SEMINAR
Seminar
Dyslipidaemia
Paul Durrington
The lowering of serum cholesterol is increasingly recognised as essential in the prevention of coronary heart disease
and other atherosclerotic disease. The success of statin trials and the need to deploy these drugs effectively in
the population has led increasingly to the identification of many people whose serum cholesterol, triglycerides, and
HDL-cholesterol require clinical assessment, and frequently treatment. Lipid disorders are mainly straightforward, but
some are complex or resistant to simple treatment strategies. I have reviewed the clinical manifestations of
disordered lipid metabolism (dyslipidaemia) and its management.
The past 8 years have brought about a transformation in the
clinical trial evidence for the effects of lowering serum
cholesterol. Earlier scepticism was so great that proof was
demanded that lipid lowering decreases not only mortality
but also morbidity from coronary heart disease (CHD) and
all-cause mortality1—proof seldom required for other
pharmacotherapies, except perhaps chemotherapy of
malignant disease. Statin treatment now presents the
greatest likelihood that a physician engaged in general
medical practice can routinely prolong life.2–10
To translate clinical trial evidence into medical practice,
many international and national recommendations have
been developed that attempt to provide the clinician with
simple algorithms to guide practice. However, not all
patients have the simple lipid disorders the guidelines
presuppose. Application of these approaches frequently
reveals complex disorders. I have, therefore, surveyed
current knowledge and practice across the whole field of
dyslipidaemia. Adopting a clinical approach, I have grouped
the disorders according to whether the biochemical
phenotype is mainly hypercholesterolaemia, a combined
increase in cholesterol and triglycerides, mainly
hypertriglyceridaemia, hypolipidaemia, or secondary
dyslipidaemia.
Lipid clinics
With the inclusion of serum lipid measurements in
screening programmes to identify individuals at high
cardiovascular risk, unusual lipid disorders and clinical-
management issues have inevitably come to light (table). A
need has arisen, therefore, for specialist clinicians, who are
generally physicians or chemical pathologists who have
trained in endocrinology (diabetes) and metabolism. Some
lipid disorders present clinical difficulties that can be treated
successfully only in a lipid clinic that provides specialised
dietetic care, and laboratory (including genetics), nursing,
and inpatient facilities. There is also a need for clinicians
who can provide expertise in lipid disorders in primary care
or district general hospitals. However, the mistakes of earlier
single-risk-factor clinics should not be repeated, such as
diabetes clinics that concentrated only on glycaemic
Lancet 2003; 362: 717–31
University Department of Medicine, Manchester Royal Infirmary,
Oxford Road, Manchester M13 9WL, UK (Prof P Durrington FMedSci)
(e-mail: pdurrington@man.ac.uk)
THE LANCET • Vol 362 • August 30, 2003 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet
control, hypertension clinics that dealt only with blood-
pressure control, and cardiology and peripheral arterial
disease clinics that specialised only in investigation and
treatment of vascular consequences of atherosclerosis.
Atherosclerosis is multifactorial, and lipid and other
specialist clinics should form part of a cohesive preventive
cardiovascular disease service that facilitates access to
various specialties.
Hypercholesterolaemia
Familial hypercholesterolaemia
The diagnosis of familial hypercholesterolaemia should
always be sought among patients who have predominant
hypercholesterolaemia, because it carries a particularly high
risk of CHD that can easily be overlooked.11–15 The existence
of a dominantly inherited form of hypercholesterolaemia
that causes tendon xanthomata was recognised for 50 years
before the LDL receptor, and its diminished expression in
familial hypercholesterolaemia was discovered in 1974.16
The gene for the LDL receptor is located on chromosome
19. The receptor allows cellular uptake of LDL from the
tissue fluid. An outline of lipoprotein metabolism is shown
in figure 1. Mutations of this receptor in familial
hypercholesterolaemia prevent it from participating
efficiently in LDL uptake because it cannot be transported
to the cell surface, cannot bind properly to LDL once it gets
there, cannot be internalised, or is not released from the
endosome.11 Well before the discovery of the LDL-receptor
defect in familial hypercholesterolaemia, the time LDL
spent in the circulation before its catabolism was shown to
be increased from the normal 2·5 days to about 4·5 days in
heterozygotes, and even longer in homozygotes.17
Search strategy
I drew early references, before 1980, largely from Havel RJ,
Goldstein JL, Brown MS. Lipoproteins and lipid transport.
In: Bondy PK, Rosenberg LE, eds. Metabolic control and
disease, 8th edn. Philadelphia: WB Saunders, 1980:
393–494. For later references, I searched the databases of
Current Opinion in Lipidology, augmented by MEDLINE and
PubMed, with the keywords: apolipoprotein, cholesterol,
dyslipidaemia, hypercholesterolaemia, hyperlipidaemia,
hyperlipoproteinaemia, hypertriglyceridaemia, lipoprotein, and
triglyceride. I made my final selection dependent on limitations
of space, whether the references quoted were a good source
of further references, and on the basis of my own clinical,
research, and teaching experience.
717
SEMINAR

