Niacin Alternatives for Dyslipidemia: Fool’s Gold or Gold Mine? Part II: Novel Niacin Mimetics

Abstract

Two cardiovascular outcome trials established niacin 3 g daily prevents hard cardiac events. However, as detailed in part I of this series, an extended-release (ER) alternative at only 2 g nightly demonstrated no comparable benefits in two outcome trials, implying the alternative is not equivalent to the established cardioprotective regimen. Since statins leave a significant treatment gap, this presents a major opportunity for developers. Importantly, the established regimen is cardioprotective, so the pathway is likely beneficial. Moreover, though effective, the established cardioprotective regimen is cumbersome, limiting clinical use. At the same time, the ER alternative has been thoroughly discredited as a viable substitute for the established cardioprotective regimen. Therefore, by exploiting the pathway and skillfully avoiding the problems with the established cardioprotective regimen and the ER alternative, developers could validate cardioprotective variations facing little meaningful competition from their predecessors. Thus, shrewd developers could effectively tap into a gold mine at the grave of the ER alternative. The GPR109A receptor was discovered a decade ago, leading to a large body of evidence commending the niacin pathway to a lower cardiovascular risk beyond statins. While mediating niacin’s most prominent adverse effects, GPR109A also seems to mediate anti-lipolytic, anti-inflammatory, and anti-atherogenic effects of niacin. Several developers are investing heavily in novel strategies to exploit niacin’s therapeutic pathways. These include selective GPR109A receptor agonists, niacin prodrugs, and a niacin metabolite, with encouraging early phase human data. In part II of this review, we summarize the accumulated results of these early phase studies of emerging niacin mimetics.

Natural approaches in metabolic syndrome management

“…High-dose niacin (vitamin B 3 ) is used in the treatment of hyperlipidemia [ 78 ]. Randomized, double-blind, placebo-controlled investigations showed that sustained-released niacin decreases LDL-C, TC, and TG and raises HDL-C [ 79 – 81 ].…”

CAT‐2003: A novel sterol regulatory element‐binding protein inhibitor that reduces steatohepatitis, plasma lipids, and atherosclerosis in apolipoprotein E*3‐Leiden mice

“…It also causes subcutaneous skin flushing, and the degree to which these activities are separable is controversial. Flushing is the result of extracellular niacin binding to G‐protein coupled receptor 109A (GPR109A) on islet of Langerhans cells, whereas niacin binding to GPR109A in adipose tissue inhibits lipolysis and blocks the release of free fatty acids. This deprives the liver of substrate for the generation of triglycerides and is thought to be a major contributor to niacin's effects on lipid lowering.…”

Hippuric acid and 3‐(3‐hydroxyphenyl) propionic acid inhibit murine osteoclastogenesis through RANKL‐RANK independent pathway

“…HA and 3‐3‐PPA are known structurally similar to nicotinic acid or niacin (vitamin B3), and nicotinic acid is reported to bind to GPR109A (Goel & Dunbar, ). GPR109A is abundantly expressed in macrophages and in mature osteoclast (Feingold, Moser, Shigenaga, & Grunfeld, ; GPR109A BioGPS).…”