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Clinical Associate Professor of Pharmacy College of Pharmacy University of Michigan 1500 East Medical Center Drive, B2D 321 Ann Arbor, Michigan 48109-0008 fax 734/936-7027 shamo{at}med.umich.edu
Assistant Professor of Internal Medicine Division of Metabolism Endocrinology and Diabetes University of Michigan
Clinical Director and Albion Walter Hewlett Professor of Internal Medicine Division of Cardiology University of Michigan
Published Online, February 3, 2009. www.theannals.com, DOI 10.1345/aph.1K666b
First, none of the available oral hypoglycemic agents was "designed" to reduce cardiovascular disease (CVD), as stated in the letter. The drugs were designed to treat hyperglycemia and were subsequently approved by the Food and Drug Administration. Secondly, the authors cite 2 meta-analyses to support their statements and add, "Another meta-analysis by Richter et al. provides the best insights into the net harm from rosiglitazone." This statement, indicating an increased risk for MI with rosiglitazone, is misleading. In fact, the study cited could not confirm statistically significant differences in the odds ratios for rosiglitazone versus controls.
Meta-analyses have important limitations, as described elsewhere.1 In our paper we discuss several meta-analyses2 regarding CV safety and the risk of MI associated with rosiglitazone. The controversy and flaws engendered by various meta-analyses have been amply addressed in the literature and are beyond the scope of this letter. An interim analysis of the ongoing RECORD (Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes) trial, designed specifically to examine CVD outcomes of rosiglitazone, revealed no statistically significant effects on MI (hazard ratio 1.17 [95% CI 0.75 to 1.82]).3 Recently, 3 large prospective randomized trials comprising more than 20,000 patients with type 2 diabetes failed to show an increased CVD risk associated with rosiglitazone.4-6 The ongoing BARI 2D (Bypass Angioplasty Revascularization Investigation 2 Diabetes) study was undertaken, in part, to address whether the type of glucose-lowering treatment could affect CVD.7 One of the hypotheses of BARI 2D is that an "insulin-sensitizing" glycemic treatment strategy will have a more favorable effect on mortality and CVD end-points compared with an "insulin-providing" treatment strategy. The results will provide a more definitive answer regarding the role of TZDs in CVD outcomes.
The American Diabetes Association and the European Association for the Study of Diabetes specifically addressed safety issues surrounding TZDs. According to their consensus statement,8 "at this time, we do not view as definitive the clinical trial data regarding increased or decreased risk of MI with rosiglitazone or pioglitazone, respectively. Nor do we think that the increased risk of heart failure (HF) or fractures with either of the available TZDs is of a magnitude to warrant their removal as one of the possible second-step medications in our algorithm, given that they cause hypoglycemia less frequently than other second-step drugs."
We critically examined TZD adverse effects including weight gain, fluid retention with peripheral edema, and increased risk of HF.2 Although prospective randomized trials have failed to demonstrate beneficial effects of intensive glucose lowering on CVD,4-6 it is well established that glycemic levels close to normal reduce microvascular risk.5,9,10 Compared with sulfonylureas, TZDs have a more durable effect on maintaining glycemic control.11 Initiating intensive blood glucose control early after diagnosis has been associated with long-term benefit in preventing strong CVD endpoints of type 2 diabetes.12 Only prospectively designed trials to evaluate CVD benefits versus risks will resolve the controversy regarding TZD safety. Until then, the information provided should prompt clinicians to weigh the risk versus benefit ratio when selecting TZDs for clinical use in selected patients with type 2 diabetes.
Footnotes
Dr. Khanderia has received speakers' honoraria from Takeda Pharmaceuticals, Pfizer, and Merck, and research grants from Pfizer and Bristol Myers.
Dr. Pop-Busui received research grants from National Institutes of Health/National Institute of Neurological Disorders and Stroke, Juvenile Diabetes Research Foundational International, and American Diabetes Association, and speakers' honoraria from GlaxoSmithKline, Pfizer, and sanofi-aventis.
Dr. Eagle has received research grants from Biosite, Bristol Myers Squibb, Cardiac Sciences Blue Cross Blue Shield of Michigan, Hewlett Foundation, Mardigian Fund, Pfizer, sanofi-aventis, and Varbedian Fund, and is on the consultant/advisory boards of National Institutes of Health; National Heart, Blood, and Lung Institute; Pfizer; sanofi-aventis; and Robert Wood Johnson Foundation.
References
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