Niacin Alternatives for Dyslipidemia: Fool’s Gold or Gold Mine? Part I: Alternative Niacin Regimens
Curr Atheroscler Rep
Niacin Alternatives for Dyslipidemia: Fool's Gold or Gold Mine? Part I: Alternative Niacin Regimens
Richard L. Dunbar 0 1 2 3 4 5
Harsh Goel 0 1 2 3 4 5
0 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
1 Department of Medicine, Division of Cardiovascular Medicine, Perelman School of Medicine at the University of Pennsylvania , Philadelphia, PA , USA
2 Richard L. Dunbar
3 Department of Medicine, York Hospital , 1001 S. George Street, York, PA 17403 , USA
4 Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania , Philadelphia, PA , USA
5 The Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania , Philadelphia, PA , USA
Niacin was the first drug demonstrating lowered cholesterol prevents coronary heart disease (CHD) events, with two clinical CHD outcome studies establishing a cardioprotective niacin regimen: 1 g thrice daily with meals. Though cardioprotective, skin toxicity limits niacin's use, fostering several variations to improve tolerability. One of these, an extended-release (ER) alternative, proved immensely successful commercially, dominating clinical practice despite departing from the established regimen in several critical ways. Hence, improved tolerability may have come at the cost of diminished efficacy, posing a conundrum: Does it still help the population at risk for CHD to broaden a drug's acceptance by Bwatering it down^? This question is crucial at this stage Richard L. Dunbar and Harsh Goel contributed equally to this work.
Niacin; Nicotinic acid; Hyperlipidemia; Niacin conjugates; Niacin prodrugs; Lipids
Published online: 15 February 2016
# The Author(s) 2016. This article is published with open access at Springerlink.com
now that the ER alternative failed to recapitulate the benefits
of the established cardioprotective niacin regimen in two trials
of the alternative approach: AIM-HIGH and HPS2-THRIVE.
Part I of this review discusses how vastly the ER alternative
departs from the established cardioprotective regimen, why
that is important physiologically, and how it may explain the
findings of AIM-HIGH and HPS2-THRIVE. Given important
gaps left by statin therapy, the established cardioprotective
niacin regimen remains an important evidence-based therapy
for the statin intolerant or statin averse.
Institute for Translational Medicine and Therapeutics, Perelman
School of Medicine at the University of Pennsylvania,
Philadelphia, PA, USA
Almost 60 years ago, Altschul discovered NIcotinic ACid
vitamIN (NI’AC’IN) suppressed lipids in man [
Subsequently found to lower cholesterol and triglycerides
(TGs) among the atherogenic lipoproteins (non-HDL-C and
LDL-C) and raise HDL-C [
], niacin became the first to
demonstrate that lowering cholesterol prevents myocardial
infarction (MI)  and, eventually, all-cause mortality [
niacin became foundational to treating hypercholesterolemia
to prevent MI. Cardioprotection was shown with 1 g thrice
daily with meals in two distinct niacin formulations: (1)
immediate-release (IR) niacin [
] and, later, (2) a
longerreleasing niacin pro-drug, pentaerythrityl tetranicotinate [
Accordingly, several consensus groups endorsed niacin to
prevent hard coronary heart disease (CHD) events: non-fatal MI
and cardiac death [
]. Attempts to capitalize on the benefits
of this regimen included titration well beyond 3 g/day to reach
specific lipid targets [
], using up to 12 g/day [
Another strategy was to re-tool the pharmacokinetics,
radically altering the dosing schedule to enhance tolerability, the
most commercially successful being prolonged-release
alternatives. An extended-release (ER) alternative attracted major
backing as Niaspan, but counter-intuitively, at a maximum
dose restricted to only 2 g/day. It is critical to appreciate the
ER alternative is an alternative rather than an equivalent to the
established cardioprotective regimen, the former bearing the
burden of proof in terms of safety, lipid efficacy, and,
ultimately, CHD event reduction.
The Alternative Versus the Established Niacin
Though fairly safe, the ER alternative is at a major
disadvantage compared to other niacin formulations, in that the FDA
limited the maximum dose to 2 g/day, whereas the established
cardioprotective dose is 3 g/day, raising the obvious question:
For practical purposes, is 2 g really less than 3 g, or is it Bclose
enough for government work?^ Ultimately, this would require
a new round of outcome trials. Importantly, IR-niacin
continues to improve lipids above 2 g/day, as demonstrated by
Knopp et al. in a head-to-head trial comparing IR-niacin to the
ER alternative among hyperlipidemics [
]. At the low end,
both formulations lowered lipids comparably at only half the
usual dose (i.e., 1.5 g daily). However, when titrated to the
established cardioprotective dose (i.e., 3 g daily), IR-niacin
clearly exceeded the ER alternative’s capability to lower lipids
]. Considering the FDA approved IR-niacin up to 6 g/day,
the top dose of the ER alternative is only 2/3 the established
cardioprotective dose and only 1/3 the maximum approved
dose of IR-niacin, raising grave doubts as to its equivalency
to the established cardioprotective regimen.
Unfortunately, the problem for the ER alternative runs much
deeper than profound underdosing. Departing further, the ER
alternative was dosed entirely at bedtime rather than throughout
fed portion of the day, abandoning the successful approach of
both trials establishing CHD benefit. Nevertheless, the ER
alternative was touted as a gentler alternative to IR-niacin, and
absent contrary evidence presumed cardioprotective long
enough to dominate clinical use, encouraged by small studies
demonstrating atheroprotection [
Commendably, major stakeholders of the exploratory
regimen mounted vascular event outcome trials to prove that the
ER alternative could limit cardiovascular events as IR-niacin
and pentaerythrityl tetranicotinate had done, this time against a
statin background. The aborted AIM-HIGH trial [
almost as large as the Coronary Drug Project (CDP), if much
], and the completed HPS2-THRIVE trial was even
larger , together promising a robust test of the alternative
regimen. Surprisingly to many, the ER alternative failed to
recapitulate benefits of the established cardioprotective regimen.
