Journal of Clinical Lipidology (2016) 10, 368–377

Non–high-density lipoprotein cholesterol target

achievement in patients on lipid-lowering drugs
and stratified by triglyceride levels in the
Arabian Gulf
Khamis Al-Hashmi, MD, PhD, Ibrahim Al-Zakwani, PhD, Wael Al Mahmeed, MD,
Mohammed Arafah, MD, Ali T. Al-Hinai, MD, Abdullah Shehab, MD,
Omer Al Tamimi, MD, Mahmoud Al Awadhi, MD, Shorook Al Herz, MD,
Faisal Al Anazi, MD, Khalid Al Nemer, MD, Othman Metwally, MD,
Akram Alkhadra, MD, Mohammed Fakhry, MD, Hossam Elghetany, MD,
Abdel Razak Medani, MD, Afzal Hussein Yusufali, MD, Obaid Al Jassim, MD,
Omar Al Hallaq, MD, Fahad Omar Ahmed S. Baslaib, MD, Haitham Amin, MD,
Raul D. Santos, MD, PhD, Khalid Al-Waili, MD, Khalid Al-Rasadi, MD*

Department of Physiology, College of Medicine & Health Sciences, Sultan Qaboos University, Muscat, Oman (Dr Al-
Hashmi); Department of Pharmacology & Clinical Pharmacy, College of Medicine & Health Sciences, Sultan Qaboos
University, Muscat, Oman (Dr Al-Zakwani); Gulf Health Research, Muscat, Oman (Dr Al-Zakwani); Heart and Vascular
Institute –Cleveland Clinic, Abu Dhabi, UAE (Dr Al Mahmeed); King Saud University Hospital, Riyadh, KSA (Dr Arafah);
Ministry of Health, Muscat, Oman (Dr Al-Hinai); UAE University, AlAin, UAE (Dr Shehab); Hamad Medical
Corporation, Doha, Qatar (Dr Al Tamimi); Al Amiri Hospital, Kuwait City, Kuwait (Dr Al Awadhi); King Fahad National
Guard Hospital, Riyadh, KSA (Dr Al Herz); Ministry of Health, Riyadh, KSA (Dr Al Anazi); Al–Imam Mohammad Ibn
Saud Islamic University (IMSIU), School of Medicine, Riyadh, KSA (Dr Al Nemer); King Fahad General Hospital, Jeddah,
KSA (Dr Metwally); King Fahad Hospital of the University, Khobar, KSA (Drs Alkhadra, Fakhry); Soliman Fakieh
Hospital, Jeddah, KSA (Dr Elghetany); Dubai Hospital, Dubai, UAE (Drs Medani, Yusufali, Al Jassim); American
Hospital, Dubai, UAE (Dr Al Hallaq); Rashid Hospital, Dubai, UAE (Dr Baslaib); Bahrain Defense Force Hospital,
Manama, Bahrain (Dr Amin); Lipid Clinic Heart Institute (InCor), University of Sao Paulo Medical School Hospital, Sao
Paulo, Brazil (Dr Santos); and Department of Biochemistry, Sultan Qaboos University Hospital, Muscat, Oman (Drs Al-
Waili, Al-Rasadi)

KEYWORDS: BACKGROUND: Atherogenic dyslipidemia is highly prevalent in the Arabian Gulf. Non–high-density
Cardiovascular diseases; lipoprotein cholesterol (non-HDL-C) reduction has been proposed as an additional goal to low-density

The CEPHEUS project was sponsored by AstraZeneca. The sponsor
had no involvement in the study conception or design; analysis or interpre-
tation of data; writing, review, or approval of the manuscript; or the deci-
sion to submit the manuscript for publication.
* Corresponding author. Department of Biochemistry, Sultan Qaboos
University Hospital, P.O. Box 38, Al-Khod, Muscat 123, Oman.
E-mail address: k.alrasadi@gmail.com
Submitted August 25, 2015. Accepted for publication December 16,
2015.

1933-2874/Ó2016 National Lipid Association. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://
creativecommons.org/licenses/by-nc-nd/4.0/).
http://dx.doi.org/10.1016/j.jacl.2015.12.021
Al-Hashmi et al Non-HDL-C target achievement in patients with high triglyceride levels in the Arabian Gulf 369