Dyslipidaemia WHO phenotype Diagnosis Estimated prevalence

(hyperlipoproteinaemia) among adults of
European descent
Mainly hypercholesterolaemia* Type IIa: raised LDL Polygenic hypercholesterolaemia; 20–80%
familial hypercholesterolaemia;† 0·2%
familial defective apolipoprotein B 0·2%
Combined hypercholesterolaemia
and hypertriglyceridaemia
Triglycerides 2·0–10·0 mmol/L‡ Type IIb: raised VLDL and LDL Familial combined if relatives have 10%
hyperlipoproteinaemia, otherwise simply
combined hyperlipidaemia
Triglycerides 5·0–20·0 mmol/L Type III: raised chylomicron Frequently called type III hyperlipoproteinaemia, 0·02%
(cholesterol typically remnants and IDL but also synonyms†
7·0–12·0 mmol/L)
Triglycerides >10·0 mmol/L Type V: raised chylomicrons Familial lipoprotein lipase deficiency or 0·1%
and VLDL; or type I: raised heterozygous lipoprotein lipase mutation
chylomicrons plus another cause for hypertriglyceridaemia†
Raised triglycerides alone‡ Type IV Familial or sporadic hypertriglyceridaemia 1%
Hypoalphalipoproteinaemia None: low HDL Most undiagnosed or associated with 10–25%
hypertriglyceridaemia. Occasionally heterozygous
ABCAI mutation, APOAI mutation
Hypobetalipoproteinaemia None: low LDL and frequently Familial—eg, truncated apolipoprotein B 0·1–0·01%
VLDL
*Serum cholesterol >5·0 mmol/L. WHO phenotype has not been updated since views about what constitutes raised cholesterol have changed. When devised,
⭓6·5 mmol/L would have been abnormal. †Diagnoses can have distinct clinical phenotype. ‡National Cholesterol Education Program recommendations III suggest
triglycerides >1·5 mmol/L are unhealthy. Disorders occurring at frequencies of <0·01% have been omitted.
Primary dyslipidaemia that could present on measurement of serum cholesterol, HDL-cholesterol, and triglycerides

In open societies, such as the UK and USA, many terolaemia, cholesterol concentrations as low as
mutations of the LDLR gene cause the clinical syndrome 5·5 mmol/L in children do not altogether exclude the
of familial hypercholesterolaemia—more than 700 diagnosis, particularly if the family is already on a
mutations have already been reported.18 This genetic cholesterol-lowering diet. Repeated measurements over
disorder is the most common in Europe and the USA, and time are required for these children.
affects about one in 500 people in its heterozygous form. Serum cholesterol in people who have familial
In societies that have sprung from small numbers of early hypercholesterolaemia, as in the general population,
settlers or migrants, familial hypercholesterolaemia may increases with advancing age. Generally, in heterozygous
be more common than in large open societies, and is familial hypercholesterolaemia values are about double
caused by a smaller number of mutations (founder effect). what they would have been in the absence of the LDL-
Thus, for example, one in 80 South Africans of Dutch or
French descent have familial hypercholesterolaemia, most Acquire apolipoproteins
eg, E, CII
of whom have one of only three different LDLR ApoB48
mutations.19 A similar situation seems to explain the high Gut
prevalence of familial hypercholesterolaemia in
descendants of French Canadian trappers20 and in the TG
Chylomicron
Christian population of the Lebanon.21
Serum cholesterol concentrations in heterozygous TG
familial hypercholesterolaemia are raised from birth. The Lipoprotein ApoAI
lipase
normal mean serum cholesterol concentration in TG
umbilical cord blood is only about 1·7–2·0 mmol/L, and it Chylomicron remnant
is much higher in familial hypercholesterolaemia. TG
However, screening by measurement of total serum Can accept LRP Liver
cholesterol is not recommended among neonates because chylomicron ApoAI
HDL-cholesterol, which is the dominant lipoprotein in remnants, VLDL,
LDL SRBI
fetal blood, can cause raised cholesterol concentrations IDL, and LDL. HDL
receptor
Down-regulated
more commonly than familial hypercholesterolaemia.22 when liver is TP
Serum cholesterol rises in the first year of life to a mean of cholesterol replete VLDL CE
ApoB100
l e s t e r ol

