Thiazolidinediones and Cardiovascular Outcomes in Older Patients With Diabetes
Lorraine L. Lipscombe, MD, MSc; Tara Gomes, MHSc; Linda E. Lévesque, BScPhm, MSc; Janet E. Hux, MD, MSc; David N. Juurlink, BPhm, MD, PhD; David A. Alter, MD, PhD
JAMA. 2007;298(22):2634-2643.
Context Thiazolidinediones (TZDs), used to treat type 2 diabetes, are associated with an excess risk of congestive heart failure and possibly acute myocardial infarction. However, the association between TZD use and cardiovascular events has not been adequately evaluated on a population level.
Objective To explore the association between TZD therapy and congestive heart failure, acute myocardial infarction, and mortality compared with treatment with other oral hypoglycemic agents.
Design, Setting, and Patients Nested case-control analysis of a retrospective cohort study using health care databases in Ontario. We included diabetes patients aged 66 years or older treated with at least 1 oral hypoglycemic agent between 2002 and 2005 (N = 159 026) and followed them up until March 31, 2006.
Main Outcome Measures The primary outcome consisted of an emergency department visit or hospitalization for congestive heart failure; secondary outcomes were an emergency department visit or hospitalization for acute myocardial infarction and all-cause mortality. The risks of these events were compared between persons treated with TZDs (rosiglitazone and pioglitazone) and other oral hypoglycemic agent combinations, after matching and adjusting for prognostic factors.
Results During a median follow-up of 3.8 years, 12 491 patients (7.9%) had a hospital visit for congestive heart failure, 12 578 (7.9%) had a visit for acute myocardial infarction, and 30 265 (19%) died. Current treatment with TZD monotherapy was associated with a significantly increased risk of congestive heart failure (78 cases; adjusted rate ratio [RR], 1.60; 95% confidence interval [CI], 1.21-2.10; P < .001), acute myocardial infarction (65 cases; RR, 1.40; 95% CI, 1.05-1.86; P = .02), and death (102 cases; RR, 1.29; 95% CI, 1.02-1.62; P = .03) compared with other oral hypoglycemic agent combination therapies (3478 congestive heart failure cases, 3695 acute myocardial infarction cases, and 5529 deaths). The increased risk of congestive heart failure, acute myocardial infarction, and mortality associated with TZD use appeared limited to rosiglitazone.
Conclusion In this population-based study of older patients with diabetes, TZD treatment, primarily with rosiglitazone, was associated with an increased risk of congestive heart failure, acute myocardial infarction, and mortality when compared with other combination oral hypoglycemic agent treatments.
Showing posts with label Thiazolidinediones. Show all posts
Showing posts with label Thiazolidinediones. Show all posts
Wednesday, December 12, 2007
Friday, September 28, 2007
Ensuring drug safety: lessons from the thiazolidinediones
Ensuring drug safety: lessons from the thiazolidinediones
Editorial
The Lancet, Current Issue, Volume 370, Number 9593, 29 September 2007
In today's Lancet, Rodrigo Lago and colleagues add to the ongoing analysis of the safety of thiazolidinediones for control of hyperglycaemia. Initial concerns about the cardiovascular risks of one of the thiazolidinediones, rosiglitazone, erupted in a firestorm of controversy when a meta-analysis by Nissen and Wolski was published online in the New England Journal of Medicine in May. Nissen and Wolski found that rosiglitazone (Avandia, GSK) was associated with a significantly increased risk of myocardial infarction, and a risk of death from cardiovascular causes that was of borderline statistical significance. The authors acknowledged that their analysis was limited by the public availability of trial results and a lack of access to patient-level data, and that the pooled studies were not designed to assess cardiovascular outcomes. But they concluded that the risks of rosiglitazone use in diabetes should be carefully considered by both doctors and their patients.
