CMAJ • April 14, 2009; 180 (8). doi:10.1503/cmaj.1090004.
© 2009 Canadian Medical Association or its licensors
All editorial matter in CMAJ represents the opinions of the authors and not necessarily those of the Canadian Medical Association.
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Letters

Two of the authors respond:

Yoon K. Loke, MBBS MD and Sonal Singh, MD MPH

School of Medicine, Health Policy and Practice, University of East Anglia, Norwich, United Kingdom
Section on General Internal Medicine, Department of Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina

Konstantinos Toulis and colleagues reanalyzed some of the data we presented in our meta-analysis1 and concluded that pioglitazone use does not carry a fracture risk (in contrast to the finding for rosiglitazone). Their conclusion illustrates the pitfalls of relying on post-hoc subgroup analyses to ascertain the effects of drugs.

According to the Cochrane Handbook for Systematic Reviews of Interventions, the probability of false-positive and false-negative findings rapidly increases as multiple subgroups are evaluated.2 Subgroups should only be evaluated for the direction of effect: in our study there was an increased risk of fractures in women with diabetes who received either pioglitazone or rosiglitazone.

In addition, in implementing a random-effects model, Toulis and colleagues not only reduced the power of the meta-analysis3 but also shifted the weight of the analysis toward smaller, short-term studies that recorded relatively few events. When one is dealing with a rare adverse event that occurs only with prolonged therapy, it is only with adequately powered trials of longer duration that one will be able to discern these effects, as seen with the thiazolidinediones and fracture risk. Indeed, use of the random-effects model has been shown to lead to biased results in the analysis of rare events.3

Finally, the manufacturers of pioglitazone have released results confirming the increase in fracture risk seen with pioglitazone (1.9 fractures per 100 patient-years in the pioglitazone group and 1.1 fractures per 100 patient-years in the comparator group in 19 company-conducted trials).4 Hence, the available biologic, clinical and epidemiologic evidence confirms that fractures are a class effect of both of the thiazolidinediones: rosiglitazone and pioglitazone.

Footnotes

Competing interests: None declared.


REFERENCES

  1. Loke YK, Singh S, Furberg CD. Long-term use of thiazolidinediones and fractures in type 2 diabetes: a meta-analysis. CMAJ 2009;180:32–9.[Abstract/Free Full Text]
  2. Deeks JJ, Higgins JPT, Altman DG, et al. What are subgroup analyses? In: Higgins JPT, Green S, editors. Cochrane handbook for systematic reviews of interventions. Version 5.0.1. Oxford (UK): The Cochrane Collaboration; 2008 Sept. Available: www.cochrane-handbook.org (accessed 2009 Mar. 12).
  3. Bradburn MJ, Deeks JJ, Berlin JA, et al. Much ado about nothing: a comparison of the performance of meta-analytical methods with rare events. Stat Med 2007;26:53–77.[CrossRef][Medline]
  4. Grossman LD. Increased incidence of fractures in female patients who received long-term treatment with ACTOS (pioglitazone hydrochloride) tablets for type 2 diabetes mellitus. Toronto (ON): Eli Lilly Canada Inc.; 2007. Available: www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/_2007/actos_hpc-cps_2-eng.php (accessed 2009 Mar. 12).




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