HDL cholesterol;
lipoprotein cholesterol (LDL-C) lowering to prevent atherosclerotic cardiovascular disease (ASCVD).
Triglycerides;
Data on non–HDL-C goal attainment in patients with high triglycerides (TGs) on lipid-lowering drugs
Non-HDL cholesterol;
(LLDs) in the region is scarce.
LDL cholesterol;
OBJECTIVE: Evaluate non–HDL-C target attainment according to the National Lipid Association in
Apolipoprotein B;
patients on LLDs stratified by TG (,150 [1.69], 150–200 [1.69–2.26], .200 [2.26] mg/dL [mmol/L])
Diabetes mellitus;
levels in the Arabian Gulf.
Middle East
METHODS: Overall, 4383 patients on LLD treatment from 6 Middle Eastern countries participating
in the Centralized Pan-Middle East Survey on the Undertreatment of Hypercholesterolemia study were
evaluated. Patients were classified according to TG levels and ASCVD risk.
RESULTS: The overall non–HDL-C goal attainment was 41% of the subjects. Non–HDL-C goal was
less likely attained in patients with high TGs (12% vs 27% vs 55%; P , .001). Very high ASCVD risk pa-
tients with high TGs attained less their non–HDL-C targets compared with those with lower TG levels (8%
vs 23% vs 51%; P ,.001). Similarly, high ASCVD risk patients with high TGs also failed more in attaining
non–HDL-C targets compared with those with lower TGs (26% vs 42% vs 69%; P , .001). In addition,
those with high TG also succeeded less in attaining LDL-C and apolipoprotein B goals (P , .001).
CONCLUSIONS: A large proportion of very high and high ASCVD patients on LLDs in the Arabian
Gulf are not at recommended non–HDL-C targets and hence remain at a substantial residual risk.
Ó 2016 National Lipid Association. Published by Elsevier Inc. This is an open access article under the CC
BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction
Non–high-density lipoprotein cholesterol (non-HDL-C)
represents the cholesterol carried by all atherogenic parti-
cles1 and is a good surrogate marker for triglyceride (TG)
and TG-rich lipoprotein particles.2 Although there is
modest evidence for the association between fasting TG
and atherosclerotic cardiovascular disease (ASCVD) risk,
recent data suggest a stronger association between
TG-rich lipoprotein particles and ASCVD.3–5
There is evidence that non–HDL-C is a better risk
estimator than low-density lipoprotein cholesterol (LDL-C)
in patients with high TG combined with diabetes mellitus,
metabolic syndrome (MetS), or chronic kidney disease.6
Moreover, non–HDL-C is considered a stronger predictor
of ASCVD morbidity and mortality,7 and changes in
non–HDL-C levels are even a better predictor of coronary
heart disease (CHD) events than on treatment levels of
LDL-C in subjects receiving lipid-lowering therapy.8,9
Therefore, several guidelines recognize non–HDL-C as a
secondary therapeutic target particularly in patients with
hypertriglyceridaemia.10–14 The US National Lipid Associ-
ation (NLA) in its recent published recommendation, rec-
ognizes both non–HDL-C and LDL-C as primary
therapeutic targets.15 In addition, a secondary optional
target, apolipoprotein B (Apo B), a marker of proathero-
genic lipoproteins, is also considered.
Data on non–HDL-C goal attainment stratified by TG
and ASCVD in patients undergoing lipid-lowering therapy
in the Arabian Gulf are scarce.16 The main objective of this
study was to evaluate non–HDL-C therapeutic target
achievement in patients on lipid-lowering drugs (LLDs)
stratified by TG levels in the Arabian Gulf region. Patients
were also stratified according to ASCVD risk. The attain-
ment of recommended LDL-C and Apo B targets was
also evaluated.
Methods
The methods have already been previously described.17
Briefly, the Centralized Pan-Middle East Survey on
the Undertreatment of Hypercholesterolemia study
(CEPHEUS) was a multicenter noninterventional survey
of patients on LLDs in 6 Middle Eastern countries (Saudi
Arabia, United Arab Emirates, Oman, Qatar, Bahrain, and
Kuwait). A total of 5457 patients from outpatient clinics
were enrolled in the survey by 177 specialists and primary
care physicians. The study was conducted between
November 22, 2009, and July 7, 2010. The inclusion
criteria were age $18 years; use of LLDs for $3 months,
with no dose change on the last 6 weeks.
A fasting blood sample was taken from each subject for
measurement of total cholesterol, HDL-C, LDL-C, TG,
apolipoprotein A1 (Apo A1), Apo B, glucose, and glycated
hemoglobin A1c (HbA1c). Blood samples were collected in
3 tubes (5 mL in a gel tube, 2 mL in a fluoride tube, and
2 mL in an EDTA tube). Blood samples were shipped by air
courier, and the tests were performed at the King Faisal
specialist Hospital and Research Centre (Riyadh, Saudi
Arabia). All laboratory tests underwent internal and
external quality control checks. Low HDL-C was defined
as levels of ,40 mg/dL (1.0 mmol/L) for men and
,50 mg/dL (1.3 mmol/L) for women.15 TG levels were
stratified into ‘‘normal’’ (,150 mg/dL [1.69 mmol/L]),
‘‘borderline’’ (150–200 mg/dL [1.69–2.26 mmol/L]), and
‘‘high’’ (.200 mg/dL [.2.26 mmol/L]).15
Criteria for ASCVD risk status was derived from the
NLA recommendations for patient-centered management
of dyslipidemia Part 1–Executive Summary.15 High-risk
group included patients with $3 major ASCVD risk
factors, diabetes mellitus (type 1 or 2) with 0/1 other major
ASCVD risk factor, or LDL-C $190 mg/dL (5.02 mmol/L;
severe hypercholesterolemia). Very high-risk group
370
included ASCVD and diabetes mellitus with $2 other
major ASCVD risk factors.15 Non–HDL-C targets were
30 mg/dL (0.8 mmol/L) higher than the recommended
LDL-C goals according to risk: ,100 mg/dL
(,2.6 mmol/L) and , 130 mg/dL (3.3 mmol/L) for high
and very high ASCVD patients, respectively.15 Because
CEPHEUS also had information about on treatment Apo
B concentrations, we also checked the attainment of Apo
B recommended goals, an optional target according to the
NLA recommendations, for example ,90 mg/dL and
80 mg/dL for high and very high ASCVD risk individuals,
respectively.15
Statistical analysis
Descriptive statistics was used to describe the data. For
categorical variables, frequencies and percentages were
reported. Differences among groups were analyzed using
Pearson’s chi-square tests. For continuous variables, mean
and standard deviation were used to summarize the data.
Analyses were performed using ordinary least squares
regression. Non–HDL-C goal attainment was also analyzed
using multivariable logistic model adjusting for age,
gender, components of MetS other than TG levels, namely:
waist circumference, glucose levels, HbA1c, HDL-C,
hypertension, and MetS itself as well as CHD, peripheral
artery disease, CVD, type of statin (atorvastatin, simva-
statin, and rosuvastatin), smoking status, LDL-C, and Apo
B levels. A priori 2-tailed level of significance was set at
.05. Statistical analyses were conducted using STATA,
version 13.1 (StataCorp, College Station, TX).
Ethics approval
This study complied with the Declaration of Helsinki.
The study had approval from the internal review bodies/
ethics committees of each participating institution in the
each of the Arabian Gulf countries. Furthermore, informed
written consent was also obtained from all patients enrolled
in the study.
Results
A total of 5457 patients participated in the survey.
Laboratory data were completely missing for 160 patients,
6 patients were underage, and 15 patients missed the
ASCVD risk level data. A further 17 patients were removed
because of missing gender and TG levels. Patients with low
and moderate ASCVD risk (n 5 876) were not included in
this study. Therefore, the final study sample comprised
4383 patients.
Table 1 outlines the demographics and clinical charac-
teristics of the cohort. The overall mean age of the cohort
was 57 6 11 years with 60% (n 5 2620) males and 75%
(n 5 3297) Gulf citizens. The average body mass index
was 31 6 7 kg/m2. The proportion of patients with CHD,
Journal of Clinical Lipidology, Vol 10, No 2, April 2016
diabetes mellitus, and MetS were 37% (n 5 1611), 77%
(n 5 3336), and 41% (n 5 1786), respectively. Most
patients (78%; n 5 3425) had very high ASCVD risk
status. The majority (94% n 5 4121) was on statin mono-
therapy. Patients on statin combination (statin plus other
lipid-modifying therapy) and other lipid-modifying thera-
pies (ezetimibe, fibrates, bile acid sequestrants, or nicotinic
acid) were 5.0% (n 5 220) and 1.0% (n 5 42), respectively.
Total cholesterol, LDL-C, non–HDL-C, HDL-C, TG (all in
mmol/L) and Apo B (in g/L) levels on treatment were
4.30 6 1.11, 2.53 6 0.94, 3.15 6 1.09, 1.15 6 0.31,
1.74 6 1.26, and 0.91 6 0.27, respectively.
Table 1 also stratifies patients according to TG levels,
‘‘normal’’ (,150 mg/dL [,1.69 mmol/L]), ‘‘borderline’’
(150–200 mg/dL [1.69–2.26 mmol/L]), and ‘‘high’’
(.200 mg/dL [.2.26 mmol/L]). The proportion of patients
with high TG was 19% (n 5 844) and low HDL-C was
found in 53% (n 5 2326). Those with high TGs were
more likely to be diabetic (81% vs 77% vs 74%;
P , .001), have low HDL-C (75% vs 63% vs 43%;
P , .001) and consequently present with the MetS (79%
vs 72% vs 18%; P , .001) when compared with those
with normal TG. Furthermore, when compared with those
with normal TG, the high TG cohort was also less likely
to attain the recommended Apo B levels (16% vs 27% vs
53%; P , .001). Of importance, patients with high TGs
were also less likely to attain both LDL-C (20% vs 22%
vs 37%; P , .001) and non–HDL-C (12% vs 27% vs
55%; P , .001) goals.
The association between non–HDL-C goal attainment
and TG levels was also reanalyzed adjusting for confound-
ing factors as stated previously. The findings were robust
and still remained the same. Therefore, higher levels of TG
were associated with lower probability of attaining non–
HDL-C goals. Specifically, those with borderline TG levels
were 64% less likely to attain their non–HDL-C goal
(adjusted odds ratio [OR], 0.36; CI, 0.27–0.49; P , .001)
compared with those with normal TG levels. In addition,
those with high TG levels were 94% less likely to attain
their non–HDL-C goal (OR, 0.06; CI, 0.04–0.09;
P , .001) compared with those with normal TG levels.
Furthermore, those with high TG levels were 83% less
likely to attain their non–HDL-C goal (OR, 0.17; CI,
0.11–0.26; P , .001) compared with those with borderline
TG levels.
The multivariate logistic model also demonstrated that
older age (OR, 0.97; 95% CI, 0.98–0.98; P , .001), higher
HbA1c levels (OR, 0.02; 95% CI, 0.01–0.48; P , .016), hy-
pertension (OR, 0.37; 95% CI, 0.28–0.48; P , .001), CHD
(OR, 0.35; 95% CI, 0.27–0.46; P , .001), higher LDL-C
levels (OR, 0.01; 95% CI, 0.01–0.02; P , .001), and higher
Apo B levels (OR, 0.01; 95% CI, 0.01–0.04; P , .001)
were all negatively associated with non–HDL-C goal
attainment. However, higher HDL-C (OR, 5.07; 95% CI,
3.12–8.23; P , .001) and rosuvastatin use (OR, 2.04;
95% CI, 1.03–4.04; P , .001) were both positively associ-
ated with non–HDL-C goal attainment. The other factors in
 Al-Hashmi et al
Table 1 Demographic, clinical, and laboratory characteristics of the CEPHEUS cohort stratified by triglyceride levels
Triglyceride levels, mg/dL (mmol/L)
Normal ,150 Borderline 150–200 High .200 (2.26),
Variable, n (%) unless specified otherwise All (N 5 4383) (1.69), n 5 2653 (1.69–2.26), n 5 886 n 5 844 P value
Gulf citizen 3297 (75) 2004 (76) 680 (77) 613 (73) .104
Age, mean 6 SD, years 57 6 11 57 6 11 56 6 11 54 6 11 ,.001

