To the Editor: Dr Lipscombe and colleagues1 conducted a retrospective study to explore the association between cardiovascular events and thiazolidinediones (TZDs) compared with other oral hypoglycemic agents. However, their study did not report on concomitant use of aspirin among patients on TZDs and oral hypoglycemics. There was no adjustment for aspirin use and dose of aspirin. Therefore, an apparent increase in the risk of adverse cardiovascular events from TZDs may have been observed because concomitant exposure to a confounder that is protective for the adverse outcome (aspirin and cardiovascular events) was not accounted for. This is particularly important since the PROactive Study, which indicated that pioglitazone reduced the composite of all-cause mortality, nonfatal myocardial infarction, and stroke in patients with type 2 diabetes mellitus, did report a similar frequency of aspirin use among patients treated with pioglitazone and placebo (75% vs 72%, respectively).2
Aspirin use may also be relevant to the effects of TZD therapy on cardiovascular events because peroxisome proliferator-activated receptor–γ agonists (like TZDs) down-regulate cyclooxygenase 2 (COX-2) while COX-1 remains unaffected.3 Accordingly, TZDs, like selective COX-2 inhibitors (which are also associated with adverse cardiovascular effects4 ), may increase the risk of adverse cardiovascular events via selective COX-2 down-regulation.5 Selective COX-2 inhibition suppresses production of prostacyclin (prostaglandin I2) from the endothelium while COX-1–derived thromboxane-A2 production from the platelets remains unaffected. This causes an exaggerated thrombotic response (increased ratio of thromboxane A2 to prostaglandin I2) to thrombotic stimuli, predisposing patients to adverse cardiovascular outcomes.5 However, if patients who are taking TZDs are also taking aspirin (a COX-1 and COX-2 inhibitor), then there would be no selective down-regulation of COX-2 since concomitant aspirin also inhibits COX-1. Therefore, the adverse effects of TZD therapy on cardiovascular end points may be restricted only to patients who are not taking concomitant aspirin.
Studies exploring the association between TZDs and cardiovascular events should balance use of aspirin between patients taking TZDs, other hypoglycemics, or placebo and should investigate whether the adverse effects of TZDs on cardiovascular end points are observed in patients both taking and not taking aspirin.
Financial Disclosures: None reported.
Country-Specific Mortality and Growth Failure in Infancy and Yound Children and Association With Material Stature
Use interactive graphics and maps to view and sort country-specific infant and early dhildhood mortality and growth failure data and their association with maternal
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