4·1 mmol/L (95th percentile 5·2 mmol/L), which persists Acquire

until the early teens, with mean concentrations being apolipoproteins eg, E, CII
IDL
similar in boys and girls before puberty.22 The normal Lipoprotein TG
Cho

range for serum cholesterol varies little with age lipase TG

TG LDL
in childhood. A diagnostic threshold for childhood Hepatic
familial hypercholesterolaemia can, therefore, be defined lipase ABCA1
and explains why total serum cholesterol higher than TG LDL receptor
SRA .
6·7 mmol/L correctly identifies 95% of heterozygotes O NRM
and only 2·5% of unaffected children.23 Cholesterol Small dense
measurements must be confined to the children of LDL
Foam Generalised
affected parents to keep the chances of the disorder being cell cell
discovered to one in two. If children in general were
screened, the chance of finding a heterozygote is one in Figure 1: Outline of lipoprotein metabolism
CETP=cholesteryl ester transfer protein. IDL=intermediate-density
500; therefore, even a 2·5% false-positive rate would lipoprotein. TG=triglyceride. LRP=LDL-receptor-like protein. SRA=scavenger
falsely identify ten unaffected children for every affected receptor A. SRB1=scavenger receptor B1. NRM=non-receptor-mediated
one. In families of probands with familial hypercholes- uptake. ABCA1=ATP binding cassette A1. O·=oxygen free radical.

718 THE LANCET • Vol 362 • August 30, 2003 • www.thelancet.com

For personal use. Only reproduce with permission from The Lancet
 SEMINAR

Figure 2: Clinical manifestations of hyperlipidaemia

A: Achilles tendon xanthoma (heterozygous familial hypercholesterolaemia). B: Tendon xanthomata on dorsum of hand (heterozygous familial
hypercholesterolaemia. C: Subperiosteal xanthomata (heterozygous familial hypercholesterolaemia). D: Planar xanthoma in antecubital fossa (homozygous
familial hypercholesterolaemia). E: Striate palmar xanthomata (type III hyperlipoproteinaemia). F: Tuberoeruptive xanthomata on elbow and extensor surface of
arm (type III hyperlipoproteinaemia). G: Milky plasma from patient with acute abdominal pain (severe hypertriglyceridaemia). H: Eruptive xanthomata on extensor
surface of forearm (severe hypertriglyceridaemia).

receptor mutation.24 By adulthood, the serum cholesterol
in heterozygous familial hypercholesterolaemia in the UK
is thus typically in the range 9·0–14·0 mmol/L.
The diagnostic hallmarks of familial hypercholestero-
laemia are tendon xanthomata.11,12 Other causes of these,
cerebrotendinous xanthomatosis and phytosterolaemia
are exceptionally rare. Xanthomata are localised infiltrates
of lipid-containing foam cells that histologically resemble
atheroma. Corneal arcus and xanthelasmata are not
specific to familial hypercholesterolaemia, but they
frequently occur much earlier in life in familial
hypercholesterolaemia than in the more common
polygenic type of hypercholesterolaemia. Nonetheless,
many heterozygotes who have familial hypercholestero-
laemia with obvious tendon xanthomata do not have
corneal arcus until much later in the disease course, and
will never develop xanthelasmata.25–27 Therefore, whether
tendon xanthomata are present should be checked in all
patients who have hypercholesterolaemia, irrespective of
the presence of corneal arcus or xanthelasmata.
The most common sites for tendon xanthomata are in
the Achilles tendons and in the tendons overlying the
knuckles (figure 2);12 less-common sites are in other
tendons. Xanthomata are also commonly firmly attached
to the tibial tuberosities at the site of insertion of the
patellar tendon (subperiosteal xanthomata, figure 2). The
skin overlying tendon xanthomata and subperiosteal
xanthomata is a normal colour and does not appear
yellow. The cholesterol accumulation is deep within the
tendons and much of the swelling is fibrous. The

