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STEOARTHRITIS (OA) IS THE most common joint disorder, accounting for significant disability and large health care expenditures. [1][2][3] Although nonsteroidal anti-inflammatory drugs (NSAIDs) have long been used to treat the pain and stiffness associated with OA, the American College of Rheumatology guidelines published in 1995, 4 and updated in 2000, 5 recommended acetaminophen as first-line therapy for the systemic treatment of symptomatic OA. This decision was partly due to concerns about gastrointestinal tract and other adverse effects associated with NSAIDs and also due to lack of data confirming their superior efficacy over simple analgesics. However, the severity of pain often prompts treatment with NSAIDs, which remain commonly used and preferred medicines by many patients with symptomatic OA. 1,6,7 The mechanism of action of NSAIDs involves inhibition of prostaglandin synthesis. In humans, prostaglandin synthesis is catalyzed by at least 2 forms of cyclooxygenase, cyclooxygenase 1 (COX-1) and cyclooxygenase 2 (COX-2). COX-1, constitutively expressed in a variety of tissues, is re-Author Affiliations, Financial Disclosures, and a list of Vioxx, Acetaminophen, Celecoxib Trial (VACT) Investigators appear at the end of this article.

Nicotinic acid (niacin) induces beneficial changes in serum lipoproteins and has been associated with beneficial cardiovascular effects. Niacin reduces low-density lipoprotein, increases high-density lipoprotein, and decreases triglycerides. It is well established that activation of the seven-transmembrane G(i)-coupled receptor GPR109A on Langerhans cells results in release of prostaglandin D₂, which mediates the well-known flushing side effect of niacin. Niacin activation of GPR109A on adipocytes also mediates the transient reduction of plasma free fatty acid (FFA) levels characteristic of niacin, which has been long hypothesized to be the mechanism underlying the changes in the serum lipid profile. We tested this "FFA hypothesis" and the hypothesis that niacin lipid efficacy is mediated via GPR109A by dosing mice lacking GPR109A with niacin and testing two novel, full GPR109A agonists, MK-1903 and SCH900271, in three human clinical trials. In mice, the absence of GPR109A had no effect on niacin's lipid efficacy despite complete abrogation of the anti-lipolytic effect. Both MK-1903 and SCH900271 lowered FFAs acutely in humans; however, neither had the expected effects on serum lipids. Chronic FFA suppression was not sustainable via GPR109A agonism with niacin, MK-1903, or SCH900271. We conclude that the GPR109A receptor does not mediate niacin's lipid efficacy, challenging the long-standing FFA hypothesis.

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