Clinica Chimica Acta 487 (2018) 117–125

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Review

Dyslipidemias in clinical practice T

a a a,b,⁎
Manuel Castro Cabezas , Benjamin Burggraaf , Boudewijn Klop
a
Department of Internal Medicine, Franciscus Gasthuis & Vlietland, Kleiweg 500, 3045 PM Rotterdam, the Netherlands
b
Department of Cardiology, Erasmus MC, ‘s Gravendijkwal 230, 3015 CE Rotterdam, the Netherlands

ARTICLE INFO ABSTRACT

Keywords: Most dyslipidemic conditions have been linked to an increased risk of cardiovascular disease. Over the past few
Lipoprotein years major advances have been made regarding the genetic and metabolic basis of dyslipidemias. Detailed
lipid disorder characterization of the genetic basis of familial lipid disorders and knowledge concerning the effects of en-
hyperlipidemia vironmental factors on the expression of dyslipidemias have increased substantially, contributing to a better
hypercholesterolemia
diagnosis in individual patients. In addition to these developments, therapeutic options to lower cholesterol
treatment
levels in clinical practice have expanded even further in patients with familial hypercholesterolemia and in
subjects with cardiovascular disease. Finally, promising upcoming therapeutic lipid lowering strategies will be
reviewed. All these advances will be discussed in relation to current clinical practice with special focus on
common lipid disorders including familial dyslipidemias.

1. Introduction
The term dyslipidemia refers to a disturbance of the lipid profile,
including both hyperlipidemia and hypolipidemia. The latter may be
associated in some cases to deficiencies of fat-soluble vitamins, like the
homozygous form of abetalipoproteinemia and hypobetalipoprotei-
nemia [1], which are characterized by the absence of apolipoprotein
(apo) B in plasma, or disorders like chylomicron retention disease in
which there is an impaired secretion of intestinally-derived lipoproteins
[2]. Recently, a novel type resulting in reduced levels of low-density
lipoprotein cholesterol (LDL-C), triglycerides (TG) and high-density li-
poprotein cholesterol (HDLeC) has been described, the so called “fa-
milial combined hypolipidemia” [3]. In the heterozygous forms, these
types of dyslipidemias do not have a clinical expression and are
therefore, infrequently diagnosed. Others like hypoalfalipoproteinemia
(low HDLeC) may in some instances be linked to increased cardio-
vascular risk [4].
In clinical practice, the most frequent and therefore the most re-
levant dyslipidemias are the hyperlipidemias [5]. Most of these dysli-
pidemic conditions have been linked to an increased risk of cardio-
vascular disease. In the case of severe hypertriglyceridemia (with
plasma TG levels > 10 mmol/l) there is also an increased risk of pan-
creatitis. The nomenclature is rather simple: the term hypercholester-
olemia is used when only plasma cholesterol is elevated, usually due to
high LDL-C levels, hypertriglyceridemia is used when only plasma TG
are increased and combined or mixed hyperlipidermia refers to both
elevated LDL-C and plasma TG. Clinicians should be aware of the fact
that TG-rich lipoproteins (very low-density lipoproteins (VLDL) and
chylomicrons and their remnants) also carry cholesterol molecules. This
explains why severely elevated TG are always accompanied by elevated
plasma cholesterol levels. One should exclusively use the term “hy-
pertriglyceridemia” when LDL-C levels are normal or low and the ele-
vated plasma cholesterol is confined to the TG-rich lipoproteins. In this
case plasma apo B is always within normal limits and this helps to
discriminate between hypertriglyceridemia (with the elevated risk of
pancreatitis) and combined or mixed hyperlipidemia (with increased
cardiovascular risk).
Finally, a distinct type of dyslipidemia is mainly observed in type 2
diabetes mellitus (DM) or situations associated to the metabolic syn-
drome and insulin resistance: the high TG-low HDL-C dyslipidemia, also
called “atherogenic dyslipidemia”.
While the recognition of a dyslipidemic condition is not so difficult,
clinicians should always try to establish the diagnosis underlying the
phenotypic expression. This is of extreme importance to determine the
prognosis and the choice of treatment. Furthermore, in the case of fa-
milial dyslipidemias, genetic counselling and family screening need to
be implemented. First, one should differentiate primary from secondary
hyperlipidemias. The latter are always the consequence of a different
condition like for example obesity, hypothyroidism, nephrotic syn-
drome, obstructive liver disease, chronic renal failure or the use of
medication [5]. When these causes have been ruled out, one should
consider primary hyperlipidemia in which a differentiation can be

⁎
Corresponding author at: Department of Cardiology, Erasmus MC, PO Box 2040, 3000 CA Rotterdam, the Netherlands.
E-mail address: boudewijn.klop@gmail.com (B. Klop).

https://doi.org/10.1016/j.cca.2018.09.010
Received 6 May 2018; Received in revised form 6 September 2018; Accepted 6 September 2018
Available online 07 September 2018
0009-8981/ © 2018 Elsevier B.V. All rights reserved.