THE LANCET • Vol 362 • August 30, 2003 • www.thelancet.com 719

For personal use. Only reproduce with permission from The Lancet
SEMINAR
xanthomata feel hard. Those in the Achilles tendons can
become inflamed and many patients who have familial
hypercholesterolaemia will, if asked, describe previous
Achilles tenosynovitis. Xanthomata in the tendons on the
dorsum of the hands are generally nodular or fusiform,
and because they frequently overlie the knuckles
(especially when the fist is clenched) and feel as hard as
bone, physicians may miss them. The hands should be
examined with the fingers extended when xanthomata are
pulled back from the knuckles and can be moved from
side to side. Achilles-tendon xanthomata may be visually
obvious, because of thickening, swelling, irregularity, or
nodularity of the tendon. They may, however, be subtle,
the nodularity in the tendon becoming obvious only on
palpation.
The other frequent striking feature of familial
hypercholesterolaemia is the adverse family history of CHD.
If they remain untreated, more than half of male and about
15% of female heterozygotes die before age 60 years.14,28
Intriguingly, this high mortality associated with the
inheritance of the LDLR mutation seems to have been
absent in some families at least until the early part of the
20th century.29 This pattern generally parallels the rise of
CHD mortality in North American and European Societies,
although the risk to the familial hypercholesterolaemia
heterozygote, particularly in early adulthood, compared
with the average risk, is increased many-fold.15 In some
present-day families, familial hypercholesterolaemia seems
particularly devastating, causing CHD in men even in their
20s and in women before the menopause. In other families,
male heterozygotes are unaffected until late middle age or
sometimes older, and women survive to extreme old age
with little evidence of CHD symptoms. The median age for
the development of CHD in men is around 50 years.
Typically, affected women in the same family develop CHD
about 9 years later than their affected male relatives.30
There has been much speculation as to why some
families with familial hypercholesterolaemia are more
susceptible to CHD than others.26,31–36 The nature of the
mutation might itself be important, because some
mutations will more severely compromise LDL uptake
than others. The particular combination of mutations
certainly affects the severity of homozygous familial
hypercholesterolaemia, but this effect is less clear in
heterozygous familial hypercholesterolaemia.32 Serum
HDL-cholesterol relates to the likelihood of CHD in
familial hypercholesterolaemia.33,34 Serum HDL choles-
terol is generally lower than would be expected in familial
hypercholesterolaemia, but in families in which this
decrease is most obvious, prognosis is frequently bad.
Generally, in familial hypercholesterolaemia, only serum
cholesterol is raised. In a few patients, triglycerides are
also raised, although seldom to more than 4·0 mmol/L,
which has also been associated with a poor prognosis.33
Many such patients are obese, and obesity can increase
their serum cholesterol, rarely even up to 20·0 mmol/L.12
Obesity is generally uncommon in familial hypercholes-
terolaemia, compared with almost all other hyperlipi-
daemias, in which obesity is over-represented. Hyper-
tension and diabetes mellitus are also noticeably
infrequent in familial hypercholesterolaemia.27 Therefore,
familial hypercholesterolaemia may not be diagnosed if
cholesterol screening is confined to patients with non-
lipid risk factors. Serum lipoprotein (a) concentrations
are raised in familial hypercholesterolaemia,36 and are
related to increased CHD risk.37 Increased intestinal
cholesterol absorption related to co-inheritance of an
apolipoprotein E ⑀4 genotype may also worsen
prognosis.33
720
