Niacin Alternatives for Dyslipidemia: Fool’s Gold or Gold Mine? Part II: Novel Niacin Mimetics
Curr Atheroscler Rep
Niacin Alternatives for Dyslipidemia: Fool's Gold or Gold Mine? Part II: Novel Niacin Mimetics
Harsh Goel 0 1 2 3 4 5
Richard L. Dunbar 0 1 2 3 4 5
0 Department of Medicine, Division of Cardiovascular Medicine, Perelman School of Medicine at the University of Pennsylvania , Philadelphia, PA , USA
1 Department of Medicine, York Hospital , 1001 S. George Street, York, PA 17403 , USA
2 Richard L. Dunbar
3 Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania , Philadelphia, PA , USA
4 The Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania , Philadelphia, PA , USA
5 Institute for Translational Medicine and Therapeutics, Perelman School of Medicine at the University of Pennsylvania , Philadelphia, PA , USA
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 l i k e l y b e n e f i c i a l . M o r e o v e r, t h o u g h e ff e c t i v e , t h e 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.
Niacin; Nicotinic acid; GPR109A agonists; Hyperlipidemia; Niacin conjugates; Niacin prodrugs; Lipids
Division of Translational Medicine and Human Genetics, Perelman
School of Medicine at the University of Pennsylvania, 3600 Spruce
Street, 9-010 Maloney Building, Philadelphia, PA 19104, USA
Dosed 1 g thrice daily with meals, niacin prevents Bhard^
coronary heart disease (CHD) events: non-fatal myocardial
infarction and CHD death [
]. An extended-release (ER)
alternative attempted to improve tolerability by cutting the
dose to only 2 g and dosing during the overnight fast.
Unfortunately, the alternative regimen thus far failed to
prevent CHD events, hard or otherwise [
3 , 4
]. The failed
alternative highlights the pitfalls inherent to presuming the
therapeutic equivalence of radically different regimens of the same
drug. We contrasted the established cardioprotective regimen
with the failed alternative at length in part I of this review [
Regrettably, statin therapy leaves several gaps in at risk
populations, including (1) significant toxicity and intolerance,
especially at higher doses [
], and more importantly, (2)
variability in response with about 40 % patients not achieving
lipid goals with monotherapy [
], and lastly, (3) residual risk
in the non-averse responders. Therefore, vigorous ongoing
attempts are underway to augment statin therapy for
underresponders and develop alternatives for the statin-averse.
Accordingly, there are over 50 novel candidates in
development, targeting over 20 molecular pathways of lipoprotein
], of which several exploit the same pathways
as one of the oldest lipid-lowering therapies, niacin.
Niacin’s cellular mechanism of action remained elusive
until the discovery of the niacin receptor, GPR109A
]. In the decade, hence a growing body of evidence
suggested the receptor has anti-inflammatory, anti-lipolytic,
and anti-atherogenic properties, presenting an attractive target
for drug development. Beyond receptor modulators, other
strategies include niacin prodrugs aimed at tissue-specific
drug delivery and a niacin metabolite. We present early phase
human data of several of these novel agents in this, part II of
Why is Niacin Cardioprotective?
As discussed in part I, two studies proved niacin prevents hard
CHD events: the Coronary Drug Project (CDP) and the
Stockholm Ischemic Heart Disease Study (SIHDS) [
Major common features include dosing 1 g thrice daily with
meals, totaling 3 grams spread throughout the postprandial
portion of the day, and avoiding exposure during the overnight
fast. This regimen led to significant reductions in hard CHD
events, thus establishing the classic cardioprotective niacin
regimen. Major contrasting features include free niacin release
rates (immediate release in CDP vs. delayed release from a
niacin prodrug in SIHDS) and combination with a fibrate in
SIHDS, whereas the same fibrate had failed to affect hard
CHD events in the CDP. The obvious reason these trials were
cardioprotective is that both regimens suppressed cholesterol,
affirming the cholesterol hypothesis. In fact, the CDP was the
first outcomes study to prove the then-controversial
cholesterol hypothesis, which predicted suppressing cholesterol would
prevent hard CHD events. Thus, the CDP findings laid the
groundwork for subsequent efforts to suppress cholesterol,
including the development of new agents such as the statins.
Newer trials of an ER alternative of a profoundly lower
dose were markedly less effective for cholesterol, predictably
having little impact on events [
3 , 4
]. Their failure reaffirms
the concept that for niacin to improve outcomes, it has to
suppress cholesterol significantly. Accordingly, on evaluating
all four trials, CHD benefit was a function of cholesterol
suppression . Though niacin might also benefit CHD by raising
HDL-C, unfortunately, a trial intending to test this was riven
by methodological problems precluding a conclusive answer
to this question [
]. Therefore, we think the strongest
evidence for niacin’s cardioprotective properties argues for
cholesterol suppression, and more specifically, suppressing the
atherogenic lipoproteins (e.g., LDL-C and non-HDL-C).
This concept is also supported by a host of smaller studies
that have found niacin atheroprotective, in that niacin may halt
or even reverse atherosclerosis progression by quantitative
imaging techniques [
]. Importantly, many of these
em plo yed mu ch hig her nia cin do ses (≥ 3 g d a i l y ) .
