Curr Atheroscler Rep (2016) 18: 17 DOI 10.1007/s11883-016-0570-9 NONSTATIN DRUGS (E. DEGOMA, SECTION EDITOR) Niacin Alternatives for Dyslipidemia: Fool’s Gold or Gold Mine? Part II: Novel Niacin Mimetics Harsh Goel1 & Richard L. Dunbar2,3,4,5,6 Published online: 1 March 2016 # The Author(s) 2016. This article is published with open access at Springerlink.com Abstract Two cardiovascular outcome trials established ni- predecessors. Thus, shrewd developers could effectively acin 3 g daily prevents hard cardiac events. However, as tap into a gold mine at the grave of the ER alternative. The detailed in part I of this series, an extended-release (ER) GPR109A receptor was discovered a decade ago, leading to alternative at only 2 g nightly demonstrated no comparable a large body of evidence commending the niacin pathway to benefits in two outcome trials, implying the alternative is a lower cardiovascular risk beyond statins. While mediating not equivalent to the established cardioprotective regimen. niacin’s most prominent adverse effects, GPR109A also Since statins leave a significant treatment gap, this presents seems to mediate anti-lipolytic, anti-inflammatory, and a major opportunity for developers. Importantly, the anti-atherogenic effects of niacin. Several developers are established regimen is cardioprotective, so the pathway is investing heavily in novel strategies to exploit niacin’sther- likely beneficial. Moreover, though effective, the apeutic pathways. These include selective GPR109A recep- established cardioprotective regimen is cumbersome, limit- tor agonists, niacin prodrugs, and a niacin metabolite, with ing clinical use. At the same time, the ER alternative has encouraging early phase human data. In part II of this re- been thoroughly discredited as a viable substitute for the view, we summarize the accumulated results of these early established cardioprotective regimen. Therefore, by phase studies of emerging niacin mimetics. exploiting the pathway and skillfully avoiding the problems with the established cardioprotective regimen and the ER alternative, developers could validate cardioprotective var- Keywords Niacin . Nicotinic acid . GPR109A agonists . iations facing little meaningful competition from their Hyperlipidemia . Niacin conjugates . Niacin prodrugs . Lipids This article is part of the Topical Collection on Nonstatin Drugs Harsh Goel and Richard L. Dunbar contributed equally to this work. * Richard L. Dunbar 3 Division of Translational Medicine and Human Genetics, Perelman [email protected] School of Medicine at the University of Pennsylvania, 3600 Spruce Street, 9-010 Maloney Building, Philadelphia, PA 19104, USA Harsh Goel [email protected] 4 Institute for Translational Medicine and Therapeutics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA 1 Department of Medicine, York Hospital, 1001 S. George Street, 5 York, PA 17403, USA The Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA 2 Department of Medicine, Division of Cardiovascular Medicine, Perelman School of Medicine at the University of Pennsylvania, 6 Institute for Diabetes, Obesity, and Metabolism, Perelman School of Philadelphia, PA, USA Medicine at the University of Pennsylvania, Philadelphia, PA, USA 17 Page 2 of 13 Curr Atheroscler Rep (2016) 18: 17 Introduction first outcomes study to prove the then-controversial cholester- ol hypothesis, which predicted suppressing cholesterol would Dosed 1 g thrice daily with meals, niacin prevents Bhard^ prevent hard CHD events. Thus, the CDP findings laid the coronary heart disease (CHD) events: non-fatal myocardial groundwork for subsequent efforts to suppress cholesterol, infarction and CHD death [1, 2]. An extended-release (ER) including the development of new agents such as the statins. alternative attempted to improve tolerability by cutting the Newer trials of an ER alternative of a profoundly lower dose to only 2 g and dosing during the overnight fast. dose were markedly less effective for cholesterol, predictably Unfortunately, the alternative regimen thus far failed to pre- having little impact on events [3••, 4]. Their failure reaffirms vent CHD events, hard or otherwise [3••, 4]. The failed alter- the concept that for niacin to improve outcomes, it has to native highlights the pitfalls inherent to presuming the thera- suppress cholesterol significantly. Accordingly, on evaluating peutic equivalence of radically different regimens of the same all four trials, CHD benefit was a function of cholesterol sup- drug. We contrasted the established cardioprotective regimen pression [5]. Though niacin might also benefit CHD by raising with the failed alternative at length in part I of this review [5]. HDL-C, unfortunately, a