Correspondence

than in those between the ages of 20 and 40 Maria T. Ochoa, M.D.

years.4 Additional study of an association be- Brandon L. Adler, M.D.
tween immunosenescence and leprosy would Los Angeles General Medical Center
seem to be warranted. Los Angeles, CA
brandon​.­adler@​­med​.­usc​.­edu
It is notable that all our patients were men. A
systematic review that was conducted from 2010 theDisclosure forms provided by the authors are available with
full text of this letter at NEJM.org.
through 2020 showed a male predominance
(63%) among global leprosy cases, possibly re- 1. Fine P. Autochthonous leprosy — epidemiological implica-
lating to disparities in social involvement, expo- tions. Presented at the 21st International Leprosy Congress, Hy-
sure risk, or health care access.5 Another poten- derabad, India, November 8–11,2022. abstract.
2. Truman RW, Singh P, Sharma R, et al. Probable zoonotic
tial association is lower socioeconomic status, leprosy in the southern United States. N Engl J Med 2011;​364:​
which was not reflected in our cohort but re- 1626-33.
3. Suárez-García I, Gómez-Barroso D, Fine PEM. Autochtho-
quires additional study. nous leprosy in Spain: has the transmission of Mycobacterium
It is important that U.S. health care providers leprae stopped? PLoS Negl Trop Dis 2020;​14(9):​e0008611.
be aware of autochthonous leprosy in patients 4. da Silva PHL, de Castro KKG, Mendes MA, et al. Presence of
without typical risk factors. With earlier detec- senescent and memory CD8+ leukocytes as immunocenescence
markers in skin lesions of elderly leprosy patients. Front Immu-
tion, multidrug therapy can be initiated in a nol 2021;​12:​647385.
timely manner and potentially prevent irrevers- 5. Yang J, Li X, Sun Y, et al. Global epidemiology of leprosy
from 2010 to 2020: a systematic review and meta-analysis of the
ible disability. proportion of sex, type, grade 2 deformity and age. Pathog Glob
Annika Belzer, M.D., M.H.S. Health 2022;​116:​467-76.
Yale School of Medicine
New Haven, CT DOI: 10.1056/NEJMc2302317

Statin Intolerance, Bempedoic Acid,

and Cardiovascular Outcomes
To the Editor: We would like to ask the investi-
gators in the CLEAR (Cholesterol Lowering via
Bempedoic Acid [ECT1002], an ACL-Inhibiting
Regimen) Outcomes trial (April 13 issue)1 to pro-
vide additional safety data to help clinicians put
the safety of bempedoic acid into better perspec-
tive. Phase 3 trials have indicated that bempedoic
acid increases the platelet count and homocyste-
ine level and decreases the hemoglobin level and
hematocrit.2,3 Such changes are of great concern,
given the potential long-term nature of this ther-
apy and the known detrimental effects of throm-
let count, homocysteine level, hemoglobin level,
and hematocrit that were observed in this ran-
domized, placebo-controlled trial, to indicate
whether the between-group differences were sig-
nificant, and whether the changes were deemed
to be clinically significant by the authors.
Pedro Lopez‑Ayala, M.D.
Noemi Glarner, M.D.
Christian Mueller, M.D.
Cardiovascular Research Institute Basel
Basel, Switzerland
christian​.­mueller@​­usb​.­ch

bocytosis, homocysteinemia, and anemia on car-
diovascular health.4,5 Therefore, many experts
were curious to see whether the CLEAR Out-
comes trial would confirm or refute the hypoth-
esis that bempedoic acid produces unfavorable
hematologic effects. If such effects did occur, ad-
ditional studies exploring the mechanisms under-
lying them would be warranted. Unfortunately,
no laboratory safety results regarding platelet
count, homocysteine level, hemoglobin level, or
hematocrit were presented in the article. Thus,
we ask the authors to report the changes in plate-
Dr. Lopez-Ayala reports receiving research grants from
the Swiss Heart Foundation and speaker’s fees from Quidel,
paid to the institution. Dr. Glarner reports receiving research
funding from the Swiss Heart Foundation. Dr. Mueller reports
receiving research support from the Swiss National Science
Foundation, the Swiss Heart Foundation, KTI (the Swiss Fed-
eral Commission for Technology and Innovation), Stiftung
für kardiovaskuläre Forschung Basel, the University of Basel,
Abbott, Beckman Coulter, Thermo Fisher Scientific, Idorsia,
LSI Medience, Novartis, Ortho Clinical Diagnostics, Quidel,
Roche, Siemens, Singulex, and SphingoTec and speaker’s fees
and consulting fees from Amgen, AstraZeneca, Bayer, Boeh-
ringer Ingelheim, BMS, Idorsia, Novartis, Osler Diagnostics,
Roche, and Sanofi, all of which were paid to the institution.
No other potential conflict of interest relevant to this letter
was reported.