Atherosclerosis studies also affirmed a major role for
suppressing the atherogenic lipoproteins and a possible role for
augmenting HDL-C. In summary, the overall evidence
consi stentl y poi nts to atheroprotect ion and ultimately
cardioprotection from niacin’s ability to alter lipoproteins
favorably. This naturally raises the question, how does niacin
alter lipoproteins? Still poorly understood, there has been
much work over the last decade, including the breakthrough
discovery of a niacin receptor, GPR109A. We will discuss this
pathway and others that can explain niacin’s lipid-altering
effects. However, we cannot be certain which if any actually
m e d i a t e n i a c i n ’s a t h e r o p r o t e c t i v e a n d e s p e c i a l l y
GPR109A and the Free Fatty Acid Hypothesis
The cardinal lipid effect of niacin is an acute, marked drop in
plasma free fatty acids (FFAs), by suppressing adipose-tissue
]. This deprives the liver of a crucial lipogenic
substrate, retarding hepatic TG assembly and release. Hence,
the FFA hypothesis emerged that niacin retards TG production
by limiting hepatic FFA availability. Supporting this, at the
turn of the century, three separate labs identified the niacin
receptor, GPR109A [
]. GPR109A is a Gi receptor
expressed most abundantly in adipocytes, with knockout mice
failing to lower plasma FFA and TG with niacin, hinting at a
central role of the receptor in effecting lipid response, and the
intense FFA suppression driving such response .
Supporting this was the lipid efficacy of closely-related
aromatic carboxylic acids acipimox and acifran [
the observation that they are also GPR109A agonists .
Per the FFA hypothesis, niacin binds to adipocyte
membrane-bound GPR109A, thereby inhibiting adenylyl
cyclase, lowering intracellular cAMP concentrations, and
subsequently reducing protein kinase A-mediated activation of
hormone-sensitive lipase (HSL). This ultimately suppresses
adipose TG mobilization and FFA output, thereby suppressing
portal vein FFA levels. This deprives the liver of an essential
substrate for TG synthesis and secretion as very low density
lipoprotein (VLDL) which, in turn, is a precursor for LDL-C
]. Thus, the FFA hypothesis predicts niacin’s anti-lipolytic
properties suppress VLDL and perhaps its atherogenic
progeny, including LDL.
Supporting the FFA hypothesis, GPR109A-knockout mice
failed to lower FFA and TGs with niacin [
]. Second, we and
others found acute FFA suppression from niacin strongly
predicted postprandial TG suppression [
]. Third, two
synthetic niacin analogues, acipimox and acifran, are GPR109A
] and, together with niacin, constitute the three
Blegacy^ GPR109A agonists. All suppress lipolysis and have
similar TG-lowering potential [
22, 27, 28
]. Regardless of the
exact cellular mechanism, the proven clinical efficacy of three
legacy GPR109A agonists implies the receptor mediates lipid
benefits, at least in part.
To clarify the FFA hypothesis, Wang et al. studied
VLDL/TG kinetics on niacin 2 g/day, using labeled palmitate
and glycerol [
]. Glycerol incorporation into VLDL-TG
dropped in the fasting state despite a non-significantly
elevated fasting FFA after only 4 weeks. After acute-on-chronic
niacin exposure, this almost completely halted during
niacininduced FFA suppression, implying GPR109A agonism
suppressed TG acutely by FFA substrate limitation.
Counter-intuitively, TG suppression persisted despite subsequent FFA
rebound. Thus, hepatic FFA limitation per se seems
responsible for initiating but not perpetuating TG suppression.
Alternatively, the initial profound FFA suppression may have
actions beyond mere hepatic substrate deprivation, inducing
regulatory changes in hepatic lipogenesis, such as inhibition
of PPARγ-coactivator-1β (PGC-1β) and enhanced apoB
degradation as a result of reduced TG synthesis [
factors could cause a lag effect whereby hepatic VLDL
synthesis remains suppressed despite increased FFA in the
systemic venous circulation. Separately, niacin has been shown to
directly inhibit hepatocyte Acyl CoA: diacylglycerol
acyltransferase 2 (DGAT2)-a key enzyme catalyzing the terminal
step in hepatic TG synthesis [
]. Thus, the FFA hypothesis is
probably not exclusive.
Mechanism of LDL-Cholesterol Lowering by Niacin
Clinical trials strongly suggest niacin is atheroprotective
and cardioprotective to the extent it suppresses the
atherogenic lipoproteins, chiefly LDL-C. Thus, the
mechanism of LDL suppression likely mediates CHD benefits.
Niacin largely lowers LDL-C by suppressing LDL
production. First, in accord with the FFA hypothesis, the
VLDL kinetic study by Wang showed niacin halts
VLDL synthesis, in turn suppressing LDL production by
substrate limitation [
]. Second, another apolipoprotein
kinetic study affirmed niacin retards apoB-100 production
rates, thus limiting LDL production [
]. Third, niacin
may directly inhibit DGAT2, which ultimately would also
retard LDL production [
]. In contrast, an apolipoprotein
kinetic study in hyperlipidemics found the ER alternative
lowered apoB-100 and apo-B48 by hastening clearance
rather than retarding production, hinting at increased
LDL uptake as a contributor to niacin-mediated
]. Along those lines, niacin was recently found to
inhibit proprotein convertase subtilisin-like/kexin-type 9
(PCSK9), a protease which accelerates hepatic
LDLreceptor degradation and increases LDL-cholesterol .