M. Castro Cabezas et al. Clinica Chimica Acta 487 (2018) 117–125

Fig. 1. Schematic overview of lipid metabolism of apolipoprotein B containing lipoproteins. Abbreviations: ANGPTL = angiopoietin-like proteins, A-
V = apolipoprotein A-V, B48 = apolipoprotein B-48, B100 = apolipoprotein B-100, C = cholesterol, CM = chylomicron, CM-R = chylomicron remnant, C-
II = apolipoprotein C-II, C-III = apolipoprotein C-III, E = apolipoprotein E, FFA = free fatty acids, GPIHBP1 = glycosylphosphatidylinositol-anchored high-density-
binding protein 1, HSPG = heparan sulphate proteoglycans, LDL = low-density lipoprotein, LDLR = low-density lipoprotein receptor, LPL = lipoprotein lipase,
LRP1 = low-density lipoprotein like receptor 1, MAG = mono-acylglycerols, MTP = microsomal triglyceride transfer protein, NPC1L1 = Niemann-Pick-C1-like 1,
PCSK9 = proprotein convertase subtilisin/kexin type 9, TG = triglycerides, VLDL = very low-density lipoprotein.

made between well-defined genetic hyperlipidemias and the so-called,
most frequent, polygenic hypercholesterolemia in which environmental
influences play a major role superimposed on a genetic predisposition.
2. Lipid metabolism of the atherogenic lipoproteins and their
respective therapeutic targets
Knowledge of lipid metabolism is necessary in order to understand
the pathophysiologic mechanisms of the different dyslipidemias but
also to understand which therapy will be most appropriate. Therefore,
lipoprotein metabolism will be discussed together with the clinically
most relevant pharmacological targets (Fig. 1).
2.1. Intestinal chylomicron synthesis
All atherogenic lipoproteins are synthesized either by the intestine
or the liver and are initially TG-rich lipoproteins. After food intake
cholesterol is actively transported from the intestinal lumen into the
enterocyte via the Niemann-Pick-C1-like 1 (NPC1L1) transporter [6].
NPC1L1 is the primary target of ezetimibe, which inhibits intestinal
cholesterol absorption resulting in 20% reductions of circulating LDL-C
levels. Ezetimibe has shown to reduce the absolute risk for major car-
diovascular events by 2.0% in patients with an acute coronary syn-
drome when added on top of a statin over a median of 6 years [7]. In
contrast to NPC1L1, the ATP binding cassette transporter-G5 and G8
(ABCG5/8) mediates cholesterol efflux from the enterocyte to the in-
testinal lumen contributing to transintestinal cholesterol excretion [8].
Food-derived TG are taken up as free fatty acids (FFA) and 2-
monoacylglycerols (MAG) by the enterocytes after hydrolysis has taken
place in the intestinal lumen. These are taken up by enterocytes through
passive diffusion and specific proteins, like CD36 and various fatty acid
transport proteins [9]. Once inside the endoplasmatic reticulum of the
enterocyte, FFA and MAG are assembled into TG again and packed with
cholesterol, phospholipids and apo B48 and apo A-IV to form lipid-rich
chylomicrons, which consist for 85–92% of TG and 1–3% of cholesterol
[10,11]. In this process, the microsomal triglyceride transfer protein
(MTP) and the editing enzyme complex are paramount factors [12,13].
Especially the latter, which in humans is only present in the intestine, is
crucial for the synthesis of apo B48, the structural protein of chylomi-
crons. Apo B48 is synthesized from the apo B mRNA strand following
posttranscriptional editing with enzymatic deamination at nucleotide
6666, which results in truncation of apo B codon 2153, so that the
mature protein consists of only 48% of the apo B100. After assembling,
the chylomicrons can have a diameter up to 1000 nm. They are secreted
into the lymphatics and enter the circulation through the thoracic duct.
Within the circulation apo A-IV is exchanged for two other apolipo-
proteins, namely apo C-II and apo E [14]. These are involved in TG
lipoprotein lipase (LPL)-mediated hydrolysis and receptor-mediated
uptake, respectively.

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M. Castro Cabezas et al.
2.2. Hepatic synthesis of VLDL
In fasting physiological conditions, plasma TG are mainly de-
termined by the VLDL concentrations secreted by the liver. This is a
continuous process, which increases postprandially when TG and FFA
derived from food reach the liver. The VLDL assembly resembles chy-
lomicron synthesis with an important role for MTP, but in this case, apo
B100 is the structural protein of the lipoprotein. Human hepatocytes do
not have an editing complex and therefore the apo B mRNA is fully
translated. The availability of TG is the most critical regulator for the
synthesis of VLDL since it lipidates the VLDL and its availability pre-
vents the proteosomal degradation of apo B100 [15]. VLDL-size may
reach diameters up to 200 nm and nascent lipoproteins are transported
from the endoplasmatic reticulum of the hepatocyte to its Golgi system
for translational modifications. Subsequently VLDL are secreted and
enter the circulation via the space of Disse.
Nicotinic acid, or vitamin B3, is a water-soluble vitamin that in-
hibits the formation of TG and lipolysis of TG from adipocytes, limiting
the release of TG into the circulation and therefore impairing VLDL
secretion [12,16]. MTP-inhibitors have also been developed but did not
reach clinical practice due to intrahepatic fat accumulation.
2.3. Intravascular hydrolysis
Both, chylomicrons and VLDL are essential for the delivery of FFA to
mainly the heart, skeletal muscle and adipose tissue for energy ex-
penditure or storage. Hydrolysis of TG in the circulation is the main
determinant of FFA delivery to tissues. Many proteins are involved in
the hydrolysis of TG with the most important proteins being lipoprotein
lipase (LPL) and its co-factor apo C-II. LPL is mainly synthesized by
myocytes and adipocytes, which secrete LPL into the surrounding in-
terstitial spaces. LPL is transported from the interstitial space to the
capillary lumen after binding to heparan sulphate proteoglycans
(HSPG). At the endothelial cell surface of small capillaries LPL is co-
anchored by glycosylphosphatidylinositol-anchored high-density-
binding protein 1 (GP1HBP1), where LPL serves as a docking station for
TG-rich lipoproteins [17]. Apo C-II, which is carried by chylomicrons
and VLDL, serves as a co-factor for LPL as is apo A-V, which facilitates
the binding of TG-rich lipoproteins to the endothelial surface via HSPG
and GPIHBP1 [18]. In contrast, apo C-III serves as an inhibitor of LPL.
