The Rosiglitazone Story -- Lessons From an FDA Advisory Committee Meeting
The Rosiglitazone Story -- Lessons From an FDA Advisory Committee Meeting
Thiazolidinediones (TZDs), such as rosiglitazone, are peroxisome proliferator-activated receptor-γ agonists that reverse or ameliorate many of the adverse cardiovascular effects of diabetes mellitus. These agents increase insulin sensitivity, enhance glucose control, provide some improvement in lipid profile, suppress inflammatory and cardiovascular risk markers, reduce proinflammatory cytokines, augment endothelial function, and improve vascular structure and function.
As for clinical endpoints, rosiglitazone substantially reduced the development of diabetes in patients with prediabetes and pioglitazone decreased mortality, stroke, and myocardial infarction (MI) rates in patients with type 2 diabetes. Yet, despite reducing fasting plasma glucose levels to normal, there has been evidence, too, of more adverse cardiovascular events with rosiglitazone versus placebo or active therapy (metformin or glyburide), including more congestive heart failure (HF).
In recent months, a controversy has emerged over the ischemic risks associated with rosiglitazone treatment. Nissen et al. presented the results of a meta-analysis of treatment trials comparing rosiglitazone versus placebo or other anti-diabetic therapy for type 2 diabetes. Rosiglitazone was associated with a significant 30-40% greater risk of MI and a borderline-significant increased risk of death from cardiovascular causes.
Accompanying the Nissen study were interim findings from the ongoing Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes (RECORD) trial of add-on rosiglitazone therapy in patients with type 2 diabetes. The unplanned interim analysis was inconclusive regarding the effect of rosiglitazone on the overall risk of hospitalization or death from cardiovascular causes. There was no evidence of any increase in death from either cardiovascular causes or all causes, but rosiglitazone was associated with an increased risk of HF.
Based on these data, the U.S. Food and Drug Administration (FDA) issued a safety alert on rosiglitazone on May 21, 2007, urging patients taking rosiglitazone, particularly those with underlying heart disease or at high risk for MI, to discuss the new information with their doctor to make "individualized treatment decisions." The alert noted that the FDA had not concluded there is a causal relationship between the drug and the reported safety concerns nor is it advising that prescriptions be discontinued.
The new data led to a number of expert commentaries. In addition to the inherent weaknesses of meta-analysis, the study had other limitations, many of which were summarized in an accompanying editorial to the Nissen meta-analysis and the interim data analysis. Even the authors of the meta-analysis were very circumspect in delineating limitations in the manuscript and cautioning readers about the conclusions that could be drawn from the data.
Nevertheless, as Anthony N. DeMaria, MD, MACC, Editor-in-Chief of the Journal of the American College of Cardiology wrote, the meta-analysis results were "trumpeted widely to the media, creating problems for both patients and physicians. This was done despite the fact that the data were inconclusive and that many authorities did not feel that any change in patient management was indicated." (Click here to access statements from ACC CEO Dr. Jack Lewin and ACC President Dr. James Dove.)
On July 30, 2007, Clifford Rosen, MD, chaired the FDA's joint Endocrinologic and Metabolic Drugs Advisory Committee and Drug Safety and Risk Management committee that was convened to discuss the myocardial ischemic risk associated with rosiglitazone therapy. They concluded that the use of rosiglitazone for the treatment of type 2 diabetes was associated with a greater risk of myocardial ischemic events than placebo, metformin, or sulfonylureas.
Dr. Rosen summarized the lessons from the FDA advisory committee meeting in a paper published online at NEJM.org on August 8, 2007. (The perspective article is to be published in the August 30, 2007, issue of the New England Journal of Medicine.)
The committee's conclusion regarding greater risk was based primarily on three independently conducted meta-analyses demonstrating an increase in the relative risk of MI, angina, or sudden death among patients taking rosiglitazone (Slide 1). However, only the increased risk of any ischemia reached statistical significance. Dr. Rosen also noted that the previously mentioned interim analysis of the RECORD trial failed to demonstrate a similar risk, despite the fact that the trial was designed specifically to assess cardiovascular risk among patients receiving rosiglitazone. In addition, he cited two large observational studies showing no appreciable signal of increased cardiovascular risk with either of the available thiazolidinediones (Slide 2 and Slide 3). One study was conducted by Tricare for the Department of Defense and the other by WellPoint (the largest health insurer in the United States) which comprised 160,000 patient records.
(Enlarge Image)
Slide 1.
Results of FDA Meta-Analysis of 42 Randomized Trials Comparing Rosiglitazone with Other Drugs or Placebo
(Enlarge Image)
Slide 2.
Risk of Acute Myocardial Infarction with Rosiglitazone and Pioglitazone as Compared with Other Oral Antidiabetic Agents, According to the WellPoint Observational Study*
(Enlarge Image)
Slide 3.