Perhaps the most obvious explanation for their apparent null
results is the exploratory ER regimen compromised several
critical features of the established cardioprotective regimen
(Table 1). Tellingly, in outcome trials, 1 g thrice daily with
meals reduces hard CHD events singly or pooled, with a pooled
odds ratio (OR) of 0.75 (95 % confidence interval [CI] = 0.60 to
0.93, p = 0.01, Fig. 1a). In contrast, such benefits appear well
beyond the reach of the exploratory regimen of 2-g single dose
before the overnight fast (OR = 1.00, 95 % CI = 0.89 to 1.13,
p = 0.97).
Whether the exploratory alternative regimen is actually
equivalent is crucial, because it affects how the established
cardioprotective regimen might be used. Substantially
underdosing the alternative is intuitively cause for pause;
indeed, there is much evidence supporting the dose–response
relationship between cholesterol suppression and CHD risk
(Fig. 1b) [20, 21]. There is also evidence that nocturnally
dosing the ER alternative does not lower postprandial lipids
[22 , 23], thus, failing to suppress an important pool of
atherogenic lipids [24, 25]. We found meal-time dosing reduced
p o s t p r a n d i a l l i p i d e m i a [ 2 2 ] , w h i c h i t s e l f m a y b e
atheroprotective [25, 26]. In contrast, nocturnal dosing of the
ER alternative confers no such benefit . The AIM-HIGH
authors also implicate nocturnal dosing because niacin causes
a multi-fold rebound of free fatty acids (FFA) several hours
post-dose. They contend Bthis metabolic perturbation repeated
every night could promote CV events via impaired myocardial
fuel supply, subsequent excess in fatty acid anion
concentrations, and/or a counter-regulatory hormone response,
including catecholamines.^ . Conversely, they reason that the
cardioprotective meal-time regimen might forego these ill
effects. At this point, to continue to presume that the alternative
regimen is equivalent to the established cardioprotective
regimen strains credibility.
Major differences between the established cardioprotective regimen and the ER alternative regimen
Strategy employed by clinical event trials Established cardioprotective regimen Dose tested Exposures per day
Exploratory regimen (cardioprotection indeterminate) 2 g/day 1
Post-absorptive (overnight fast)
a Lipid changes are from a meta-analysis by Birjmohun et al. (J Am Coll Cardiol 2005;45:185–97)
Revisiting the Established Cardioprotective Regimen
Clearly, a convincing failure of an alternative to live up to
the standard invalidates the alternative; however, such
failure does not invalidate the standard. Now that the
presumption of equivalency between the two opposing
regimens has been debunked, we think it is important to
rev i s i t t h e e v i d e n c e s u p p o r t i n g t h e e s t a b l i s h e d
cardioprotective regimen. The CDP compared five
cholesterol-lowering strategies to placebo among MI
survivors . At 1 g thrice daily, IR-niacin prevented
recurrent MI after 5 years, whereas the other four strategies
]. Interestingly, among the four failed therapies
was a fibrate; thus, in a head-to-head matchup, niacin
proved cardioprotective whereas a fibrate failed [
seco n d s t u d y a f f i r m e d t h e p r o - d r u g p e n t a e r y t h r i t y l
tetranicotinate 1 g thrice daily combined with the same
failed fibrate from the CDP, preventing MI after 5 years
in the Stockholm Ischemic Heart Disease Study (SIHDS)
]. Since the fibrate had proven powerless to prevent MI
as monotherapy, reconciling the results with CDP further
commends niacin as a cardioprotective agent. Because it
used monotherapy, CDP is by far the cleaner study and
more definitively establishes niacin 1 g thrice daily as
cardioprotective. Having used combination therapy, the
SIHDS is corroboratory but less definitive than the CDP.
Furthermore, having used a longer acting pro-drug ,
we think SIHDS supports the concept that dosing 1 g thrice
daily is more important than the release rate of free
nicotinic acid. Long-term follow-up of CDP revealed the
niacin-treated group had lower all-cause mortality despite
stopping niacin after 5 years [
]. Such legacy benefits
imply prior niacin use fundamentally altered the long-term
disease course rather than simply keeping it in abeyance
during active treatment, the sine qua non for
diseasemodifying therapy. Long the only lipid-lowering therapy
to decisively prevent CHD events, niacin became first-line
therapy along with bile acid sequestrants, as reflected by
the Adult Treatment Panel (ATP) guidelines from 1988 to
2001 [30, 31]. Per public records, between 1957 and 2015,
the US FDA approved 39 niacin drug/dose combinations
as prescription-only pharmaceuticals to improve lipids.
These include 26 approved applications featuring niacin:
16 for IR niacin and, more recently, 10 for the ER
alternative [32 ]. Importantly, the FDA approved the broad claim
that BIn patients with a history of myocardial infarction and
hyperlipidemia, niacin is indicated to reduce the risk of
recurrent nonfatal myocardial infarction.^ (http://www.
The Major Problem with Niacin
Despite benefits, a major limitation of niacin has been the
universally disagreeable dermal side effect, dubbed
Bflushing^, a misleading metonym because it emphasizes
one of the least bothersome symptoms, skin reddening .
Though flushing or rubor is cosmetically unappealing, the
bothersome symptoms arise from dermal calor, dolor, tumor,
and especially, pruritus. Since Bflushing^ misdirects attention
from more bothersome symptoms, we prefer the more general
term niacin-associated skin toxicity (NASTy). Despite
demonstrable CHD benefits, niacin fell short of its potential
due to NASTy effects. Over the years, several measures
emerged to improve tolerability: slow titration, meal-time
dosing, pretreatment with non-steroidal anti-inflammatory drugs
(NSAIDs), especially aspirin, and developing
prolongedrelease alternatives dosed once at bedtime [
Despite partially improving symptoms, overall niacin
adoption remained poor.
Log-Transformed Odds Ratio for Hard CHD Events (CHD Death and NFMI)
by Regimen (Established vs Exploratory)
1. Established Cardioprotective Regimen: Multiple Daily/Post-Prandial/Diurnal Dosing, 3g Daily
2. Exploratory Regimen (ER Alternative): Once-Daily/Pre-Fast/Nocturnal Dosing, << 3g Daily
Parity Favors Usual Care
Meta-Regression of Hard CHD Events
As a Function of Cholesterol Suppression
tau 2 =0.0005,
I 2 =0.0%, R 2 =98.4%
Drop in Cholesterol
Statins Displaced Niacin…
High incidence and morbidity/mortality of CHD and the
strong association with dyslipidemia, along with improved
outcomes from cholesterol suppression spawned new
lipidlowering drugs, most successfully the statins. Picking up
where niacin left off, statins multiply proved the cholesterol
hypothesis, refined as the LDL hypothesis. More effective at
lowering LDL-C [37, 38], better tolerated, and enjoying
superlative evidence for preventing CHD events , statins
displaced niacin as first-line therapy, reflected in the 2001
ATP and subsequent guidelines [
9, 40, 41
…but Statins Leave Much to Be Desired
Despite strengths, statins have significant limitations: Though
better tolerated than niacin, a very conservative estimate is that
10 % of patients remains statin intolerant [42, 43].