Recently, it was discovered that apo C-III also impairs hydrolysis via
different LPL-independent pathways [19]. The angiopoietin-like pro-
teins (ANGPTL) 3, 4 and 8, which share their molecular structure with
the members of angiopoietin protein family have also been described to
reduce hydrolysis by inhibiting LPL [20]. Hydrolysis results in TG de-
pleted chylomicrons and VLDL, which shrink in diameter and also be-
come enriched with cholesterol due to the interaction with high-density
lipoproteins (HDL) by the action of cholesterol ester transfer protein
(CETP) and other transfer proteins [21].
Fibrates affect different genes regulating hydrolysis including LPL,
APOC3 and APOA5 by binding to the peroxisome proliferator-activated
receptor-α. Many studies have shown that fibrates upregulate the LPL
and downregulate APOC3 expression, facilitating hydrolysis and re-
sulting in increased clearance of chylomicron remnants and VLDL to-
gether with concomitant reduced secretion of VLDL [12,16].
2.4. Hepatic uptake of lipoproteins
Further hydrolysis of the lipoprotein remnants by hepatic lipase
(HL), which is only present in the capillary endothelium in the liver, is
necessary for hepatic uptake by engaging the LDL-receptor (which re-
cognizes both, apo B and apo E as ligands), HSPG or LDL receptor-
related protein (LRP1) via their receptor-binding apo E. This process is
completely sufficient for chylomicron remnants, but not for VLDL,
which are either taken up by the liver or loose apo E and become LDL
after HL-mediated hydrolysis [12,18,22]. Apo B100 does not bind to
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Clinica Chimica Acta 487 (2018) 117–125
LRP1 and its binding affinity to the LDL-receptor is 20 times less than
apo E. In addition, only one apo B100 is present per LDL, whereas
several apo E molecules are present on every chylomicron remnant and
VLDL [23]. Finally, LDL is internalized after binding to the LDL-re-
ceptor where it is catabolized within the cell. The unesterified choles-
terol is then used for the synthesis of bile acids and the regulation of
pathways to limit cellular accumulation of cholesterol.
Statins reduce the hepatic biosynthesis of cholesterol by competi-
tively inhibiting HMG-CoA-reductase and therefore stimulating in-
creased LDL-receptor expression, as elegantly demonstrated by the
Nobel prize laureates Goldstein and Brown [24]. Subsequently, hepatic
uptake of LDL from the circulation, but also of the TG-rich lipoproteins,
is increased. This results in both lower levels of plasma LDL-C and
remnant-C with significant clinical benefit. A meta-analysis from 26
statin trials with almost 170,000 study participants have shown that
statin use was associated with a 22% proportional reduction in cardi-
ovascular events per mmol/l LDL-C reduction over a median of 5 years
[25,26].
Once the LDL-receptor-bound LDL is internalized into the hepato-
cyte, the receptor is degraded in the lysosome when proprotein con-
vertase subtilisin/lexin type 9 (PCSK9) forms a complex with the LDL-
receptor and LDL. However, if PCSK9 is absent the PCSK9-mediated
degradation of the LDL-receptor is inhibited allowing recycling of the
LDL-receptor and subsequent increased uptake of LDL [27]. The re-
cently developed PCSK9-inhibitors are specific polyclonal antibodies
against PCSK9 to increase the expression of the LDL-receptor by im-
pairing the PCSK9-initiated LDL-receptor degradation thereby lowering
LDL-C by approximately 50–60% on top of statin therapy [28–30]. A
large randomized, double-blind, placebo-controlled trial successfully
demonstrated a further reduction in major cardiovascular events with
evolocumab on top of high-intensity statin therapy and results with
another compound, alirocumab are promising [30,31]. Both, ezetimibe
and bile acid sequestrants indirectly increase hepatic LDL-receptors.
The reduced intestinal cholesterol absorption by ezetimibe also leads to
an increase in LDL-receptor expression. In contrast, bile acid-binding
resins remove bile acids from the enterohepatic circulation leading to
increased hepatic production of bile acids and subsequent cholesterol
catabolism, which results in a compensatory increase in hepatic LDL-
receptors, thereby stimulating LDL removal from the circulation. Since
the introduction of statins, bile acid sequestrants have become less
popular in clinical practice, mainly due to weaker effects on LDL-C le-
vels and the gastrointestinal side effects of these drugs [16,28]. A low
cholesterol diet also results in a similar compensatory increase in LDL-
receptors due to its feedback regulation by the sterol regulatory ele-
ment-binding preotein-1 (SREBP-1). SREBP-1 activates LDL-receptor
transcription when intracellular cholesterol levels fall below a certain
threshold, which lowers plasma LDL-C levels [24].
3. Primary versus secondary lipid disorders
The first step in managing lipid disorders is establishing the diag-
nosis. Primary dyslipidemias should be distinguished from secondary
lipid disorders, but environmental factors are always important de-
terminants of the phenotypic expression. The most common lipid dis-
orders will be discussed, although it should be noted that overlap be-
tween the different lipid disorders may exist [32]. The prevalence of the
most common primary lipid disorders are shown in Table 1.