Hence, niacin could very well suppress LDL-C by PCSK9
inhibition. In summary, there is support for niacin
suppressing LDL-C by both retarding LDL production and
Mechanism of HDL Cholesterol-Raising Effects of Niacin
The mechanism whereby niacin raises HDL is complex,
perhaps involving the liver, adipocyte, and macrophage;
thus, the FFA hypothesis is somewhat tangential to HDL.
Whereas FFA suppression is clearly mediated via the
GicAMP pathway, HDL biogenesis and hepatic uptake may
involve transcriptional regulation of key enzymes/
transport proteins via distinct post-receptor pathways.
Candidate pathways include the
LXR-RXR-ABCA-1mediated reverse cholesterol transport ,
LXRα-DR4ABCA1-mediated hepatic HDL biogenesis , and
reduced hepatic HDL uptake . Intriguingly, SNPs in
GPR109A have been associated with variability in
HDLC but not TG and LDL-C [39, 40], implying distinct
pathways modulate HDL-C versus other lipids by the
rec ep t o r. P e r h ap s m o r e i m p or t a nt t ha n to t a l H D L
cholesterol is the concept of HDL Bfunctionality^, for
example, the ability of different HDL fractions to mediate
reverse cholesterol transport between peripheral tissues
and the liver and exert anti-inflammatory, anti-oxidative,
and vasodilatory effects . Though niacin increases
total HDL, and specifically the more atheroprotective HDL2
fraction , it does not seem to enhance the HDL
functionality in terms of reverse cholesterol transport and
antiinflammatory effects [43–45]. Whether this could explain
AIM-HIGH’s null result and whether enhanced HDL
functionality would translate into benefit on clinical
outcomes remains to be tested.
Mechanism of Niacin-Associated Skin Toxicity
Besides adipocytes, GPR109A is abundantly expressed on
immune cells including macrophages, monocytes,
neutrophils, dendritic cells, and epidermal Langerhans cells .
Frustratingly, while mediating the beneficial effects,
GPR109A also stimulates these, most notably in dermal
immune cells. Activating epidermal cell membrane-bound
receptors induces vasodilatory eicosanoids, specifically
prostaglandin D2 (PGD2) from Langerhans cells and E2 (PGE2)
from keratinocytes, prompting rubor [47, 48]. Though rubor
(aka Bflushing^) is the most visible result, this is accompanied
by a host of much more irritating symptoms, including dermal
calor, dolor, tumor, and pruritus, collectively
NiacinAssociated Skin Toxicity (NASTy). These effects limit
niacin’s tolerability, thus motivating better-tolerated alternatives.
What Properties Should the Optimal Niacin Mimetic
In part I of this review, we discussed major ways the failed ER
alternative departed from the established cardioprotective
]. These present a sort of road map for developers, and
we intuitively submit they would do well to hew closely to the
established cardioprotective regimen and avoid the detours of
the failed ER alternative. That said the ultimate test of efficacy
would have to come from outcomes studies. The optimal
mimetic should reduce NASTy symptoms enough to allow
dosing emulating the established cardioprotective regimen, to wit
(a) diurnal dosing to ensure postprandial activity and (b)
dosing whose non-HDL- and ideally HDL-altering effects
match or exceed the minimal established cardioprotective
niacin dose. Clinical trials consistently show suppressing
atherogenic lipoproteins are strongly associated with niacin’s
cardiovascular benefits [
]; accordingly, non-HDL-C and LDL-C
suppression should guide dose-finding and efficacy
assessments for mimetics [
]. That said, atherosclerosis studies
suggest a role for raising HDL-C. Frustratingly, the problematic
AIM-HIGH study failed to convincingly rule in or rule out
CHD benefits from raising HDL-C. Thus, new mimetics
would do well to replicate niacin’s HDL effects until the
HDL hypothesis undergoes a decisive test. Encouragingly,
major efforts to overcome the apparent flaws of the
exploratory regimen are underway using high-potency niacin mimetics.
We divide these as (1) niacin prodrugs and (2) niacin
mimetics: (a) niacin metabolites, (b) novel GPR109A agonists,
and (c) other mimetics. Encouragingly, there is emerging
proof-of-principle evidence supporting each approach, in
terms of both lipid effects and in some cases, diminished
There are several important limitations to consider. First,
novel mimetics are in early development, most only recently
reporting human results; often information is scant and not
peer-reviewed. Moreover, results may not be reported
completely (e.g., lacking mean and variability), at times
necessitating graph decomposition software to extract numeric
results from published graphs or calculate confidence intervals
or p values ourselves to fill in gaps and standardize reporting.
Second, early-phase studies are usually small and seldom
adequate to assess efficacy; worse, they may not even enroll
dyslipidemics, and for all these reasons lipid-altering results
may not be apparent. Third, perhaps most limiting, many
studies involve ultra-short exposure of only a few weeks.