Risk of Acute Myocardial Infarction or Unstable Angina with Rosiglitazone and Pioglitazone as Compared with Other Oral Antidiabetic Agents, According to the WellPoint Observational Study*
One important potential limiting factor for the use of TZDs in HF patients is their tendency to cause fluid retention. This can lead to the development of peripheral edema, although this may not necessarily represent deterioration in cardiac function.
A key question that remains unanswered is whether rosiglitazone can be administered safely to patients with mild to moderate HF and what effect it has on cardiac function in these patients. In a recent paper published in Journal of the American College of Cardiology, Dargie and colleagues performed a 1-year placebo-controlled trial on the effects of rosiglitazone on patients with a left ventricular (LV) ejection fraction <45% and New York Heart Association functional class I-II heart failure. (A summary of this trial appears in the ACC Clinical Trials database as Rosiglitazone in Diabetic Patients with Heart Failure.)
Over 1 year, there were no significant changes in the echocardiographic parameters studied, including measures of both systolic and diastolic function. However, approximately one-quarter of the patients randomized to rosiglitazone developed some new or worsening edema and almost one-third required an increase in HF medications, both of which were significantly increased compared to patients randomized to placebo. However, there were no statistically significant between-group differences for major events such as all-cause mortality, cardiovascular death, or hospitalization for worsening HF.
Does this study help physicians who are confronted with a patient with HF and type 2 diabetes for whom TZD therapy might improve glycemic control? In an accompanying editorial, JoAnn Lindenfeld, MD, and Frederick A. Masoudi, MD, FACC, wrote that "on the basis of this study, it seems unlikely that there is a clinically significant effect of TZDs on LV systolic function." They noted that the results could be due to other mechanisms of fluid retention and edema, including sympathetic activation, increased vascular permeability, and the response to vasodilatation, which have been suggested as mechanisms of this phenomenon.
They also cited increasing evidence in animal models suggesting that the fluid retention with TZDs is due to sodium retention in the distal nephron. If this is the case in humans, too, Lindenfeld and Masoudi stated, "...it also raises the possibility that the fluid retention seen with TZD therapy may be treated with diuretics that target the distal nephron (i.e., amiloride or spironolactone)."
In this interview, Dr. Rosen discusses the continuing controversy regarding TZD therapy in general and rosiglitazone in particular. He reviews what practitioners need to consider, in terms of the implications for patient management, and the effect of this class of drugs in patients with HF.
Abstract
Thiazolidinediones (TZDs), such as rosiglitazone, are peroxisome proliferator-activated receptor-γ agonists that reverse or ameliorate many of the adverse cardiovascular effects of diabetes mellitus. These agents increase insulin sensitivity, enhance glucose control, provide some improvement in lipid profile, suppress inflammatory and cardiovascular risk markers, reduce proinflammatory cytokines, augment endothelial function, and improve vascular structure and function.
As for clinical endpoints, rosiglitazone substantially reduced the development of diabetes in patients with prediabetes and pioglitazone decreased mortality, stroke, and myocardial infarction (MI) rates in patients with type 2 diabetes. Yet, despite reducing fasting plasma glucose levels to normal, there has been evidence, too, of more adverse cardiovascular events with rosiglitazone versus placebo or active therapy (metformin or glyburide), including more congestive heart failure (HF).
In recent months, a controversy has emerged over the ischemic risks associated with rosiglitazone treatment. Nissen et al. presented the results of a meta-analysis of treatment trials comparing rosiglitazone versus placebo or other anti-diabetic therapy for type 2 diabetes. Rosiglitazone was associated with a significant 30-40% greater risk of MI and a borderline-significant increased risk of death from cardiovascular causes.
Accompanying the Nissen study were interim findings from the ongoing Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes (RECORD) trial of add-on rosiglitazone therapy in patients with type 2 diabetes. The unplanned interim analysis was inconclusive regarding the effect of rosiglitazone on the overall risk of hospitalization or death from cardiovascular causes. There was no evidence of any increase in death from either cardiovascular causes or all causes, but rosiglitazone was associated with an increased risk of HF.
Based on these data, the U.S. Food and Drug Administration (FDA) issued a safety alert on rosiglitazone on May 21, 2007, urging patients taking rosiglitazone, particularly those with underlying heart disease or at high risk for MI, to discuss the new information with their doctor to make "individualized treatment decisions." The alert noted that the FDA had not concluded there is a causal relationship between the drug and the reported safety concerns nor is it advising that prescriptions be discontinued.
Considering the Data
The new data led to a number of expert commentaries. In addition to the inherent weaknesses of meta-analysis, the study had other limitations, many of which were summarized in an accompanying editorial to the Nissen meta-analysis and the interim data analysis. Even the authors of the meta-analysis were very circumspect in delineating limitations in the manuscript and cautioning readers about the conclusions that could be drawn from the data.
