Tag Archives: rosiglitazone risk

“Where’s the Beef?” for Avandia’s Risk?

Readers may remember the 1984 through 1985 Wendy’s hamburger television commercials with the famous line, “Where’s the beef?”   The idea was that some other hamburgers were all bun and no meat–all show and no substance.  The same could be said for the controversies surrounding rosiglitazone (Avandia, Avandamet, Avandaryl; GlaxoSmithKline).

The evidence suggesting that rosiglitazone increases the risks of myocardial infarctions (“heart attacks”) and cardiovascular events (“heart attacks,” anginal chest pain, strokes, and sudden death) was always extremely weak1 (See also my previous posts, “Steven Nissen and The Not-So-Great Avandia Controversy,” December 18, 2013; “Nissen, Wolski, and How Not to Do Meta-Analyses,” December 19, 2013; “What is the Risk of Avandia?” December 23, 2013; and “Avandia’s TIDE Is Stopped,” December 24, 2013.).

A reviewer for the Food and Drug Administration was critical of Nissen and Wolski’s original meta-analysis2

  • for including highly heterogeneous studies  (They mixed studies that were extremely different from each other.)
  • for combining head-to-head trials of drugs with trials in which the drugs were merely added on when others failed (They mixed studies that had a strong design with those that had a weak design, and then treated them as the same.)
  • for arbitrarily excluding the half of the trials that lacked cardiovascular deaths (primarily “heart attacks”) (They biased their results against rosiglitazone.)
  • for falsely implying a comparison between rosiglitazone and insulin that did not exist
  • for otherwise misrepresenting the designs of the studies, and
  • for only using a single statistical technique to analyze the results (In other words, even with all of their errors, they may not have obtained the results that they did, if they had used different–and arguably more appropriate–statistical techniques.).3

Basing their analysis primarily on short-term (six-month) studies was of questionable validity, in the first place.  To illustrate:  if Nissen and Wolski had been honest enough to look at the six-month time point of PROactive, a study of the rival drug, pioglitazone (Actos, Actosplus Met, Actosplus Met XR, Duetact, Osini; Takeda), their results would have suggested an increased cardiovascular risk  that was not apparent at the end of the study.3  As we will see, the same pattern applies to rosiglitazone (Avandia, Avandamet, Avandaryl, GlaxoSmithKline).  Short-term results, such as these, are largely due to chance fluctuations in the occurrence of rare evens; with the passage of time averages them out.  Besides, which matters for drugs that are intended to be used for many years–the results at the end of a few months, or those after a few years?

Even an editorial that accompanied Nissen and Wolski’s highly controversial original meta-analysis had to admit “the fragility of their findings.”4

Their results were fragile, indeed.  Even Nissen and Wolski were unable to get the same results in their own later meta-analysis.5  In response to Nissen and Wolski’s claims,2,5 the Food and Drug Administration (FDA) did its own meta-analysis.6  It suggested that rosiglitazone might increase myocardial ischemia (mostly anginal chest pain from the heart), but not myocardial infarctions (“heart attacks”), all-cause deaths, or the combination of myocardial infarctions, strokes, and cardiovascular deaths.6  In fact, the Food and Drug Administration observed that, “When the meta-analysis was performed by placebo- vs active-controlled trials, the increase in ischemic risk was observed in only the placebo-controlled trials.  This finding suggests that the risk of myocardial ischemia is similar between rosiglitazone and other oral anti-diabetic agents to which it was compared (metformin and sulfonylureas).”7  Once again, Nissen and Wolski’s conclusions depended upon weak evidence.

“When considering all data available at this time [2010], however, the overall evidence of increased myocardial ischemic event risk with rosiglitazone is weak.”1

What was true then, as we will see, is even more true, now.  No matter how much Steven Nissen, M.D., wants us to focus on outside appearances, a closer look shows that the evidence for increased myocardial infarctions (“heart attacks”) and myocardial ischemia (anginal chest pain from the heart) with rosiglitazone (Avandia, Avandamet, Avandaryl, GlaxoSmithKline) is all bun and no beef.

Even worse, as we will also see, Dr. Nissen’s less than honorable behaviors may stem from less than honorable motives to viciously attack rosiglitazone (Avandia, Avandamet, Avandaryl, GlaxoSmithKline) and spare pioglitazone (Actos, Actosplus Met, Actosplus Met XR, Duetact, Osini; Takeda).

© 2014 Myron Shank, M.D., Ph.D.

1 Parks Mary H. (Untitled).  In:  FDA Briefing Document Advisory Committee Meeting for NDA 21071 Avandia (rosiglitazone maleate) tablet July 13 and 14, 2010.  http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM218493.pdf

2 Nissen Steven E., Wolski Kathy.  Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes.  The New England Journal of Medicine 2007; 356:2457-2471.