trial intending to test this was riven Regrettably, statin therapy leaves several gaps in at risk pop- by methodological problems precluding a conclusive answer ulations, including (1) significant toxicity and intolerance, es- to this question [4, 5]. Therefore, we think the strongest evi- pecially at higher doses [6, 7], and more importantly, (2) var- dence for niacin’s cardioprotective properties argues for cho- iability in response with about 40 % patients not achieving lesterol suppression, and more specifically, suppressing the lipid goals with monotherapy [8], and lastly, (3) residual risk atherogenic lipoproteins (e.g., LDL-C and non-HDL-C). in the non-averse responders. Therefore, vigorous ongoing This concept is also supported by a host of smaller studies attempts are underway to augment statin therapy for under- that have found niacin atheroprotective, in that niacin may halt responders and develop alternatives for the statin-averse. or even reverse atherosclerosis progression by quantitative Accordingly, there are over 50 novel candidates in develop- imaging techniques [13–18]. Importantly, many of these ment, targeting over 20 molecular pathways of lipoprotein employed much higher niacin doses (≥3 g daily). metabolism [9•], of which several exploit the same pathways Atherosclerosis studies also affirmed a major role for sup- as one of the oldest lipid-lowering therapies, niacin. pressing the atherogenic lipoproteins and a possible role for Niacin’s cellular mechanism of action remained elusive augmenting HDL-C. In summary, the overall evidence con- until the discovery of the niacin receptor, GPR109A sistently points to atheroprotection and ultimately [10–12]. In the decade, hence a growing body of evidence cardioprotection from niacin’s ability to alter lipoproteins fa- suggested the receptor has anti-inflammatory, anti-lipolytic, vorably. This naturally raises the question, how does niacin and anti-atherogenic properties, presenting an attractive target alter lipoproteins? Still poorly understood, there has been for drug development. Beyond receptor modulators, other much work over the last decade, including the breakthrough strategies include niacin prodrugs aimed at tissue-specific discovery of a niacin receptor, GPR109A. We will discuss this drug delivery and a niacin metabolite. We present early phase pathway and others that can explain niacin’s lipid-altering human data of several of these novel agents in this, part II of effects. However, we cannot be certain which if any actually our review. mediate niacin’s atheroprotective and especially cardioprotective effects. Why is Niacin Cardioprotective? As discussed in part I, two studies proved niacin prevents hard GPR109A and the Free Fatty Acid Hypothesis CHD events: the Coronary Drug Project (CDP) and the Stockholm Ischemic Heart Disease Study (SIHDS) [1, 2]. The cardinal lipid effect of niacin is an acute, marked drop in Major common features include dosing 1 g thrice daily with plasma free fatty acids (FFAs), by suppressing adipose-tissue meals, totaling 3 grams spread throughout the postprandial lipolysis [19, 20]. This deprives the liver of a crucial lipogenic portion of the day, and avoiding exposure during the overnight substrate, retarding hepatic TG assembly and release. Hence, fast. This regimen led to significant reductions in hard CHD the FFA hypothesis emerged that niacin retards TG production events, thus establishing the classic cardioprotective niacin by limiting hepatic FFA availability. Supporting this, at the regimen. Major contrasting features include free niacin release turn of the century, three separate labs identified the niacin rates (immediate release in CDP vs. delayed release from a receptor, GPR109A [10–12]. GPR109A is a Gi receptor niacin prodrug in SIHDS) and combination with a fibrate in expressed most abundantly in adipocytes, with knockout mice SIHDS, whereas the same fibrate had failed to affect hard failing to lower plasma FFA and TG with niacin, hinting at a CHD events in the CDP. The obvious reason these trials were central role of the receptor in effecting lipid response, and the cardioprotective is that both regimens suppressed cholesterol, intense FFA suppression driving such response [11]. affirming the cholesterol hypothesis. In fact, the CDP was the Supporting this was the lipid efficacy of closely-related Curr Atheroscler Rep (2016) 18: 17 Page 3 of 13 17 aromatic carboxylic acids acipimox and acifran [21, 22]and atherogenic lipoproteins, chiefly LDL-C. Thus, the mech- the observation that they are also GPR109A agonists [12]. anism of LDL suppression likely mediates CHD benefits. Per the FFA hypothesis, niacin binds to adipocyte Niacin largely lowers