3.1. Familial hypercholesterolemia
Familial hypercholesterolemia (FH) is an autosomal-dominant lipid
disorder, which can be caused by mutations in different genes. > 90%
of the mutations are found in the LDL-receptor (LDLR) gene causing
either receptor deficiency or defective receptors, but mutations in genes
encoding for apo B (APOB) or PCSK9 (PCSK9) can also cause FH, albeit
much less frequent (< 10%). Mutations in APOB gene lead to impaired
M. Castro Cabezas et al.
Table 1
The prevalence of the most common primary lipid disorders in the general
population.
Prevalence
Familial hypercholesterolemia 1:250
Familial combined hyperlipidemia 1:100 to 1:50
Familial hypertriglyceridemia 1:100 to 1:50
(TG > 10 mmol/l)
Familal dysbetalipoproteinemia 1:1000 to 1:250
Lipoprotein(a) hyperlipoproteinemia 1:20 to 1:12
binding affinity with the receptor, whereas gain of function mutations
in the PCSK9 gene lead to enhanced degradation of receptors [33].
Currently, > 1800 mutations have been described in familial hyperch-
olesterolemia, but approximately 50% need further evidence before
they can be confirmed as disease-causing mutations [34]. The national
and international registries for FH have shown to be of great relevance
to further clarify the relationship between genotypes and phenotypes
[35]. The heterozygous form of FH is one of the most common genetic
disorders associated with cardiovascular disease with a prevalence of
approximately 1:250 [36]. Recently, it has been shown that 8.3% of
patients with atherosclerotic cardiovascular disease have FH [37]. In
contrast, the homozygous form of FH is very rare (1 per million). In FH,
elevated LDL-C levels may cause xanthomas and atherosclerosis with a
3- to 13-fold increased risk for the development of cardiovascular dis-
ease. The individual risk increases further when other risk factors are
present such as obesity, insufficiently controlled hypertension, Lp(a)
levels > 50 mg/dl, smoking and a history of cardiovascular disease
[38].
The FH diagnostic criteria from the Dutch Lipid Clinic Network are
one of the most frequently used to establish the diagnosis. Priority is
given to genetic testing, but also non-genetic criteria composed of
clinical and laboratory variables are included (Table 2). One drawback
of these criteria is the use of untreated LDL-C levels, since establishing
the diagnosis is also important in patients who are already treated with
lipid lowering therapy because of the necessity for cascade screening
and optimizing medical therapy once the diagnosis is established. Re-
cently, a validated online application has been developed to impute
baseline LDL-C in patients already treated with a statin or ezetimibe
Table 2
Diagnostic criteria for establishing the diagnosis familial hypercholesterolemia
(FH) using the Dutch Lipid Network Criteria. A total of > 8 points is definite
FH, 6–8 points is probable FH, 3–5 points possible FH and < 3 points is unlikely
FH [28,123].
Dutch network lipid criteria for FH
Family history
First-degree relative with known premature atherosclerotic vascular
disease OR first degree relative with known LDL-C above 95th
percentile.
First-degree relative with tendinous xanthomata and/or arcus
cornealis OR children aged < 18 years with LDL-C above 95th
percentile.
Clinical history
Patient with premature coronary artery diseasea
Patient with premature cerebral or peripheral vascular diseasea
Physical examination
Tendinous xanthomata
Arcus cornealis prior to age 45 years
Untreated cholesterol levels
LDL-C ≥ 8.5 mmol/l (330 mg/dL)
LDL-C 6.5–8.4 mmol/l (250–329 mg/dL)
LDL-C 5.0–6.4 mmol/l (190–249 mg/dL)
LDL-C 4.0–4.9 mmol/l (155–189 mg/dL)
D0NA analysis
Functional mutation in the LDLR, APOB or PCSK9 gene
a
Premature ≤ 55 years in men and < 60 years in women.
Clinica Chimica Acta 487 (2018) 117–125
Table 3
Causes of polygenic hypercholesterolemia.
Contributing causes of polygenic hypercholesterolemia
References
Diet High saturated fat intake
[36] High trans fat intake
[52] High cholesterol intake
[62,122] Lifestyle Sedentary lifestyle
Obesity
[67] Diseases Cushing syndrome
[89,91] Diabetes mellitus
HIV-infection
Hypothyroidism
Insulin resistance
Metabolic syndrome
Nonalcoholic fatty liver disease
Medication Amiodarone, betablockers, corticosteroids, cyclosporine, estrogens,
thiazide diuretics
Genetics > 30 SNPs
(http://www.circl.ubc.ca/english/web_fh.html) [39]. Lipid lowering
therapy is focussed on LDL-C lowering using statins, ezetimibe and, if
necessary PCSK9-inhibitors. In addition, treatment of other con-
comitant cardiovascular risk factors is important to further lower the
residual cardiovascular risk. Finally, cascade screening is very im-
portant to search for other family members with FH since early primary
prevention with lipid lowering therapy is most beneficial in reducing
lifetime risk for cardiovascular disease. Statin therapy is generally in-
itiated between the ages of 8 to 10 years in children with FH in order to
achieve lifelong cardiovascular risk reduction [28]. This should only be
done in specialized centers with experience treating families.