Fig. 1 a Meta-analysis of odds ratio for hard CHD events (CHD death
and nonfatal myocardial infarction) comparing the exploratory ER
alternative to the established cardioprotective regimen. The event rates for
active and comparator groups are as reported in the four cardiovascular
outcomes trials (CDP, SIHDS, AIM-HIGH, and HPS2-THRIVE) [
18 , 19
]. We used random-effects meta-analysis techniques to pool the
corresponding log-transformed odds ratios (OR) by the metan procedure
in Stata v14. Initially, we analyzed the exploratory regimen as if it were
equivalent to the established cardioprotective regimen, pooling all four
trials. Unsurprisingly, treating such different approaches as equivalents
revealed a high degree of heterogeneity, I2, as high as 73 % (p = 0.012),
indicating the overwhelming amount of variation between trials is
attributable to heterogeneity. Thus, pooling the trials proved unsupportable. In
marked contrast, treating the exploratory regimen as distinct from the
established cardioprotective regimen rendered heterogeneity insignificant
and inconsequential, as shown. Among trials of the exploratory regimen,
I2 was very low (13 %, p = 0.3), indicating agreement. Specifically, these
trials agreed on inefficacy of the alternative regimen (OR = 1.0, p = 1).
Likewise, among trials of the established cardioprotective regimen, I2 was
low (36 %, p = 0.2), again indicating agreement. Specifically, these trials
agreed on efficacy of the established cardioprotective regimen
(OR = 0.75, p = 0.01). The high heterogeneity when pooling all four trials
but low heterogeneity when distinguishing the exploratory from the
established regimen further supports the concept that the alternative is
not an equivalent with respect to outcomes. This is even more apparent
when considering the clinical effects on hard CHD events (i.e., no benefit
from the alternative, but an odds ratio of 0.75 for the established regimen).
Clinically, this analysis affirms a role for the established regimen and
denies a role for the ER alternative. CI confidence interval, IRNA
immediate-release niacin, PENA pentaerythrityl tetranicotinate, ERNA
extended-release niacin. b Meta-regression between log-transformed
odds ratio for hard CHD events and percent change in cholesterol. As
with Fig. 1, we assessed the odds ratios for hard CHD events for the four
cardiovascular outcome trials, now evaluating whether cardioprotection
is consistent with the cholesterol hypothesis. Specifically, we regressed
the odds ratio for CHD against the drop in total cholesterol for each study
by the metareg procedure in Stata v 14. Meta-regression revealed an
extraordinarily strong relationship, with virtually no heterogeneity
(I2 = 0 %) and nearly perfect correlation (R2 = 98 %). At the low end, it
is intuitive that the alternative regimen of AIM-HIGH and
HPS2THRIVE conferred no meaningful CHD benefit, as the reduction in
cholesterol was modest at best (∼5 %). This accords with the cholesterol
hypothesis, which predicts that minimal reductions in cholesterol
translate to minimal benefits on CHD events. On the other hand, the regimens
of CDP and SIHDS present progressive reductions in cholesterol that
correspond to dose-responsive CHD benefits (dose referring to
cholesterol reduction). This also accords with the cholesterol hypothesis, which
predicts that greater reductions in cholesterol should translate to greater
CHD benefits in a dose-responsive fashion. In addition to distinguishing
the alternative regimen from the established regimen, the strong linear
relationship between cholesterol lowering and CHD prevention by niacin
supports the concept that the lipid-targeting strategy would improve on
the already-substantial benefits of the established regimen
Additionally, statin response varies substantially, with up to
40 % of patients unable to achieve lipid goals with
monotherapy, thus leaving a big therapeutic gap in at-risk populations
[44 ]. Moreover, despite reducing hard CHD events 25–35 %
among those who will take them, statins leave substantial
residual risk . Hence, there is a dire need for both an
alternative and adjunct to statins. Obviously, besides
exploiting novel therapeutic pathways, one logical and less
costly approach should be to study the cumulative effect of
established cardioprotective agents added to statins.
Supporting this, when added to baseline statin therapy, niacin
further drops LDL-C and triglycerides and raises HDL-C,
regressing atherosclerotic plaque [
15, 17, 46
] providing a
sound basis to study clinical outcomes with the established
cardioprotective regimen against a statin background.
Unfortunately, this has never been investigated, and
lamentably, failure of the exploratory ER alternative could frustrate
attempts to fund such a test of the established cardioprotective
The Spectacular Failure of the Extended-Release
The two failed trials of the exploratory regimen had very
different purposes. Most straightforward, the HPS2-THRIVE trial
assessed outcomes by adding the exploratory ER alternative
regimen to the background statin therapy . The
AIMHIGH trial was designed for a much different reason: to test
the BHDL hypothesis^, namely that raising HDL-C per se
would decrease the residual risk beyond the reach of statins .
The HPS2-THRIVE Trial: A Relatively Straightforward
Design to Test the Exploratory Niacin Alternative
The HPS2-THRIVE enrolled patients with established
cardiovascular disease but without any pre-specified lipid thresholds
for eligibility. Standardization of baseline therapy with
simvastatin 40 mg/day ± ezetimibe 10 mg/day was followed by
randomization to ER niacin (ERN)-laropiprant 2 g/40 mg daily or
placebo. On baseline statin therapy, ERN-laropiprant lowered
LDL-C further, −10 mg/dL (−16 %), and raised HDL-C,
+6 mg/dL (+14 %), compared to placebo over a median
follow-up of 4 years. There was no difference between groups
in any primary or secondary event end-points besides a
significant 10 % reduction in revascularization procedures in the
ERN-laropiprant group. Notably, however, baseline LDL-C
was 63 mg/dL and HDL-C was 44 mg/dL, making the results
difficult to extrapolate to the real-world population of
dyslipidemics. Thus, subjects may have simply been too well
treated to make any further impact. Perhaps
hypercholesterolemia is analogous to other atherosclerotic risks, such as
diabetes or hypertension: At some point, further treatment has
diminished or no returns.
