Short Report

Annals of Clinical Biochemistry

2015, Vol. 52(1) 180–182
! The Author(s) 2014
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DOI: 10.1177/0004563214533515
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LDL cholesterol variability in patients with Type 2

diabetes taking atorvastatin and simvastatin: a
comparison of two formulae for LDL-C estimation

T Sathyapalan1, SL Atkin1 and ES Kilpatrick2

Abstract
Background: A new formula was recently proposed by Cordovo et al. that was more highly correlated with low-density
lipoprotein (LDL) measured directly than the Friedewald LDL formula. We conducted this prospective study to establish
whether the new formula allows true variations in LDL within the same individual to be tracked more closely than that of
the Friedewald formula.
Methods: A cross-over study of biological variation of lipids in 26 patients with Type 2 diabetes (T2DM) taking either a
short half-life statin, simvastatin 40 mg (n ¼ 10), or a long half-life statin, atorvastatin 10 mg. After three months on one
statin, fasting lipids were measured on 10 occasions over a five-week period. The same procedure was then followed for
the other statin. The LDL was measured by a direct LDL immunoassay and was compared to the LDL estimated by the
Friedewald and Cordova (0.7516)  (total cholesterol [TC]high-density lipoprotein cholesterol [HDL-C]) formulae.
Results: As a group, the calculated or measured mean LDL was no different between statins. However, the biological
coefficient of variation (CV) of directly measured LDL was far larger with simvastatin than atorvastatin. This difference
was detected by Cordova LDL but not found with the Friedewald LDL formula.
Conclusions: In contrast to Friedewald LDL, Cordova LDL estimation revealed LDL to be much more stable in T2DM
patients taking atorvastatin rather than simvastatin that was in accord with LDL when measured directly. Therefore,
Cordova LDL which is a measure of non-HDL-cholesterol is the simplest, cheapest and the most convenient measure-
ment for assessment of response to statin treatment.

