CJASN ePress. Published on December 5, 2017 as doi: 10.2215/CJN.
12021017
Lowering Expectations with Niacin Treatment for
CKD-MBD
Tilman B. Drüeke1 and Ziad A. Massy1,2
Clin J Am Soc Nephrol 13: ccc–ccc, 2018. doi: https://doi.org/10.2215/CJN.12021017
With the progression of CKD, increasingly severe
disturbances of mineral and bone metabolism are
observed, which are reflected by the term CKD-related
mineral and bone disorder. The clinician’s goal is to
prevent or correct these complications and many other
CKD-associated complications as early and as com-
pletely as deemed adequate, taking into consideration
both efficacy and safety.
Hyperphosphatemia represents one among several
modifiable risk factors, and the avoidance of hyper-
phosphatemia is a well-established goal. This is on
the basis of a large body of preclinical, clinical, and
epidemiologic evidence indicating harmful effects of
phosphate excess in CKD. Hyperphosphatemia may
contribute to the development of vascular calcification,
cardiovascular events, and increased mortality risk
either directly or indirectly via the induction of various
endocrine and metabolic abnormalities. However,
many unsolved questions remain, including the fol-
lowing: (1) which type of hyperphosphatemia control
should be preferred?, (2) should action be taken al-
ready early in the course of CKD progression to prevent
hyperphosphatemia?, and (3) how intensively should
established hyperphosphatemia be corrected?
Because the optimal control of hyperphosphatemia
remains challenging, the most recent approach chosen
is pharmacologic interference with active intestinal
phosphate transport using either already available
drugs or developing novel inhibitors. Already avail-
able drugs include nicotinamide and nicotinic acid (also
called niacin, which is transformed to nicotinamide in
the body) (1,2). They inhibit the intestinal sodium-
dependent phosphate transporter NaPi2b (also called
Ntp2b). Nicotinic acid and nicotinamide have slightly
different mechanisms of action. Nicotinic acid alone
causes flushing due to stimulation of prostaglandin D2
and E2 secretion by subcutaneous Langerhans cells via
the G protein–coupled receptor 109A niacin receptor (3).
Nicotinamide does not bind to this receptor (4). The sec-
ond approach is the synthesis of tenapanor, an inhibitor of
the sodium/hydrogen exchanger isoform 3, which re-
duces sodium and phosphate absorption in the gut (5).
Figure 1 shows a schematic representation of the action of
these inhibitors compared with that of intestinal phos-
phate binders. Here, we focus on nicotinamide and niacin.
In the last decade, several clinical studies have shown
that the administration of niacin or nicotinamide
www.cjasn.org Vol 13 January, 2018
Editorial
reduced hyperphosphatemia in patients on dialysis 1
Institut National de la
together with a lower pill burden. However, the ma- Santé et de la Recherche
jority of these studies were limited by short treatment Médicale U-1018, Team
5, Centre de Recherche
periods, small sample size, and uncontrolled study en Epidémiologie et
design (i.e., failure to include a phosphate binder as a Santé des Populations,
comparator in patients with CKD on dialysis or patients Versailles Saint-
with CKD not on dialysis or a placebo in patients with Quentin-en-Yvelines
University (Paris-Ile-
CKD not yet on dialysis). Attempts to overcome these
de-France-Ouest
limitations were made in two recent studies. University), Paris-Sud
In this issue of the Clinical Journal of the American University and Paris
Society of Nephrology, Malhotra et al. (6) report the effects Saclay University,
of extended release niacin, 1500 or 2000 mg/d, com- Villejuif, France; and
2
Division of Nephrology,
pared with placebo on plasma phosphate in 352 Ambroise Paré Hospital,
individuals with CKD stages 3 and 4 (eGFR,60 ml/min Assistance Publique-
per 1.73 m2). This was a subgroup analysis of the Hôpitaux de Paris,
randomized, controlled AIM-HIGH Trial that enrolled Boulogne Billancourt/
Paris, France
3414 individuals with prevalent cardiovascular dis-
ease, low serum HDL cholesterol, and high triglyceride
Correspondence:
levels who were all on statin therapy (7). Because of Dr. Tilman B. Drüeke,
flushing effects of niacin, the placebo was designed to Inserm U-1018, Equipe
contain a small dose (50 mg) of immediate release niacin 5, CESP, Hôpital Paul
to mask the identity of blinded treatment. The parent Brousse, 16 Avenue
Paul Vaillant Couturier,
trial failed to show a reduction by niacin of recurrent
94807 Villejuif Cedex,
cardiovascular disease over 3 years. In this subgroup France. Email: tilman.
