association of Clinical Endocrinologists and medical director of the Scripps Whittier Diabetes Institute, said in an interview. First, "it takes time to digest data generated by large clinical trials," he said, noting that "nuances" of the population and concomitant treatments, subgroup analyses, and other factors "routinely refine our understanding of the findings of large studies."
BARI 2D reflects real-life situations for people with access to good care, since intensive treatment of CV risk factors is the goal of appropriate therapy in the United States, he noted. As with pioglitazone (the other TZD marketed in the United States), "there are plausible and extensively researched mechanisms whereby rosiglitazone would be expected to confer cardiovascular benefit" given its mechanism(s) of action, he said.
Finally, the previous FDA panel meetings on rosiglitazone were characterized by a "politicized and media grandstanding climate ... which is not conducive to the best science," while the recent panel meeting in June "appeared more dispassionate," he added.
But even with generic formulations available, neither TZD is likely to be used extensively "because of years of safety concerns, including those regarding bone and cancer, the effect of TZDs to cause weight gain and fluid retention, patient/family concerns raised by ads from lawyers, and the advent of newer agents with a seemingly less concerning safety profile."
Dr. Einhorn has been an adviser to Halozyme Therapeutics, MannKind, and Freedom Meditech, and a consultant to Eli Lilly, Novo Nordisk, Sanofi-Aventis, Bristol-Myers Squibb/AstraZeneca and Novartis.
The study was funded by the National Heart, Lung, and Blood Institute and the National Institute of Diabetes and Digestive and Kidney Diseases, with funding from companies that included rosiglitazone manufacturer GlaxoSmithKline. The lead author, Dr. Bach, disclosed ties to several pharmaceutical companies, but not GSK; one author disclosed having received honoraria from GSK.
The results of the post hoc analysis of the BARI 2D data were first reported at the American Diabetes Association meeting in 2009.
Treatment with rosiglitazone was not associated with an increased risk of major ischemic cardiovascular events in a large, international study of patients with type 2 diabetes and coronary artery disease.
"Our analyses did not detect any significant hazard of increased ischemic cardiovascular risk with rosiglitazone treatment despite its use in this particularly vulnerable, higher risk population," Dr. Richard Bach of Washington University, St. Louis, and the other authors concluded.
The study, an analysis of data from the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial, was published online July 15 (doi: 10.1161/CIRCULATIONAHA.112.000678).
The primary outcomes of the study were published in 2009 (N. Engl. J. Med. 2009; 360:2503-15).
The cardiac safety of rosiglitazone, a thiazolidinedione (TZD) marketed as Avandia by GlaxoSmithKline, has been mired in controversy for several years because of analyses of data showing that rosiglitazone may increase the risk of MI or death. The Food and Drug Administration issued an alert about the safety of the drug and limited its use in 2010. The agency also halted a long-term prospective cardiovascular safety study of rosiglitazone. In 2010, the Europeans Medicines Agency took rosiglitazone off the market in Europe, citing the same data.
In June 2013, at an FDA advisory panel meeting held to review the readjudicated results of a cardiovascular safety trial of rosiglitazone – which did not identify a greater rate of adverse cardiovascular outcomes among those on the drug – the majority of the panel recommended loosening or lifting the restrictions that had been placed on prescribing the drug in 2010. (The FDA has not yet acted on the panel’s recommendations.)
In the post hoc analysis of the BARI 2D data, the investigators compared the rates – between those on rosiglitazone and those not on a TZD – of mortality, MI, stroke, and other outcomes, and composite outcomes among nearly 2,400 patients with type 2 diabetes and coronary artery disease in the study. Over an average of 4.5 years, about 990 patients were on rosiglitazone at some point during the study (for up to 3,025 patient-years of exposure) and 485 were treated with rosiglitazone for at least 80% of the time. About 1,200 were not on a TZD.
After adjustment for differences in multiple baseline characteristics and other antidiabetes medications, the results were as follows:
• The incidence of all-cause death was similar among those on rosiglitazone, compared with those not on a TZD (hazard ratio, 0.83), a statistically nonsignificant difference.
• The composite of death, MI, and stroke was significantly lower among those on rosiglitazone (HR, 0.72).
• The incidence of stroke alone was significantly lower among those on rosiglitazone (HR, 0.36).