3.2. Polygenic hypercholesterolemia
Polygenic hypercholesterolemia is the most frequent form of hy-
percholesterolemia. In comparison with FH, polygenic hypercholester-
olemia is caused by accumulation of small effects of lipid-affecting al-
leles often in combination with secondary lipid modifying factors
including diet, lifestyle, underlying diseases or medication (Table 3)
[40,41]. Interestingly, in approximately 60% of patients with clinically
diagnosed FH no pathogenic mutations in candidate genes can be
identified, but in up to 88% of those patients the presence of multiple
alleles with LDL-C raising effects has been observed [42,43]. To date,
over 100 of single nucleotide polymorphisms (SNPs) have been dis-
covered associated with lipid disturbances including 30 SNPs affecting
LDL-C concentrations [43–46]. These include several specific SNPs in
APOB, LDLR and PCSK9 genes among others. Recently, it has been
Points shown that patients with clinically diagnosed FH who do not carry a
monogenic mutation may have a milder lipid phenotype and lower
degree of subclinical atherosclerosis than genetically defined FH. In
1
addition, LDL-C had a normal distribution in those families in contrast
to a bimodal distribution in FH families, which supports the polygenic
2 concept [47,48]. The contribution of risk alleles for high LDL-C varies
greatly among families underscoring the complexity and heterogeneity
of polygenic hypercholesterolemia and the importance of secondary
2 lipid modifying factors [49].
1 Polygenic hypercholesterolemia is characterized by moderately
elevated levels of LDL-C, normal to mildly elevated TG but no clinical
6 features such as xanthomas. The cardiovascular risk is less severely
4
elevated than in FH [50,51]. It is important to rule out secondary causes
8 of hypercholesterolemia. These should be eliminated or optimally
5 treated before starting lipid-lowering medication. Current guidelines
3 recommend to treat patients with clinically ‘definite’ or ‘probable’ FH
1
on a polygenic basis, similarly intensive as patients with genetically
8 defined FH. Initiation of medical lipid-lowering therapy in patients with
polygenic hypercholesterolemia and a less severe phenotype should be
considered according to risk score charts [28].
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M. Castro Cabezas et al.
3.3. Familial combined hyperlipidemia
The term familial combined hyperlipidemia (FCH) derives from the
classical studies by Goldstein and co-workers in 1973 [52]. The pre-
senting phenotype is a combined hyperlipidemia with elevated LDL-C
and plasma TG but also elevated plasma apo B is necessary to establish
the diagnosis [53]. FCH is characterized by increased hepatic VLDL
secretion, predominance of small-dense LDL, impaired postprandial
chylomicron remnant and FFA metabolism and insulin resistance [54].
Recently it has been shown that apo C-III, insulin, adiponectin and apo
A-II are major determinants that affect VLDL composition in FCH after
adjusting for waist circumference [55].
This condition has been shown to have an autosomal dominant in-
heritance pattern in the past, but there is no monogenic component.
Some individuals carry a high burden of small-effect polymorphisms
while others carry a large effect mutation in the LDLR or LPL gene. In
addition, non-genetic lifestyle factors such as obesity, diet and alcohol
consumption add to the continuous quantitative trait. Therefore, the
phenotype between family members can vary and also within in-
dividuals over time [56]. FH should be included in the differential di-
agnosis since approximately 4.8% of the patients with FCH showed a
loss of function mutation in LDLR [57].
Therapy should focus on reducing the hepatic VLDL overproduction
and the plasma LDL concentration. For this purpose, lifestyle inter-
vention always in combination with drug therapy is warranted. Weight
loss of approximately 9% has been shown to reduce endogenic cho-
lesterol synthesis with a reduction of non-HDL-C levels by 9% and TG
by 27% [58]. The drugs of choice are statins, sometimes in combination
with fibrates. One should be aware of the risk of myopathy and rhab-
domyolysis when using this combination. In addition, periodic
screening for the development of T2DM is necessary since patients with
FCH have a significantly higher risk for developing T2DM with a 10-
year risk of 20% when compared to age-matched patients with FH [59].
3.4. Familial hypertriglyceridemia
The major clinical risk in familial hypertriglyceridemia (FHTG) is
pancreatitis and not cardiovascular disease [60,61]. In contrast to FCH,
the phenotype of the dyslipidemia is not an elevated number of
atherogenic apo B containing lipoproteins, but rather the presence of
large TG-rich lipoproteins. Typically, plasma apo B is normal in FHTG
reflecting normal numbers of circulating atherogenic lipoproteins.
FHTG is a polygenic disorder in contrast to the very rare familial chy-
lomicronemia syndrome, which is a monogenic disorder with a loss of
function mutation in LPL or APOCII. Identification of pathogenic mu-
tations in FHTG remains challenging with rare variants found in only
12.3% of patients in a Spanish population study [62]. Overlap exists
with FCH with multiple genes involved with common genetic variants.
In FHTG, these variants have a larger effect on TG metabolism than on
the cholesterol pathways [56,63]. In our opinion, the biggest difference
with FCH is the fact that VLDL production is not increased in FHTG. The
most likely reason is the fact that FFA metabolism, and specially per-
ipheral fatty acid trapping, may not be impaired in FHTG, leading to a
lesser flux of FFA to the liver. However, detailed studies on this subject
in FHTG are lacking.
The clinical relevance to identify patients with FHTG is the asso-
ciated increased risk for pancreatitis, which warrants treatment. It has
been shown that 5.4% of patients with TG levels > 10 mmol/l devel-
oped acute pancreatitis one year after the diagnosis [64]. The therapy
of choice in FHTG is lifestyle intervention with restriction of alcohol,
saturated fats and carbohydrates. In addition, TG lowering therapy with
fibrates or nicotinic acid should also be considered when TG remain
markedly elevated [12,65]. Genetic analysis is not routinely advised
due to the low frequency of rare mutations and should only be con-
sidered in case of strong clinical criteria for a monogenic disorder
causing severe hypertriglyceridemia [62,66].