Keywords
Lipids, clinical studies, diabetes
Accepted: 8th April 2014

Introduction
Low-density lipoprotein cholesterol (LDL-C) is a major 1
Department of Endocrinology, Diabetes and Metabolism, University of
lipid parameter in cardiovascular risk assessment.
Hull, Hull, UK
The Friedewald formula is widely used for estimating 2
Department of Clinical Biochemistry, Hull and East Yorkshire Hospitals
LDL-C but has known limitations, including its use in NHS Trust, Hull, UK
patients with Type 2 diabetes (T2DM). More recently,
Corresponding author:
a simpler formula has been proposed to estimate T Sathyapalan, Michael White Diabetes Centre, Brocklehurst Building,
LDL-C with higher accuracy and simplicity for general Hull Royal Infirmary, 220–235 Anlaby Road, Hull HU3 2JZ, UK.
clinical use as well as have a higher correlation with Email: thozhukat.sathyapalan@hyms.ac.uk
Sathyapalan et al.
directly measured LDL-C (Cordova LDL-C).1 Using
an immunoassay to directly measure LDL-C, we have
shown that the biological coefficient of variation (CV)
of directly measured LDL-C in T2DM patients was far
larger with simvastatin than with atorvastatin even
though the mean value of LDL-C achieved by individ-
uals taking simvastatin 40 mg was not inferior to that of
atorvastatin 10 mg.2 In contrast, there were no signifi-
cant differences in this biological variability between
atorvastatin and simvastatin when Friedewald’s for-
mula was used,3 which may in part be because
Friedewald LDL-C is known to be less reliable in
patients with Type 2 diabetes. The current study was
undertaken to see if the biological variation of calcu-
lated LDL-C using Cordova’s formula was closer to
that of directly measured LDL-C than of the
Friedewald LDL-C formula.
A cross-over study of biological variation of lipids in
26 patients with T2DM taking either a short half-life
statin, simvastatin 40 mg (n ¼ 10), or a long half-life
statin, atorvastatin 10 mg. After three months on one
statin, fasting lipids were measured on 10 occasions
over a five-week period.3 The same procedure was
then followed with the other statin. The LDL-C was
estimated by the Friedewald and Cordova
(0.7516)  (total cholesterol [TC]high-density lipopro-
tein cholesterol [HDL-C]) formulae, and measured by a
direct LDL-C immunoassay. The direct LDL was mea-
sured using a Synchron DxC analyser (Beckman-
Coulter, High Wycombe, UK). The sensitivity for the
direct LDL assay was <8 mg/dL (<0.21 mmol/L).
Within-patient biological variability of LDL-C was
calculated by subtracting the analytical variance (esti-
mated from duplicate samples) from the within-subject
variance.4
Results
The baseline demographics, duration of diabetes and
glycaemic control were comparable in both groups.3
The (mean  standard deviation [SD]) calculated LDL-
C concentration using Cordova’s formula on atorvasta-
tin 10 mg was no different than when taking simvastatin
40 mg (2.21  0.15 mmol/L vs. 2.12  0.25, respectively,
P ¼ 0.52 using an unpaired t-test), confirming that the
simvastatin and atorvastatin drug dosages were equiva-
lent. In contrast, the variability of estimated LDL-C
using Cordova’s formula, expressed as SD, was lower
on atorvastatin (average SD  standard error of mean
[SEM]) (0.15  0.02 mmol/L) than on simvastatin
(0.25  0.04 mmol/L; P ¼ 0.02) (Figure 1). This equated
to a CV of 6.78% for atorvastatin and 11.83% for sim-
vastatin for estimated LDL-C using Cordova’s formula.
This was less than the CV of 10.30% for atorvastatin
and 13.10 for simvastatin for LDL-C calculated using
181
Friedwald’s formula. On the other hand, the variability
in direct LDL-C, expressed as SD, was much lower on
atorvastatin (average SD  SEM) (0.01  0.003 mmol/L)
than on simvastatin (0.17  0.02 mmol/L, P < 0.0001)
when direct LDL-C was used.
Conclusion
This study has shown that the biological variability of
LDL-C cholesterol when measured using Cordova’s for-
mula was significantly lower while taking atorvastatin
10 mg compared to simvastatin 40 mg daily, despite the
mean LDL-C values on both treatments being the same.
This pattern is consistent with the biological variability
of LDL-C measured using direct LDL-C measurement.2
These findings contrast with the biological variabil-
ity we found when LDL-C was calculated using the
Friedewald equation on the same samples. Although
useful in most cases, Friedewald’s formula applies
poorly to a number of atypical situations, such as
extremes of triglyceride (TG) and TC values as well
as in patients with Type 2 diabetes. In addition, the
Corvodo’s formula also has the advantage of not
requiring a fasting blood sample as it has been demon-
strated that a regular fasting period does not signifi-
cantly interfere with TC and HDL-C determination.
The greater improvement seen when Cordova’s for-
mula is applied to the atorvastatin data could be the
reflection of greater CV of triglyceride on atorvastatin.
The key difference between the formulas of Friedewald
and Cordova is that the triglyceride level is factored
into the former but not the latter. The CV of triglycer-
ides on simvastatin was 12.06%, whereas the CV on
atorvastatin was 19.71%. When compared to ultracen-
trifugation, which is the gold standard, LDL-C calcu-
lated by Cordova’s formula did not perform well.5
However, the most useful additional observation
would be that non-fasting non-HDL-cholesterol is the
simplest, cheapest and the most convenient measure-
ment for assessment of response to statin treatment
and is recommended in preference to LDL cholesterol
as the goal for lipid lowering therapy by the recent Joint
British Societies’ consensus recommendations for the
prevention of cardiovascular disease guidelines.6
In summary, this study has found marked differences
in the biological variability of Cordova LDL-C when
taking simvastatin compared to atorvastatin that is in
accord with directly measured LDL-C. This is in con-
trast to the lack of a difference found when calculating
LDL-C using Friedewald’s formula. While it is
unknown whether the increased variability of LDL-C
on simvastatin can influence cardiovascular risk, it has
direct implications on maintaining an LDL-C concen-
tration below target that will be more effectively
achieved using longer half-life treatments such as
182 Annals of Clinical Biochemistry 52(1)

Figure 1. Means (range) of Cordova calculated LDL-C in the same patients taking either simvastatin 40 mg or atorvastatin
10 mg daily.
atorvastatin. These findings suggest that using the
Cordova formula to estimate LDL measurement has
a potential clinical advantage over LDL calculated
using the Friedewald formula when used in patients
with T2DM taking statin treatment.
Declaration of conflicting interests
None declared.
Funding
The study was partially funded by an unrestricted educational
grant from Pfizer.
Ethical approval
South Humber Local Research Ethics Committee (ref: 04/
Q1105/40).
Guarantor
ESK.
Contributorship
ESK, SLA and TS are involved in conceiving, conducting,
analysing and drafting the manuscript.
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