Intuitively, niacin suppressed LDL-C much more in those
with high baseline LDL-C: −7 mg/dL for LDL-C ≤ 58 mg/dL
vs. −15 mg/dL for LDL-C ≥ 77 mg/dL. In accordance with the
LDL hypothesis, one would expect those with more
substantial LDL-C suppression fare better. As predicted, baseline
LDL-C drove substantial heterogeneity in vascular outcomes,
indicating some groups had more of a response than others
(p < 0.05). Indeed, the group with baseline LDL-C < 58 mg/dL
had no benefit from niacin, consistent with their optimal LDL
(OR = 1.08, 95 % CI = 0.96 to 1.20, Fig. 2a). In contrast,
pooling the groups with LDL ≥ 58 mg/dL eliminated
heterogeneity (now p = 0.8), and importantly, those with LDL ≥ 58 mg/
dL had fewer vascular events (OR = 0.89, 95 % CI = 0.81 to
0.97, NNT 74, p = 0.012). Similar benefits were seen in those
with suboptimal ApoB (Supplemental Figure).
Thus, although HPS-THRIVE proved ERN + laropiprant is
no Bpanacea,^ it does point to efficacy among people who
actually have suboptimal LDL-C. Since that is precisely what
one would predict from the LDL hypothesis, we performed a
meta-regression of event reduction as a function of LDL-C
suppression (Fig. 2b). Though this supports a relationship
(R2 = 61 %), there was some heterogeneity suggesting a
threshold effect as an alternative to a strictly linear dose
response. In either case, the results accord with the LDL
hypothesis. Given unimpressive LDL-C reductions from up to 2 g of
the ER alternative, this naturally raises an important question:
Since the established cardioprotective regimen suppresses
LDL-C more aggressively, could we achieve more robust
CHD benefits with the reference dose of 3 g daily? Would a
lipid-targeting strategy work even better? If the LDL
hypothesis is correct, one would expect a trial pushing the dose to
maximize LDL-C or non-HDL-C suppression to fare much
better. Nevertheless, the HPS2-THRIVE subset reassures
clinicians that in all likelihood the ER alternative would benefit
the not-exactly uncommon group of patients with
LDLC ≥ 58 mg/dL or ApoB ≥ 60 mg/dL despite statin therapy.
Apart from efficacy, safety took on unusual significance for
HPS2-THRIVE because of the laropiprant component. As
background, the FDA approved 39 niacin drug/dose
combinations. In a stunning departure, when laropiprant was
proposed to be added to niacin, the FDA rejected the combination
in 2008. In retrospect, this is understandable considering
laropiprant was a novel chemical entity lacking long-term
safety from large populations. Thus, rejection of the only
niacin formulation with laropiprant motivated HPS2-THRIVE,
providing the first major long-term safety profile. The trial
validated safety concerns by a high prevalence of adverse
effects. Some were unexpected based on niacin literature,
notably, serious bleeding events (2.5 vs. 1.9 %, p < 0.001),
including the intracranial and gastrointestinal bleeding.
Disconcertingly, laropiprant absent niacin inhibits platelet
responsiveness to collagen and enhances the antiplatelet
effects of aspirin and clopidogrel [
]. Accordingly, changes
in platelet function in silico translated to prolonged bleeding
time in vivo among dyslipidemics exposed to laropiprant
absent niacin. Indeed, bleeding time was underestimated
because the protocol censored the maximal bleeding time, but
laropiprant-exposed subjects were still bleeding when they
reached the contrived maximum . Hence, laropiprant’s
penchant to prolong bleeding implicates the novel chemical
Fig. 2 a Meta-analysis of odds ratio for a composite of soft vascular
events from the HPS2-THRIVE study, stratified by baseline LDL-C.
Importantly, pooling groups across the baseline LDL-C led to a high
degree of heterogeneity (I2 = 70.3 %, p < 0.05), thus arguing against
pooling all three groups. One group (LDL-C < 58 mg/dL) had an
OR > 1.0, and the other two (LDL-C ≥ 58 mg/dL) had OR < 1.0, and the
latter two had almost identical OR’s (0.89 and 0.87). Affirming this, when
we pooled the latter two groups, heterogeneity was minimized (I2 = 0 %,
p = 0.8). Again, those with optimized LDL-C (i.e., LDL-C < 58 mg/dL)
differed from those with higher LDL-C, having no discernable benefit
from ERN + laropiprant compared to placebo (OR = 1.08, p = 0.2). In
contrast, those with LDL-C ≥ 58 mg/dL appear to benefit from ERN +
laropiprant (OR = 0.89, CI = 0.81 to 0.97, p = 0.01). Oddly, the study was
severely skewed toward people with lower LDL-C, with a minority
having LDL-C > 77 mg/dL. These results suggest that a study enrolling
people with higher LDL-C (e.g., LDL-C > 70 or >100 mg/dL) might be
the ideal way to test the incremental benefit of the ER alternative. b
Metaregression between log-transformed odds ratio for soft vascular events
from the HPS2-THRIVE and percent change in LDL-C based on
baseline LDL-C. The findings from (a) suggest the study’s primary aim
suffered from targeting a population who does not necessarily benefit
from further LDL lowering. Conversely, the apparent benefit among
those with suboptimal LDL-C suggests higher degrees of LDL
suppression do confer benefits, in accordance with the LDL hypothesis.
To illustrate this, we conducted a meta-regression showing fewer events
with more aggressive LDL-C suppression (R2 = 61 %). Though we used
linear regression, there was heterogeneity (I2 = 51 %), suggesting a
nonlinear model may fit better. In any case, the relationship is
consistent with the LDL hypothesis. As such, this promising result
might be exploited to greater effect using the established
cardioprotective regimen or better yet, the lipid-targeting strategy of
niacin. Both strategies achieve more aggressive LDL-C lowering.