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Clinica Chimica Acta 487 (2018) 117–125
3.5. Familial dysbetalipoproteinemia
Familial dysbetalipoproteinemia (FD) is a recessive autosomal dis-
order caused by homozygous mutations in the apolipoprotein E gene
(APOE), however 10% is caused by an autosomal dominant mutation in
APOE [67–69]. Patients with the autosomal dominant variant have the
same clinical presentation as those with the more common autosomal
recessive form of FD. Three common alleles of APOE exist (E2, E3 and
E4) with the E2/2 genotype present in 91% of the patients with FD,
resulting in decreased binding of intermediate density lipoproteins
(IDL) to the LDL-receptor and remnant receptors. However, only 15% of
the people with the E2/2 genotype develop FD [67,69,70]. Therefore, it
is thought that the development of FD is associated with additional
genetic and environmental factors, such as gender, obesity, hypothyr-
oidism, insulin resistance and dietary factors [71–73].
Apo E is present on the TG-rich lipoproteins (chylomicrons and
VLDL and their respective remnants) and functions both as a structural
protein and as a ligand for the LDL-receptor and remnant receptors. Due
to mutations, binding between apo E and its receptor is impaired with
decreased clearance of chylomicrons, VLDL and their respective rem-
nants in combination with reduced conversion of VLDL to LDL. This will
lead to increased transfer of TG from the TG-rich lipoproteins to HDL
and transfer of cholesterolesters vice versa, leading to an increase in
non-HDL-C and decrease in HDLeC. This was recently demonstrated in
a clinical study, showing that patients with FD have a low HDL-C to apo
A-II ratio. In addition, non-HDL-C levels were almost doubled in FD
whereas apo B was only increased with 20% [67,74]. Recently, it was
also shown that uptake of remnants by HSPG is reduced in FD, in
contrast to subjects with similar genotypes but a normal phenotype.
Therefore, it seems that remnant clearance is adequately compensated
in those subjects with a normal lipid phenotype but not in patients
expressing the disease [69]. All these metabolic disturbances typically
lead to elevated TG, total cholesterol and non-HDL-C levels with con-
comitant low LDL-C and HDL-C together with relatively normal apo B
levels. Therefore, we suggest that a mismatch between elevated non-
HDL-C with a relatively normal apo B may be suggestive of FD. It
should also be noted that LDL-C can be falsely elevated when the re-
ported LDL-C is calculated using the Friedewald formula.
FD is clinically relevant since it is associated with an increased risk
for premature cardiovascular disease in index patients and their kin-
dred [75,76]. Clinical features of FD are tubero-eruptive xanthomas on
the elbows and xanthoma striatum palmare (orange and red dis-
coloration on the palms) [77,78]. In patients with a mixed hyperlipi-
demia and these skin abnormities, DNA genotyping should be per-
formed. Recently it has been shown that undertreatment is common in
FD [79]. Therapy includes reduction of lipid levels by dietary and
lifestyle modifications with special emphasis on carbohydrate and cal-
orie restriction [80,81] and lipid lowering therapy with statins and or
fibrates. Fibrates have been shown to reduce postprandial hyperlipi-
demia in FD in addition to fasting lipid levels [69,82]. Non-HDL-C is
favored over LDL-C as treatment target since FD is characterized by a
mixed hyperlipidemia.
3.6. Diabetic dyslipidemia
In uncontrolled type 1 DM the presenting dyslipidemia is usually
hypertriglyceridemia, due to the lack of insulin and therefore severely
impaired hydrolysis of TG-rich lipoproteins in the circulation. This is
exacerbated by an uninhibited adipose tissue lipolysis causing a mas-
sive release of FFA, which in the liver will give rise to large VLDL [83].
Of course, the most efficient and necessary therapy is insulin adminis-
tration and short-term starvation. In most instances this will result in a
rapid and dramatic decrease of plasma TG. The reason that not all
subjects with type 1 DM express such a severe hypertriglyceridemia
suggests that there must also be a genetic predisposition in the TG-
handling pathway for such a presentation to occur.
M. Castro Cabezas et al.
The most frequently observed diabetic dyslipidemia is the high TG/
low HDL-C type, which is characteristic for type 2 DM. The underlying
mechanism may be an impairment of fat storage and mobilization in
adipose tissue [84]. In this case subjects usually have increased levels of
small-dense LDL, which contributes to the increased cardiovascular
risk. It is now generally accepted that statins reduce the cardiovascular
risk significantly in T2DM. However, some evidence has also been
provided for the use of fibrates in this condition, especially in the high
TG/low HDL-C presentation [85]. Current guidelines recommend low-
ering LDL-C as primary treatment target, which automatically will de-
crease the concentrations of small-dense LDL and remnant cholesterol
[28]. Since LDL-C is not invariably elevated in diabetic dyslipidemia,
we and others have recommended to use apo B or non-HDL-C as a
secondary treatment target [28,86].
3.7. Lipoprotein(a) hyperlipoproteinemia
Lipoprotein(a) (Lp(a)) is a highly polymorphic lipoprotein particle
that consists of a large, hydrophilic glycoprotein apo (a) attached to apo
B-100 on LDL. Plasma concentrations of Lp(a) and isoform size of the
apo (a) are mainly determined by genetic variation in the LPA gene
encoding apo (a), which can vary up to 1000-fold between individuals.
It is an independent, causal and heritable cardiovascular risk factor
with Lp(a) plasma levels > 30 mg/dl considered atherogenic [87,88].