Non-HDL-C target achievement in patients with high triglyceride levels in the Arabian Gulf
Male gender 2620 (60) 1557 (59) 531 (60) 532 (63) .081
Weight, mean 6 SD, kg 82 6 17 81 6 17 84 6 17 84 6 18 ,.001
Waist circumference, mean 6 SD, cm 104 6 14 103 6 14 105 6 13 104 6 14 .002
Body mass index, mean 6 SD, kg/m2 31 6 7 31 6 7 32 6 8 32 6 7 ,.001
Smoking status, current 561 (13) 280 (11) 130 (15) 151 (18) ,.001
Coronary heart disease 1611 (37) 1054 (40) 302 (34) 255 (30) ,.001
Peripheral artery disease 149 (3.4) 93 (3.5) 27 (3.1) 29 (3.5) .807
Cerebrovascular disease 191 (4.4) 131 (5.0) 31 (3.5) 29 (3.4) .066
Diabetes mellitus 3336 (77) 1969 (74) 682 (77) 685 (81) ,.001
HbA1c, mean 6 SD, % (in diabetics only) 8.6 6 3.7 8.2 6 3.2 8.8 6 4.0 9.3 6 4.7 ,.001
Glucose levels, mean 6 SD, mmol/L 7.8 6 3.7 7.3 6 3.3 8.0 6 3.6 9.2 6 4.4 ,.001
Metabolic syndrome 1786 (41) 486 (18) 635 (72) 665 (79) ,.001
Hypertension 3067 (70) 1879 (71) 621 (70) 567 (67) .132
Blood pressure (BP), mean 6 SD, mm Hg
Systolic BP 133 6 18 133 6 19 133 6 18 133 6 18 .851
Diastolic BP 79 6 10 78 6 11 80 6 10 80 6 10 ,.001
ASCVD risk status
High risk 958 (22) 589 (22) 195 (22) 174 (21) .620
Very high risk 3425 (78) 2064 (78) 691 (78) 670 (79)
Dyslipidemia therapy
Statin monotherapy 4121 (94) 2522 (95) 832 (94) 767 (91) ,.001
Statin combination 220 (5.0) 117 (4.4) 47 (5.3) 56 (6.6) .033
Others 42 (1.0) 14 (0.5) 7 (0.8) 21 (2.5) ,.001
Lipid levels on treatment, mean 6 SD, mmol/L, unless specified otherwise
TC 4.30 6 1.11 4.01 6 0.98 4.49 6 1.08 4.99 6 1.20 ,.001
LDL-C 2.53 6 0.94 2.37 6 0.86 2.74 6 0.98 2.82 6 1.01 ,.001
HDL-C 1.15 6 0.31 1.23 6 0.31 1.09 6 0.27 0.99 6 0.25 ,.001
Non–HDL-C 3.15 6 1.09 2.79 6 0.90 3.41 6 0.99 4.01 6 1.15 ,.001
Apo B, g/L 0.91 6 0.27 0.83 6 0.23 0.99 6 0.26 1.10 6 0.29 ,.001
TG 1.74 6 1.26 1.15 6 0.29 1.91 6 0.17 3.43 6 2.00 ,.001
(continued on next page)

