Monday, May 21, 2007
Rosiglitazone (Avandia) in perspective
Today the New England Journal of Medicine released, on line ahead of print, a meta-analysis of 42 trials looking at the effect of rosiglitazone on cardiovascular outcomes. The use of rosiglitazone, compared against placebo or other regimens for type 2 diabetes, was associated with a statistically significant increase in myocardial infarction and a non-statistically significant trend toward increased cardiovascular mortality.
This finding begs the question of whether the apparent adverse effect is a class effect of thiazolidinediones (TZDs) or is unique to rosiglitazone. The meta-analysis findings are in contrast to the PROactive study of the other TZD approved in the U.S., pioglitazone, which showed improved cardiovascular outcomes.
A new analysis of PROactive published in the Journal of the American College of Cardiology (JACC), looking at recurrent MI in the cohort of patients with previous MI (2,445, just under half of the PROactive population) showed a statistically significant reduction in the pioglitazone group. The official PROactive web page contains updates.
Is there an explanation for these apparently disparate effects? It may lie in the fact that while rosiglitazone is a pure PPAR gamma agonist pioglitazone is a mixed PPAR gamma and PPAR alpha agonist. PPAR alpha agonism may confer more favorable lipid effects on pioglitazone. Specifically, while both drugs raise HDLC, pioglitazone has little or no effect on LDLC while rosiglitazone raises LDLC. Pioglitazone seems to lower triglycerides more effectively than does rosiglitazone.
Pasty and Furberg commented on the meta-analysis findings in this editorial. They point out that although ongoing trials may shed favorable light on rosiglitazone, a lack of positive outcome data in the long period since approval in 1999 is concerning, and reach this sobering conclusion: “On the basis of this meta-analysis, however, the possibility of cardiovascular benefit associated with the use of rosiglitazone seems remote.”
Other commentaries:
Monday, May 21, 2007
Avandia and heart attack
Could Avandia be the next Vioxx?
The NEJM with some smoke. Will fire be far behind?
Rosiglitazone was associated with a significant increase in the risk of myocardial infarction and with an increase in the risk of death from cardiovascular causes that had borderline significance. Our study was limited by a lack of access to original source data, which would have enabled time-to-event analysis. Despite these limitations, patients and providers should consider the potential for serious adverse cardiovascular effects of treatment with rosiglitazone for type 2 diabetes.
Update 1 –
The author of the study, Dr. Steven Nissen backs away from suggesting what to do:
Is there a case for prescribing Avandia? Are there some patients for whom the benefits outweigh the risks?Again, I don’t think I want to go there. It’s important for me as a physician-scientist to put the data out there in a very neutral fashion, and not cast judgment about what people ought to do. We’re going to let everybody read our paper and make up their own minds.
I'll be expecting a lot of patient calls tomorrow.
Update 2 –
MedPage Today with the best perspective thus far, comparing the findings to PremPro and Vioxx:
A meta-analysis of data from 42 clinical trials found a 43% increase in relative risk of myocardial infarction among type 2 diabetics treated with rosiglitazone (Avandia).
The odds ratio for MI was 1.43 (95% confidence interval 1.03-1.98, P=0.03), said Steven E. Nissen, M.D., of the Cleveland Clinic, lead author of the meta-analysis, which was released online today by the New England Journal of Medicine . . .
To put those data in perspective, the Women's Health Initiative (WHI), which used patient-level data, found that use of Prempro was associated with a 29% increase in relative risk in the combined endpoint of non-fatal MI and death from coronary heart disease.
A 2001 study co-authored by Dr. Nissen (JAMA 2001; 286:954-959) reported that rofecoxib (Vioxx) was associated with a 2.38 OR for thromboembolic events (95% CI, 1.49-4.00 P=0.002).