Response to these findings was swift. An editorial that accompanied the paper, while acknowledging the findings' “fragility”, called for urgent regulatory action; GSK vigorously defended its product, saying that studies show Avandia's cardiovascular profile to be comparable to other oral antidiabetes agents; and this journal counselled against a rush to judgment, advising patience until the final results of RECORD, a phase III trial designed to assess cardiovascular outcomes, were available. Media coverage was extensive. A US Congressional hearing was hastily called, as was a Food and Drug Administration (FDA) Advisory Committee meeting. The Congressional hearing was a spectacular display of partisan agendas and bipartisan ignorance. The FDA meeting resulted in a 22 to 1 vote to keep Avandia on the market, and to add a “black box” warning on the label of the risks of the drug's use in patients with congestive heart failure. If this sequence of events sounds familiar, it is because a nearly identical path was trodden when the safety of selective cyclo-oxygenase 2 (COX-2) inhibitors was called into question. Then, as now, the question was about the drugs' cardiovascular effects.
Other analyses of the thiazolidinedione have followed the NEJM paper, including two papers that appeared in JAMA on Sept 12, one on the risk of cardiovascular events with pioglitazone, the only other available agent in the thiazolidinedione class (Actos, Takeda), and one assessing long-term cardiovascular risk with rosiglitazone. Here, both drugs were associated with an increased risk of heart failure, though without an associated increase in mortality. This is the same conclusion reached by Lago and colleagues: patients taking thiazolidinediones seem to have a higher risk of congestive heart failure, but do not have a higher risk of death from cardiovascular causes.
Is there then a bottom line to all these bits of evidence? What should doctors and patients do? Is there in fact enough good evidence on which to decide anything? It seems that the jury is still out for the thiazolidinediones as a class. But there are many interim take-home messages. Some of these are highlighted by Comments in today's issue. First, it must be remembered that meta-analysis is a technique with important limitations. And the studies on which the thiazolidinedione meta-analyses are based have thus far all involved surrogate markers; the studies were not designed to assess cardiovascular outcomes, but rather improved glycaemic control. This outcome, as Victor Montori and colleagues note, is not a patient-centred one. The current clinical emphasis on glucose control (as measured by HbA1c) skirts the outcomes that matter most to patients—microvascular and macrovascular complications, quality of life, and survival.
These commentators highlight issues that must be taken into account in the ongoing debate about thiazolidinediones. Future trials ought to be designed with these issues firmly in mind. Further, it is no secret that the regulatory system is also in urgent need of repair. Manufacturers must do—in a timely fashion—postmarketing studies that assess the long-term safety of their drugs, and regulatory agencies must hold manufacturers' feet to the fire to ensure that these are performed, performed properly, thoroughly evaluated, and made available to guide decisions about prescribing. Agencies like the US FDA must have the resources and authority to close what is now a potentially dangerous gap. Unless limitations on the understanding, analysis, and communication of drug safety issues are addressed, the thiazolidinediones might simply become the latest in a series of preventable drug disasters.
The Lancet
Editorial
The Lancet, Current Issue, Volume 370, Number 9593, 29 September 2007
In today's Lancet, Rodrigo Lago and colleagues add to the ongoing analysis of the safety of thiazolidinediones for control of hyperglycaemia. Initial concerns about the cardiovascular risks of one of the thiazolidinediones, rosiglitazone, erupted in a firestorm of controversy when a meta-analysis by Nissen and Wolski was published online in the New England Journal of Medicine in May. Nissen and Wolski found that rosiglitazone (Avandia, GSK) was associated with a significantly increased risk of myocardial infarction, and a risk of death from cardiovascular causes that was of borderline statistical significance. The authors acknowledged that their analysis was limited by the public availability of trial results and a lack of access to patient-level data, and that the pooled studies were not designed to assess cardiovascular outcomes. But they concluded that the risks of rosiglitazone use in diabetes should be carefully considered by both doctors and their patients.
Response to these findings was swift. An editorial that accompanied the paper, while acknowledging the findings' “fragility”, called for urgent regulatory action; GSK vigorously defended its product, saying that studies show Avandia's cardiovascular profile to be comparable to other oral antidiabetes agents; and this journal counselled against a rush to judgment, advising patience until the final results of RECORD, a phase III trial designed to assess cardiovascular outcomes, were available. Media coverage was extensive. A US Congressional hearing was hastily called, as was a Food and Drug Administration (FDA) Advisory Committee meeting. The Congressional hearing was a spectacular display of partisan agendas and bipartisan ignorance. The FDA meeting resulted in a 22 to 1 vote to keep Avandia on the market, and to add a “black box” warning on the label of the risks of the drug's use in patients with congestive heart failure. If this sequence of events sounds familiar, it is because a nearly identical path was trodden when the safety of selective cyclo-oxygenase 2 (COX-2) inhibitors was called into question. Then, as now, the question was about the drugs' cardiovascular effects.