Importantly, niacin itself takes several months to fully
manifest lipid effects [49–51]. Fourth, and somewhat bafflingly
given the previous limitations, few studies included niacin
itself as positive control, obfuscating comparison to reference
therapy. Despite these caveats, several new agents have
already developed proof-in-principle for lipid improvement
Several niacin-based prodrugs are already in use, often as
simple sugars bound to one or more niacin molecules,
including nicotinyl alcohol, tetranicotinoyl fructose, pentaerythrityl
tetranicotinate, sorbitol hexanicotinate, and inositol
hexanicotinate. Interestingly, pentaerythrityl tetranicotinate,
given to a largely hypertriglyceridemic population at a dose
of 1 g thrice daily for 5 years, reduced total mortality by 26 %
and ischemic heart disease mortality by 36 % combined with a
], according with a prior trial where niacin
monotherapy was also protective, but the fibrate was not [
niacin from the parent molecule takes enough time to delay
free nicotinic acid appearance, thus mitigating NASTy
symptoms. Accordingly, novel prodrugs are less prone to NASTy
effects, despite lipid effects suggesting equal or greater niacin
exposure at cellular levels.
CAT-2003, a Niacin-Fish Oil Prodrug (Niacin-Eicosapentaenoic Acid Conjugate)
C a t a b a s i s P h a r m a c e u t i c a l s d e v e l o p e d a n i a c i n
eicosapentaenoic acid (EPA) conjugate, CAT-2003.
Fascinatingly, the conjugate purportedly bypasses the
membrane-bound GPR109A and directly inhibits sterol
regulatory element-binding proteins (SREBPs), key transcription
factors inducing expression of crucial genes involved in
hepatic lipogenesis and lipid uptake . Bypassing GPR109A
could improve tolerability. In a phase I clinical trial of healthy
volunteers, CAT-2003 suppressed postprandial TGs 90 % and
fasting TGs 30 % (p < 0.001) after only 14 days, without
evidence of NASTy effects . Intriguingly, TG suppression
was unaccompanied by FFA changes, suggesting
nonengagement of GPR109A. Dose-dependent increases in
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parent molecule. Interestingly, CAT-2003 reduced sterol
regulatory element-binding protein (SREBP) in HepG2 cells 50 %
and decreased expression of several SREBP target genes ,
presenting mechanistic possibilities for
non-GPR109Amediated niacin benefits. Administered to ApoE*3 mice for
16 weeks, CAT-2003 dropped total cholesterol 41 %
(p < 0.0001) and TGs 33 % (p = 0.0034).
Several phase II studies yielded encouraging results among
dyslipidemics [55 ]. In a randomized, double-blind,
placebocontrolled phase II trial of 72 hypertriglyceridemics (TG 200–
500 mg/dL) and 27 statin-treated hypercholesterolemics
(LDL-C = 100–190 mg/dL and TG = <200 mg/dL),
CAT2003 was dosed at 300, 500, or 300 mg BID for 28 days.
Fasting TG dropped 16 % in the 500 mg/day group.
Notably, TG suppression was a much more robust 27 %
pooled across all doses and 44 % with 500 mg/day in those
with baseline TG >350 mg/dL. Among 27 statin-treated
subjects taking CAT-2003 500 mg/day, LDL-C declined a further
11 % (p < 0.01 vs. baseline, p = 0.03 vs. placebo). In a further
investigation of CAT-2003 500 mg/day for 4 weeks, among 14
severe hypertriglyceridemics (fasting TG >500 mg/dL),
fasting TG dropped from a median of 658 mg/dL after a
2 week placebo run-in to 467 mg/dL (p < 0.02 vs. baseline).
Notably, in four of the subjects who were on concomitant
fibrate or statin therapy TG declined from a median of 760
to 452 mg/dL. TG suppression after such brief exposure is
very encouraging. Figure 1 shows TG changes for
CAT2003 and several other niacin mimetics.
CAT-2054, the Next Generation Niacin-Eicosapentaenoic
CAT-2054, another niacin-fish-oil prodrug, is also being
developed by Catabasis pharmaceuticals as an SREBP
modulator, differing from CAT-2003 by the linker molecule [56 ].
The linker in CAT-2054 is cleaved significantly slower than
that in CAT-2003, thus enabling greater hepatic delivery.