n engl j med 388;26 nejm.org June 29, 2023 2487

The New England Journal of Medicine
Downloaded from nejm.org by Marco Gonzalez on November 7, 2023. For personal use only. No other uses without permission.
Copyright © 2023 Massachusetts Medical Society. All rights reserved.
 The n e w e ng l a n d j o u r na l
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. 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.
3. Swissmedic, Swiss Agency for Therapeutic Products. Swiss
public assessment report: nilemdo. February 5, 2021 (https://
www​.­swissmedic​.­ch/​­dam/​­swissmedic/​­de/​­dokumente/​­zulassung/​
­s wisspar/​­67583​-­n ilemdo​-­01​-­s wisspar​-­20210205​.­pdf​.­download​
.­pdf/​­SwissPAR_Nilemdo_final​.­pdf).
4. Lawton JS, Tamis-Holland JE, Bangalore S, et al. 2021 ACC/
AHA/SCAI guideline for coronary artery revascularization: a re-
port of the American College of Cardiology/American Heart
Association joint committee on clinical practice guidelines. Cir-
culation 2022;​145(3):​e18-e114.
5. Mueller C, Neumann F-J, Hochholzer W, et al. The impact of
platelet count on mortality in unstable angina/non-ST-segment
elevation myocardial infarction. Am Heart J 2006;​151(6):​1214.e1-
1214.e7.
DOI: 10.1056/NEJMc2305917
To the Editor: The CLEAR Outcomes trial
showed that in patients with high cardiovascular
risk who are unwilling or unable to take statins,
bempedoic acid is an effective alternative. Con-
sideration of whether this medication improves
outcomes and adds value as compared with alter-
natives such as ezetimibe is important. Trials of
ezetimibe1,2 showed smaller cardiovascular bene-
fits than those in the CLEAR Outcomes trial but
used placebo instead of drug comparators in pa-
tients taking statins. Conclusions that are drawn
from indirect comparisons and dissimilar patient
populations may be misleading. The pleotropic
effects unique to statins and bempedoic acid may
be reason to question whether lowering of the
low-density lipoprotein (LDL) cholesterol level
alone with ezetimibe or other agents would be
equally effective. However, the liver-specific ac-
tivity of bempedoic acid may limit potential off-
target effects beyond lowering of the LDL choles-
terol level. Ezetimibe has established outcomes
data available, has a good side-effect profile, and
is more affordable than bempedoic acid. Com-
parative effectiveness trials evaluating statin
alternatives such as ezetimibe are needed to ad-
vance practice and provide cost-effective care for
patients who are unwilling or unable to take
statins.
Lance Spacek, M.D.
South Texas Veterans Health Care System
San Antonio, TX
lance​.­spacek@​­va​.­gov
Dr. Spacek reports serving as co-chair of the Veterans Af-
fairs–Department of Defense Clinical Practice Guideline for the
Management of Dyslipidemia for Cardiovascular Risk Reduc-
2488 n engl j med 388;26 nejm.org
The New England Journal of Medicine
Downloaded from nejm.org by Marco Gonzalez on November 7, 2023. For personal use only. No other uses without permission.
Copyright © 2023 Massachusetts Medical Society. All rights reserved.
of m e dic i n e
tion. No other potential conflict of interest relevant to this letter
was reported.
1. Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe
added to statin therapy after acute coronary syndromes. N Engl
J Med 2015;​372:​2387-97.
2. Zhan S, Tang M, Liu F, Xia P, Shu M, Wu X. Ezetimibe for the
prevention of cardiovascular disease and all-cause mortality
events. Cochrane Database Syst Rev 2018;​11(11):​CD012502.
DOI: 10.1056/NEJMc2305917
To the Editor: The investigators in the CLEAR
Outcomes trial found a lower risk of relevant
clinical end points with bempedoic acid than
with placebo because of a reduction in the LDL
cholesterol level with bempedoic acid therapy.
However, surprising findings from subgroup
analyses indicate that patients in secondary pre-
vention appeared to have less benefit than those
in primary prevention, despite having a higher
incidence of cardiovascular events. This result
contradicts the expectation that patients at high-
er cardiovascular risk may have greater benefits
from a reduction in the LDL cholesterol level.
One possible explanation for this counterin-
tuitive result may be additive therapy that in-
cludes lipid-lowering or antiatherosclerotic drugs.
As described in the article, patients in the pla-
cebo group were more likely to receive add-on
therapy than those in the bempedoic acid group
(15.6% vs. 9.4%), a situation that led to a conver-
gence of LDL cholesterol levels in the two trial
groups. However, it remains unclear whether
add-on therapy in this trial was used differently
in patients in primary prevention and those in
secondary prevention and how LDL cholesterol
levels differed between these populations. Thus,
further information is necessary to understand
the effect of compensatory treatment on the re-
sults of the CLEAR Outcomes trial in secondary
prevention.
Eva Steinacher, M.D.
Patrick Sulzgruber, M.D., Ph.D.
Alexander Niessner, M.D.
Medical University of Vienna
Vienna, Austria
patrick​.­sulzgruber@​­muv​.­ac​.­at
No potential conflict of interest relevant to this letter was
reported.
DOI: 10.1056/NEJMc2305917
To the Editor: In the CLEAR Outcomes trial,
stroke outcomes did not differ significantly be-
tween the two groups (hazard ratio, 0.85; 95%
June 29, 2023
 Correspondence