According to the LDL hypothesis, this should build upon the promising
event reductions from the ER alternative in HPS2-THRIVE. The dark
box on the graph represents the hypothesized effect of more robust
niacin regimens. Based on HPS2-THRIVE, we predict that a future trial
using aggressive LDL-C suppression would have a result somewhere
within the dark box (i.e., OR < <0.87)
entity in the serious bleeding events in HPS2-THRIVE. The
latter also found an unexpected increase in infections (8 vs.
6.6 %, p < 0.001). Accordingly, by antagonizing the
prostaglandin D2 (PGD2) receptor DP1, laropiprant may enhance
the PGD2-mediated regulation of the immune response via a
distinct PGD2 receptor-CRTH2 and increase propensity to
]. Thus, pre-clinical work supports the concept
that laropiprant may have promoted bleeding and infections in
HPS2-THRIVE. Far from assuaging safety concerns,
HPS2THRIVE instead raised new concerns, translating theoretical
safety problems into confirmed serious adverse events,
seemingly validating the FDA’s denial.
Strictly speaking, the study design does not permit one to
separate adverse effects from laropiprant and the ER
alternative. Although IR-niacin has been studied for many decades
longer than the ER alternative, extensive experience with the
former does not necessarily rule out novel side effects from
the latter, especially since the dosing regimen is so different
(cf. Table 1). The high incidence of adverse events in
HPS2THRIVE prompted a letter attempting an unplanned post hoc
analysis of the aborted AIM-HIGH trial comparing serious
Log-Transformed Odds Ratio for Soft Vascular Events by Baseline LDL Status
in the HPS2-THRIVE Study
1. Baseline LDL Optimal (<58 mg/dL)
2. Higher LDL Levels at Baseline (>= 58 mg/dL)
adverse events on the ER alternative to low-dose IR-niacin
]. In contrast to HPS2-THRIVE, the incidence of serious
bleeding events did not differ (3.4 % on the ER vs. 2.9 % on
IR-niacin, p = 0.36). However, serious infections occurred
with similar frequency as HPS2-THRIVE (8.1 on ER vs.
5.8 % on IR-niacin, p = 0.008). The authors cite several factors
that mandate caution while interpreting the AIM-HIGH
findings, concluding Blacking additional clinical and scientific
confirmation, we believe that they should be considered to be
provisional and exploratory.^ Nevertheless, we will probably
never be able to decisively attribute the serious adverse events to
laropiprant alone, since it was promptly withdrawn from the
global market. Other adverse effects in HPS2-THRIVE were
predictable from the niacin literature, including gastrointestinal
adverse effects (4.8 vs. 3.8 %, p < 0.001), new-onset diabetes
(5.7 vs. 4.3 %, p < 0.001), and worsened glycemic control
among diabetics (11.1 vs. 7.5 %, p < 0.001). Though niacin’s
propensity to perturb glucose homeostasis has been widely
reported, the effects are inconsistent in occurrence, persistence,
and severity [
]. Notably, statins consistently raise glucose,
especially intensive statin therapy [
]. Though not novel,
the HPS2-THRIVE findings of the effect on diabetes with
combination therapy reaffirm longstanding advice that niacin can be
used cautiously in pre-diabetics and diabetics.
The AIM-HIGH Trial: An Aborted Test of the HDL
Whereas HPS2-THRIVE assessed the overall utility of the
alternative as an adjunctive lipid-altering drug, AIM-HIGH
tried to dissect its HDL-raising potential from its
LDLlowering properties. Doing so addresses the HDL hypothesis,
namely, that raising HDL-C per se would prevent
cardiovascular events. This study was motivated in part by the HDL
Intervention Trial (HIT) trial, where as little as 6 % higher
HDL-C from a fibrate prevented hard CHD events (RRR
22 %) absent LDL-C effects in patients whose primary lipid
problem was low HDL-C [
]. Tellingly, CHD prevention
was related to raising HDL-C . Likewise, the Helsinki
Heart Study (HHS) also found gemfibrozil cardioprotective
; again, CHD benefit was a function of raising HDL-C
. Since niacin is much more effective at raising HDL-C,
it presented an obvious choice to exploit the apparent benefits
of raising HDL-C. Accordingly, AIM-HIGH enrollees had
cardiovascular disease and low HDL-C, but optimal LDL-C
levels. Participants initially took the ER alternative 1500–
2000 mg all at night, and after titration, were randomized to
continue the ER alternative or switch to IR-niacin 100–
150 mg/night. The decision to give the comparator group an
active intervention rather than a bona fide placebo was
motivated by a desire to maintain blinding by inducing NASTy
symptoms in both groups. Since the purpose of the trial was to
isolate the HDL-raising effect of niacin, the investigators had
to account for LDL-lowering by niacin, necessitating rigorous
efforts to equalize LDL-C levels between groups
post-randomization. Thus, throughout the trial, LDL-C was forced
below 80 mg/dL in both groups by titrating simvastatin to
80 mg/dL and adding ezetimibe 10 mg/day as needed.