For personal use. Only reproduce with permission from The Lancet
CHD is by far the most common manifestation of
atheroma in heterozygous familial hypercholesterolaemia.
In homozygous familial hypercholesterolaemia particularly,
but also occasionally in heterozygotes, atheromatous
deposits may be present in the root of the aorta and can
extend into the aortic valve cusps.36,39 This form of
supravalvar aortic stenosis can cause sudden death in
severely affected heterozygotes and in homozygotes. Some
patients also develop carotid and cerebrovascular atheroma,
although less commonly than CHD. Femoropopliteal
atheroma is uncommon and is really encountered only in
cigarette smokers who have familial hypercholesterolaemia.
The discovery of a new case of familial hyper-
cholesterolaemia provides the opportunity to detect
affected relatives. Such an approach, known as cascade
family screening, is better than general or selective
screening, and should be introduced, involving trained
nurses working from regional lipid clinics to ensure family
members receive adequate treatment and access to
medical services.13,27,40 The Simon Broome register
definition of heterozygous familial hypercholesterolaemia
provides a good guideline for identification of affected
relatives:15 serum cholesterol concentrations higher than
6·7 mmol/L in children younger than 16 years or more
than 7·5 mmol/L in adults, plus tendon xanthomata in the
patient or first-degree or second-degree relatives.
Whether the familial hypercholesterolaemia genotype
can be present in people without the clinical syndrome
and whether, therefore, genetic testing could be useful is
debated.13 The high numbers of mutations involved,
however, mean no simple widely applicable means of
genetic testing is likely to be generally feasible in the UK
and USA. Some encouraging results have been reported
in South Africa and in the Netherlands, where fewer
mutations account for a higher proportion of familial
hypercholesterolaemia.41 Although the controversy over
genetic testing continues, many people with obvious
clinical features of familial hypercholesterolaemia who are
at risk of premature CHD go undetected or the
importance of the diagnosis and the rigour with which this
disorder must be treated is not appreciated.13
The statin drugs have been a major advance in the
management of familial hypercholesterolaemia in
adults.42,43 Most familial hypercholesterolaemia heterozy-
gotes can achieve serum cholesterol concentrations lower
than 7·0 mmol/L, and some even lower than 5·0 mmol/L.
The most potent of the statins may be required at
maximum dose to lower the highest cholesterol
concentrations. Occasionally the response to statins alone
is inadequate, and addition of a bile-acid-sequestrating
agent is the most logical approach. The development of
more potent statins or use of the cholesterol-absorption
inhibitor, ezetimibe may supersede this approach.
Nicotinic acid in doses up to 7 g daily is also effective in
lowering cholesterol, but must be carefully monitored and
is rarely acceptable to patients because of the severe
flushing it invariably produces. Partial ileal bypass is
frequently successful in lowering serum cholesterol,44 but
has been used less since the advent of statins.
The penetrance of familial hypercholesterolaemia
judged in terms of CHD risk generally breeds true in
families.30 This information can be helpful in making
decisions about the age at which to introduce statin
treatment. Generally, despite the need for more evidence
about the safety of statins in childhood,45 in male
heterozygotes statin treatment should be started in the late
teens, but could be started earlier if the family history is
particularly adverse. In many women the introduction of
cholesterol-lowering medication can safely be left until
THE LANCET • Vol 362 • August 30, 2003 • www.thelancet.com