confidence interval [CI], 0.67 to 1.07). Although
this trial was not powered to find a significant
difference with respect to these outcomes, Table
S2 in the Supplementary Appendix (available
with the full text of the article at NEJM.org)
shows that the risk of ischemic stroke appeared
to be lower with bempedoic acid than with pla-
cebo (hazard ratio, 0.78; 95% CI, 0.61 to 0.99)
and that the risk of hemorrhagic stroke appeared
to be higher (hazard ratio, 2.21; 95% CI, 1.01 to
4.85). These data explain in part the nonsignifi-
cant difference that was observed in the overall
risk of stroke.
Similar results have been found with atorva­
statin treatment in the Stroke Prevention by Ag-
gressive Reduction in Cholesterol Levels (SPARCL)
trial,1 which used placebo as the comparator, but
not in the Treat Stroke to Target trial, in which
a lower-target group (LDL cholesterol level
reached, <70 mg per deciliter) was compared
with a higher-target group (LDL cholesterol level
reached, 100 mg per deciliter).2 In those trials,
hemorrhagic strokes were not associated with a
low attained level of LDL cholesterol3,4; in the
SPARCL trial, hemorrhagic strokes were mainly
associated with uncontrolled hypertension and
randomization of patients with small-vessel dis-
ease. What were the factors in the CLEAR Out-
comes trial that were associated with hemor-
rhagic strokes?
Pierre Amarenco, M.D.
Université Paris Cité
Paris, France
pierre​.­amarenco@​­aphp​.­fr
Dr. Amarenco reports having received unrestricted grants
from Pfizer, AstraZeneca, and Althera Pharmaceuticals, speak- pooled analysis of other clinical trials. A media-
trials, bempedoic acid therapy increased the
platelet count, decreased the hematocrit, and in-
creased the homocysteine level in the CLEAR
Outcomes trial. At 6 months, the median platelet
count had increased 7.2% with bempedoic acid
and 0.8% with placebo. The mean hematocrit de-
creased 2.3% with bempedoic acid, as compared
with an increase of 0.1% with placebo. Homocys-
teine was not measured. These changes are too
small to represent a clinical concern. The two
references suggesting harm that are cited by
these authors include an observational study
showing a lower event rate in the second quin-
tiles of platelet count among patients with acute
coronary syndromes and a coronary revascular-
ization guideline that addresses bleeding in pa-
tients undergoing coronary interventions. Neither
study is relevant to the clinical use of bempedoic
acid. The important finding from our trial was a
23% lower risk of myocardial infarction and a
19% lower risk of coronary revascularization in
the bempedoic acid group than in the placebo
group. The observed lower risks of cardiovascu-
lar events should alleviate concerns about ad-
verse cardiovascular effects of these small hema-
tologic changes.
We agree with Spacek that antiinflammatory
effects of bempedoic acid may have played a role
in the larger treatment effect that was observed
in our trial than in the trial investigating cardio-
vascular outcomes with ezetimibe.1 We also agree
that cross-trial comparisons are not reliable. The
importance of antiinflammatory effects on car-
diovascular outcomes was confirmed in a recent
2

