Correspondence
Evaluating the effect of of bempedoic acid on organic anion
bempedoic acid on
kidney function:
call for cautious
implementation
We read with interest the Article
by Ray and colleagues, 1 which
showed that bempedoic acid
compared with placebo reduced
the risk of cardiovascular events
in statin-intolerant patients with
type 2 diabetes without previous
atherosclerotic cardiovascular disease.
They also showed treatment-related
improvements in LDL cholesterol
and non-HDL cholesterol and
improvements in high-sensitive
C-reactive protein concentrations, all
independent of patients’ glycaemic
and cardiovascular disease status.
Because existing treatments, such
as proprotein convertase subtilisin/
kexin type 9 (PCSK9) inhibitors,
often fail to sufficiently reduce LDL
cholesterol concentrations when
used as monotherapy, Ray and
colleagues’ findings concerning
bempedoic acid are promising for
clinical practice.2 However, we would
like to raise a point of concern
that deserves attention before
implementing bempedoic acid as
primary prevention of cardiovascular
disease in populations at high risk of
cardiovascular events.
Ray and colleagues 1 reported
an increased incidence of kidney
impairment under bempedoic acid
compared with placebo in their
appendix, particularly in patients
with prediabetes or diabetes, which
appeared to be largely attributable to
elevations in creatinine con­centrations
from baseline. This finding is similar
to previous research indicating
a reversible 6% increase in creatinine
concentrations with bempedoic
acid treatment. 3 In the paper by
Bays and colleagues,3 the authors
state that unpublished pre-clinical
studies suggest an inhibitory effect
228
2 Ray KK, Dhalwani N, Sibartie M, et al.
transporter 2 (OAT2), which is integral
to tubular creatinine secretion, as
a possible explanation. We agree with
the authors that this observation is in
line with the observed reversibility of
increased creatinine concentrations
more than other potential causes
for a sudden reduction in creatinine
concentrations, such as abrupt muscle
loss, reduced dietary intake, or acute
liver failure. Yet, the authors also
noted persistent increases in blood
urea nitrogen with bempedoic acid,3
which could indicate genuine kidney
function decline besides isolated
transporter effects. Furthermore, the
increased incidence of muscle-related
adverse events (odds ratio 0·75,
95% CI 0·55–0·99; p=0·046)4 together
with a baseline weight-adjusted mean
weight loss of 0·64 kg could have
indicated potential treatment-related
muscle loss. As creatinine production
is proportional to muscle mass,
muscle loss could influence creatinine
concentrations, 5 complicating the
interpretation of post-treatment
creatinine reversibility.
Because of the high prevalence of
diabetic kidney disease, which affects
approximately 40% of people with
diabetes and often culminates in
kidney failure, a careful evaluation
of bempedoic acid is crucial in this
population. Part of this evaluation
could involve analysing treatment
effects on kidney function via muscle
mass-independent markers such as
cystatin C,5 for which samples are
readily available per the protocol of the
CLEAR Outcomes trial.1
We declare no competing interests.
*Dion Groothof, Stephan J L Bakker
d.groothof@umcg.nl
Department of Internal Medicine, Division of
Nephrology, University Medical Center Groningen,
University of Groningen, Groningen 9713 GZ,
Netherlands (DG, SJLB)
1 Ray KK, Nicholls SJ, Li N, et al. Efficacy and
safety of bempedoic acid among patients
with and without diabetes: prespecified
analysis of the CLEAR Outcomes randomised
trial. Lancet Diabetes Endocrinol 2024;
12: 19–28.
www.thelancet.com/diabetes-endocrinology Vol 12 April 2024
Low-density lipoprotein cholesterol levels
exceed the recommended European
threshold for PCSK9i initiation: lessons
from the HEYMANS study.
Eur Heart J Qual Care Clin Outcomes 2022;
8: 447–60.
3 Bays HE, Banach M, Catapano AL, et al.
Bempedoic acid safety analysis: pooled data
from four phase 3 clinical trials. J Clin Lipidol
2020; 14: 649–59.
4 Ray KK, Bays HE, Catapano AL, et al. Safety
and efficacy of bempedoic acid to reduce
LDL cholesterol. N Engl J Med 2019;
380: 1022–32.