In vitro studies in hepatocytes showed a significant decline
in levels of SREBP and several of its target proteins, including
PCSK9 and enzymes of the cholesterol synthesis pathway,
HMG-CoA reductase, ATP citrate lyase, mevalonate
decarboxylase, and squalene epoxidase. CAT-2054 also seemed to
dose-dependently induce hepatocyte surface LDL-receptor
-60% -50% -40% -30% -20% -10% 0% +10% +20%
Percent Change in TG (%)(Mean, 95%CI)
Fig. 1 Top section—triglyceride (TG) reductions are presented for
studies involving months of therapy. For reference, legacy agonists are
presented, including ER niacin, acipimox, IR niacin, and
sustainedrelease niacin [
]. The novel agonist GSK256073 had a mean
reduction in TG considerably better than what would be expected from
ER niacin (shaded area), but with wide confidence intervals. Bottom
section—TG reductions from ultra-short exposures to novel mimetics
are shown, with reference to ER niacin (shaded area) which was
included in one of the studies [
]. Much less is expected of such
fleeting exposures, since niacin itself requires months of therapy for
efficacy to fully develop. Nevertheless, most of the novel agents are
comparable to niacin in early-stage clinical studies. Since they have not
reported baseline TGs, the question marks for ARI-3037 percent drops for
hypothetical baseline TGs. Mean TGs are 107 mg/dL for healthy
American adults [
]. If this were the baseline TG for this dose group,
the 57 mg/dL drop would be a 53 % reduction. Similarly, if the baseline
was 150 mg/dL, it would be a 38 % drop, and at 200 mg/dL, this would
still be a promising 28 % drop. These possibilities are shown as question
marks. The average triglycerides for all ARI-3037 dose groups was
157 mg/dL (Claude Benedict, personal conversation); thus, if the group
on 6 g had this baseline TG, this would be a 36 % drop
expression. Intriguingly, some of these features accord with
PCSK9 inhibition from niacin itself . In preclinical
studies, high fat, high cholesterol diet fed rhesus monkeys dosed
with CAT-2054 500 mg/day for 6 weeks experienced a 31 %
decline in LDL-C (p < 0.05 vs. baseline). Similarly, normal
diet fed cynomolgus monkeys given CAT-2054 100 mg/kg/
day for 14 days dropped LDL-C 21 % (p = NR), with the
decline being directly proportional to baseline LDL-C levels.
Single ascending doses in healthy volunteers achieved
significantly greater plasma levels than CAT-2003. Administered to
40 normal volunteers in an ascending dose (100–750 mg/day)
for 14 days, doses >500 mg/day resulted in a 20 % drop in
LDL-C (p < 0.05 vs. baseline) without NASTy symptoms. A
phase II clinical trial was to be initiated in late 2015.
ST 0702: a Niacin-Aspirin Prodrug (Isosorbide-5-nicotinate-2-aspirinate)
Solvotrin therapeutics developed an aspirin prodrug
connecting niacin and aspirin by ester to the sugar isosorbide,
isosorbide-5-nicotinate-2-aspirinate, or ST0702. Plasma and
hepatic esterases release niacin, aspirin, and salicylate, thereby
avoiding gastrointestinal toxicity from aspirin  and
ameliorating NASTy effects. Acutely-dosed for 48 h in six
cynomolgus monkeys, ST0702 dropped LDL-C 38 % (p = 0.027
vs. control) and apoB 40 % (p = 0.012) with TG dropping
7.9 % (p = NS vs. baseline, p = 0.03 vs. niacin), whereas niacin
had little effect on LDL-C (−32 %, NS), apoB (−25 %, NS), or
TG (+23.3 %, NS) . Again, ultra-short exposure precludes
any meaningful statement on chronic lipid lowering. Aspirin
inhibits PGD2 synthesis, ameliorating NASTy symptoms.
Accordingly, ST0702 suppressed serum PGD2 compared to
niacin: 48 h AUC = 16.2 ± 6.4 vs. 128.3 ± 38.2 ng/mL*h
(p = 0.012), suggesting ST0702 may be better tolerated.
TRIA-662: a Niacin Metabolite (1-Methylnicotinamine, or 1-MNA)
Pharmena SA developed a nicotinamide metabolite,
1methynicotinamide (1-MNA) [59, 60]. Topical 1-MNA is
anti-inflammatory in several skin disorders including rosacea,
acne vulgaris, and eczema [61, 62]. Furthermore, 1-MNA had
TG-lowering, anti-diabetic, and anti-thrombotic properties
in vivo [63–65]. In humans, unpublished data from patent
filings reveals robust TG-lowering by 1-MNA [
]. In 20
dyslipidemics, 1-MNA 30 mg thrice daily dropped TG
47.2 % (p < 0.05) after 2 weeks without changing HDL-C or
LDL-C. Given 50 mg twice daily to two dyslipidemic
subjects, TG dropped 67 and 47 % and HDL rose 57 and 61 %,
whereas LDL dropped 61 % in one subject and rose 45 % in
the other after 13 months. Though difficult to interpret lipid
effects from ultra-short exposures or longer exposures in just
two subjects, we find the overall TG-lowering effects
promising. A phase 2 clinical trial is underway (NCT02008084,
personal communication with principal investigator, Jean-Claude
Tardif, December 7th, 2015).