later, but there are reproductive issues. Women should be
advised against pregnancy while they are taking statins
since the risks are unknown. Many women do not,
however, contemplate motherhood until their 30s or early
40s by which time they should have started statin therapy.
In planned pregnancies women can discontinue
medication while they are attempting to conceive and
during pregnancy. The time to start statin treatment
must, therefore, be negotiated with each female patient,
but generally women choose to begin statin treatment in
their early 20s because they know they will stop for
around a year per planned pregnancy, dependent on how
long conception takes.
I believe there is no justification for use of bile-acid
sequestrants in children, even if these drugs are judged
safe.46 This treatment is poorly tolerated by children and,
thus, adherence is inadequate; therefore, these drugs serve
no function in preventing vascular disease. The poor
tolerance can also alienate children from the clinic, which
means they can be lost altogether during the rebellious
years of adolescence when effective treatment with statins
should be considered. For the same reasons, repeated
blood testing in children should be avoided between
diagnosis and the time when statin intervention is being
considered. Children should generally receive no
treatment other than a healthy diet, exercise, and
avoidance of smoking.
The introduction of lipid-lowering treatment is not the
only reason for identifying heterozygotes for familial
hypercholesterolaemia. The disorder is still not widely
recognised. Therefore, when patients present with
manifestations of CHD they are frequently inappro-
priately managed. Many physicians do not believe that
such young apparently fit people can have severe CHD,
which commonly leads to delay in investigations,
especially coronary angiography. Certainly, exercise
electrocardiography should be done promptly if any
symptom even slightly suggestive of CHD occurs, and
patients who have familial hypercholesterolaemia should
be encouraged to report such symptoms. Coronary
angiography should be done since it frequently reveals
surprisingly extensive disease, despite non-severe
symptoms. Measurement of the pressure gradient across
the aortic valve with echocardiography should also be
undertaken if a systolic murmur is present.
Homozygous familial hypercholesterolaemia rarely
occurs by chance. The odds of two unrelated
heterozygotes marrying is one in 250 000, and the chances
of them having a child who is homozygous is one in four,
meaning that the theoretical incidence of homozygous
familial hypercholesterolaemia is one in 1 million. The
chances of a marriage between heterozygotes is increased
greatly when there is, for example, a tradition of first-
cousin marriage. In such circumstances both the LDLR
mutations in homozygotes are likely to be the same. These
people are thus true homozygotes (strictly compound
homozygotes), as opposed to homozygotes that arise from
random unions, in which LDLR mutations are probably
different for each allele. Serum cholesterol concentrations
in homozygous familial hypercholesterolaemia are almost
invariably higher than 15·0 mmol/L and can be as high as
30·0 mmol/L.11,12 Xanthomata develop in childhood. In
addition to florid tendon xanthomata, orange-yellow
cutaneous planar xanthomata develop, particularly in the
popliteal and antecubital fossae (figure 2), buttocks, and
in the webs between the fingers. They can also develop on
the palms of the hands and front of the knees.
Polyarthralgia is common and supravalvar aortic stenosis
can cause sudden death. Many homozygotes develop
THE LANCET • Vol 362 • August 30, 2003 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet
SEMINAR
angina of effort in childhood due to the aortic stenosis and
coronary atheroma. Myocardial infarction has been
recorded as early as age 2 years, and life expectancy does
not generally extend beyond the early 20s. Although
homozygous familial hypercholesterolaemia is always
serious, the worst prognosis seems to occur when both
LDLR mutations are of the type that completely prevent
LDL receptors appearing on the cell surface.11
The most potent statins can lower serum cholesterol by
up to 30% in homozygous familial hypercholesterolaemia,
and ezetimibe can produce a further 20% decrease.47
However, even then substantial hypercholesterolaemia
will remain. Plasmapheresis or LDL apheresis is the best
approach to treatment.48,49 Generally the procedure must
be done every 2 weeks. Liver transplantation has also met
with some success.50 Normal donor hepatic LDL
receptors are introduced; the liver is the site of about half
of LDL catabolism in normal people. The LDLR gene can
be transfected into LDLR knockout mice, in which it is
expressed and lowers serum cholesterol, albeit briefly,
before it is cleared from the cell nuclei along with viral
DNA.51 As soon as a vector that allows foreign DNA to
persist safely in mammalian cells become available,
homozygous familial hypercholesterolaemia will probably
be one of the first genetic disorders to be treated by this
technique.
Other defects in LDL catabolism in familial
