Editorial
Lipid-Lowering Guidelines and Statin Use in CKD: A Time for Change
Related Article, p. 753
T he paradigm of accelerated atherosclerosis was
postulated rst by Lindner et al 1 more than
30 years ago to explain the excess burden of cardio-
vascular disease in patients with advanced dialysis-
dependent chronic kidney disease (CKD). Since then,
a large body of epidemiologic evidence has accumu-
lated, both conrming these ndings in dialysis
patients and extending the initial observations to the
much larger nondialysis-dependent CKD popula-
tion.2 Despite the increased awareness of the strong
links between CKD and cardiovascular disease, the
National Cholesterol Education Program Adult Treat-
ment Panel (ATP) IIIs lipid-lowering guideline did
not include CKD as a coronary heart disease (CHD)
risk equivalent.3,4 Similarly, in 2013, the American
College of Cardiology/American Heart Association
(ACC/AHA) Guideline on the Treatment of Blood
Cholesterol to Reduce Atherosclerotic Cardiovascular
Risk in Adults, CKD is not included as a predened
high-risk group that would necessarily benet from
statin therapy.5 This stance is controversial given
the marked benets of statins in both primary and sec-
ondary cardiovascular disease prevention,6 coupled
with randomized data suggesting comparable cardio-
vascular disease risk reduction associated with statin
use for patients with and without CKD.7
It is within this context that Foster et al8 have
examined the implications of reclassifying CKD as a
CHD risk equivalent for the number of adults in the
United States who would warrant lipid-lowering
therapy according to the ATP III approach. In this
cross-sectional study from NHANES (National Health
and Nutrition Examination Survey) 2007-2010, the
authors simulated 2 scenarios for including CKD as a
CHD risk equivalent: one that only includes CKD
stages 3-5 (scenario 1) and another that includes CKD
stages 1-5 (scenario 2). The authors report several
important ndings. First, although the use of lipid-
lowering therapy was higher among individuals with
more severe CKD, the proportion of individuals not
achieving their target low-density lipoprotein choles-
terol (LDL-C) goal as dened by ATP III was
Address correspondence to Paul Muntner, PhD, University
of Alabama at Birmingham, 1665 University Blvd, Ryals
Public Health Bldg, Ste 230J, Birmingham, AL 35294. E-mail:
pmuntner@uab.edu
2014 by the National Kidney Foundation, Inc.
0272-6386/$36.00
http://dx.doi.org/10.1053/j.ajkd.2014.02.001
736
substantially higher for individuals with CKD versus
those without. Specically, the percentage of US
adults not meeting their LDL-C goal was 22.9% in
those without CKD, 28.6% in those with stages 1-2
CKD, and 41.6% in those with stages 3-5 CKD.
Although this represents an improvement compared
with studies from the late 1990s and early 2000s, these
ndings highlight the clinical challenges of achieving
treatment goals in patients with CKD. Similar results
also have been reported for hypertension treatment in
CKD and the use of secondary preventive therapy,
such as b-blockers and antiplatelet agents, after
myocardial infarction (MI).9 Another important
nding of Foster et al8 was that the number of US
adults who would require lipid-lowering treatment
increased substantially under either scenario. For
example, for those with CKD (n 5 30 million), the
numbers of US adults meeting criteria for initiating
lipid-lowering therapy were 4.6, 7.8, and 13.2 million
under the ATP III guidelines, scenario 1, and scenario
2, respectively. These results are consistent with
earlier NHANES data demonstrating a large impact of
CKD reclassication on the number of individuals
who would be recommended statins.10 Although
certainly informative from a public health perspective,
the clinical relevance of these ndings is contingent on
cardiovascular disease risk in patients with CKD, the
association of LDL-C level with cardiovascular dis-
ease incidence in patients with CKD, and the efcacy
of statin therapy in CKD.
The rst assumption is whether patients with CKD
exhibit a high enough risk for CHD to be called a risk
equivalent. Recent data suggest that patients with
CKD do not have a CHD risk similar to individuals
who have had a prior MI. This was shown most
clearly by Tonelli et al11 in a population-based cohort
study involving more than 1 million community-
dwelling Canadian adults. In this study, risk for
a hospitalized MI was higher among those with a
prior MI (18.5/1,000 person-years) compared with
those who did not have a prior MI but had CKD (6.9/
1,000 person-years). Although it does not reach the
same level of risk as prior MI, it is clear that MI
risk in CKD is comparable or even greater than
for other conditions that are considered high-risk
states warranting aggressive lipid-lowering therapy,
such as diabetes mellitus. For example, in the
study by Tonelli et al,11 the incidence of MI in
those without prior MI but with diabetes was 5.4/
1,000 person-years. In addition, it is important to
note that cardiovascular disease risk in the setting of
CKD is heterogeneous, which complicates preventive
Am J Kidney Dis. 2014;63(5):736-738
Editorial
approaches that assume a uniformly high-risk prole
across the spectrum of CKD. In the study by Foster
et al,8 for example, w35% of individuals with CKD
were considered low risk using ATP III criteria.