er’s fees from Amgen and Viatris, and fees for serving on an tion analysis examining the role of the antiin-
advisory board or steering committee from Amgen, Novartis, flammatory and cholesterol-lowering effects of
and Kowa. No other potential conflict of interest relevant to this
letter was reported. bempedoic acid in the CLEAR Outcomes trial is
under way. For patients who were unable or un-
1. Amarenco P, Bogousslavsky J, Callahan A III, et al. High- willing to take statins owing to unacceptable
dose atorvastatin after stroke or transient ischemic attack. N Engl
J Med 2006;​355:​549-59. adverse effects, we think the most reasonable
2. Amarenco P, Kim JS, Labreuche J, et al. A comparison of two approach is the combination of ezetimibe and
LDL cholesterol targets after ischemic stroke. N Engl J Med 2020;​ bempedoic acid rather than either agent alone.
382:​9-19.
3. Goldstein LB, Amarenco P, Szarek M, et al. Hemorrhagic This combination therapy lowers the LDL cho-
stroke in the Stroke Prevention by Aggressive Reduction in Cho- lesterol level by 35 to 40%, an effect that is
lesterol Levels study. Neurology 2008;​70:​2364-70. similar to that with a moderate-intensity statin.3
4. Amarenco P, Kim JS, Labreuche J, et al. Intracranial hemor-
rhage in the TST trial. Stroke 2022;​53:​457-62. Steinacher et al. point out that the primary
DOI: 10.1056/NEJMc2305917 prevention subgroup in our trial appeared to
have a lower risk of cardiovascular events than
the secondary prevention subgroup. We do not
The authors reply: Lopez-Ayala et al. request consider this outcome surprising. The last two
confirmation whether, as reported in previous cardiovascular outcome trials that studied

n engl j med 388;26 nejm.org June 29, 2023 2489

The New England Journal of Medicine
Downloaded from nejm.org by Marco Gonzalez on November 7, 2023. For personal use only. No other uses without permission.
Copyright © 2023 Massachusetts Medical Society. All rights reserved.
 The n e w e ng l a n d j o u r na l of m e dic i n e

statins in patients in primary prevention showed A. Michael Lincoff, M.D.

