Rosiglitazone safety questioned, again, this time in population-based study

-TheHeart.org

08/20/2009 - Toronto, ON - The risk of dying or being hospitalized with heart failure, but not of MI, is lower among older diabetic patients taking pioglitazone (Actos, Takeda Pharmaceuticals North America) than in those taking rosiglitazone (Avandia, GlaxoSmithKline), suggests a retrospective analysis based on outpatient data from across Ontario.

The assertions aren't new, but there have been no randomized comparisons of the two thiazolidinediones (TZDs) and few prior opportunities to directly compare them for outcomes, especially in such a diverse population.

Published online August 18, 2009 in BMJ, the findings strengthen the mass of evidence pointing to safety hazards with rosiglitazone compared with pioglitazone and other diabetes drugs. The authors of the research, led by Dr David N Juurlink ( University of Toronto, ON), suggest that by now, the evidence is convincing enough to avoid use of the drug altogether.

There's not a single advantage, even a theoretical one, to rosiglitazone. Why anyone would want to continue to prescribe it or why any patient would want to take it, I don't know. "Given the accumulating evidence of harm with rosiglitazone treatment and the lack of a distinct clinical advantage for the drug over pioglitazone, questioning whether ongoing use of rosiglitazone is justified in any circumstance is reasonable," they write.

Juurlink on his own was more explicit. "We have two drugs with identical indications. They both decrease insulin resistance, they both lower blood sugar, and yet we have good reason to believe that one is less safe than the other," he told heartwire. "There's not a single advantage, even a theoretical one, to rosiglitazone. Why anyone would want to continue to prescribe it or why any patient would want to take it, I don't know."

An accompanying editorial questions that position, however, contending that differences between recipients of the two drugs could have obscured the outcomes comparison: "Longer-term safety data are needed before a change in practice is warranted."

Significant doubts about the safety of rosiglitazone stem largely from the controversial assertion in 2007 that the drug poses an increased risk of MI. Over the next few years, observational studies and meta-analyses variously concluded that rosiglitazone raises mortality or poses an increased risk of MI, heart failure, or both compared with pioglitazone, as extensively reported by heartwire.

The current analysis takes a firm side in the debate. "This is not a myocardial-infarction story. This is a death and heart-failure story, even though a lot of the original concerns pertained to myocardial infarction," Juurlink said.

The group looked at diabetics in the community at least 66 years old who received a first prescription for one or the other TZD over a six-year period ending March 2008; those also taking insulin were excluded. Over a median follow-up of about 293 days, the 16 951 patients taking pioglitazone had significantly reduced adjusted risks of the primary outcome measure of death, MI, or heart-failure hospitalization and of both death and HF hospitalization as individual end points than the 22 785 who received rosiglitazone.

Hazard ratioa (95% CI) for primary and secondary end points, diabetics >66 years of age treated with pioglitazone vs rosiglitazone

End points

HR (95% CI)

Primary end pointb

0.83 (0.76-0.90)

Heart failure

0.77 (0.69-0.87)

MI

0.95 (0.81-1.11)

Death

0.86 (0.75- 0.98)

a. Composite of death, MI, or HF hospitalization

b. Adjusted for age; sex; duration of diabetes; residence in long-term care facility; socioeconomic level; year of cohort entry; hospitalization for cardiac or renal disease; other comorbidities; recent therapy with cardiovascular or diabetes drugs or nonsteroidal anti-inflammatory drugs

"In terms of absolute risk, we estimate that approximately one additional composite outcome would be expected to occur annually for every 93 patients treated with rosiglitazone rather than pioglitazone," the authors write.

In their editorial, Dr Corinne S de Vries ( University of Bath, UK) and Dr David L Russell-Jones ( University of Surrey, Guildford, UK) laud the analysis for a "rigorous design" but also raise doubts about its conclusions. In particular, they propose that because those taking rosiglitazone had been diabetic significantly longer, they may have been in worse clinical shape at baseline than those taking pioglitazone.

"This leaves clinicians unsure about the implications for prescribing," the pair writes, especially given the drugs' other safety issues. Both appear to increase the risk of bone fractures and both can precipitate heart failure, for example.

The heart-failure risk certainly appears to be a class effect, Juurlink noted. "It is fair to say that while there are studies that show no difference between rosiglitazone and pioglitazone, there are studies that show that rosiglitazone appears to be less safe than pioglitazone. And there's not a single study that suggests that pioglitazone might somehow have a different safety profile than rosiglitazone," he said. "They have similar side effects but one is worse than the other."

In their report, Juurlink et al note that "rosiglitazone is a far more potent agonist of [peroxisome proliferator-activated receptor-gamma] PPAR- than is pioglitazone, and activation of PPAR- in the kidney seems to be an important mechanism of thiazolidinedione-induced salt and water retention. These observations may explain the higher risk of heart failure with rosiglitazone, and we speculate that they also underlie the increased risk of death in patients taking the drug."

As for whether the patients who received rosiglitazone in the analysis started off in worse clinical condition than those taking pioglitazone, Juurlink said, "We found no difference in the risk for myocardial infarction. It's difficult to overstate the importance of that finding. If the patients on rosiglitazone really were sicker at baseline, and that's why they died more often and had more heart failure than those on pioglitazone, they should have had more myocardial infarctions, and they didn't."

Juurlink et al declare no competing interests; the analysis was publicly funded. "The University of Bath has received grants for research, travel, and consultancy from Novo Nordisk, Takeda, Pfizer, and GlaxoSmithKline," the editorial notes. In addition, Russell-Jones reports receiving research grants, lecture fees, and honoraria from Lilly, Merck Sharp & Dohme, GlaxoSmithKline, Takeda, Novo Nordisk, Aventis, Novartis, Boehringer Ingelheim, and Pfizer.

If you or a loved one have experienced an Avandia heart attack, or Avandia stroke, Avandia congestive heart failure, Avandia cardiovascular disease or if you have lost a loved one to an Avandia death you may be entitled to compensation. Contact the Avandia attorneys of Ennis & Ennis today for a free confidential case evaluation. Our on staff nurse and lawyers are standing by to answer any questions you may have regarding Avandia's side effects, a possible Avandia class action lawsuit, or any other type of Avandia litigation.