analysis, 297 patients (84%) had plasma samples avail- drueke@inserm.fr
able for measurement of mineral markers at year 1, and
140 (40%) had plasma samples available for measurement
of mineral markers at year 3. Randomization to niacin led
to a decrease of serum phosphate from 3.4 to 3.3 mg/dl
compared with an increase from 3.4 to 3.6 mg/dl in
placebo group. In intent to treat analysis, a summary
estimate showed that active treatment led to 0.08-mg/dl
lower plasma phosphate per year of treatment compared
with placebo. Although statistically significant (P,0.01),
the clinical relevance of the observed effect seems to be
poor, at least when considered solely on the basis of
changes in essentially normal plasma levels at baseline.
Information on changes in urinary phosphate excretion
might have helped to obtain a more favorable view of
niacin’s effect on phosphate control. Deceivingly, how-
ever, randomization to niacin was also not associated with
significant changes in plasma intact fibroblast growth
factor, parathyroid hormone, calcium, or vitamin D me-
tabolites over 3 years. Finally, patients on niacin treatment
had higher rates of flushing than those receiving placebo.
Lenglet et al. (8) randomized 100 patients on chronic
hemodialysis to either oral nicotinamide or sevelamer
Copyright © 2018 by the American Society of Nephrology 1
2 Clinical Journal of the American Society of Nephrology
Figure 1. | Schematic view of the action of oral inhibitors of active intestinal phosphate absorption compared with the chelation of phosphate
in the gut lumen by oral phosphate binders. Modified from reference 15, with permission.
hydrochloride treatment for 24 weeks to examine noninfer-
iority and safety; they observed a comparable decrease in
serum phosphate from 6.5 to 5.6 mg/dl and from 7.1 to 5.3
mg/dl, respectively. The criterion for noninferiority was,
however, not met due to a more limited number of patients
being included than planned. It is worth mentioning that
serum C-terminal FGF23 levels decreased by nearly 50% in
the sevelamer group, whereas they increased by nearly 30%
in the nicotinamide group, and serum a-Klotho levels de-
creased in the nicotinamide group but increased in the
sevelamer group. These differences were highly significant.
Treatment discontinuation due to adverse events was 1.6 times
higher in the nicotinamide group than in the sevelamer group,
with only 55% of study completers in the nicotinamide arm
versus 90% in the sevelamer arm. Thrombocytopenia was
observed in four nicotinamide-treated patients. Of further
concern is the observation of a large increase of nicotinamide
metabolite N-methyl-2-pyridone-5-carboxamide (2PY), espe-
cially in patients on dialysis treated with nicotinamide. Its
derivatives may be uremic toxins, enhancing oxidative stress
and disturbing cellular repair processes via an inhibition of
poly(ADP-ribose) polymerase-1 activity. Inhibitors of poly
(ADP-ribose) polymerase are under development in cancer
treatment, and the first studies show that they frequently
induce hematologic disorders, including thrombocytopenia,
in a dose-dependent manner (9).
Classic, more widely used means of controlling phosphate
retention in CKD in the clinic are briefly mentioned here.
Phosphate excess in CKD can be avoided by restricting
protein intake and other foods and beverages rich in phosphate.
However, this approach is generally of limited efficacy. More-
over, overzealous protein restriction may favor malnutrition.
In patients with CKD stage G5, the use of optimal renal
replacement modalities is an established, although generally
insufficient means to control hyperphosphatemia.
The most efficacious therapeutic approach in advanced
stages of CKD is the prescription of oral phosphate binders.