large reductions in the risks of cardiovascular Cleveland Clinic
Cleveland, OH
events.4,5
Since publication of their article, the authors report no fur-
Amarenco comments on the directionally dif- ther potential conflict of interest.
ferent treatment effects with regard to ischemic
1. Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe
and hemorrhagic strokes. We urge caution in in- added to statin therapy after acute coronary syndromes. N Engl
terpreting these observations. The type of stroke J Med 2015;​372:​2387-97.
is one of many end-point components, the 2. Ridker PM, Bhatt DL, Pradhan AD, et al. Inflammation and
cholesterol as predictors of cardiovascular events among pa-
analyses were not adjusted for multiplicity, and tients receiving statin therapy: a collaborative analysis of three
there were small numbers of events, which re- randomised trials. Lancet 2023;​401:​1293-301.
sulted in wide confidence intervals. 3. Ballantyne CM, Laufs U, Ray KK, et al. Bempedoic acid plus
ezetimibe fixed-dose combination in patients with hypercholes-
Steven E. Nissen, M.D. terolemia and high CVD risk treated with maximally tolerated
statin therapy. Eur J Prev Cardiol 2020;​27:​593-603.
Cleveland Clinic Center for Clinical Research 4. Yusuf S, Bosch J, Dagenais G, et al. Cholesterol lowering in
Cleveland, OH intermediate-risk persons without cardiovascular disease. N Engl
nissens@​­ccf​.­org J Med 2016;​374:​2021-31.
5. Ridker PM, Danielson E, Fonseca FAH, et al. Rosuvastatin to
Stephen J. Nicholls, M.B., B.S., Ph.D. prevent vascular events in men and women with elevated C-reac-
Monash University tive protein. N Engl J Med 2008;​359:​2195-207.
Melbourne, VIC, Australia DOI: 10.1056/NEJMc2305917

Inaxaplin for Proteinuric Kidney Disease

in Persons with Two APOL1 Variants
To the Editor: In a proof-of-concept study, Dr.
Egbuna and colleagues (March 16 issue)1 found
that in participants with two APOL1 risk variants
(G1 or G2) and focal segmental glomerulosclero-
sis lesions on kidney biopsy, targeting apolipo-
protein L1 (APOL1) channel function with
inaxaplin reduced proteinuria. However, renin–
angiotensin blockade and immunosuppressive
therapy were not standardized, and the time
course of proteinuria in the weeks preceding day
1 of the study was not provided. It is important to
ensure that proteinuria is stable or increasing be-
fore initiation of proteinuria-modulating ther-
apy.2 Four participants were enrolled within
4 months after biopsy. The modulating effect
of blood-pressure control and renin–angiotensin
blockade on proteinuria may still have been oc-
curring at day 1. Two of these four participants
received immunosuppressive therapy, with marked
reduction in proteinuria. Remission of protein-
uria equals long-term kidney survival in patients
with primary glomerulopathies and heavy pro-
teinuria.3 Whether reduction of proteinuria in
patients with APOL1-related nephropathy, a con-
dition resembling a microvascular disease and
associated with low-grade proteinuria,4 will re-
sult in long-term preservation of estimated glo-
merular filtration rate (GFR) remains to be
shown in adequately controlled studies.
Maria Jose Soler, M.D., Ph.D.
Hospital Universitari Vall d’Hebron
Barcelona, Spain
Richard J. Glassock, M.D.
Geffen School of Medicine at the University of California,
Los Angeles
Los Angeles, CA
Fernando C. Fervenza, M.D., Ph.D.
Mayo Clinic College of Medicine and Science
Rochester, MN
fervenza​.­fernando@​­mayo​.­edu
No potential conflict of interest relevant to this letter was
reported.
1. Egbuna O, Zimmerman B, Manos G, et al. Inaxaplin for pro-
teinuric kidney disease in persons with two APOL1 variants.
N Engl J Med 2023;​388:​969-79.
2. Fervenza FC, Abraham RS, Erickson SB, et al. Rituximab
therapy in idiopathic membranous nephropathy: a 2-year study.
Clin J Am Soc Nephrol 2010;​5:​2188-98.
3. Thompson A, Cattran DC, Blank M, Nachman PH. Complete
and partial remission as surrogate end points in membranous
nephropathy. J Am Soc Nephrol 2015;​26:​2930-7.
4. Hughson MD, Hoy WE, Mott SA, et al. APOL1 risk alleles are
associated with more severe arteriosclerosis in renal resistance
vessels with aging and hypertension. Kidney Int Rep 2016;​1:​10-
23.
DOI: 10.1056/NEJMc2304780

2490 n engl j med 388;26 nejm.org June 29, 2023

The New England Journal of Medicine

Downloaded from nejm.org by Marco Gonzalez on November 7, 2023. For personal use only. No other uses without permission.
Copyright © 2023 Massachusetts Medical Society. All rights reserved.