Other analyses of the thiazolidinedione have followed the NEJM paper, including two papers that appeared in JAMA on Sept 12, one on the risk of cardiovascular events with pioglitazone, the only other available agent in the thiazolidinedione class (Actos, Takeda), and one assessing long-term cardiovascular risk with rosiglitazone. Here, both drugs were associated with an increased risk of heart failure, though without an associated increase in mortality. This is the same conclusion reached by Lago and colleagues: patients taking thiazolidinediones seem to have a higher risk of congestive heart failure, but do not have a higher risk of death from cardiovascular causes.
Is there then a bottom line to all these bits of evidence? What should doctors and patients do? Is there in fact enough good evidence on which to decide anything? It seems that the jury is still out for the thiazolidinediones as a class. But there are many interim take-home messages. Some of these are highlighted by Comments in today's issue. First, it must be remembered that meta-analysis is a technique with important limitations. And the studies on which the thiazolidinedione meta-analyses are based have thus far all involved surrogate markers; the studies were not designed to assess cardiovascular outcomes, but rather improved glycaemic control. This outcome, as Victor Montori and colleagues note, is not a patient-centred one. The current clinical emphasis on glucose control (as measured by HbA1c) skirts the outcomes that matter most to patients—microvascular and macrovascular complications, quality of life, and survival.
These commentators highlight issues that must be taken into account in the ongoing debate about thiazolidinediones. Future trials ought to be designed with these issues firmly in mind. Further, it is no secret that the regulatory system is also in urgent need of repair. Manufacturers must do—in a timely fashion—postmarketing studies that assess the long-term safety of their drugs, and regulatory agencies must hold manufacturers' feet to the fire to ensure that these are performed, performed properly, thoroughly evaluated, and made available to guide decisions about prescribing. Agencies like the US FDA must have the resources and authority to close what is now a potentially dangerous gap. Unless limitations on the understanding, analysis, and communication of drug safety issues are addressed, the thiazolidinediones might simply become the latest in a series of preventable drug disasters.
The Lancet
Thursday, September 13, 2007
Meta-analyses contrast CV effects of pioglitazone and rosiglitazone
Latest meta-analyses contrast CV effects of pioglitazone and rosiglitazone
12 September 2007
MedWire News: Two separate meta-analyses of the thiazolidinediones pioglitazone and rosiglitazone published in the Journal of the American Medical Association point to contrasting effects of these glucose-lowering drugs on ischemic cardiovascular disease.
The latest meta-analysis in a series that has provoked much controversy indicates that, in line with some previous reports, rosiglitazone increases the risk for myocardial infarction (MI) by around 40%.
Meanwhile, the meta-analysis of pioglitazone shows that patients taking the drug have almost a 20% lower risk for death, MI, or stroke than those on alternative glucose-lowering medication.
Sonal Singh (Wake University School of Medicine, Winston-Salem, North Carolina, USA) and colleagues systematically reviewed the long-term cardiovascular risks associated with rosiglitazone. Unlike the initial meta-analysis by Steven Nissen and Kathy Wolski, and subsequent re-analyses of that study, Singh and colleagues included only studies of at least 12 months' duration.
Four studies, involving 6421 Type 2 diabetic patients treated with rosiglitazone and 7870 receiving control therapy, and with between 1 and 4 years of follow-up, met all inclusion criteria. The analysis of the pooled data from the four trials showed that rosiglitazone was associated with an increased risk for MI compared with control therapy, at a relative risk (RR) of 1.42 (p=0.02), and for heart failure compared with active control therapy or placebo, at a RR of 2.09 (p<0.001).