371
372 Journal of Clinical Lipidology, Vol 10, No 2, April 2016

the adjusted logistic model (gender, waist, glucose levels,

Age was missing in 8 patients, weight in 4 patients, waist in 123 patients, body mass index in 15 patients, metabolic syndrome in 26 patients, glucose levels in 84, systolic and diastolic BP in 8, and Apo B
Criteria for ASCVD risk status was adapted from the National Lipid Association criteria for atherosclerotic cardiovascular disease. High risk group included patients with $3 major ASCVD risk factors,
diabetes mellitus (type 1 or 2) with 0/1 major ASCVD risk factor or LDL-C $190 mg/dL (5.02 mmol/L; severe hypercholesterolemia). Very high risk group included ASCVD (coronary heart disease, peripheral
Apo B, apolipoprotein B; ASCVD, atherosclerotic cardiovascular disease; CEPHEUS, Centralized Pan-Middle East Survey on the Undertreatment of Hypercholesterolemia study; HDL-C, high-density lipoprotein

*Despite the lack of a recommended HDL-C goal by guidelines, satisfactory HDL-C was defined as ,40 mg/dL (1.03 mmol/L) for males or ,50 mg/dL (1.29 mmol/L) for females. Therapeutic lipoprotein
targets for the high-risk patients were LDL-C ,100 mg/dL (2.6 mmol/L), apo B , 90 g/dL (0.90 g/L), and non–HDL-C ,130 mg/dL (3.3 mmol/L). For the very high ASCVD risk group, therapeutic lipoprotein
P value

,.001
,.001
,.001
,.001
MetS, peripheral artery disease, CVD, atorvastatin, simva-
statin, and smoking status) were not significantly associated
with non–HDL-C goal attainment.
Figure 1 summarizes the percentage of patients
achieving LDL-C, non–HDL-C, and Apo B therapeutic tar-
gets in those with very high ASCVD risk stratified by TG
High .200 (2.26),

levels (N 5 3425). The proportion of patients who attained

LDL-C, non–HDL-C, and Apo B targets was 26%, 37%,
and 39%, respectively. Those with higher TGs were less
(25)
(20)
(12)
(16)
n 5 844

likely to attain LDL-C (17% vs 19% vs 32%; P , .001),

non–HDL-C (8% vs 23% vs 51%; P , .001), and Apo B
208
172
102
134

(15% vs 26% vs 51%; P , .001) recommendations.

Figure 2 summarizes the percentage of patients
achieving LDL-C, non–HDL-C, and Apo B therapeutic
targets in those with high ASCVD risk stratified by TG
(1.69–2.26), n 5 886

levels (N 5 958). The proportion of patients who achieved

Borderline 150–200

LDL-C, non–HDL-C, and Apo B therapeutic targets was

46%, 56%, and, 48%, respectively. Those with higher
TGs were less likely to attain their LDL-C (34% vs 35%
(37)
(22)
(27)
(27)

vs 53%; P , .001), non–HDL-C (26% vs 42% vs 69%;

Triglyceride levels, mg/dL (mmol/L)

P , .001), and Apo B (20% vs 31% vs 61%; P , .001)

329
197
240
237

goals.
targets were LDL-C ,70 mg/d/L (1.8 mmol/L), apo B ,80 g/dL (0.80 g/L), and non–HDL-C ,100 mg/dL (2.6 mmol/L).18

Figure 3 summarizes the prevalence of low HDL-C in

very high and high ASCVD risk patients as well as
cholesterol; LDL-C, low-density lipoprotein cholesterol; SD, standard deviation; TC, total cholesterol; TG, triglyceride.

controlled non–HDL-C stratified by TG levels

(N 5 1809). The proportion of patients who had low
(1.69), n 5 2653

HDL-C in those with very high and high ASCVD risk

Normal ,150

were 53% and 41%, respectively. Those with higher TGs

(57)
(37)
(55)
(53)

were more likely to have low HDL-C in very high ASCVD

risk (84% vs 75% vs 48%; P , .001) and high ASCVD risk
1521
971
1467
1404

(67% vs 56% vs 35%; P , .001), respectively.

Figure 4 summarizes the percentage of patients
artery disease, and CVD) and diabetes mellitus with $2 other major ASCVD risk factors.

achieving LDL-C, non–HDL-C, and Apo B therapeutic tar-

gets in those with diabetes mellitus stratified by TG levels
All (N 5 4383)

(47)
(31)
(41)
(41)
2058
1340
1809
1775
Variable, n (%) unless specified otherwise
Lipid goal attainments
(continued )

Figure 1 Lipid target achievements (LDL-C, non–HDL-C, and

Apo B) in very high atherosclerotic cardiovascular disease
(ASCVD)–risk patients stratified by triglyceride levels
Non–HDL-C

in 14 patients.