When effectively taken, they reduce elevated serum phos-
phate levels, although normalization is generally difficult
if not impossible to achieve. One of the major issues is failing
long-term compliance owing to high pill burden and
gastrointestinal intolerance. Lack of compliance is difficult
to assess. It certainly is highly variable depending on each
patient’s acceptance of ingesting large amounts of bulky
drugs and specific gastrointestinal side effects. Another issue
is that of potentially harmful effects on organs and tissues
other than the digestive tract. Prescription of highly effica-
cious aluminum-containing phosphate binders has been
largely abandoned because of serious aluminum toxicity.
The prescription of high doses of calcium-based phosphate
binders should be avoided because of recent evidence from
three randomized, controlled trials showing that excess
exposure to calcium through diet, medications, or dialysate
may be harmful in patients with CKD (10).
Given the above limitations of available means to control
serum phosphate in CKD, several new compounds have
been developed more recently with the goal to increase
efficacy and compliance. Novel magnesium-based binders
include iron/magnesium hydroxycarbonate and calcium
acetate/magnesium carbonate, novel iron-based phosphate
binders include sucroferric oxyhydroxide and ferric citrate,
and iron-magnesium hydroxycarbonate contains both
magnesium and iron. Although these new compounds may
present advantages over the classic phosphate binders, none of
them have provided definitive evidence of superiority in terms
of hyperphosphatemia control, not to speak of intermediate or
hard patient outcomes (11,12).
Although starting phosphate binder use in early CKD
stages can slightly reduce phosphate retention, it remains
uncertain whether this translates into clinical benefit (13,14).
The 2017 Kidney Disease Improving Global Outcomes
(KDIGO) Clinical Practice Guideline Update states the
following: “There is an absence of data supporting that
efforts to maintain phosphate in the normal range are of
benefit to CKD G3a–G4 patients, including some safety
concerns” (10). The work group, therefore, suggested that
treatment should be aimed at overt hyperphosphatemia and
that decisions about phosphate-lowering treatment should
be on the basis of progressively or persistently elevated
serum phosphate (10).
Clin J Am Soc Nephrol 13: ccc–ccc, January, 2018
To date, no prospective randomized trial has convincingly
shown improved survival for patients with CKD as a
consequence of hyperphosphatemia correction or preven-
tion. Therefore, the work group of the 2017 KDIGO Clinical
Practice Guideline Update for the Diagnosis, Evaluation,
Prevention, and Treatment of CKD-Related Mineral and
Bone Disorder suggested lowering elevated phosphate
levels toward the normal range (10), meaning that they
must not necessarily be completely normalized. This for-
mulation expresses persisting uncertainty as to which degree
of hyperphosphatemia should be corrected without creating
more harm than benefit.
In conclusion, the results of the trials with oral inhibitors
of active phosphate transport do not support the use of niacin
or nicotinamide alone in the control of serum phosphate in
CKD. It remains to be seen whether low-dose nicotinamide
treatments, such as the ones used in the ongoing trials COMBINE
(https://clinicaltrials.gov/ct2/show/NCT02258074) (15) and
NOPHOS (https://www.clinicaltrialsregister.eu/ctr-search/
trial/2013-000488-95/AT), will show clinically meaningful
efficacy together with fewer side effects. These trials exam-
ine the effect of nicotinamide as add-on therapy to classic
phosphate binders in patients with moderate to severe CKD
and patients on dialysis. As to nicotinic acid alone, it probably
has lost the battle.
Disclosures
T.B.D. reports personal fees from Amgen, FMC, Genentech-Roche,
Kyowa Hakko Kirin, Sanofi, and Vifor. Z.A.M. reports grants for CKD
Réseau Epidémiologie et Information en Néphrologie (REIN) and
other research projects from Amgen, Baxter, Fresenius Medical Care,
GlaxoSmithKline, Merck Sharp and Dohme-Chibret, Sanofi-Genzyme,
Lilly, Otsuka, and the French government as well as fees and grants to
charities from Amgen, Bayer, and Sanofi-Genzyme.
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Published online ahead of print. Publication date available at www.
cjasn.org.
See related article, “The Effect of Extended Release Niacin on
Markers of Mineral Metabolism in CKD,” on pages XXX–XXX.