However, rosiglitazone did not increase the risk for cardiovascular mortality (RR=0.90) or all-cause mortality (RR=0.99) compared with control treatment.
There was no evidence for heterogeneity among the trials for any of these endpoints, the authors note.
They write: "These data suggest a reversal of the benefit-to-harm balance for rosiglitazone present at the time of approval. Thus, currently there appear to be much safer treatment alternatives."
Singh et al urge physicians not to wait for regulatory action, but to avoid using rosiglitazone in patients at risk for cardiovascular events.
For the second meta-analysis, Michael Lincoff (Cleveland Clinic, Ohio, USA) and colleagues included the complete set of patient-level, time-to-event data from all 19 randomized controlled trials of pioglitazone to date. These involved a total of 16,390 patients.
The primary outcome of death, MI, or stroke was significantly less frequent in the pioglitazone-treated patients, at 4.4% compared with 5.7% in those receiving control therapy (hazard ratio [HR]=0.82, p=0.005).
However, the increased risk for heart failure associated with pioglitazone was underlined, with serious heart failure reported in 2.3% of patients who received pioglitazone compared with 1.8% of control patients (HR=1.41).
The authors say that their findings, following inconclusive results of the PROactive trial, "provide reasonably strong evidence that [pioglitazone] does, in fact, reduce the risk of cardiovascular ischemic endpoints among patients with Type 2 diabetes."
LINK:
JAMA 2007; 298: 1180-1188, 1189-1195
12 September 2007
MedWire News: Two separate meta-analyses of the thiazolidinediones pioglitazone and rosiglitazone published in the Journal of the American Medical Association point to contrasting effects of these glucose-lowering drugs on ischemic cardiovascular disease.
The latest meta-analysis in a series that has provoked much controversy indicates that, in line with some previous reports, rosiglitazone increases the risk for myocardial infarction (MI) by around 40%.
Meanwhile, the meta-analysis of pioglitazone shows that patients taking the drug have almost a 20% lower risk for death, MI, or stroke than those on alternative glucose-lowering medication.
Sonal Singh (Wake University School of Medicine, Winston-Salem, North Carolina, USA) and colleagues systematically reviewed the long-term cardiovascular risks associated with rosiglitazone. Unlike the initial meta-analysis by Steven Nissen and Kathy Wolski, and subsequent re-analyses of that study, Singh and colleagues included only studies of at least 12 months' duration.
Four studies, involving 6421 Type 2 diabetic patients treated with rosiglitazone and 7870 receiving control therapy, and with between 1 and 4 years of follow-up, met all inclusion criteria. The analysis of the pooled data from the four trials showed that rosiglitazone was associated with an increased risk for MI compared with control therapy, at a relative risk (RR) of 1.42 (p=0.02), and for heart failure compared with active control therapy or placebo, at a RR of 2.09 (p<0.001).
However, rosiglitazone did not increase the risk for cardiovascular mortality (RR=0.90) or all-cause mortality (RR=0.99) compared with control treatment.
There was no evidence for heterogeneity among the trials for any of these endpoints, the authors note.
They write: "These data suggest a reversal of the benefit-to-harm balance for rosiglitazone present at the time of approval. Thus, currently there appear to be much safer treatment alternatives."
Singh et al urge physicians not to wait for regulatory action, but to avoid using rosiglitazone in patients at risk for cardiovascular events.
For the second meta-analysis, Michael Lincoff (Cleveland Clinic, Ohio, USA) and colleagues included the complete set of patient-level, time-to-event data from all 19 randomized controlled trials of pioglitazone to date. These involved a total of 16,390 patients.
The primary outcome of death, MI, or stroke was significantly less frequent in the pioglitazone-treated patients, at 4.4% compared with 5.7% in those receiving control therapy (hazard ratio [HR]=0.82, p=0.005).
However, the increased risk for heart failure associated with pioglitazone was underlined, with serious heart failure reported in 2.3% of patients who received pioglitazone compared with 1.8% of control patients (HR=1.41).
The authors say that their findings, following inconclusive results of the PROactive trial, "provide reasonably strong evidence that [pioglitazone] does, in fact, reduce the risk of cardiovascular ischemic endpoints among patients with Type 2 diabetes."
