Search and retrieval
We retrieved 847 potentially eligible articles, as judged by their citation link to the index publications; evaluation of their content enabled the exclusion of 634 articles (that is, the articles did not comment on rosiglitazone and the risk of myocardial infarction or use of rosiglitazone). We could not obtain the full text of four articles, which were, therefore, excluded. We also excluded seven articles written by the authors of the index articles. Thus, 202 articles were included in the analyses, including 18 articles that were translated to English before assessment. After accounting for multiple contributions from a single author, 180 unique authors were used for analysis. The article selection process is depicted in the figure. Individual studies are described in the web extra file.
Prevalence and disclosure of financial conflicts of interest
Of the 202 eligible studies (10 reported original research, 91 were letters, editorials, or commentaries, and 101 were reviews, meta-analyses, or guidelines), 108 articles (53%) included a conflict of interest statement (nine of the 10 (90%) original research articles, 39 of the 91 (43%) letters, editorials, or commentaries, and 60 of the 101 (59%) reviews, meta-analyses, or guidelines).
A total of 90 (45%) of the 202 articles were authored by individuals who had financial conflicts of interest. Of the 90 studies with conflicts of interest, 69 (77%) had a statement disclosing the conflict of interest in the article itself. The other 21 studies with financial conflicts of interest (23%) did not disclose these relationships, which were discovered through searching other publications by the same author or the internet. Three (14%) of these 21 studies published a statement declaring no conflicts of interest. Detailed description of included articles, conflict of interest prevalence, and disclosures are in the web extra file.
Classification of authors’ positions
In terms of the risk of myocardial infarction associated with rosiglitazone, 31 (17%) of the 180 unique authors offered favourable views, 84 (47%) were neutral, and 65 (36%) had unfavourable views about the safety of rosiglitazone. In terms of recommendations regarding the use of rosiglitazone, 26 authors had favourable views (that is, recommended continued use), 116 were neutral, and 38 held unfavourable opinions.
A large proportion of the authors who offered favourable views about the safety of rosiglitazone had financial conflicts of interest with pharmaceutical companies in general (29/31 (94%)), with rosiglitazone manufacturers (27/31 (87%)), and with pioglitazone manufacturers (20/31 (65%)), compared with those authors expressing unfavourable views (18/65 (28%), 13/65 (20%), and 14/65 (22%), respectively). Authors who had favourable views on the safety of rosiglitazone were more than three times more likely to have a financial conflict of interest with a pharmaceutical company than were authors who had unfavourable views (rate ratio 3.38, 95% CI 2.26 to 5.06). There was likewise a strong association between favourable recommendations on the use of rosiglitazone and financial conflicts of interest (rate ratio 3.36, 95% CI 1.94 to 5.83; table 2).
Table 2 Author position on rosiglitazone safety and financial conflicts of interest
The use of pioglitazone
Both the meta-analysis by Nissen and Wolski1
and the RECORD trial11
looked into the cardiovascular safety of rosiglitazone but not of pioglitazone. The PROactive study, however, suggested that pioglitazone may be cardioprotective.15
Authors who had favourable views about the use of rosiglitazone were more likely to have a financial conflict of interest with a manufacturer of pioglitazone than were authors with unfavourable views (73% (19/29) v 26% (10/44); rate ratio 3.28, 95% CI 1.88 to 5.73). However, 29 articles overall strongly recommended using pioglitazone rather than rosiglitazone, 25 (86%) of which were authored by individuals with financial conflicts of interest with a pioglitazone manufacturer.
All sensitivity analyses are presented in part E of the web extra file. Our results were similar when we performed analyses using Stelfox and colleagues’ combined scale2
: 42 (23%) authors were classified as having a favourable opinion on the risk of myocardial infarction with rosiglitazone, 70 (39%) were neutral, and 68 (38%) had an unfavourable view. One author had disparate views on the risk of myocardial infarction and its continued use and was thus classified as neutral. When we looked at the link between authors’ views on the safety of rosiglitazone and financial conflicts of interest, the results were similar to those in our original analysis. A total of 79% (33/42) of authors who expressed a favourable view had financial conflicts of interest with the manufacturer of rosiglitazone, compared with 22% (15/68) of authors who expressed an unfavourable opinion (rate ratio 3.65, 95% CI 2.31 to 5.77).
When we used each article as a unit of analysis, we found that 35 (17%) were favourable, 95 (47%) were neutral, and 72 (36%) were unfavourable in terms of risk of myocardial infarction with rosiglitazone. In total, 86% (30/35) of favourable articles were associated with a financial conflict of interest with the manufacturer of rosiglitazone, compared with 18% (13/72) of articles that reported an unfavourable viewpoint (rate ratio 4.69, 95% CI 2.84 to 7.72).
When we restricted the analysis to the 105 articles in which the rosiglitazone controversy was the main focus, we found that articles whose authors had favourable views on the risk of myocardial infarction with rosiglitazone were more likely to have financial conflicts of interest with the manufacturer of rosiglitazone than articles expressing unfavourable views (84% (21/25) v 14% (7/51); rate ratio 6.00, 95% CI 2.98 to 12.10). We also found this relation when we undertook an analysis of recommendations on use: 81% (13/16) of articles expressing a favourable recommendation had financial conflicts of interest with the manufacturer of rosiglitazone, compared with 13% (4/31) of articles expressing an unfavourable recommendation (rate ratio 6.50, 95% CI 2.56 to 16.53).
Results were also consistent when the analysis was restricted to the 92 publications that were a commentary, letter, or editorial: 90% (19/21) of articles expressing a favourable view on the risk of myocardial infarction with rosiglitazone had financial conflicts of interest with the manufacturer of rosiglitazone, compared with 14% (5/35) of articles expressing an unfavourable view (rate ratio 6.15, 95% CI 2.71 to 13.99). Analysis of the authors’ recommendations on rosiglitazone use yielded nearly identical numbers (80% (12/15) v 13% (3/23); rate ratio 6.29, 95% CI 2.15 to 18.38).
A total of 27 articles were published before the FDA issued a black box safety warning for rosiglitazone. Of these 27 articles, eight (30%) were favourable, 10 (37%) were neutral, and nine (33%) were unfavourable about rosiglitazone safety. Of the articles in which authors expressed favourable views on rosiglitazone safety, 75% (6/8) were associated with financial conflicts of interest with rosiglitazone manufacturers compared with 22% (2/9) in which authors had an unfavourable view (rate ratio 3.43, 95% CI 0.99 to 11.82). Similar results were obtained for the recommendations on rosiglitazone use for this subset of articles (75% (3/4) v 17% (1/6); rate ratio 4.50, 95% CI 0.69 to 29.39).
We then repeated our analysis for articles published after the FDA warning. We found that 89% (24/27) of articles in which authors presented favourable views were associated with financial conflicts of interest with the rosiglitazone manufacturer compared with 17% (11/63) of articles written by unfavourable authors. Similar results were obtained for the recommendations on rosiglitazone use for this subset of articles (84% (21/25) v 24% (9/38); rate ratio 3.75, 95% CI 2.10 to 6.72).