Niacin Receptor Mimetics
Coincident with the discovery of cholesterol-lowering effects
of niacin was the finding that nicotinamide, the amide of
niacin, was ineffective in this regard [
]. This, along with
activity of acipimox and acifran, led to the early inference that
a carboxyl group may be essential for activity of niacin
receptor agonists [
]. Structure-activity relationship (SARs)
studies confirmed that not only the carboxyl group but also
the aromatic ring structure is important for GPCR activation in
adipocyte membranes [
]. Using competitive dissociation
studies, pyridazine, pyrazine, and furan derivatives and
several classes of heterocyclic carboxylic acids have been found to
have activity at GPR109A in vitro [
GSK256073: a Next Generation GPR109A Agonist
GSK256073 was developed by GlaxoSmithKline as a potent
and selective GPR109A agonist with 10 times the potency of
]. Consistent with GPR109A agonism, animal
studies confirmed acute, dose-dependent, peak FFA, and TG
suppression up to 90 %, with much lesser NASTy effects. As
expected, single doses of 5–150 mg GSK256073 to healthy
volunteers suppressed FFA longer than 100–400 mg IR
niacin, accompanied by a 30–35 % reduction in TG 6 h
postdose. Interestingly, there was no FFA rebound as with niacin,
indicating a much longer duration of action. NASTy
symptoms were rare, being reported by only 1/47 subjects. Given
the relationship between elevated plasma FFA and insulin
resistance, prolonged FFA suppression with GSK256073
inspired further investigation of its efficacy as an antidiabetic
]. At doses of 5–50 mg/day for 2 days, GSK256073
significantly lowered fasting glucose, mean 24–48 h plasma
glucose concentrations and the HOMA-IR index. Encouraged by
this, GSK256073 at doses of 5–50 mg/day was tested for
12 weeks in type 2 diabetics (n ≈ 20 in each group) [
Unfortunately, the drug failed to maintain the
glucoselowering benefits seen in the acute-dose study. However, total
cholesterol still declined about 14 % while TG declined
almost 36 % after 12 weeks. This study provides an important
affirmation that GPR109A agonism provokes niacin-like lipid
changes, corroborating similar properties of the older
SCH 900271: a Next Generation GPR109A Agonist (5-[3-cyclopropylpropyl]-2-[difluoromethyl] -3Hpyrano[2,3-d]pyrimidine-4,7-dione)
Schering-Plough (now Merck) developed a potent GPR109A
agonist, SCH900271 [
]. In rats, SCH900271 suppressed
plasma FFA 70 % and TG 49 % 1 h post-dose with a longer
duration of TG suppression (8 h) compared with niacin
(<6 h). Dogs had similar FFA suppression without increasing
cutaneous blood flow. In humans, comparing 10 mg/day
SCH900271 (n = 22) with 2 g/day ER-niacin (n = 25) and
placebo (n = 24) among dyslipidemics, the placebo-corrected
change in HDL-C on SCH900271 was about +10 %
(p < 0.05 vs. placebo) and +17 % on ER-niacin (p < 0.0001),
adjusting for about a 12 % drop in HDL-C on placebo [
SCH900271 did not differ from placebo by TG or LDL-C.
ER-niacin dropped LDL-C about 17 % beyond a drop seen
on placebo (p < 0.001), without altering TG. Importantly, the
ER alternative and SCH900271 were indistinguishable from
each other in their TG and HDL-C effects, but ER-niacin
lowered LDL significantly more than SCH900271. The niacin
control arm illustrates the problem with ultra-short exposure.
Not surprisingly, niacin itself did not always induce
clinicallyor commercially-meaningful lipid changes in just 4 weeks. In
particular, 4 weeks of the ER alternative raised HDL-C, but
the rise fell short of what may be expected after 4 months;
likewise, the ER alternative failed to lower TGs in 4 weeks,
but does so after 4 months (Fig. 1) [
]. This underscores the
need for a niacin control, especially in ultra-short studies
where even reference therapy may be bereft of meaningful
effects. As expected from animal studies, SCH900271 did
not elicit NASTy symptoms. In a longer, 8-week,
placebocontrolled study of dyslipidemic volunteers using 1 to
15 mg/day (n ≈ 100 in each group), 5 mg SCH900271 dropped
LDL-C, −5.7 % (p < 0.01), 15 mg dropped TG, −7.4 %
(p < 0.05), whereas HDL-C was unchanged (about +2.5 %,
]. The 8-week study did not employ niacin as a
control. Thus, we can say that SCH900271 causes significant
changes in lipids, but cannot be certain as to how this might
compare with niacin clinically. Nevertheless, the results
provide further proof-in-principle that yet another GPR109A
agonist alters lipids similarly to niacin.
MK1903: a GPR109A Agonist ([1aR,5aR]
1a,3,5,5a-Tetrahydro-1H-2,3-diaza-cyclopropa[a] pentalene-4-carboxylic Acid)
Merck developed a GPR109A agonist, MK-1903 [
MK1903 lowered plasma FFA 90 % in rats and increased
dermal blood flow 30 % in mice, indicating engagement of
both adipocyte and macrophage GPR109A. In a phase I study,
healthy volunteers took single doses of 5 to 200 mg MK-1903.
Doses >50 mg suppressed FFA 90 % within 1–2 h and lasting
8 h. The PGD2 metabolite urinary PGD-M increased in a
dose-linear fashion, indicating robust macrophage GPR109A
stimulation. In a phase IIa study of dyslipidemics, MK-1903
150 mg thrice daily significantly dropped TGs, −10.3 %
(p < 0.05) after adjustment for placebo and raised HDL-C,
+4.6 % (p < 0.05) despite an ultra-short exposure of only
4 weeks, without changing LDL-C [
]. HDL-C changes
at an intermediate time point of 2 weeks revealed ongoing
improvement without signs of plateauing by 4 weeks,
consistent the observation that niacin requires months of exposure to
reach its expected clinical results. MK-1903 affirms results
from GSK256073 and SCH900271 by providing
proof-inconcept that still another synthetic GPR109A agonist can
effect significant lipid changes in only a few weeks, resembling
legacy GPR109A agonists (Fig. 1). Tellingly, MK1903
appears indistinguishable from the ER alternative in that mean
changes in TG and HDL-C are similar and the CIs are not only
overlapping, but in fact nesting. Thus, MK1903 is
indistinguishable from niacin itself, affirming GPR109A mediates
niacin’s changes in TGs and HDL-C to some extent. Indeed,
ultra-short exposure to both SCH900271 and MK1903 appear
indistinguishable from ultra-short exposure to the ER
alternative, with overlapping and/or nesting confidence intervals.
