Trial of New Oral Antidiabetic Agent Provides Both Answers and More Questions |
by David
W. Sharp
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WHAT'S
HOT IN MEDICINE |
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This Period (Jan-
Feb 07) |
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Last Period (Nov-Dec 06) |
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1 |
J.A. Lieberman, et al., "Effectiveness of antipsychotic drugs in patients with chronic
schizophrenia," New Engl. J. Med.,
353(12): 1209-23, 22 September 2005. [8 U.S. institutions] *966DS |
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J.G.F. Cleland, et al., "The effect of cardiac resynchronization on morbidity and mortality in heart failure," New Engl. J. Med.,
352(15): 1539-49, 14 April 2005. [7 U.K. and European institutions] *915SH |
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O. Abe, et al. (Early Breast Cancer Trialists’ Collaborative Group), "Effects of chemotherapy and
hormonal therapy for early
breast cancer on recurrence and 15-year survival: an overview of the randomised trials," Lancet,
365(9472): 1687-1717, 14 May 2005. [c. 150 institutions worldwide] *925VV |
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R.J. Klein, et al., "Complement factor H polymorphism in age-related macular degeneration," Science,
308(5720): 385-9, 15 April 2005. [6 U.S. institutions] *917TL |
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F.A. Shepherd, et al., "Erlotinib in previously treated non-small-cell lung cancer," New Engl. J. Med.,
353(2): 123-32, 14 July 2005. [15 institutions worldwide] *944OP |
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M.-S. Tsao, et al., "Erlotinib in lung cancer—Molecular and clinical predictors of outcome," New Engl. J. Med., 353(2): 133-44, 14 July 2005. [U. Toronto, Canada; U. Ottawa, Canada; OSI Pharma.,
Boulder, CO; Queen’s U., Kingston, Canada] *944OP |
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J.A. Dormandy, et al., "Secondary prevention of macrovascular events in patients with type 2
diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial," Lancet,
366(9493): 1279-89, 8 October 2005. [13 U.S. and European institutions]
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R. Stupp, et al., "Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma," New Engl. J. Med.,
352(10): 987-96, 10 March 2005. [15 European and Canadian institutions]
*904JC |
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R.J. Motzer, et al., "Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma," J. Clin. Oncol.,
24(1): 16-24, 1 January 2006. [8 U.S. institutions] *998QS |
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R.S. Bresalier, et al., "Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial," New Engl. J. Med.,
352(11): 1092-1102, 17 March 2005. [8 institutions worldwide] *906PU |
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SOURCE:
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Read
the Legend. |
rotocols for clinical trials are drawn up (and their results analyzed and reported) following strict guidelines. These include calculation of trial size, which involves assumptions about what benefit the test drug might achieve. However, even the best designs sometimes yield results that are tantalizingly short of conventional statistical significance. The PROspective pioglitAzone Clinical Trial in Macrovascular Events (PROactive) illustrates this frustration (paper #7).
Type 2
diabetes is typically managed by diet, oral drugs, strict blood-glucose monitoring and, sometimes, insulin injections. A novel class of oral drug—the glitazones for short, or, to be more chemically correct, thiazolidinediones, or, by mode of action, peroxisome proliferator-activated receptor gamma agonists—has been attracting attention. PROactive used pioglitazone, which is given in combination with other agents. Indeed, tablets combining this drug with metformin or with glimepiride have been licensed. Serious complications of diabetes include the microvascular (e.g., diabetic retinopathy) and the macrovascular (heart disease, stroke, severe leg abnormalities), the latter being the target in PROactive.
The primary endpoint, upon which the trial size of 5,000 patients was determined, was a composite of death, non-fatal myocardial infarction, stroke, acute coronary syndrome, leg amputation, or revascularization of the leg or coronary vessels. The 514 such events in the pioglitazone group were less than the 572 in patients on the placebo but not significantly so; the 95% confidence interval for the hazard ratio of 0.90 in pioglitazone’s favor spanned 1.00. This has to be the main result. However, many other clinical and biochemical endpoints were looked at. For example, a predetermined secondary endpoint favored pioglitazone, as did the numbers of patients switched to insulin during the trial or admitted to hospital because of diabetes. There were fewer strokes in those on the active drug, and a later subset analysis of PROactive patients who had had a history of stroke at trial entry indicated benefit to those randomized to pioglitazone (R. Wilcox,
et al., Stroke, 38[3]: 865-73, 2007).
On the other hand, the increase in heart failure and the greater rise in body weight in the pioglitazone group has worried commentators, and an October, 2006, Cochrane systematic review of 22 clinical trials of pioglitazone (including PROactive) was cautious: "…the benefit-risk ratio of pioglitazone remains unclear" (B. Richter,
et al., Cochrane Database Syst. Rev., 4: CD006060, 2006). Also cautious was Prof. Hannele Yki-Jarvinen (University of Helsinki, Finland) in a commentary accompanying #7 (Lancet,
366[9493]; 1241-2, 2005). In short, PROactive, it seems, does not tell clinicians who should be treated with pioglitazone. Nor is it clear how far the most recent spin-off from the full study helps resolve this dilemma. Besides stroke, the PROactive team has now looked separately at the 2,445 patients who had had a myocardial infarction before trial entry (E. Erdmann,
et al., J. Am. Coll. Cardiol., 49[17], 1772-80, 2007). This time there was a significant 28% reduction in the main endpoint, which was fatal and non-fatal myocardial infarction. However, 7.5% of the pioglitazone patients had heart failure requiring admission to hospital and 17 of these 92 died; the numbers for the placebo group were 5.2% and 11 out of 63.
The cardiovascular profile of rosiglitazone is also under scrutiny. In May of this year the manufacturer, GlaxoSmithKline, issued a robust defense of the drug when concerns were raised in a meta-analysis of 42 trials (S.E. Nissen, K. Wolski,
New Engl. J. Med. Epub, 21 May 2007). An accompanying statement from the U.S. Food and Drug Administration, carefully noting that rosiglitazone and pioglitazone are different drugs, said that the FDA "is evaluating whether they have the same or different heart-related risks."
Note: as this issue went to press, the agency was seeking the
strictest “black box” warning labels for both compounds.] An apparent increase in fractures in women taking these drugs has also to be resolved.
A former deputy editor of The Lancet, David W.
Sharp, M.A. (Cambridge),
is a freelance writer living in Minchinhampton, Gloucestershire, U.K.
Science
Watch®, July/August 2007, Vol. 18, No. 4
Citing URL:
http://www.sciencewatch.com/july-aug2007/sw_july-aug2007_page5.htm |
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