5 Groothof D, Post A, Polinder-Bos HA, et al.
Muscle mass and estimates of renal function:
a longitudinal cohort study.
J Cachexia Sarcopenia Muscle 2022; 13: 2031–43.
Authors’ reply
We thank Groothof and Bakker for
their query and the opportunity
to offer clarification. There are
extensive published data on the
safety of bempedoic acid from
the CLEAR Outcomes trial, in which
13 970 statin-intolerant patients at high
cardiovascular risk received bempedoic
acid.1,2 The small, placebo-corrected
increase in creatinine with bempedoic
acid of 0·04 mg/dL in patients both
with and without diabetes 3 was
consistent with findings in the overall
popula­tion from CLEAR Outcomes1
and previous phase 3 studies.4 In
all four previous phase 3 studies,
bempedoic acid treatment was
associated with small increases in
creatinine that appeared within the
first 4 weeks, were stable over time,
and were consistent regardless of
baseline renal function. Bempedoic
acid has also been associated with
small placebo-corrected changes of
8–10% in blood urea nitrogen (BUN),
which appear early and are stable over
time irrespective of baseline estimated
glomerular filtration rate (eGFR).2,4
The numerically increased rates of
adverse events summarised under
the heading renal impairment reflect
small changes in renal laboratories (eg,
increased creatinine, decreased eGFR,
or increased BUN) rather than clinically
meaningful acute or chronic changes
in renal function. Acute kidney injury
occurred in 1·1% of patients receiving

bempedoic acid and 1·0% of patients
receiving placebo, and renal failure
occurred in 1·1% of patients receiving
bempedoic acid and 0·9% of patients
receiving placebo; 0·2% of patients in
both treatment groups had an eGFR less
than 15 mL/min per 1·73m² at any time
during the trial.2 These small changes in
creatinine and BUN are reversible and
are probably related to inhibition of
the renal transporter OAT2.2
Modest changes in weight in
people with diabetes and prediabetes
with bempedoic acid have been
reported.3 This finding could be due
to the role of ATP citrate lyase, the
molecular target of bempedoic acid,
in lipid and carbohydrate metabolism,
which is supported by Mendelian
randomisation data.5 Groothof and
Bakker question whether the small
changes in creatinine and weight
could be associated with muscle
loss. We assessed the correlation of
weight change with renal laboratory
parameters in patients on the basis
of glycaemic status and baseline
BMI. The Spearman correlation
r values were all less than 0·1,
suggesting that less than 1% of the
change in renal laboratories were
explained by change in weight. At
36 months, patients treated with
bempedoic acid with a baseline
BMI less than 25 kg/m² had a mean
change in bodyweight of 0·43 kg (vs
0·66 for placebo), with a 6% mean
increase in creatinine (vs 3% for
placebo). Patients with baseline BMI
of 30 kg/m² or more had a mean
change in bodyweight of –2·28 kg
(vs –1·37 kg for placebo) and a 7%
mean increase in creatinine (vs 4%
for placebo). Finally, bempedoic acid
is a prodrug that requires enzyme
activation by very long chain acyl-
coenzyme A synthetase 1, which is
present in liver cells but absent from
muscle tissue. Muscle-related side-
effects have been balanced with
placebo in phase 3 trials. 1,2,4 Thus,
the comprehensive clinical data
suggest that the small changes in
creatinine and BUN do not appear
www.thelancet.com/diabetes-endocrinology Vol 12 April 2024
to be of clinical significance and are
independent of the small changes in
weight seen in people with obesity.