(N 5 3425). Therapeutic lipoprotein targets for the very high

HDL-C*

ASCVD risk group were LDL-C ,70 mg/dL (,1.8 mmol/L),

Apo B
LDL-C
Table 1

Apo B ,80 mg/dL (,0.80 g/L), and non–HDL-C ,100 mg/dL

(,2.6 mmol/L). Apo, apolipoprotein; LDL-C, low-density lipo-
protein; HDL-C, high-density lipoprotein.
Al-Hashmi et al Non-HDL-C target achievement in patients with high triglyceride levels in the Arabian Gulf
Figure 2 Lipid target achievements (LDL-C, non–HDL-C, and
Apo B) in high atherosclerotic cardiovascular disease
(ASCVD)–risk patients stratified by triglyceride levels
(N 5 958). Therapeutic lipoprotein targets for the high ASCVD
risk group were LDL-C ,100 mg/dL (2.6 mmol/L), Apo
B ,90 mg/dL (0.90 g/L), and non–HDL-C ,130 mg/dL
(3.3 mmol/L). Apo, apolipoprotein; LDL-C, low-density lipopro-
tein; HDL-C, high-density lipoprotein.
(N 5 2755). The proportion of patients who achieved LDL-
C, non–HDL-C, and Apo B therapeutic targets was 26%,
36%, and 38%, respectively. Those with higher TGs were
less likely to attain their LDL-C (17% vs 19% vs 32%;
P , .001), non–HDL-C (8% vs 24% vs 51%; P , .001),
and Apo B (15% vs 26% vs 51%; P , .001) goals.
Figure 5 summarizes the percentage of patients
achieving LDL-C, non–HDL-C, and Apo B therapeutic tar-
gets in those without diabetes mellitus stratified by TG
Figure 3 Prevalence of low HDL-C in very high and high
atherosclerotic cardiovascular disease (ASCVD)–risk patients
and controlled non–HDL-C stratified by triglyceride levels
(N 5 1809). Despite the lack of a recommended HDL-C goal
by guidelines, satisfactory HDL-C was defined as ,40 mg/dL
(,1.03 mmol/L) for males or ,50 mg/dL (,1.29 mmol/L) for fe-
males. Therapeutic non–HDL-C targets for high and very high
ASCVD risk patients were ,130 mg/dL (,3.3 mmol/L) and
,100 mg/dL (,2.6 mmol/L), respectively. Apo, apolipoprotein;
LDL-C, low-density lipoprotein; HDL-C, high-density
lipoprotein.
373
levels (N 5 670). The proportion of patients who achieved
LDL-C, non–HDL-C, and Apo B therapeutic targets was
26%, 41%, and 42%, respectively. Those with higher
TGs were less likely to attain their LDL-C (18% vs 15%
vs 30%; P 5 .001), non–HDL-C (12% vs 20% vs
52%; P , .001), and Apo B (16% vs 23% vs 52%;
P , .001) goals.
Discussion
To our knowledge, this is the first study in the Arabian
Gulf region evaluating the non–HDL-C therapeutic target
attainment in patients on LLDs. Non–HDL-C goals were
achieved in only 41% of the overall cohort and was
significantly inferior in patients with high TG levels.
Moreover, recommended non–HDL-C, LDL-C, and
optional Apo B values were achieved significantly lower
in those with higher TG concentrations and in those with
greater ASCVD risk. Finally, the prevalence of low HDL-C
levels increased according to higher TG levels and a greater
ASCVD risk.
Despite the modest evidence from interventional studies
showing that reduction of plasma TG levels prevents
cardiovascular events,3 recent data from both Mendelian
randomization18 and epidemiologic studies19 show
that TG-rich lipoproteins are indeed proatherogenic.
Non–HDL-C and Apo B are markers not only of LDL par-
ticles but also of TG-rich lipoprotein concentrations.2,15
Moreover, a post hoc evaluation of both Treat to New
Figure 4 Lipid target achievements (LDL-C, non–HDL-C, and
Apo B) in diabetic patients stratified by triglyceride levels
(N 5 2755). Therapeutic lipoprotein targets for the high athero-
sclerotic cardiovascular disease (ASCVD)–risk group were
LDL-C ,100 mg/dL (2.6 mmol/L), non–HDL-C ,130 mg/dL
(3.3 mmol/L), and Apo B ,90 mg/dL (0.90 g/L). Therapeutic
lipoprotein targets for the very high ASCVD risk group were
LDL-C ,70 mg/dL (,1.8 mmol/L), non–HDL-C ,100 mg/dL
(,2.6 mmol/L), and Apo B ,80 mg/dL (,0.80 g/L). Apo, apoli-
poprotein; LDL-C, low-density lipoprotein; HDL-C, high-density
lipoprotein.
374
Figure 5 Lipid target achievements (LDL-C, non–HDL-C, and
Apo B) in nondiabetic patients stratified by triglyceride levels
(N 5 670). Therapeutic lipoprotein targets for the high atheroscle-
rotic cardiovascular disease (ASCVD)–risk group were LDL-C
,100 mg/dL (2.6 mmol/L), non–HDL-C ,130 mg/dL
(3.3 mmol/L), and Apo B ,90 mg/dL (0.90 g/L). Therapeutic
lipoprotein targets for the very high ASCVD risk group were
LDL-C ,70 mg/dL (,1.8 mmol/L), non–HDL-C ,100 mg/dL
(,2.6 mmol/L), and Apo B ,80 mg/dL (,0.80 g/L). Apo, apoli-
poprotein; LDL-C, low-density lipoprotein; HDL-C, high-density
lipoprotein.
Targets and Incremental Decrease in End Points through
Aggressive Lipid Lowering studies has shown that the
persistent elevation of non–HDL-C was independently
associated with a greater risk of cardiovascular events
even when LDL-C was intensively reduced.8 Therefore,
several guidelines recognize non–HDL-C as an additional
therapeutic target, particularly in patients with hypertrigly-
ceridemia after achieving the primary LDL-C target.10–14
The NLA in its recent published recommendation recog-
nizes both non–HDL-C and LDL-C as the primary targets
of therapy.15 Furthermore, the International Atherosclerosis
Society13 and the UK’s National Institute for Health and
Care Excellence recommend the control of non–HDL-C
for ASCVD prevention.14 Hence, a persistent elevation of
TG and especially non–HDL-C concentrations indicate an
elevated risk of ASCVD events and should therefore be
controlled.
This analysis of the CEPHEUS population shows clearly
that there is a high degree of uncontrolled atherogenic
dyslipidemia in the Gulf region that is greater in those with
higher TG levels and very high ASCVD risk. Indeed, in
both high and very high ASCVD risk categories those with
higher TG levels significantly achieved lower rates of
success in attaining not only their non–HDL-C targets but
also LDL-C and Apo B recommendations.
The levels of TG were the dominant factor associated