Treating such low-risk patients with statin therapy
may not yield substantial cardiac benets while
exposing them to unnecessary costs and toxicity.
A second important assumption warranting exami-
nation prior to widespread implementation of admin-
istering statin therapy to patients with CKD is that the
link between LDL-C level and cardiovascular risk,
which forms the biological basis for statin therapy, is
similar across levels of kidney function. Among those
with nondialysis-dependent CKD, higher LDL-C
levels confer an increased, albeit attenuated, risk for
MI that persists as kidney function worsens.12 In addi-
tion, atherosclerotic plaque in CKD is characterized by
greater amounts of necrotic core13 and inammatory
mediators14 compared with those without CKD. Given
the favorable effects of statins on modulating plaque
composition15 and inammation,16 it is plausible that
statin therapy may yield benets beyond LDL-C
lowering in nondialysis-dependent patients with CKD.
Third, and perhaps most clinically relevant, are
ndings from pooled analyses and a single random-
ized study demonstrating the benets of statins in
lowering cardiovascular disease risk in the setting of
CKD.7,17 In the randomized SHARP (Study of Heart
and Renal Protection), the combination of simvastatin
and ezetemibe signicantly reduced a composite
cardiovascular end point over a 5-year follow-up
period compared to placebo.7 While very reassuring
from a clinical standpoint, these ndings may not be
generalizable to all patients with CKD because
SHARP primarily included patients with stages 3-5
CKD. As a result, the question of whether similar
benets also would be observed in those with albu-
minuria alone (stages 1-2 CKD) warrants further
investigation. These concerns notwithstanding, the
aggregate evidence to date strongly favors the use of
statins to lower cardiovascular disease risk for most
patients with nondialysis-dependent CKD.
Although the ATP III guideline was the cholesterol
guideline in place at the time the study by Foster et al8
was conducted, future studies should examine the
ndings of Foster et al8 within the context of the 2013
ACC/AHA and the KDIGO (Kidney Disease:
Improving Global Outcomes) lipid-lowering guide-
lines.5,18 Rather than relying on LDL-C thresholds to
initiate or target treatment, new guidelines recom-
mend starting lipid-lowering therapy according to a
patients predicted 10-year cardiovascular disease risk
irrespective of baseline LDL-C level. Under the new
ACC/AHA recommendations, any individual with an
estimated 10-year atherosclerotic cardiovascular dis-
ease risk . 7.5% is a candidate for statin therapy.5
Am J Kidney Dis. 2014;63(5):736-738
Similarly, in the KDIGO guidelines, all adults with
CKD older than 50 years who are not dialysis
dependent automatically qualify for statin therapy,
whereas younger adults with CKD do so if their
10-year CHD risk is .10%.18 Because most adults
with CKD are older than 50 years, the KDIGO
approach may be aligned more closely with the sec-
ond scenario in the report by Foster et al8 in which all
adults with CKD, irrespective of stage, are classied
as CHD risk equivalents. However, it is important to
note that there are limited data on the benets of
statins among individuals older than 75 years, in
whom the prevalence of CKD is substantial. Aban-
doning LDL-C thresholds to inform decision making
vis a vis statin therapy in patients with CKD also is
consistent with recent clinical observations demon-
strating that thrombotic risk is much higher among
those with versus without CKD irrespective of LDL-C
level.12
In conclusion, the study by Foster et al8 provides
important contemporary insight on the health services
implications of classifying all patients with CKD to a
higher risk state using the approach outlined in the
ATP III guideline. Irrespective of which guideline is
used to inform clinical decision making, it is clear
that individuals with CKD are at increased risk for
thrombotic events and that cardiovascular disease risk
reduction therapies are underused in these patients.
The continued underuse of statins for individuals with
CKD represents a missed opportunity to reduce the
burden of cardiovascular disease, which highlights the
need for approaches to increase the appropriate use of
statins among patients with CKD.
Usman Baber, MD, MS
Icahn School of Medicine at Mount Sinai
New York, New York
Paul Muntner, PhD
University of Alabama at Birmingham
Birmingham, Alabama
ACKNOWLEDGEMENTS
Support: None.
Financial Disclosure: Dr Muntner has served on an advisory
board for Amgen, Inc. Dr Baber declares that he has no relevant
nancial interests.
REFERENCES
1. Lindner A, Charra B, Sherrard DJ, Scribner BH. Accelerated
atherosclerosis in prolonged maintenance hemodialysis. N Engl J
Med. 1974;290(13):697-701.