This was complicated by an FDA Bblack box^ warning
strongly discouraging simvastatin 80 mg/dL after the
To most of the investigators’ shock, both niacin
formulations raised HDL-C robustly: median change +9.8 % on
lowdose IR-niacin after 2 years and +25 % on 2 g of the ER
alternative, a net differential of about 15 %. By 3 years on
low-dose IR-niacin, HDL-C rose from 34.9 to 39.1 mg/dL
(+4.2 mg/dL, mean = +12 %, median = +11.8 %). On the ER
alternative, HDL-C rose from 34.5 to 44.1 mg/dL (+9.6 mg/
dL, mean = +28 %, median = 25 %), for a differential of
+5.4 mg/dL between the two forms of niacin favoring the
group on the ER alternative. To put this into context, the
motivating HIT study found a +6 % rise in HDL-C prevented
hard CHD events, but here, niacin was so much more potent
that even the low dose of IR niacin in the intended control
group inadvertently had double the increment of HDL-C from
HIT (+12 vs. +6 %, Fig. 3). The use of such a robustly
effective HDL-raising dose of the active intervention in what was
HDL Increment from Low−Dose Niacin vs Full−Dose Gemfibrozil
(0.47 to 0.93)
(0.62 to 0.92)
IR Niacin 100 to 150 mg
H rupo +8%
I−HG lr"oG +6%
IAM tonC +4%
0% mg3/2dL mg4/7dL mg4/3dL mg4/3dL mg3/5dL 0%
Study: HIT HHS CeWnsinokr,ed WFiunlkl, HAIIGMH−
Dose/Day (mg):1200 1200 100 100 100−150
Full−Dose Fibrate Low−Dose Immediate−Release Niacin
Fig. 3 Left panel indicates two outcome trials affirmed the HDL
hypothesis with the fibrate gemfibrozil, HIT, and HHS [58, 59]. The
HIT study is more comparable to AIM-HIGH, having enrolled
highrisk patients with low HDL-C at the baseline. Thus, the dashed red
line provides a benchmark for an HDL-C increment expected to
prevent CHD events. Both the HIT and HHS demonstrated the
fibrate prevented hard CHD (OR = 0.66 to 0.76) with an HDL-C
increment of 6 to 10 %. Right panel indicates two studies where
low-dose niacin was added to a statin-treated background
demonstrating low-dose niacin achieves similar to HDL-C increments
as the fibrate studies [
18 , 61
]. The study by Wink et al. reported the
HDL-C increment from low-dose niacin in two ways. They censored
their dataset to exclude one subject on low-dose niacin who had an
unusually robust rise in HDL-C, but also reported the full dataset. This
suggests a variable response to low-dose niacin, where some subjects
are hyper-responders and cause analytical problems due to their very
high increments. The AIM-HIGH “control” group received even more
immediate-release niacin than in the Wink study, in most cases 150 %
of the Wink dose. Not surprisingly, the stronger doses used in
AIMHIGH stimulated a prodigious rise in HDL-C that is not only higher
than the Wink study but also considerably higher than the benchmark
HIT study. Remarkably, by pushing the dose, the AIM-HIGH
investigators managed to double the increment in HDL-C: +12 %
(+4.2 mg/dL) in AIM-HIGH vs. +6 % (+2 mg/dL) in HIT. If the
HDL hypothesis supported by the fibrate studies also translates to
niacin, one would expect the AIM-HIGH “control” group to have
similar benefits as HIT or HHS, and since the HDL-C increment is
so much more robust, perhaps even greater benefits. Unfortunately,
this invalidates the intended control group in AIM-HIGH, because
the control by necessity should represent the untreated state,
specifically a group lacking an HDL-raising dose of niacin, and
preferably lacking niacin altogether. IR immediate release, OR odds
ratio, Hard CHD non-fatal myocardial infarction and/or cardiac death,
HIT HDL intervention trial, HHS Helsinki heart study
to be the control group had a catastrophic effect on the validity
of the study’s primary aim, to prove the HDL hypothesis.
Superiority of the ER alternative over low-dose IR-niacin
would have affirmed the HDL hypothesis. Regrettably, the
study was unable to distinguish the two active therapies,
resulting in the Bnightmare^ scenario of an un-interpretable
null result. The problem is actually worse than stated, because
contaminating the control group with a highly-efficacious
dose of the experimental intervention unwittingly converted
the study from a controlled experiment of drug efficacy to an
uncontrolled dose–response study, bizarrely lacking the
requisite drug-free arm. A dose–response study requires a drug-free
control to prove efficacy given a flat dose response. Without a
niacin-free arm, AIM-HIGH’s null results are uninterpretable.
On the one hand, the null could mean raising HDL-C 28 %
with the ER alternative is no better than raising it a robust
12 % with low-dose IR-niacin, but both improve upon usual
care, perhaps more than HIT or HHS since the starting HDL-C
increment was better, hence, proving the HDL
hypothesis. On the other hand, the null could mean neither dose
is effective, failing to affirm the HDL hypothesis at these
doses. So, which is it? Frustratingly, we have no way to
know. Thus, foregoing a valid control group became a
Bshow-stopper,^ rendering it hard defend AIM-HIGH as
a reliable test of the HDL hypothesis. Indeed, many
reviewers have expressed significant misgivings about the
validity of the trial’s results [62–64].
Beyond the invalid control group are several other scenarios
to explain null results (Table 2). Any null result invites scrutiny
of a study’s power. Adding the experimental intervention to its
The HDL hypothesis is operative, but the motivating studies also involved unmeasured benefits that inflated the apparent HDL effect. Absent a way
to identify such effects, the elaborate machinations to isolate the HDL benefit in AIM-HIGH inadvertently nullified related benefits, undermining
The HDL hypothesis is operative, but the ER alternative (1) has countervailing properties that undermine CHD benefits and/or (2) fails to recapitulate
essential properties of the established cardioprotective regimen that augment CHD benefits (cf Table 1). Thus, the AIM-HIGH null result occurred
because the ER alternative is markedly less effective than the established cardioprotective regimen and less effective than expectations, undermining
The HDL hypothesis is operative, but the effect of niacin was diluted in both groups by enrolling patients who were already treated with niacin. This
is problematic because the legacy effect of niacin in the CDP trial indicates niacin is a disease-altering drug. As such, participants who were already
on niacin might have fewer events than planned, undermining power calculations.
Faulty assumptions doomed the experiment
The HDL hypothesis is operative when HDL-C rises more than 6 % (cf HIT), but has a flat dose response beyond the unexpected 12 % increase from
IR niacin in the Bcontrol^ group. Thus, the AIM-HIGH null occurred because further increments in HDL-C from the ER alternative were past the
point of diminished returns. This implies the 12 % increase from IR niacin, like the 6 % increase from HIT, is beneficial, but to an unknown extent
because there was no niacin-free control group. In this scenario, the experiment was doomed by the demonstrably false assumption that low doses of
IR niacin had no impact on HDL-C, invalidating the control group.
The HDL hypothesis is operative, but the AIM-HIGH doses of niacin were not sufficient to raise HDL enough to detect the benefit. This could be
because HIT and HHS involve a second, unmeasured benefit of fibrate, or the ER alternative is simply inferior to the established cardioprotective
The experiment was compromised by bias
The HDL hypothesis is operative, but AIM-HIGH was undermined by introducing a third cardioprotective agent (ezetimibe) in an unbalanced
manner that disproportionately benefited the Bcontrol^ group. Thus, AIM-HIGH was null to the extent that the Bcontrol^ group received
gamechanging Bhelp,^ and the study could not cope with this bias, rendering null results untrustworthy.