• The incidence of MI was lower among those on rosiglitazone (HR, 0.77) and the incidence of heart failure was higher (HR, 1.22), but these differences were not statistically significant.
When compared with those not on a TZD, the incidence of fractures was higher in those on a TZD (HR, 1.62), a risk that appeared to be more pronounced among women.
The investigators did not find a significant interaction between rosiglitazone and coadministration with other antidiabetes and cardiovascular medications (insulin, metformin, gemfibrozil, other fibrates, sulfonylureas, nitrates, or ACE inhibitors) on the composite rate of death, MI and stroke, or on individual rates of death, MI, stroke, or fractures. There was a significant interaction, however, with rosiglitazone and metformin on the risk of heart failure associated with rosiglitazone, with a relative risk of heart failure significantly greater among those patients on rosiglitazone but not on metformin, than on those who were on both.
These results "provide no evidence that use of rosiglitazone is associated with increased rates of major adverse ischemic cardiovascular events among patients with type 2 diabetes and established CAD," the authors concluded.
While the study had limitations, the researchers noted that a possible difference between this study and studies that found adverse cardiovascular effects associated with rosiglitazone was that in BARI 2D, patients received intensive medical therapy for ischemic heart disease, angina, and/or lowering cholesterol and blood pressure. Therefore, they concluded, the results "may imply that, in the context of intensive treatment of cardiovascular risk factors, rosiglitazone may provide benefit with retained safety, alone or in combination with other hypoglycemic medications, for high-risk patients with type 2 diabetes and established CAD."
There are several lessons to be drawn from these results, "some generalizable and others very specific to this study," Dr. Daniel Einhorn, president of the American Association of Clinical Endocrinologists and medical director of the Scripps Whittier Diabetes Institute, said in an interview. First, "it takes time to digest data generated by large clinical trials," he said, noting that "nuances" of the population and concomitant treatments, subgroup analyses, and other factors "routinely refine our understanding of the findings of large studies."
BARI 2D reflects real-life situations for people with access to good care, since intensive treatment of CV risk factors is the goal of appropriate therapy in the United States, he noted. As with pioglitazone (the other TZD marketed in the United States), "there are plausible and extensively researched mechanisms whereby rosiglitazone would be expected to confer cardiovascular benefit" given its mechanism(s) of action, he said.
Finally, the previous FDA panel meetings on rosiglitazone were characterized by a "politicized and media grandstanding climate ... which is not conducive to the best science," while the recent panel meeting in June "appeared more dispassionate," he added.
But even with generic formulations available, neither TZD is likely to be used extensively "because of years of safety concerns, including those regarding bone and cancer, the effect of TZDs to cause weight gain and fluid retention, patient/family concerns raised by ads from lawyers, and the advent of newer agents with a seemingly less concerning safety profile."
Dr. Einhorn has been an adviser to Halozyme Therapeutics, MannKind, and Freedom Meditech, and a consultant to Eli Lilly, Novo Nordisk, Sanofi-Aventis, Bristol-Myers Squibb/AstraZeneca and Novartis.
The study was funded by the National Heart, Lung, and Blood Institute and the National Institute of Diabetes and Digestive and Kidney Diseases, with funding from companies that included rosiglitazone manufacturer GlaxoSmithKline. The lead author, Dr. Bach, disclosed ties to several pharmaceutical companies, but not GSK; one author disclosed having received honoraria from GSK.
The results of the post hoc analysis of the BARI 2D data were first reported at the American Diabetes Association meeting in 2009.
FROM CIRCULATION
Major finding: No increased risk of major cardiovascular events associated with rosiglitazone was identified in a study of patients with type 2 diabetes and coronary artery disease, including a nonsignificant lower risk (23%) of MI among those treated with the thiazolidinedione (TZD) compared with those who had not received a TZD.
Data source: A post hoc analysis of data from BARI 2D, a large, randomized international study of patients with type 2 diabetes and heart disease, which analyzed the CV outcomes among those treated with rosiglitazone and those who had not received a TZD.
Disclosures: The study was funded by the National Heart, Lung, and Blood Institute and the National Institute of Diabetes and Digestive and Kidney Diseases, with funding from companies that included rosiglitazone manufacturer GlaxoSmithKline. The lead author, Dr. Bach, disclosed ties to several pharmaceutical companies, but not GSK; one author disclosed having received honoraria from GSK.