MK0354: a partial GPR109A Agonist (3-[1H-Tetrazol-5-yl] -1,4,5,6-tetrahydro-cyclopentapyrazole)
Merck developed a partial GPR109A-agonist, MK0345 [
whose phase II trial enrolled 60 dyslipidemics, completing
4 weeks MK0345 2500 mg or placebo daily [
did not provoke greater NASTy effects than placebo. Despite
exposure for only 4 weeks, MK0354 dropped LDL-C 9.8 %
vs. placebo (p = <0.05) without changing HDL-C (+0.4 %,
NS) or TG (−5.8 %, NS), but again, with such a short
exposure, it is hard to infer what the partially-active compound
might do during a clinically-meaningful treatment period.
Overall Evidence Supports GPR109A as a Mediator of Niacin’s Effects
Long before the novel GPR109A agonists, efficacy of the
early synthetic niacin analogs acipimox and acifran helped
prove the concept that niacin exerted its lipid effects at least
partly through this receptor. The novel agonists apparently
corroborate this, impressively, even in studies poorly
equipped to assess efficacy. To take TGs as an example, at
least two of the novel agonists performed as well or better than
the ER alternative (GSK256073 and MK1903, Fig. 1) and one
as well or worse (SCH900271). Thus, the collective evidence
from the legacy and the novel GPR109A agonists affirm the
receptor as an important mechanism for niacin.
Reports of the Death of GPR109A are Greatly
One of the first reports on the newer GPR109A agonists was
based on a pair of ultra-short, early-phase studies that
awkwardly referenced chronic therapy studies as the benchmark for
meaningful efficacy rather than a bona fide experimental niacin
]. As often happens, the Bhistorical control^ does
not hold up as a valid comparator, because niacin itself does not
always show appreciable efficacy given such short exposures.
Ironically, one of the experiments actually contained an
ERniacin arm whose participants were also subjected to
ultrashort exposure. Predictably, niacin itself failed to recapitulate
its own expected benefits [
], nicely illustrating the hazards
of preferring historical over experimental controls.
Importantly, efficacy can be cautiously ruled in when it
turns up in such ultra-short, early-phase studies, but cannot
be ruled out from a null result. Expecting efficacy from
fleeting GPR109A agonism is particularly problematic because
niacin itself is well known to take months to Bkick in^. In
the ADMIT trial, LDL-C, TG, and HDL-C remained largely
unchanged until week 8–12 . Following the 12-week
runin, HDL-C and LDL-C did not plateau until 18 weeks.
Likewise, a 6-month trial of the ER alternative by
Maccubbin et al. revealed very modest lipid efficacy at
4 weeks, with LDL-C, TG, and HDL-C altering just about
10 %, and not reaching a plateau before 12-24 weeks .
In perhaps the best experimental design to demonstrate this
phenomenon, Luria used niacin 1 g/day for 6 months, but also
assessed intermediary efficacy, showing maximal HDL-C
raising took well beyond 3 months (Fig. 2) .
Mirroring delayed efficacy, studies of both MK1903 and
SCH900271 showed lipid parameters just beginning to improve
at 4 weeks, with no plateau at that time. Despite these limitations,
these two agonists were nevertheless compared to historical
Bcontrols^ on chronic niacin therapy, leaving the first impression
that (1) the new drugs and oddly, niacin itself, were weaker than
niacin and (2) GPR109A agonism did not contribute to niacin’s
mechanism of action. We offer an alternative interpretation: the
new agonists did alter lipids significantly and were not
convincingly different than niacin itself when dosed for such a short
time. Thus, compared to niacin under the same conditions, these
experiments affirm rather than deny a role of GPR109A.
That said, there is a world of difference between showing
results from the novel agonists are statistically- or
clinicallysignificant versus showing them commercially-significant.
Even if novel agonists perform as well as niacin, they might
not be viable commercially. For example, if the synthetic
analog is no better but is much harder to produce, it could affirm
the mechanism but still not be worth developing into a drug. In
this way, we agree with the tenor of the early report on
MK1903 and SCH900271, in that these particular entries
would seem unlikely to outperform niacin commercially. On
Time Course for Lipid Response On Long-Acting Niacin 1g Daily
1 3 6
Month of Long-Acting Niacin
Fig. 2 Luria started patients with cardiovascular disease on long-acting
niacin 1 g daily as 250 mg four times daily, following lipids on this dose
at 3 and 6 months later . Despite a fixed dose throughout follow up,
lipids had not clearly reached a plateau at 6 months. This suggests a major
limitation to some of the proof-of-concept studies of the novel niacin
mimetics. Studies of less than 3 months and especially less than 1 month
are susceptible to miss clinically-meaningful effects if they behave like
niacin. This further suggests how niacin itself can fail to demonstrate
clinically-meaningful effects when used as a control for such studies. The
shaded area denotes the 1-month mark. Assuming linearity between
initiation and 3 months, that region gives an appreciation for how a study
of ultra-short duration might miss a lipid effect entirely. We imputed the SD
from total cholesterol to estimate SEM for non-HDL-c
the other hand, GSK256073 may do so, since its ability to
lower TG compares well to ultra-short and long-term niacin
studies (Fig. 1).