with failure in attaining non–HDL-C goals even after
adjusting for other risk factors like glucose levels,
HbA1c, HDL-C, hypertension, and MetS. Specifically,
those with high TG levels were 94% and 83% less likely
to attain their non–HDL-C goal than normal and
Journal of Clinical Lipidology, Vol 10, No 2, April 2016
borderline TG levels, respectively. Moreover, the multi-
variate logistic model also demonstrated that older age,
higher HbA1c, hypertension, CHD, higher LDL-C, and
Apo B levels were all negatively associated with
non–HDL-C goal attainment. On the other hand, higher
HDL-C and rosuvastatin use were both positively asso-
ciated with non–HDL-C goal attainment. Switching from
other statin to rosuvastatin has been shown, by many
studies, to achieve a better control of non–HDL-C.20,21
These findings indicate the presence of residual risk
and implicate severe clinical consequences if these levels
of proatherogenic lipoproteins persist.
In the CEPHEUS study, a lower rate of non–HDL-C
control was found in comparison with the multinational
Lipid Treatment Assessment Project 2 (LTAP-2)22 that was
performed in the Americas, Europe, and in the Asia Pacific
regions. In the LTAP-2, non–HDL-C target attainment
occurred in 63% of study patients overall when compared
with 41% in the CEPHEUS project. Furthermore, the
CEPHEUS project also shows that a lower rate of control
than LTAP-2 when patients were stratified according to
TG levels, 12% vs 27% vs 55% (,150, 150–200,
.200 mg/dL) in the former in comparison with 35% vs
69% (#200, .200) in the latter. These findings can be ex-
plained in part by the elevated rate of diabetes and the MetS
in the CEPHEUS study; 77% and 41% in comparison with
31% and 32%, respectively in the LTAP-2 study. In those 2
conditions, characterized by insulin resistance and central
obesity, atherogenic dyslipidemia predominates. In our
study, those with diabetes mellitus and higher TGs were
less likely to attain their LDL-C (17% vs 19% vs 32%;
P , .001) and non–HDL-C (8% vs 24% vs 51%;
P , .001) goals when compared with those with normal
TG levels. Moreover, HbA1c, which reflect diabetes melli-
tus control, was higher in the group with higher TGs when
compared with those with normal levels (9.3% vs 8.8% vs
8.2%; P , .001) and was a significant negative predictor of
non–HDL-C achievement. Although in non–diabetes melli-
tus, higher TGs were also less likely to attain their LDL-C
(18% vs 15% vs 30%; P 5 .001), non–HDL-C (12% vs
20% vs 52%; P , .001) goals, the proportion of patients
with diabetes mellitus, and higher TGs levels (81%) were
more than non–diabetes mellitus and higher TGs (19%)
group in our study.
Some studies have shown Apo B to be a better marker
of ASCVD risk than LDL-C and non–HDL-C, and
therefore, suggest Apo B as the preferred therapeutic
lipid-lowering target.23–28 However, a recent analysis of
contemporary statin trials has found this to be the con-
trary and reinforces the recommendation of non–HDL-
C as the main lipid target.9 In the CEPHEUS study,
significantly fewer patients with high TG levels attained
the Apo B goal in the overall cohort and, in the high and
very high ASCVD groups, a finding similar to what was
encountered for non–HDL-C.
Few studies have evaluated the prevalence of low
HDL-C and high TG in patients treated with LLDs in the
Al-Hashmi et al Non-HDL-C target achievement in patients with high triglyceride levels in the Arabian Gulf
Arabian Gulf.29–31 In the present study, the prevalence of
high TG and low HDL-C in patients on LLDs was 19%
and 53%, respectively. High TG levels were associated
with diabetes, the MetS, and higher body weight. Indeed,
type 2 diabetes and the MetS are highly prevalent in the
Arabian Gulf region in general, and specifically in patients
with acute coronary syndrome. In the Gulf Registry of
Acute Coronary Events, a multinational registry of 8176
patients admitted with acute coronary syndromes in 6
Arabian Gulf countries, 67% were overweight or obese,
40% of the patients had a history of diabetes, and 46%
had the MetS.32,33
In the CEPHEUS study, the prevalence of low HDL-C in
those with high TGs but controlled non–HDL-C target was
significantly higher than those with normal TGs. This
occurred in the overall cohort and in high and very high
ASCVD groups. HDL-C is independently and inversely
related to ASCVD risk, and it is a useful component of
global risk assessment. However, recent trials failed to
show benefits of increasing HDL-C concentrations.34
Nevertheless a low HDL-C remains a target for interven-
tion, but predominately through lifestyle therapies that
have proven beneficial in ASCVD reduction like exercise35
and smoking cessation.36
A subanalysis from the major fibrate clinical trial
suggests37,38 reduction of cardiovascular events in patients
with low HDL-C and high TG levels. This is occurring
even in those individuals treated with statins. In the
CEPHEUS study, most (94%) patients were on statin ther-
apy, whereas only 5.0% was on combination LLDs and
1.0% was on other LLDs. In the Arabian Gulf region,
because of the high prevalence of atherogenic dyslipidemia,
combination therapy beyond statins for those with high
non–HDL-C, due to either high TG or low HDL-C, may
benefit patients at high ASCVD risk. However, prospective
and well-designed trials are needed to corroborate this
hypothesis.
In the present study, the possible reasons for the very
high failure rate of reaching lipid targets in these high and
very ASCVD risk patients could be related to different
medical practice standards among Gulf States. We have
shown in previous CEPHEUS Middle East study on the
same cohort of patients that high doses of LLDs were
seldom used and patients were on average doses of
rousvastatin 14 mg, atorvastatin 30 mg, and simvastatin
24 mg for the very high ASCVD risk category.17 This could