LINK:
JAMA 2007; 298: 1180-1188, 1189-1195
Wednesday, September 12, 2007
Pioglitazone and Rosiglitazone: Different Effects on Heart Disease
Pioglitazone and Rosiglitazone: Different Effects on Heart Disease
Physician's First Watch for September 12, 2007
Two new meta-analyses in JAMA confirm the increased risk for heart failure associated with pioglitazone and rosiglitazone, but they show disparate results for other cardiovascular outcomes.
In an analysis of data from 19 randomized controlled trials involving some 16,000 patients with type 2 diabetes, those randomized to pioglitazone showed an 18% reduced risk for the composite of death, MI, and stroke. There was also a nonsignificant reduction in risk for MI alone. The drug manufacturer contributed all data.
Another research group analyzed four long-term, randomized controlled trials of rosiglitazone in which cardiovascular safety was a prespecified endpoint; some 14,000 patients were included. Overall, rosiglitazone increased the risk for MI by 42%.
Editorialists note that the increased risk for MI observed with rosiglitazone is similar to the risk reported in a recent, much publicized meta-analysis. They add that "with many other available oral agents for diabetes, the potential benefit of [thiazolidinediones] requires reevaluation."
JAMA article on pioglitazone (Free abstract; full text requires subscription)
JAMA article on rosiglitazone (Free abstract; full text requires subscription)
JAMA editorial (Subscription required)
Physician's First Watch for September 12, 2007
Two new meta-analyses in JAMA confirm the increased risk for heart failure associated with pioglitazone and rosiglitazone, but they show disparate results for other cardiovascular outcomes.
In an analysis of data from 19 randomized controlled trials involving some 16,000 patients with type 2 diabetes, those randomized to pioglitazone showed an 18% reduced risk for the composite of death, MI, and stroke. There was also a nonsignificant reduction in risk for MI alone. The drug manufacturer contributed all data.
Another research group analyzed four long-term, randomized controlled trials of rosiglitazone in which cardiovascular safety was a prespecified endpoint; some 14,000 patients were included. Overall, rosiglitazone increased the risk for MI by 42%.
Editorialists note that the increased risk for MI observed with rosiglitazone is similar to the risk reported in a recent, much publicized meta-analysis. They add that "with many other available oral agents for diabetes, the potential benefit of [thiazolidinediones] requires reevaluation."
JAMA article on pioglitazone (Free abstract; full text requires subscription)
JAMA article on rosiglitazone (Free abstract; full text requires subscription)
JAMA editorial (Subscription required)
Wednesday, August 15, 2007
FDA Announces Boxed Warnings on All Thiazolidinediones
FDA Announces Boxed Warnings on All Thiazolidinediones
The entire class of thiazolidinedione drugs used to treat type 2 diabetes must carry boxed warnings about the drugs' ability to cause or worsen heart failure, the FDA announced late yesterday.
The affected drugs are Avandia (rosiglitazone), Actos (pioglitazone), Avandaryl (rosiglitazone and glimepiride), Avandamet (rosiglitazone and metformin), and Duetact (pioglitazone and glimepiride).
The action addresses the FDA's worry that "despite the warnings and information already listed in the drug labels, these drugs are still being prescribed to patients without careful monitoring for signs of heart failure," says the agency's chief of drug evaluation and research.
FDA announcement (Free)
Rosiglitazone alert (Free)
Pioglitazone alert (Free)
The entire class of thiazolidinedione drugs used to treat type 2 diabetes must carry boxed warnings about the drugs' ability to cause or worsen heart failure, the FDA announced late yesterday.
The affected drugs are Avandia (rosiglitazone), Actos (pioglitazone), Avandaryl (rosiglitazone and glimepiride), Avandamet (rosiglitazone and metformin), and Duetact (pioglitazone and glimepiride).
The action addresses the FDA's worry that "despite the warnings and information already listed in the drug labels, these drugs are still being prescribed to patients without careful monitoring for signs of heart failure," says the agency's chief of drug evaluation and research.
FDA announcement (Free)
Rosiglitazone alert (Free)
Pioglitazone alert (Free)
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