Full article and abstract (free):
http://content.nejm.org/cgi/content/full/NEJMoa072761
Other links:
http://doctorrw.blogspot.com/
http://www.kevinmd.com/blog/2007/05/avandia-and-heart-attacks.html
Rosiglitazone (Avandia) in perspective
Today the New England Journal of Medicine released, on line ahead of print, a meta-analysis of 42 trials looking at the effect of rosiglitazone on cardiovascular outcomes. The use of rosiglitazone, compared against placebo or other regimens for type 2 diabetes, was associated with a statistically significant increase in myocardial infarction and a non-statistically significant trend toward increased cardiovascular mortality.
This finding begs the question of whether the apparent adverse effect is a class effect of thiazolidinediones (TZDs) or is unique to rosiglitazone. The meta-analysis findings are in contrast to the PROactive study of the other TZD approved in the U.S., pioglitazone, which showed improved cardiovascular outcomes.
A new analysis of PROactive published in the Journal of the American College of Cardiology (JACC), looking at recurrent MI in the cohort of patients with previous MI (2,445, just under half of the PROactive population) showed a statistically significant reduction in the pioglitazone group. The official PROactive web page contains updates.
Is there an explanation for these apparently disparate effects? It may lie in the fact that while rosiglitazone is a pure PPAR gamma agonist pioglitazone is a mixed PPAR gamma and PPAR alpha agonist. PPAR alpha agonism may confer more favorable lipid effects on pioglitazone. Specifically, while both drugs raise HDLC, pioglitazone has little or no effect on LDLC while rosiglitazone raises LDLC. Pioglitazone seems to lower triglycerides more effectively than does rosiglitazone.
Pasty and Furberg commented on the meta-analysis findings in this editorial. They point out that although ongoing trials may shed favorable light on rosiglitazone, a lack of positive outcome data in the long period since approval in 1999 is concerning, and reach this sobering conclusion: “On the basis of this meta-analysis, however, the possibility of cardiovascular benefit associated with the use of rosiglitazone seems remote.”
Other commentaries:
Monday, May 21, 2007
Avandia and heart attack
Could Avandia be the next Vioxx?
The NEJM with some smoke. Will fire be far behind?
Rosiglitazone was associated with a significant increase in the risk of myocardial infarction and with an increase in the risk of death from cardiovascular causes that had borderline significance. Our study was limited by a lack of access to original source data, which would have enabled time-to-event analysis. Despite these limitations, patients and providers should consider the potential for serious adverse cardiovascular effects of treatment with rosiglitazone for type 2 diabetes.
Update 1 –
The author of the study, Dr. Steven Nissen backs away from suggesting what to do:
Is there a case for prescribing Avandia? Are there some patients for whom the benefits outweigh the risks?Again, I don’t think I want to go there. It’s important for me as a physician-scientist to put the data out there in a very neutral fashion, and not cast judgment about what people ought to do. We’re going to let everybody read our paper and make up their own minds.
I'll be expecting a lot of patient calls tomorrow.
Update 2 –
MedPage Today with the best perspective thus far, comparing the findings to PremPro and Vioxx:
A meta-analysis of data from 42 clinical trials found a 43% increase in relative risk of myocardial infarction among type 2 diabetics treated with rosiglitazone (Avandia).
The odds ratio for MI was 1.43 (95% confidence interval 1.03-1.98, P=0.03), said Steven E. Nissen, M.D., of the Cleveland Clinic, lead author of the meta-analysis, which was released online today by the New England Journal of Medicine . . .
To put those data in perspective, the Women's Health Initiative (WHI), which used patient-level data, found that use of Prempro was associated with a 29% increase in relative risk in the combined endpoint of non-fatal MI and death from coronary heart disease.
A 2001 study co-authored by Dr. Nissen (JAMA 2001; 286:954-959) reported that rofecoxib (Vioxx) was associated with a 2.38 OR for thromboembolic events (95% CI, 1.49-4.00 P=0.002).
Full article and abstract (free):
http://content.nejm.org/cgi/content/full/NEJMoa072761
Other links:
http://doctorrw.blogspot.com/
http://www.kevinmd.com/blog/2007/05/avandia-and-heart-attacks.html
No comments:
Post a Comment