Considering GPR109A agonists as a whole, we now have six
that appear capable of improving lipids in addition to niacin
itself: the novel drugs GSK256073, SCH900271, MK1903,
and MK-0354, as well as the legacy synthetic GPR109A
agonists, acipimox and acifran. The affirmation that half a dozen
GPR109A agonists are capable of improving lipids supports
the concept that this pathway is beneficial and Bdruggable.^
That said, the failure thus far to test all of these compounds for
clinically-meaningful periods makes it impossible to know if all
would ultimately result in commercially-meaningful
improvements in lipids. Tellingly, all three of the synthetic GPR109A
agonists tested for clinically-meaningful periods have produced
encouraging results: GSK256073, acipimox, and acifran.
A Niacin Mimetic
ARI-3037: GPR109A Agonist or Novel Niacin Mimetic?
Arisaph pharmaceuticals developed 6-substituted pyridine
derivatives with lipid-lowering properties, selecting ARI-3037 for
initial development. Though the patent suggests some agonize
GPR109A, it is not clear whether ARI-3037 does so; nor has
Arisaph elsewhere disclosed whether it is a GPR109A agonist
or other mimetic. Interestingly, in vitro assays did not show
recruitment of β-arrestin in GPR109A-expressing cells,
indicating avoidance of the NASTy-inducing pathway [
high doses failed to provoke NASTy symptoms in multiple
animal species, and its lipid efficacy was compared to niacin
in hamsters with diet-induced hyperlipidemia . After only
18 days, ARI-3037 dropped total cholesterol 60 % (p < 0.01),
LDL-C 55 % (p < 0.001), TG 87 % (p < 0.001), and FFA 62 %
(p < 0.001), whereas niacin dropped total cholesterol 39 %
(p = 0.05) and LDL-C 33 % (p < 0.05) without changing TG
and FFA. In a dose-ranging study of healthy volunteers, the
top dose of 6 g daily dropped TG 56.7 mg/dL (p < 0.05) and
raised HDL-C 7.7 mg/dL (+15 %, p < 0.05) after only a single
]. There were no NASTy symptoms even at 6 g, which
is equimolar to about 4 g niacin. At up to 2 g/day, ARI-3037
significantly lowered TG after only 28 days, again without
NASTy symptoms, nor was glucose homeostasis perturbed. A
12-week trial in severe hypertriglyceridemics is underway
comparing ARI-3037 3 g twice daily to placebo (NCT02250105).
The decade following GPR109A’s discovery saw prolific
research into niacin’s lipid-altering mechanism, and perhaps more
importantly, development of several potent niacin-mimetics.
First, like the legacy GPR109A agonists natural and synthetic,
novel agonists reaffirm the receptor’s role in mediating adipose
lipolysis suppression and a variety of lipid effects, though few
have been subjected to clinically-meaningful exposures.
Perhaps some may well outperform niacin itself if taken to that
stage. More broadly, novel pro-drugs and other mimetics have
also shown very promising lipid-altering effects.
Given that niacin has already proven cardioprotective, we
agree that potent niacin mimetics remain an attractive target
for development. If niacin mimetics successfully avoid
NASTy symptoms, they could return us to cardioprotective
exposures and diurnal meal-time dosing, overcoming two
major flaws of the failed ER alternative. Encouragingly, several
mimetics appear to deliver just that, and impressively, with
only brief exposures thus far. This approach could enhance
cardioprotection from statins or provide it to the
statinaverse with no meaningful competition from its predecessors.
Based on the long time course for niacin’s benefits, there is
much hope that the novel mimetics would match niacin’s
effects if given for clinically meaningful periods.
Acknowledgments Support provided by NIH grant K23HL091130
(R.L. Dunbar) from the NHLBI. Dr. Dunbar participated in one of the
studies involving MK-1903 by Merck and has consulted for Catabasis.
Compliance with Ethical Standards Richard L. Dunbar declares NIH
grant K23HL091130 (R.L. Dunbar) from the NHLBI. Dr. Dunbar also
served as a local investigator for the AIM-HIGH study, overseeing 30
participants from the Philadelphia VA Medical Center and 14 from the
University of Pennsylvania. Dr. Dunbar was a local investigator for a
clinical trial of MK1903 funded by Merck & Co. and has received
personal fees for consulting for Catabasis.
Conflict of Interest Harsh Goel served as a sub-investigator for the
AIM-HIGH study, assisting Dr. Dunbar.
Human and Animal Rights and Informed Consent This article does
not contain any studies with human or animal subjects performed by any
of the authors.
Open Access This article is distributed under the terms of the
Creative Commons Attribution 4.0 International License (http://
creativecommons.org/licenses/by/4.0/), which permits unrestricted
use, distribution, and reproduction in any medium, provided you give
appropriate credit to the original author(s) and the source, provide a link
to the Creative Commons license, and indicate if changes were made.
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