3 Mele Joy, Sahlroot Todd.  Statistical review and evaluation:  addendum to review completed 6/4/07.  In:  FDA Briefing Document Advisory Committee Meeting for NDA 21071 Avandia (rosiglitazone maleate) tablet July 13 and 14, 2010.  http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM218493.pdf

4 Psaty Bruce M., Furberg Curt D.  Rosiglitazone and cardiovascular risk.  New England Journal of Medicine 2007; 356:2522-2524.

5 Nissen Steven E., Wolski Kathy.  Rosiglitazone revisited: an updated meta-analysis of risk for myocardial infarction and cardiovascular mortality.  Archives of Internal Medicine 2010; 170:1191-1201.

6 Mahoney Karen Murry.  Preliminary Endocrine Medical Officer review of the RECORD (Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycemia in Diabetes) trial, and update on cardiovascular safety information from large clinical trials of rosiglitazone new drug application 21071 Avandia® (rosiglitazone maleate) 9 Jun 2010.  In:  FDA Briefing Document Advisory Committee Meeting for NDA 21071 Avandia (rosiglitazone maleate) tablet July 13 and 14, 2010.  http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM218493.pdf

7 Parks Mary H.  Inter-office background memo and draft questions for July 13 and 14, 2010 Advisory Committee Meeting for Avandia® (rosiglitazone).  In:  FDA Briefing Document Advisory Committee Meeting for NDA 21071 Avandia (rosiglitazone maleate) tablet July 13 and 14, 2010. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM218493.pdf

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Steven Nissen and The Not-So-Great Avandia Controversy

Controversy about Avandia (rosiglitazone) began with the rushed publication of an article in the New England Journal of Medicine.  The article, which itself has always controversial, suggested that Avandia was associated with an increased risk of myocardial infarctions1–doctor-speak for “heart attacks.”

The authors, Steven Nissen, M.D., and Kathy Wolski, used data that had been published by GlaxoSmithKline, Avandia’s manufacturer, on its website,1 without the data having been first critically examined (“adjudicated”).  In fact, Nissen and Wolski’s “verification” of the data consisted of checking the data from the website against articles published in the medical literature, but, whenever there was a discrepancy, simply ignoring the discrepancy and using the data from the website anyway.1  Nissen and Wolski made no attempt to find all of the studies that might have yielded evidence.2  Avandia is not to be used in patients with congestive heart failure, but Nissen and Wolski included a study of in patients with congestive heart failure.2  Three of the studies that they included were of non-diabetics with either Alzheimer’s disease or psoriasis, and they included other studies of patients who were merely at risk for diabetes.2  The designs and assessment of outcomes of the studies were a hodgepodge; Nissen and Wolski combined them, since a statistical test for variability did not confirm that variability;1 however, the statistical test they used was not suitable for sparse data,2 such as theirs.  Again, rather than using statistical techniques that would have allowed the use of data from studies without any myocardial infarctions and deaths, Nissen and Wolski ignored the studies.1  Furthermore, the statistical technique that they used requires balance between the numbers in the Avandia groups and the comparison groups, but there were two- and three-fold differences.2  Only by discarding part of the data and using improper statistical techniques were Nissen and Wolski able to conclude that the “data suggest a cardiovascular risk associated with the use of rosiglitazone.”1

Notwithstanding the problems with the studies selected by Nissen and Wolski, using appropriate statistical techniques and all of the data from those same studies yields very different conclusions:  “The risk for myocardial infarction and death from cardiovascular disease for diabetic patients taking rosiglitazone is uncertain.  Neither increased nor decreased risk is established.”2

Nissen and Wolski were sloppy, at best, but is that all?  Dr. Nissen acknowledged receiving research support from Takeda.1  What he did not mention is that Takeda manufacturers the rival drug, ACTOS (pioglitazone), which he pointedly compared to Avandia.  Was his campaign against Avandia punitive, because GlaxoSmithKline did not support his research?  In addition, he was widely promoted for the top position at the Food and Drug Administration3,4 for his muckraking.  Whether or not he actively sought the position, he apparently never demurred, either.  Dr. Nissen’s campaign against Avandia seems incompatible with a love of the truth, but it has all the hallmarks of an ego-inspired crusade.

As will become apparent in future posts, whatever his motives, Dr. Nissen has since demonstrated conspicuous lack of objectivity and unprofessional intolerance for other points of view about Avandia.

© 2013 Myron Shank, M.D., Ph.D.    

1 Nissen Steven E., Wolski Kathy.  Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes.  The New England Journal of Medicine 2007; 356:2457-2471.

2 Diamond George A., Bax Leon, Kaul Sanjay.  Uncertain effects of rosiglitazone on the risk for myocardial infarction and cardiovascular death.  Annals of Internal Medicine 2007; 147:578-581.

3 Reuters.  FDA chief to leave post when Obama takes office.  December 16, 2008.

4 Mundy Alicia.  Horse race begins for new leaders at FDA and HHS.  Health Blog November 5, 2008.