Nicotinic acid remains the most effective therapeutic agent for the treatment and prevention of atherosclerosis resulting from low HDL-cholesterol. Nicotinic acid’s therapeutic actions are mediated by GPR109A, a Gi-protein coupled receptor, expressed primarily on adipocytes, Langerhans cells and macrophage. Unfortunately, a severe, cutaneous flushing side-effect limits its use and patient compliance. The mechanism of HDL elevation is not clearly established but assumed to be influenced by an inhibition of lipolysis in the adipose. The flushing side-effect appears to be mediated by the release of prostaglandin D2 (PGD2) from Langerhans cells in the skin. We hypothesized that the signal transduction pathways mediating the anti-lipolytic and PGD2/flushing pathways are distinct, and that agonists may be identified that are capable of selectively eliciting the therapeutic, anti-lipolytic pathway while avoiding the activation of the parallel flush-inducing pathway. We have identified a number of GPR109A pyrazole agonists that are capable of fully inhibiting lipolysis in vitro and in vivo and not only fail to elicit a flushing response, but can antagonize nicotinic acid’s ability to elicit a flush response in vivo. In contrast to flushing agonists, exposure of cells expressing GPR109A to the non-flushing agonists fails to induce internalization of the receptor or to activate Erk 1/2 MAP kinase phosphorylation.