be attributed to the concerns among treating physicians
about higher risk of adverse drug reactions from high doses
of LLDs. However, one cannot also discard the influence of
low patient compliance. In this CEPHEUS study, when
patients were asked ‘‘approximately how often do you
forget to take your cholesterol-lowering tablets,’’ about
32% indicated $ once per week.17 In addition, the presence
of multiple risk factors, like the high prevalence of obesity,
hypertension, diabetes mellitus, and MetS in our population
may have contributed to this low compliance of lipid target
achievements. Furthermore, the threshold goal post in the
375
prior LTAP-2 study22 for the very high ASCVD risk cohort
was 100 mg/dL but in the current CEPHEUS study, the
threshold is significantly lower, at 70 mg/dL. Therefore,
intensive lifestyle interventions and the use of more potent
statins is indicated for better control of therapeutic lipid tar-
gets in these high risk population. Moreover, continuous
education of physicians in the region about the importance
of recognizing non–HDL-C as an important therapeutic
target beyond LDL-C particularly in patients with high
TG levels.
Our results provide a useful overview of current lipid
management and treatment outcomes in the Middle East
Area. However, it has several limitations: it is an observa-
tional cross-sectional trial that did not assess long-term
outcomes. A prospective follow-up study is required to
evaluate medical treatment and attainment in relation to
mortality in patients treated with lipid-lowering agents. The
population studied is relatively small and considerable
variability in practice patterns across the countries exists,
and probably even among study sites, and therefore, caution
should be exercised when extrapolating the results to the
general population. In addition, the population included
only patients who were already on some form of lipid-
lowering medication. It was not clear what proportion of
eligible patients with appropriate risk factors were offered
LLDs in different countries. Such information would be
important to evaluate the overall burden of the disease
among untreated patients in various countries.
Conclusion
A large proportion of dyslipidemia patients on LLDs
with high and very high ASCVD risk in the Arabian Gulf
are not at their recommended non–HDL-C therapeutic
targets. This was more evident on those with higher TG
levels and greater ASCVD risk. Those individuals, hence,
remain at a substantial residual risk for cardiovascular
diseases despite treatment.
Acknowledgments
The authors thank the patients, physicians, nurses, and
support staff who participated in the CEPHEUS project for
their invaluable cooperation. Thanks also go to ClinArt
MENA for organizing the survey.
Financial disclosures
R.D.S. has received honoraria for consulting and speaker
activities from: Amgen, AstraZeneca, Boehringer-
Ingelheim, Biolab, Eli-Lilly, Genzyme, Jansen, Kowa,
Merck, Pfizer, Praxis, Sanofi/Regeneron, Torrent, and
Unilever. The other authors disclose that they have no
significant relationships with or financial interests in any
commercial companies related to this study or article.
376
References
1. Blaha MJ, Blumenthal RS, Brinton EA, Jacobson TA. National lipid
association task force on non-HDL cholesterol. The importance of
non-HDL cholesterol reporting in lipid management. J Clin Lipidol.
2008;2:267–273.
2. The Emerging Risk Factors Collaboration. Major lipids, apolipopro-
teins, and risk of vascular disease. JAMA. 2009;302:1993–2000.
3. Jun M, Foote C, Lv J, et al. Effects of fibrates on cardiovascular out-
comes: a systematic review and meta-analysis. Lancet. 2010;375:
1875–1884.
4. Kotseva K, Wood D, De Backer G, et al, EUROASPIRE Study Group.
EUROASPIRE III: a survey on the lifestyle, risk factors and use of
cardioprotective drug therapies in coronary patients from 22 European
countries. Eur J Cardiovasc Prev Rehabil. 2009;16:121–137.
5. Triglyceride Coronary Disease Genetics Consortium and Emerging
Risk Factors Collaboration, Sarwar N, Sandhu MS, Ricketts SL,
et al. Triglyceride-mediated pathways and coronary disease: collabo-
rative analysis of 101 studies. Lancet. 2010;375:1634–1639.
6. Robinson JG, Wang S, Smith BJ, Jacobson TA. Meta-analysis of the
relationship between non-high-density lipoprotein cholesterol reduction
and coronary heart disease risk. J Am Coll Cardiol. 2009;53:316–322.
7. Liu J, Sempos CT, Donahue RP, Dorn J, Trevisan M, Grundy SM.
Non-high-density lipoprotein and very-low-density lipoprotein choles-
terol and their risk predictive values in coronary heart disease. Am
J Cardiol. 2006;98:1363–1368.
8. Kastelein JJ, van der Steeg WA, Holme I, et al, TNT Study Group;
IDEAL Study Group. Lipids, apolipoproteins, and their ratios in rela-
tion to cardiovascular events with statin treatment. Circulation. 2008;
117:3002–3009.
9. Boekholdt SM, Arsenault BJ, Mora S, et al. Association of LDL
cholesterol, non-HDL cholesterol, and apolipoprotein B Levels with
risk of cardiovascular events among patients treated with statins.
JAMA. 2012;307:1302–1309.
10. Grundy SM. Low-density lipoprotein, non–high-density lipoprotein,
and apolipoprotein B as targets of lipid-lowering therapy. Circulation.
2002;106:2526–2529.
11. Brunzell JD, Davidson M, Furberg CD, et al, American Diabetes
Association; American College of Cardiology Foundation. Lipopro-
tein management in patients with cardiometabolic risk. Consensus
statement from the American Diabetes Association and the American
College of Cardiology Foundation. Diabetes Care. 2008;31:811–822.
12. Reiner Z, Catapano A, de Backer G, et al. ESC/EAS guidelines for the
management of dyslipidaemias. The task force on the management of
dyslipidaemias of the European Society of Cardiology (ESC) and the
European Atherosclerosis Society (EAS). Eur Heart J. 2011;32:
1769–1818.
13. Expert Dyslipidemia Panel of the International Atherosclerosis Soci-
ety. An International Atherosclerosis Society Position Paper: global
recommendations for the management of dyslipidemia—Full report.
J Clin Lipidol. 2014;8:29–60.
14. Rabar S, Harker M, O’Flynn N, Wierzbicki AS, Guideline Develop-
ment Group. Lipid modification and cardiovascular risk assessment
for the primary and secondary prevention of cardiovascular disease:
summary of updated NICE guidance. BMJ. 2014;349:g4356.
15. Jacobson TA, Ito MK, Maki KC, et al. National Lipid Association rec-
ommendations for patient-centered management of dyslipidemia: part
1—executive summary. J Clin Lipidol. 2014;8:473–488.
16. Al-Rasadi K, Al-Zakwani I, Al Mahmeed W, et al. Therapeutic lipid
target achievements among high and highest risk patients: results
from the CEPHEUS study in the Arabian Gulf. Curr Med Res Opin.
2014;30:2429–2435.
17. Arafah M, Al-Hinai AT, Mahmeed WA, et al. Centralized Pan-Middle
East Survey on the undertreatment of hypercholesterolemia: results
from the CEPHEUS study in Arabian Gulf countries. Angiology.
2014;65:919–926.
Journal of Clinical Lipidology, Vol 10, No 2, April 2016
18. Varbo A, Benn M, Tybjaerg-Hansen A, Jørgensen AB,
Frikke-Schmidt A, Nordestgaard BG. Remnant cholesterol as a causal
risk factor for ischemic heart disease. J Am Coll Cardiol. 2013;61:
427–436.
19. Nordestgaard BG, Varbo A. Triglycerides and cardiovascular disease.
Lancet. 2014;384:626–635.
20. Karlson BW, Toth PP, Palmer MK, Barter PJ, Nicholls SJ.
Achievement of combined goals of low-density lipoprotein
cholesterol and non-high-density lipoprotein cholesterol with
three different statins: results from VOYAGER. IJC Metab En-
docr. 2014;5:61–66.
21. Ballantyne CM1, Bertolami M, Hernandez Garcia HR, et al.
Achieving LDL cholesterol, non-HDL cholesterol, and apolipoprotein
B target levels in high-risk patients: Measuring Effective Reductions
in Cholesterol Using Rosuvastatin therapY (MERCURY) II. Am Heart
J. 2006;151:975.e1–975.e9.
22. Santos RD, Waters DD, Tarasenko L, et al. Low- and high-density
lipoprotein cholesterol goal attainment in dyslipidemic women: the
Lipid Treatment Assessment Project (L-TAP) 2. Am Heart J. 2009;
158:860–866.
23. Walldius G, Jungner I, Holme I, Aastveit AH, Kolar W, Steiner E.
High apolipoprotein B, low apolipoprotein A-1, and improvement in
the prediction of fatal myocardial infarction (AMORIS study): a pro-
spective study. Lancet. 2001;358:2026–2033.
24. Talmud PJ, Hawe E, Miller GJ, Humphries SE. Non-fasting apolipo-
protein B and triglyceride levels as a useful predictor of coronary heart
disease risk in middle-aged UK men. Arterioscler Thromb Vasc Biol.
2002;22:1918–1923.
25. Corsetti JP, Zareba W, Moss AJ, Sparks CE. Apolipoprotein B deter-
mines risk for recurrent coronary events in postinfarction patients with
metabolic syndrome. Atherosclerosis. 2004;177:367–373.
26. Sniderman A, Williams K, de Graaf J. Non-HDL C equals apolipopro-
tein B: except when it does not! Curr Opin Lipidol. 2010;21:518–524.
27. Sniderman AD, Williams K, Contois JH, et al. A meta-analysis of
low-density lipoprotein cholesterol, non-high-density lipoprotein
cholesterol, and apolipoprotein B as markers of cardiovascular risk.
Circ Cardiovasc Qual Outcomes. 2011;4:337–345.
28. Sniderman AD, Islam S, Yusuf S, McQueen MJ. Discordance analysis
of apolipoprotein B and non-high density lipoprotein cholesterol as
markers of cardiovascular risk in the INTERHEART study. Athero-
sclerosis. 2012;225:444–449.
29. Al Sifri SN, Almahmeed W, Azar S, et al. Results of the Dyslipidemia
International Study (DYSIS)-Middle East: clinical perspective on the
prevalence and characteristics of lipid abnormalities in the setting of
chronic statin treatment. PloS One. 2014;9:e84350.
30. Alsheikh-Ali AA, Omar MI, Raal FJ, et al. Cardiovascular risk factor
burden in Africa and the Middle East: the Africa Middle East Cardio-
vascular Epidemiological (ACE) study. PloS One. 2014;9:e102830.
31. Al-Rasadi K, Al-Zakwani I, Zubaid M, et al. Prevalence, predictors,
and impact of low high-density lipoprotein cholesterol on in-hospital
outcomes among acute coronary syndrome patients in the Middle
East. Open Cardiovasc Med J. 2011;5:203–209.
32. Zubaid M, Rashed WA, Almahmeed W, et al. Management and out-
comes of Middle Eastern patients admitted with acute coronary syn-
dromes in the Gulf Registry of Acute Coronary Events (Gulf
RACE). Acta Cardiol. 2009;64:439.e46.
33. Al Suwaidi J, Zubaid M, El-Menyar AA, et al. Prevalence of the meta-
bolic syndrome in patients with acute coronary syndrome in six mid-
dle eastern countries. J Clin Hypertens (Greenwich). 2010;12:
890–899.
34. Keene D, Price C, Shun-Shin MJ, Francis DP. Effect on cardiovascular
risk of high density lipoprotein targeted drug treatments niacin, fi-
brates, and CETP inhibitors: meta-analysis of randomised controlled
trials including 117,411 patients. BMJ. 2014;349:g4379.
35. Tanasescu M, Leitzmann MF, Rimm EB, Willett WC, Stampfer MJ,
Hu FB. Exercise type and and intensity in relation to coronary heart
disease in men. JAMA. 2002;288:1994–2000.
Al-Hashmi et al Non-HDL-C target achievement in patients with high triglyceride levels in the Arabian Gulf 377

36. Mons U, M€ uezzinler A, Gellert C, et al, CHANCES Consortium.
Impact of smoking and smoking cessation on cardiovascular events
and mortality among older adults: meta-analysis of individual partici-
pant data from prospective cohort studies of the CHANCES
consortium. BMJ. 2015;350:h1551.
37. Robins SJ, Bloomfield HE. Fibric acid derivatives in cardiovascular
disease prevention: results from the large clinical trials. Curr Opin
Lipidol. 2006;17:431–439.
38. Sacks FM, Carey VJ, Fruchart JC. Combination lipid therapy in type
2 diabetes. N Engl J Med. 2010;363:692–694.