KKR reports unrestricted research grants in the past
3 years, paid to Imperial College London, from
Amgen, Sanofi, Regeneron, Daiichi Sankyo, and
Ultragenix; consulting fees from Novartis, Daiichi
Sankyo, Kowa, Esperion, Novo Nordisk, MSD, Lilly,
Silence Therapeutics, AstraZeneca, New Amsterdam
Pharma, Bayer, Beren Therapeutics, Cleerly,
EmendoBio, Scribe, CRISPR, Vaxxinity, Amarin,
Regeneron, Ultragenix, Cargene, and Resverlogix
for being a member of steering committees and
executive committees of clinical trials and for roles
as principle investigator and national lead
investigator; attends advisory boards, provides
advice on data, its interpretation, and future lines
of research, and lecture fees from Novartis,
Boehringer Ingelheim, AstraZeneca, Novo Nordisk,
Viatris, Amarin, Biologix Pharma, Sanofi, Amgen,
Esperion, Daiichi Sankyo, and Macleod Pharma;
holds stock options from New Amsterdam Pharma
and PEMI31; and is European Atherosclerosis
Society President (unpaid). NL and LB are
employees of Esperion Therapeutics. SEN received
grant support from Esperion Therapeutics for the
CLEAR Outcomes Trial; and the Cleveland Clinic
Center for Clinical Research has received funding to
perform clinical trials from Abbvie, AstraZeneca,
Arrowhead, Amgen, Bristol Myers Squibb, Eli Lilly,
Medtronic, MyoKardia, New Amsterdam
Pharmaceuticals, Novartis, and Silence
Therapeutics, in which SEN is involved in these
clinical trials but receives no personal remuneration
for his participation.
*Kausik K Ray, LeAnne Bloedon, Na Li,
Steven E Nissen, on behalf of the
co-authors
k.ray@imperial.ac.uk
Centre for Cardiovascular Disease Prevention,
Department of Primary Care and Public Health,
Imperial College London, London, UK (KKR);
Esperion Therapeutics, Ann Arbor, MI, USA (LB, NL);
Cleveland Clinic, Cleveland, OH, USA (SEN)
1 Nissen SE, Lincoff AM, Brennan D, et al.
Bempedoic acid and cardiovascular outcomes
in statin-intolerant patients. N Engl J Med
2023; 388: 1353–64.
2 Bays HE, Bloedon LT, Lin G, et al. Safety of
bempedoic acid in patients at high
cardiovascular risk and with statin
intolerance. J Clin Lipidol 2023; published
online Oct 31. https://doi.org/10.1016/j.
jacl.2023.10.011.
3 Ray KK, Nicholls SJ, Li N, et al. Efficacy and
safety of bempedoic acid among patients
with and without diabetes: prespecified
analysis of the CLEAR Outcomes randomised
trial. Lancet Diabetes Endocrinol 2024;
12: 19–28.
4 Bays HE, Banach M, Catapano AL, et al.
Bempedoic acid safety analysis: pooled data
from four phase 3 clinical trials. J Clin Lipidol
2020; 14: 649–59.
5 Ference BA, Ray KK, Catapano AL, et al.
Mendelian randomization study of ACLY and
cardiovascular disease. N Engl J Med 2019;
380: 1033–42.
Correspondence
Bridging the worlds of
research and policy
making
The first Editorial of 2024 in
The Lancet Diabetes & Endocrinology
was entitled “From research to policy:
still a long way to go”.1 It explored
potential reasons why much research
in the field, despite its transformative
potential for impact, is not taken up
and implemented into health policy.
It also explored actions that both
researchers and journal editors might
take to improve the strike rate.
An additional contributor not
mentioned is worthy of consideration.
To accurately assess clinical and cost
effectiveness, impact on population
health, affordability, and value for
health systems and the populations
that they serve, policy makers need
some indication as to the effectiveness
of interventions when implemented
in the real world. Effect sizes can be
attenuated when pragmatic inter­
ventional implementation within
the real world is compared with
interventional testing in randomised
controlled trial (RCT) settings.
RCTs involve ideal circumstances
and ideal participants, often highly
selected from much larger potential
participant populations, to derive
maximum interventional efficacy.
Interventional implementation in the
real world involves the application
to populations at scale and therefore
must include affordable circumstances,
often involving lower unit costs than
those invested in the corresponding
RCTs, where participants who might
have the greatest interventional and
health needs have characteristics
that are very different to those
of the ideal participants involved
in RCTs. For example, those from
more socioeconomically deprived
communities, and those of non-White
ethnicity, are often under-represented
in RCTs.2 This discrepancy between
RCT and real-world results has been
previously described by Wareham as
229