2. Muntner P, He J, Astor BC, Folsom AR, Coresh J. Tradi-
tional and nontraditional risk factors predict coronary heart disease
in chronic kidney disease: results from the Atherosclerosis Risk in
Communities Study. J Am Soc Nephrol. 2005;16(2):529-538.
3. Grundy SM, Cleeman JI, Merz CN, et al. Implications of
recent clinical trials for the National Cholesterol Education
737

Program Adult Treatment Panel III guidelines. J Am Coll Cardiol.
2004;44(3):720-732.
4. Third Report of the National Cholesterol Education Program
(NCEP) Expert Panel on Detection, Evaluation, and Treatment of
High Blood Cholesterol in Adults (Adult Treatment Panel III) nal
report. Circulation. 2002;106(25):3143-3421.
5. Stone NJ, Robinson J, Lichtenstein AH, et al. 2013 ACC/
AHA Guideline on the Treatment of Blood Cholesterol to Reduce
Atherosclerotic Cardiovascular Risk in Adults: a report of the
American College of Cardiology/American Heart Association
Task Force on Practice Guidelines [published online ahead of print
November 12, 2013]. Circulation. http://dx.doi.org/10.1161/01.
cir.0000437738.63853.7a.
6. Baigent C, Blackwell L, Emberson J, et al. Efcacy and
safety of more intensive lowering of LDL cholesterol: a meta-
analysis of data from 170,000 participants in 26 randomised tri-
als. Lancet. 2010;376(9753):1670-1681.
7. Baigent C, Landray MJ, Reith C, et al. The effects of
lowering LDL cholesterol with simvastatin plus ezetimibe in
patients with chronic kidney disease (Study of Heart and Renal
Protection): a randomised placebo-controlled trial. Lancet.
2011;377(9784):2181-2192.
8. Foster MC, Rawlings AM, Marrett E, et al. Potential effects of
reclassifying CKD as a coronary heart disease risk equivalent in the
US population. Am J Kidney Dis. 2014;63(5):753-760.
9. Fox CS, Muntner P, Chen AY, et al. Use of evidence-based
therapies in short-term outcomes of ST-segment elevation myocar-
dial infarction and non-ST-segment elevation myocardial infarction
in patients with chronic kidney disease: a report from the National
Cardiovascular Data Acute Coronary Treatment and Intervention
Outcomes Network registry. Circulation. 2010;121(3):357-365.
10. Hyre AD, Fox CS, Astor BC, Cohen AJ, Muntner P. The
impact of reclassifying moderate CKD as a coronary heart disease
738
Baber and Muntner
risk equivalent on the number of US adults recommended lipid-
lowering treatment. Am J Kidney Dis. 2007;49(1):37-45.
11. Tonelli M, Muntner P, Lloyd A, et al. Risk of coronary events
in people with chronic kidney disease compared with those with
diabetes: a population-level cohort study. Lancet. 2012;380(9844):
807-814.
12. Tonelli M, Muntner P, Lloyd A, et al. Association between
LDL-C and risk of myocardial infarction in CKD. J Am Soc
Nephrol. 2013;24(6):979-986.
13. Baber U, Stone GW, Weisz G, et al. Coronary plaque
composition, morphology, and outcomes in patients with and
without chronic kidney disease presenting with acute coronary
syndromes. JACC Cardiovasc Imaging. 2012;5(3 suppl):S53-S61.
14. Pelisek J, Hahntow IN, Eckstein HH, et al. Impact of
chronic kidney disease on carotid plaque vulnerability. J Vasc
Surg. 2011;54(6):1643-1649.
15. Kini AS, Baber U, Kovacic JC, et al. Changes in plaque lipid
content after short-term intensive versus standard statin therapy: the
YELLOW trial (reduction in yellow plaque by aggressive lipid-
lowering therapy). J Am Coll Cardiol. 2013;62(1):21-29.
16. Sukhova GK, Williams JK, Libby P. Statins reduce
inammation in atheroma of nonhuman primates independent of
effects on serum cholesterol. Arterioscler Thromb Vasc Biol.
2002;22(9):1452-1458.
17. Strippoli GF, Navaneethan SD, Johnson DW, et al. Effects
of statins in patients with chronic kidney disease: meta-analysis
and meta-regression of randomised controlled trials. BMJ.
2008;336(7645):645-651.
18. Tonelli M, Wanner C. Lipid management in chronic kidney
disease: synopsis of the Kidney Disease: Improving Global Out-
comes 2013 clinical practice guideline [published online ahead of
print December 10, 2013]. Ann Intern Med. http://dx.doi.org/
10.7326/M13-2453.
Am J Kidney Dis. 2014;63(5):736-738