Niacin Lipid Efficacy Is Independent of Both the Niacin Receptor GPR109A and Free Fatty Acid Suppression
Science Translational Medicine • 22 Aug 2012 • Vol 4, Issue 148 • p. 148ra115 • DOI: 10.1126/scitranslmed.3003877
Breaking Free of the “FFA Hypothesis”
Free fatty acids (FFAs) appear in the blood plasma after a meal. Niacin—a vitamin that helps to regulate lipid levels in the body—is given to patients to reduce the amount of FFAs. It also works to raise “good” cholesterol [high-density lipoprotein (HDL)] and lower both “bad” cholesterol [low-density lipoprotein (LDL)] and triglycerides. The “FFA hypothesis” suggests that niacin works to exert these beneficial lipid effects by limiting the amount of FFAs available to synthesize triglycerides. Lauring, Taggart, and colleagues now challenge this long-standing theory. In studies in mice and humans, the authors debunk the hypothesis, showing that the effect on HDL, LDL, and triglycerides is not directly linked to FFAs.
To study the lipid-modifying effects of niacin (nicotinic acid), Lauring et al. used a genetic, humanized mouse model lacking the LDL receptor. In these animals, niacin increased HDL cholesterol levels, as expected. Lack of GPR109A in these animals blocked the anti-lipolytic effect of nicotinic acid on FFAs but had no effect on drug-related changes in plasma HDL and LDL cholesterol or triglyceride levels. Treatment of the mice with a GPR109A agonist, MK-1903, also caused an anti-lipolytic effect but did not affect levels of triglyceride or LDL and HDL cholesterol. Together, these in vivo preclinical studies suggest that niacin works to lower FFAs through GPR109A but has an independent mechanism of action on other lipids. The authors addressed the role of GPR109A in humans by testing the effects of MK-1903 and of another synthetic GPR109A agonist in clinical trials. Both agonists affected FFA lipolysis but had only minor effects on HDL cholesterol and triglyceride levels in patients, thus mirroring results seen in animals and showing that niacin works independently of GPR109A to modify dyslipidemia.
The studies by Lauring et al. point to a new, yet-uncovered mechanism of action for niacin’s beneficial effects on lipids in the blood. Despite overturning the FFA hypothesis and potentially redirecting drug development away from GPR109A agonists, niacin could still be useful for treating other diseases in patients, including atherosclerosis and inflammation, where GPR109A plays a major role in cell signaling.
Abstract
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 Gi-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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Supplementary Material
Summary
Materials and Methods
Fig. S1. Structure of SCH900271 and summary of preclinical pharmacology and pharmacokinetics.
Fig. S2. SCH900271 phase 2B study design.
Table S1. Baseline demographics in the MK-1903 phase 2A trial.
Table S2. Adverse events reported during the MK-1903 phase 2A trial.
Table S3. MK-1903 phase 2A safety summary.
Table S4. Change in plasma FFA levels over an 8-hour period after dose on day 1 versus day 28 of the MK-1903 phase 2A trial.
Table S5. Baseline demographics in the SCH900271 phase 1B trial.
Table S6. Pharmacokinetic parameters as measured after the final dose on day 28 of the SCH900271 phase 1B trial.
Table S7. Plasma FFA reduction over a 10-hour period after dose on day 28 of the SCH900271 phase 1B trial.
Table S8. Baseline demographics in the SCH900271 phase 2B trial.
Table S9. Change in mean plasma fasting blood glucose concentrations versus baseline in the SCH900271 phase 2B trial.
Table S10. Summary of adverse events for patients in the SCH900271 phase 2B trial.
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Information & Authors
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Published In
Science Translational Medicine
Volume 4 | Issue 148
August 2012
August 2012
Copyright
Copyright © 2012, American Association for the Advancement of Science.
Submission history
Received: 14 February 2012
Accepted: 29 June 2012
Acknowledgments
We thank C. McCrary Sisk and K. Newcomb (Merck Sharp & Dohme Corp.) for their assistance in the preparation of this manuscript. Funding: Merck & Co. Inc. R.D. is supported by K23HL091130 from the National Heart, Lung, and Blood Institute, and the substudy performed by R.D. was supported by UL1RR024134 from the National Center for Research Resources. Author contributions: B.L., A.K.P.T., J.R.T., R.D., J. Cote, J. Chin, S.K., A.A.M., J.F.P., L.B.P., W.S., T.-J.W., L.J., K.W., P.D.B., G.S., D.P.B., D.T.C., J.A.W., S.D.W., C.C., Y.B.M., D.J.R., M.G.W., and A.P. were involved in the planning and conduct of the studies, development of models, collection of data, and interpretation of results. A.B.P., W.-L.L., J.L., and X.L. supervised and/or conducted statistical analyses of data and interpretation of results. L.C., S.L.C., E.L., K.C., J. Cote, and J. Chin were involved in the collection of data and interpretation of results. All authors reviewed the manuscript and provided comments for revision. Competing interests: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Heart, Lung, and Blood Institute, the National Center for Research Resources, or the NIH. The authors have competing interests that might be perceived to influence the results and/or discussion reported in this article. B.L., A.K.P.T., J.R.T., L.C., K.C., J. Chin, S.L.C., J. Cote, S.K., J.L., W.-L.L., A.A.M., J.F.P., L.B.P., A.B.P., W.S., T.-J.W., X.L., L.J., K.W., E.L., J.A.W., S.D.W., C.C., Y.B.M., M.G.W., and A.P. are current or former employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co. Inc., and may own stock or stock options in the company. R.D. reports receiving consulting fees from Merck & Co. Inc., Abbott Laboratories, and D.S., and payment for lectures, including speaker bureaus, from Merck & Co. Inc. and Abbott Laboratories. G.S., D.P.B., and D.T.C. own stocks or stock options in Arena Pharmaceuticals. D.J.R. reports receiving consulting fees from Merck & Co. Inc. and previously from Schering-Plough. Merck holds the following patents related to the compounds discussed in this manuscript: WO 06069242, WO 05044816, U.S. 7612106, and WO 2006/124490. Data and materials availability: Adverse event data are on file with authors.
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