The HDL hypothesis is operative, but went undetected because AIM-HIGH was aborted before one of the niacin-treated groups hit an inflection
point that would separate the event curves. Aborting a trial midway not only invalidates power calculations, but far worse, can introduce bias. For
example, if the analytical and especially the biological assumptions used to rationalize aborting the trial were faulty, the decision to not see the
protocol through completion can become a self-fulfilling/self-defeating prophecy. Thus, under this scenario, the AIM-HIGH was null due from
undermining power at best and from investigator bias at worst, rendering null results especially untrustworthy.
HDL hypothesis is actually incorrect
The HDL hypothesis is fundamentally misguided and incorrect, and the HIT and HHS regimens were primarily cardioprotective due to an
unmeasured benefit of gemfibrozil rather than raising HDL-C. If so, and niacin did not recapitulate fibrates’ unmeasured benefits, both low-dose IR
and the ER alternative would not have conferred benefits despite achieving HDL increments that were multiples of that of HIT. Thus, if and only if
all of the prior possibilities are immaterial, the AIM-HIGH null result would argue against the HDL hypothesis.
own control severely narrowed the HDL-C differential between
IR- and ER-niacin in AIM-HIGH. Outcome benefits from
narrow group-wise differences were probably well beyond the
detection limit of AIM-HIGH, powered to detect a 25 % reduction
in Bsofter^ clinical events. Complicating matters, almost 20 % of
patients in both groups, had previously been treated with niacin,
having discontinued 30 days before enrollment. The legacy
benefits of niacin seen in the CDP several years after niacin
discontinuation imply niacin is a disease-modifying drug, thus
fundamentally altering CHD risk for many years. Such legacy effects
would have persisted throughout the foreshortened AIM-HIGH
trial, reducing overall events, hence further diminishing the
study’s power to detect differences in outcomes.
Additionally, there were more insidious problems. For
example, there were significant group-wise differences in
simvastatin dose and use of ezetimibe (21.5 % on IR vs. 9.5 % on
ER niacin), mandated by on-study LDL-C matching.
Complicating matters, the IMPROVE-IT trial found further
reduction in cardiovascular events when ezetimibe is added
to statins [65 ]. Thus, AIM-HIGH allowed unbalanced use of
another cardioprotective agent, introducing a bias to the
Bcontrol^ group, insofar as that group was more likely to
receive Bhelp^ that could have disproportionately affected
outcomes. Compounding these challenges, AIM-HIGH was
prematurely terminated after a mean follow-up of only 3 years,
ostensibly for lack of expected benefit from an early peek at the
data and a non-significant increase in ischemic strokes in the
ER alternative group. This is a Bdouble-whammy^ because
aborting the study can decimate the power to detect meaningful
differences, but worse, can introduce bias. It appears the
investigators assumed event curves should exhibit a visible
separation at the time they made their decision, and finding none,
stopped the trial. But what if that assumption was wrong?
What if the curves separate later? Disconcertingly, the CDP
did not show divergent event rate curves for niacin and placebo
until well after 4 years. Thus, AIM-HIGH’s decision to stop the
study prematurely may have irretrievably biased results.
Of course one of the many possibilities behind a null result
is that the HDL hypothesis is incorrect. Given so many
unchallenged alternatives, we find the null results of AIM-HIGH
uninterpretable. Barring new post hoc subanalyses that might
distinguish the groups, results from AIM-HIGH should be
considered hypothesis-generating at best.
Would the ER Alternative Help When Statins Don’t
Regrettably, neither HPS2-THRIVE nor AIM-HIGH
decisively addresses the gap left in the statin-averse, non-responders,
and incomplete responders, almost half the total population at
risk of cardiovascular disease. Thus, we have no way to know
if the exploratory regimen with the ER alternative is helpful in
that population. In contrast, at 1000 mg thrice daily, we do
have evidence supporting IR-niacin and pentaerythrityl
tetranicotinate to prevent CHD events when statins do not
deliver. Likewise, since both trials of the ER alternative studies
enrolled subjects with fairly low LDL-C, neither adequately
assessed whether the exploratory alternative regimen would
prove cardioprotective when LDL-C is uncontrolled. That said,
the HPS2-THRIVE subgroup with LDL ≥ 58 mg/dL or
ApoB ≥ 60 mg/dL strongly suggests the ER alternative would
prove beneficial in people with suboptimal lipids.
The Lipid-Targeting Strategy
The other alternative to the established cardioprotective
regimen has been to titrate niacin to achieve specific lipid targets.
Though this has been tested in small studies of atherosclerosis,
the strategy has not found the backing to be scaled up to larger
outcomes trials. Thus, while atheroprotective, we cannot
conclude that the lipid-targeting approach is cardioprotective.
Using ≥2–3 g/day, the FATS, HATS, CLAS, and AFREGS
trials affirmed decisive lipid benefits [
]. Using higher
doses of niacin than in AIM-HIGH or HPS2-THRIVE, these
studies achieved much more robust differentials in HDL-C
(+25 to +40 %) accompanied by improvements in coronary
atherosclerosis. The differential between the IR- and
ERniacin arms of AIM-HIGH only resulted in a 15 to 16 %
differential in HDL-C, much less than the lipid-targeting
studies. What if it actually takes an HDL-C differential on the
order of +25 to +40 % to distinguish a benefit on
cardiovascular events? If so, the decision to abandon the
atheroprotective lipid-targeting strategy in favor of the ER
alternative with its severe dose restriction may have doomed
AIM-HIGH and HPS2-THRIVE, as they had nothing more
than inconsequential niacin doses to work with. There is a
difficulty in interpreting the lipid-targeting strategy, because
these studies also achieved significant LDL-C changes.
Hence, atheroprotection cannot be attributed to HDL-C or
LDL-C changes separately. Admittedly, that distinction would
be somewhat academic if the strategy proved cardioprotective.
If Not by Raising HDL, How Does Niacin Prevent CHD
The first outcomes trial of the HDL hypothesis outside the
fibrate class was a wash, since the troubled AIM-HIGH study
did not clearly confirm or deny a role for raising HDL-C. For
the sake of discussion, suppose AIM-HIGH was a valid null
that ruled out the HDL hypothesis. How could we rectify that
with compelling evidence that niacin is cardioprotective? The
simple answer would be that the ER alternative is so inferior
as to be inert. Perhaps AIM-HIGH and HPS2-THRIVE were
hamstrung by capping the ER alternative at 2 g/day, thus
limiting the lipid suppression by underdosing.