Recently, it was shown that a 10 mg/dl increase in Lp(a) was associated
with a 2–4% higher likelihood of having a myocardial infarction below
the age of 60 years [89]. In addition, Lp(a) adds to an increased car-
diovascular risk especially in patients with other risk factors like T2DM
or the co-existence of FH or FCH [87,90,91]. Although Lp(a) is an es-
tablished cardiovascular risk factor, the exact atherogenic mechanisms
of Lp(a) have not been clarified, although there is evidence that Lp(a)
has antifibrinolytic and pro-inflammatory effects and promotes oxida-
tive stress.
Treatment of high levels of Lp(a) remains challenging since Lp(a)
hyperlipoproteinemia is resistant to lifestyle interventions and there are
no specific drugs available yet to lower Lp(a) [92], besides androgens
and nicotinic acid. Statins and ezetimibe have little to no clinically
relevant effect on Lp(a), whereas nicotinic acid and PCSK-9-inhibitors
lower Lp(a) by approximately 30%, which is probably still not sufficient
in the case of very high Lp(a) levels [92–94]. The only available therapy
to effectively lower plasma Lp(a) levels is weekly lipoprotein apheresis,
which is recommended for patients with Lp(a) > 60 mg/dl and pro-
gressive cardiovascular disease despite LDL-C within target range. Li-
poprotein apheresis reduces Lp(a) by approximately 70% with potential
regression of atherosclerosis, but no prospective randomized studies on
cardiovascular outcomes have been performed yet [95–98]. Currently,
the most reasonable option to treat patients with Lp(a) hyperlipopro-
teinemia is an intensified treatment of modifiable cardiovascular risk
factors including lifestyle management and LDL-C lowering [28].
4. General recommendations regarding treatment of
dyslipidemias
The guidelines from the European Society of Cardiology (ESC) and
European Atherosclerosis Society (EAS) for the management of dysli-
pidemias advice to estimate the cumulative 10-years cardiovascular risk
in order to determine the strategy and intensity of treatment. However,
patients with documented cardiovascular disease, T2DM, very high
levels of individual risk factors including FH or chronic kidney disease
are automatically classified as high or very high risk making active
treatment necessary. A treatment target of LDL-C < 2.5 mmol/l is ad-
vised for patients with high risk (markedly elevated total cholesterol
of > 8 mmol/l, FH, most patients with T2DM or in subjects with a 10-
year cardiovascular risk of ≥5% to < 10%). A more strict treatment
target of LDL-C < 1.8 mmol/l is recommended for patients with very
high risk (known cardiovascular disease, T2DM with end-organ
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Clinica Chimica Acta 487 (2018) 117–125
damage, severe chronic kidney disease or a 10-year cardiovascular risk
of ≥10%). It is recommended to use apo B or non-HDL-C as secondary
treatment target in the case of a combined hyperlipidemia since apo B
takes all atherogenic lipoproteins into account and non-HDL-C includes
remnant cholesterol besides LDL-C. The treatment target of apo B
is < 1.0 g/l for high risk patients and < 0.8 g/l in the case of very high
risk, whereas the treatment target of non-HDL-C is 0.8 mmol/l higher
than the advised LDL-C treatment target [28]. The ESC/EAS guidelines
focus strongly on treatment targets, whereas the guidelines from the
American College of Cardiology (ACC) and American Heart Association
(AHA) focus more on the treatment process without specific treatment
targets [99].
Both, the ESC and ACC have recently published updates for their
existing guidelines with special emphasis on clinical guidance for when
to consider PCSK9-inhibition in patients with cardiovascular disease or
FH [100,101]. PCSK9-inhibition may be considered when LDL-C re-
mains > 3.6 mmol/l in patients with cardiovascular disease despite a
high-intensity statin in combination with ezetimibe or when LDL-C
remains > 2.6 mmol/l in the case of additional risk factors (rapidly
progressive atherosclerotic cardiovascular disease, DM, complex mul-
tivessel or polyvascular atherosclerotic disease). A PCSK9-inhibitor may
be considered in FH when LDL-C remains > 4.5 mmol/l on maximum
treatment or > 3.6 mmol/l in the case of additional risk factors
(marked hypertension, smoking, Lp(a) > 50 mg/dl, presence of pre-
mature cardiovascular disease in first degree relatives, DM with target
organ damage, > 40 years of age without treatment). The rationale
behind these thresholds is a balance between health care costs and a
higher absolute risk reduction in case of higher LDL-C levels when in-
itiating PCSK9-inhibition although cost-effectiveness studies are
lacking.
Patients with markedly elevated TG (≥10 mmol/l) have an in-
creased risk for pancreatitis, which warrants treatment. A paradoxical
increase in LDL-C is frequently observed after effective TG lowering
with lifestyle intervention and fibrates due to improved hydrolysis of
VLDL. Subsequently, the need for additional cholesterol lowering
therapy can be determined by calculating the 10-year cardiovascular
risk. However, it was recently shown that patients with
TG > 3.0 mmol/l who were not eligible for statin therapy according to
current guidelines showed a similar risk as statin-eligible patients in
primary prevention [102].
5. Potential new pharmaceutical strategies to treat dyslipidemias
5.1. Mipomersem
Mipomersem is an antisense oligonucleotide that binds to the mRNA
responsible for the synthesis of apo B100 and therefore inhibits the
production of apo B100. It is dosed subcutaneously once weekly and
lowers non-HDL-C, LDL-C, TG and Lp(a) since apo B100 is an essential
component of VLDL and LDL. A phase 3 trial showed LDL-C reduction of
37% in patients with hypercholesterolemia [103]. Currently, mipo-
mersem is only approved in the United States for the treatment of
homozygous FH, in particular when current standard of care fails [104].