hypercholesterolaemia syndrome
The familial hypercholesterolaemia phenotype is generally
caused by an LDLR mutation. Rarely, however, the same
syndrome is caused because apolipoprotein B, the
component of LDL that allows it to bind to the LDL
receptor, has a mutation that interferes with binding.
Thus, a similar defect in LDL catabolism is produced,
called familial defective apolipoprotein B. This disorder is
most commonly due to an aminoacid substitution at
position 3500 in the aminoacid sequence of apolipopro-
tein B.52 This mutation has a frequency of about one
in 600 in the general population, although usually it
does not produce a particularly severe hyperlipidaemia.
However, as many as 4% of people with clinical familial
hyercholesterolaemia may have familial defective
apolipoprotein B.53 These patients’ hypercholesterolaemia
seems to respond more easily to treatment than is
generally the case in familial hypercholesterolaemia.
Currently, about half the patients in the UK and USA
who have a clinical diagnosis of heterozygous familial
hypercholesterolaemia will have identifiable mutations of
the LDLR gene.54 Genetic techniques might be failing to
detect LDLR mutations in some of these patients.
However, another gene or genes involved in LDL
catabolism might be discovered, which, when they
undergo mutation, will explain the presence of familial
hypercholesterolaemia in some patients. A type of familial
hypercholesterolaemia that is inherited as an autosomal
recessive has been reported to be due to mutations of a
gene involved in the internalisation of the LDL and LDL-
receptor complex from the cell surface by endocytosis.55
The mutation produces a clinical phenotype intermediate
between heterozygous and homozygous familial
hypercholesterolaemia, and has so far been described
mainly, but not exclusively, in people from Sardinia.55,56
Polygenic hypercholesterolaemia
The most common cause of raised LDL cholesterol is not
an inherited catabolic defect but a hepatic overproduction
of VLDL, which is converted to LDL sufficiently rapidly
that VLDL triglyceride concentrations remain within
721
SEMINAR
normal limits but LDL cholesterol rises.57 The main causes
are high fat intake, particularly saturated fat, and obesity.
Genetic factors are also assumed to be important, because
individuals vary in their cholesterol response to diet.
However, there is no clear pattern of inheritance; a
combination of more than one genetic variant is generally
required for this type of hypercholesterolaemia (polygenic
inheritance). Hypercholesterolaemia is prevalent in Europe
and the USA and countries that have adopted features of
their cultures,58,59 particularly lifestyle, values, and so on.
Treatment has proved troublesome. There is no shortage
of good evidence that lowering cholesterol decreases CHD
risk,2–10,60 but difficulty lies in the translation of this
approach into clinical and public-health practice.
Countries with high CHD mortality are those in which the
typical cholesterol concentration of their inhabitants is
much higher than that in countries where lower CHD risk
is the rule.58,59 Within apparently healthy populations there
is an exponential relation between serum cholesterol and
coronary risk.61 The slope of this relation is greater among
younger than older people. In middle-age, the risk
increases by about 2% for each 1% increase in cholesterol.
Even in countries such as China, where the average
cholesterol concentration is less than 4·0 mmol/L, this
gradient of risk is still evident, although set at a lower level
than, for example, in the UK, where the average
cholesterol in middle age is around 6·0 mmol/L.62
The great difficulty for clinicians has been to
comprehend that in a society in which cholesterol
concentrations and coronary risk are generally high, CHD
events occur most frequently among people whose serum
cholesterol is average, and that even at low
concentrations, cholesterol can contribute to high CHD
risk. Most heart attacks will occur in people whose
cholesterol and CHD risk are average simply because they
are more numerous than those with higher degrees of
risk.63 Thus, the expectation that the typical individual
who has a myocardial infarction will also have
substantially higher-than-average cholesterol is wrong.
For too long opportunities to prevent CHD or
recurrent CHD have been missed because practitioners in
societies in which risk factors for CHD are prevalent have
sought to treat only patients with exceptionally high
cholesterol concentrations. In the UK, for example, the
typical patient with acute myocardial infarction will have a
cholesterol concentration of around 6·0 mmol/L, the
average for the middle-aged and older population. There
is excellent evidence that lowering cholesterol irrespective
of its initial concentration will lessen the likelihood of a
recurrence.2–6 Of course, it is perfectly reasonable to ask
why some people will have a heart attack with low
cholesterol concentrations but others will not. This issue
poses the greatest difficulty in primary prevention if we are
not to treat huge numbers of people, many of whom will
be treated needlessly.