Nevertheless, as Anthony N. DeMaria, MD, MACC, Editor-in-Chief of the Journal of the American College of Cardiology wrote, the meta-analysis results were "trumpeted widely to the media, creating problems for both patients and physicians. This was done despite the fact that the data were inconclusive and that many authorities did not feel that any change in patient management was indicated." (Click here to access statements from ACC CEO Dr. Jack Lewin and ACC President Dr. James Dove.)
July 2007 FDA Meeting
On July 30, 2007, Clifford Rosen, MD, chaired the FDA's joint Endocrinologic and Metabolic Drugs Advisory Committee and Drug Safety and Risk Management committee that was convened to discuss the myocardial ischemic risk associated with rosiglitazone therapy. They concluded that the use of rosiglitazone for the treatment of type 2 diabetes was associated with a greater risk of myocardial ischemic events than placebo, metformin, or sulfonylureas.
Dr. Rosen summarized the lessons from the FDA advisory committee meeting in a paper published online at NEJM.org on August 8, 2007. (The perspective article is to be published in the August 30, 2007, issue of the New England Journal of Medicine.)
The committee's conclusion regarding greater risk was based primarily on three independently conducted meta-analyses demonstrating an increase in the relative risk of MI, angina, or sudden death among patients taking rosiglitazone (Slide 1). However, only the increased risk of any ischemia reached statistical significance. Dr. Rosen also noted that the previously mentioned interim analysis of the RECORD trial failed to demonstrate a similar risk, despite the fact that the trial was designed specifically to assess cardiovascular risk among patients receiving rosiglitazone. In addition, he cited two large observational studies showing no appreciable signal of increased cardiovascular risk with either of the available thiazolidinediones (Slide 2 and Slide 3). One study was conducted by Tricare for the Department of Defense and the other by WellPoint (the largest health insurer in the United States) which comprised 160,000 patient records.
(Enlarge Image)
Slide 1.
Results of FDA Meta-Analysis of 42 Randomized Trials Comparing Rosiglitazone with Other Drugs or Placebo
(Enlarge Image)
Slide 2.
Risk of Acute Myocardial Infarction with Rosiglitazone and Pioglitazone as Compared with Other Oral Antidiabetic Agents, According to the WellPoint Observational Study*
(Enlarge Image)
Slide 3.
Risk of Acute Myocardial Infarction or Unstable Angina with Rosiglitazone and Pioglitazone as Compared with Other Oral Antidiabetic Agents, According to the WellPoint Observational Study*
Heart Failure
One important potential limiting factor for the use of TZDs in HF patients is their tendency to cause fluid retention. This can lead to the development of peripheral edema, although this may not necessarily represent deterioration in cardiac function.
A key question that remains unanswered is whether rosiglitazone can be administered safely to patients with mild to moderate HF and what effect it has on cardiac function in these patients. In a recent paper published in Journal of the American College of Cardiology, Dargie and colleagues performed a 1-year placebo-controlled trial on the effects of rosiglitazone on patients with a left ventricular (LV) ejection fraction <45% and New York Heart Association functional class I-II heart failure. (A summary of this trial appears in the ACC Clinical Trials database as Rosiglitazone in Diabetic Patients with Heart Failure.)
Over 1 year, there were no significant changes in the echocardiographic parameters studied, including measures of both systolic and diastolic function. However, approximately one-quarter of the patients randomized to rosiglitazone developed some new or worsening edema and almost one-third required an increase in HF medications, both of which were significantly increased compared to patients randomized to placebo. However, there were no statistically significant between-group differences for major events such as all-cause mortality, cardiovascular death, or hospitalization for worsening HF.
Does this study help physicians who are confronted with a patient with HF and type 2 diabetes for whom TZD therapy might improve glycemic control? In an accompanying editorial, JoAnn Lindenfeld, MD, and Frederick A. Masoudi, MD, FACC, wrote that "on the basis of this study, it seems unlikely that there is a clinically significant effect of TZDs on LV systolic function." They noted that the results could be due to other mechanisms of fluid retention and edema, including sympathetic activation, increased vascular permeability, and the response to vasodilatation, which have been suggested as mechanisms of this phenomenon.
They also cited increasing evidence in animal models suggesting that the fluid retention with TZDs is due to sodium retention in the distal nephron. If this is the case in humans, too, Lindenfeld and Masoudi stated, "...it also raises the possibility that the fluid retention seen with TZD therapy may be treated with diuretics that target the distal nephron (i.e., amiloride or spironolactone)."
In this interview, Dr. Rosen discusses the continuing controversy regarding TZD therapy in general and rosiglitazone in particular. He reviews what practitioners need to consider, in terms of the implications for patient management, and the effect of this class of drugs in patients with HF.
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