A more nuanced answer returns us full circle: niacin is
cardioprotective to the extent it suppresses cholesterol, as
illustrated in Fig. 1b. By this model, CDP and SIHDS prevented
CHD because they dosed niacin to robustly lower cholesterol,
whereas HPS2-THRIVE and AIM-HIGH delivered modest
cholesterol reductions owing to sparing use of niacin. Indeed,
some investigations using ≤2 g/day of the ER alternative failed
to show LDL-C benefits at all, even after several months [66,
67]. Especially viewed in the context of all four niacin outcome
studies, both new studies nicely accord with the LDL
hypothesis. First, the HPS2-THRIVE affirmed patients with optimal
baseline LDL-C or ApoB had little LDL suppression and
accordingly, no benefit. Strikingly, the more Bclinical^
population with suboptimal lipids had greater LDL-C suppression
and, accordingly, benefit from the ER alternative, just as the
LDL hypothesis predicts. Second, the null result from the
AIM-HIGH study suggests a benefit from LDL suppression,
because both groups underwent intensive, fastidious LDL-C
management to suppress LDL-C below 80 mg/dL. One group
reached that target by driving simvastatin all the way to 80 mg,
whereas the other added 2 g of the ER alternative first, and both
groups utilized ezetimibe to reach the target. Consider this:
What does it mean that two aggressive strategies to further
suppress LDL-C did just that, and then achieved identical
effects on cardiovascular outcomes?
Parity of CHD events after equalizing LDL-C implies
adding even a modestly LDL-lowering dose of niacin actually
prevents CHD to the same extent as driving simvastatin all the
way to 80 mg to force LDL-C below 80 mg/dL. Thus,
Bneutral^ CHD outcomes from AIM-HIGH actually validate
either method to force LDL that low. This is actually very
helpful information to clinicians who might be concerned
about putting a given patient on 80 mg of simvastatin for fear
of harmful effects. As an eerily apt affirmation of this
realworld concern, during the AIM-HIGH simvastatin 80 mg
became strongly discouraged by the FDA due unacceptable
risks, underscoring the frustrating reality that maximizing
statins may be easier said than done for many. In conclusion,
the overall evidence suggests niacin prevents CHD events by
the cholesterol hypothesis after all and as such should be used
to suppress the atherogenic lipoproteins rather than raise
If Used At All, How Should Niacin Be Used?
If niacin is to be used to prevent MI, we find it harder to
support the exploratory regimen based around the ER
alternative. Instead, the overall evidence supports a return to the
established cardioprotective regimen, namely 1 g thrice daily
with meals. Practically, we find it surprisingly easy to switch
patients from the ER alternative 2 g nightly to IR-niacin 1 g
thrice daily, probably because they have substantial tolerance
to NASTy symptoms by the time they accommodate 2 g of the
ER alternative. For patients intolerant, averse, or
nonresponsive to statins, this regimen remains evidence-based
monotherapy to prevent MI, whereas under-dosing the ER
alternative before the overnight fast provides little such
assurance. Whether niacin per se would benefit statin-responsive
patients remains unanswered, since the established
cardioprotective regimen has never been tested against a statin
background. For that matter, when introduced the statins were
never subjected to the same standard of being formally tested
against a niacin background to determine incremental benefit.
Thus, formal testing of incremental effects of new lipid drugs
remains in its infancy, with much work to be done.
We submit the exploratory ER regimen (≤2 g/day) has thus
far failed to impress because it strays so far from the established
regimen, but not because of the delayed-release formulation
itself. Since the niacin pro-drug pentaerythrityl tetranicotinate
also delays niacin release, niacin release rates may well prove
immaterial. Accordingly, were the established cardioprotective
regimen tested against a statin background, we predict even the
ER alternative dosed 1 g thrice daily with meals would prevent
CHD among subjects with suboptimal lipids, much as the
longer-acting pentaerythrityl tetranicotinate did. That said, we
suspect a more efficacious approach would be to combine the
established cardioprotective regimen with the lipid-targeting
strategy. Thus, subjects randomized to niacin would receive
the established cardioprotective regimen as a condition of
enrollment, but would then titrate upwards if they were short of
study-determined non-HDL-C and HDL-C goals, capped at the
highest tolerated approved dose (i.e., up to 2 g thrice daily).
Conclusions: Whither Niacin?
The spectacular failure of the exploratory ER alternative
introduces a new barrier to progress. It is tempting to
reappropriate failure of the ER alternative into a more general
failure of the established cardioprotective regimen,
notwithstanding compelling evidence to the contrary (cf. Fig. 1). As
an analogy, we could appreciate how frustration over the
inopportune failure of a $20 knockoff Rolex could damage the
Rolex brand, unless the buyer were sufficiently streetwise to
distinguish the knockoff from the genuine article. We fear
further research might be chilled unless a broad coalition of
stakeholders were open to the possibility that the profoundly
disappointing results from the ER alternative in AIM-HIGH
and HPS2-THRIVE do not generalize to the duly-established
cardioprotective regimen. Failing that, developers and their
funders who are already banking on that prospect could
exploit the intense Bbuyer’s remorse^ for the ER alternative and
thereby blaze a new trail by proving the merits of novel niacin
mimetics with little competition from niacin itself. Stoking an
ongoing failure to distinguish the dubious exploratory
alternative from the established cardioprotective regimen could
quash competition from niacin in perpetuity. Thus, by delving
deeper into the overall evidence and skirting prior pitfalls,
canny prospectors could effectively open a goldmine at the
ER alternative’s grave site. In part II of this review, we will
walk through how several developers have leveraged the
overall pre-clinical and clinical evidence to develop novel niacin
mimetics, concluding with a review of several mimetics that
have already demonstrated encouraging lipid effects in small,
early phase human trials.
Acknowledgments Support provided by NIH grant K23HL091130
(R.L. Dunbar) from the NHLBI.
Compliance with Ethical Standards
Conflict of Interest Richard L. Dunbar declares an NIH grant from the
NHLBI; he also declares a grant from the NIH for the AIM-HIGH study,
where he served as the local principal investigator, overseeing 30
participants from the Philadelphia VA Medical Center and 14 from the
University of Pennsylvania.
Harsh Goel also participated in the AIM-HIGH study, assisting Dr.
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.
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