The most common side effects are injection site reactions, flu like
symptoms and elevations of plasma alanine aminotransferase.
5.2. Bempedoic acid
Bempedoic acid is the first in its class. It is an oral agent that inhibits
adenosine triphosphate citrate lyase, which is an enzyme involved in
the cholesterol synthesis by catalysing acetyl-CoA. It lowers LDL-C by
approximately 25% as monotherapy or on top of a statin and up to 48%
when combined with ezetimibe [105–107]. Efficacy and safety of
bempedoic acid on top of ezetimibe was recently confirmed in statin
intolerant patients, showing similar adverse events to placebo [108].
Currently, the effects of bempedoic acid on cardiovascular morbidity
M. Castro Cabezas et al.
and mortality are evaluated in the CLEAR OUTCOMES trial, which
randomizes 180 mg of bempedoic acid versus placebo in an estimated
12,600 high-risk, statin intolerant patients [109].
5.3. Volanesorsen
A second-generation antisense inhibitor of APOC3 synthesis, vola-
nesorsen, lowers TG by approximately 70% in patients with hyper-
triglyceridemia [110,111]. It specifically degrades APOC3 mRNA in
order to prevent the production of the apo C-III protein. Therefore, li-
polysis of TG-rich lipoproteins is enhanced with concomitant reduction
in plasma TG. Several phase 3 trials have now been completed in-
cluding the APPROACH trial (in patients with familial chylomicronemia
syndrome) and the COMPASS trial (in patients with hypertriglycer-
idemia), which have successfully met their primary endpoint with sig-
nificant reductions in TG of 71.2% and 77% after 26 weeks and
52 weeks of treatment, respectively [112–114]. These results are pro-
mising for the treatment of patients with severe hypertriglyceridemia,
but large studies with coronary heart disease and pancreatitis as out-
come are needed.
5.4. Antisense oligonucleotides targeting apolipoprotein(a)
Recent advances using antisense oligonucleotides have led to the
promising development of compounds targeting apo (a) to reduce
plasma Lp(a) concentrations. The first phase 1 study with the second
generation antisense drug to reduce the hepatic synthesis of apo(a),
IONIS-APO(a)-Rx, resulted in a potent, dose-dependent reduction of
plasma Lp(a) up to 77.8% [115]. Its safety and efficacy was confirmed
in a phase 2 trial (N = 64) with plasma Lp(a) reductions up to 71.6%,
but injection-site reactions occurred in 12% of the participants [116].
IONIS-APO(a)-Lrx is a variant of IONIS-APO(a)-Rx, which is also in
development and allows for rapid and specific uptake within hepato-
cytes via the asialoglycoprotein receptor and resulted in a maximally
92% reduction in Lp(a) without any injection-site reactions. Therefore,
IONIS-APO(a)-Lrx seems to be the most promising of the two and it may
reduce Lp(a) hyperlipoproteinemia-related cardiovascular risk or pro-
gression of calcified aortic valve stenosis [116].
5.5. CETP-inhibition
Inhibitors of CETP were developed in order to raise HDL-C levels,
but they lower LDL-C as well, albeit to a lesser extent than statins.
Despite their favourite modulation of the lipid profile, most CETP-in-
hibitors have not shown its potential to lower cardiovascular risk.
Torcetrapib, which was the first CETP-inhibitor that reached an ad-
vanced stage of clinical development, showed a 58% increase in mor-
tality and 25% increase in the primary cardiovascular endpoint during
the prematurely stopped ILLUMINATE study [117]. There is evidence
that the disappointing results of torcetrapib were due to off-target
toxicity and not due to CETP-inhibition itself. Currently, anacetrapib is
the only CETP-inhibitor that showed a reduction in cardiovascular
events, with a modest but significant 9% reduction in cardiovascular
events during a mean follow-up of 4.1 years. This outcome was prob-
ably mainly driven by its LDL-C lowering effect [118]. It was chosen not
to pursue regulatory approval for anacetrapib due to its modest clinical
benefit. It remains uncertain whether CETP-inhibition with further
improved agents will result in a potential cardioprotective strategy
[119].
5.6. Gene therapy
Alipogene tiparvovec was the first registered gene therapy in Europe
and approved for the treatment of patients with a chylomicronemia
syndrome due to LPL-deficiency. Its viral vector was based on an adeno-
associated virus, which contained the LPL S447X gene construct with a
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Clinica Chimica Acta 487 (2018) 117–125
constitutive expression promotor. Up to 64 intra-muscular injections
were given in major skeletal muscle groups under ultrasound guidance.
Plasma TG reductions up to 40% were achieved at three to six weeks
after injections, but TG levels returned to baseline after 12 weeks. A
50% reduction in pancreatitis events was observed after 2 years after
treatment when compared with a historic cohort despite the dis-
appearance of its TG lowering effect after 12 weeks [120]. Nevertheless,
alipogene tiparvovec was withdrawn in 2017 due to poor commercial
prospects and uncertainties about reimbursement [121].
6. Conclusions
The first step in clinical care of patients with dyslipidemias is es-
tablishing the diagnosis. This will determine the prognosis, the choice
of treatment and the necessity of genetic counselling. Many dyslipide-
mias have a polygenic basis interacting with lifestyle factors. Therefore,
genetic screening is currently only advised when FH or another, but
rare monogenetic lipid disorder is considered (for example FD) due to
the necessity of family cascade screening with subsequent clinical
consequences for affected family members. The pathophysiologic me-
chanism of the dyslipidemia determines the optimal pharmacological
treatment strategy besides lifestyle management in order to reach the
optimal treatment targets.
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