Identification of people who have high susceptibility to
CHD is easy if they already have some manifestation of
CHD or other atherosclerotic disease. The relation
between serum cholesterol (or HDL-cholesterol) and
CHD risk is steeper in myocardial infarction survivors
than in the general population,64 and in half of people who
die from CHD the disease has been previously
symptomatic,65 frequently early enough for preventive
measures to have been effective.2–6
Ideally we should be able to identify people most
susceptible to cholesterol even before symptoms develop
(primary prevention) and treat them. In practice we can
identify some of these people by taking into account risk
factors other than serum cholesterol,65–68 such as sex,
722
For personal use. Only reproduce with permission from The Lancet
HDL-cholesterol concentration, blood pressure, smoking,
diabetes, and family history. The Framingham risk
equation has found favour in the identification of
individuals more likely to benefit from statin
treatment.67–72 However, this high-risk approach will not
prevent most heart attacks, which will occur at an average
concentration of serum cholesterol and in the presence of
average CHD risk.
Currently, the only hope of preventing such typical
events is to reduce the levels of risk factors in the
population as a whole. To achieve this reduction would
require a concerted public-health policy aimed at
reducing smoking, improving nutrition, and encouraging
exercise. Cholesterol reduction has a special place in
CHD prevention because, in societies in which the typical
concentrations are low, such as those in Asia, other CHD
risk factors, such as smoking, hypertension, and diabetes
seem to have much less impact on CHD risk than in
societies with high cholesterol concentrations.58,73,74 This
effect is consistent with our concepts of atherogenesis, in
which LDL is intimately involved, and the other risk
factors operate by increasing its atherogenicity by
modifying its chemical and physical structure or by
facilitating its passage into the arterial wall.75
Furthermore, the reasons for the substantial differences
in CHD risk between different societies have been
consistently attributed to nutritional differences: countries
with the highest energy consumption, particularly in the
form of saturated fats as opposed to carbohydrate, have
the highest CHD rates.58 Obesity and high consumption
of saturated fats both raise serum cholesterol.76,77 Sadly, as
people migrate from Asian societies and consume the diet
more typical of countries with high CHD rates, their
CHD risk increases.78,79 Similarly, as the diet in Asian
countries becomes increasingly more like European and
US diets, they are poised to experience an epidemic of
CHD. This epidemic will be worse than in other countries
because Asian countries are so highly populated and the
financial resources to deal with it are limited. In addition,
metabolic polymorphisms present in Asian populations
that may have survival potential on a subsistence-level diet
with low fat content, might, if a high-fat diet is adopted,
lead to higher rates of dyslipidaemia, glucose intolerance,
and CHD than in people of European descent.80
High-risk patients will derive little individual benefit
from public-health policy; a higher proportion of them
will benefit from lipid-lowering drug therapy. Treatment
should be directed not so much at cholesterol
concentrations, but at high CHD risk. Certainly, among
patients with clinical CHD or equivalent risk, serum
cholesterol concentrations as low as 4·0 mmol/L should
be treated.3–6 Evidence is strongest for statins. Dietary
intervention should not, however, be abandoned, but
realistically it frequently does not achieve an adequate
reduction in serum cholesterol outside the metabolic
ward.81 This inadequate effect may be related to
commercial and cultural pressures or to more complex
issues of early nutritional effects, perhaps as early as in
utero,82 which produce metabolic resistance in later life.
There have been nine major randomised statin trials
with clinical endpoints (figure 3).2–8,60,83 The trials were
done in patients with a wide range of CHD risk, from
around 5%2 to less than 1% for each year of study.8 The
results show decreases in CHD and stroke risk of about a
third, irrespective of cholesterol concentration at entry, at
least down to 3·5 mmol/L among men and women for
primary and secondary prevention.5,8,9 The trials show that
the improvement in risk with statins is maintained in old
age, despite the relative decrease in the predictive power
THE LANCET • Vol 362 • August 30, 2003 • www.thelancet.com

45
GREACE
40
Decrease in LDL cholesterol (%)
4S
35
30 HPS
PROSPER CARE WOSCOPS
25 AFCAPS/TexCAPS
LIPID
20
ALLHAT
15
0 decrease in CHD risk. This patient may have a similar
0 10 20 30 40 50 60
Decrease in CHD risk (%)
Figure 3: Decrease in combined CHD morbidity and mortality as a
function of average LDL-cholesterol reduction in randomised
clinical trials of statin treatment
Endpoint in AFCAPS/TexCAPS was fatal and non-fatal myocardial infarction,
otherwise it was death from CHD or non-fatal myocardial infarction. Bars
show 95% CI.
of cholesterol with advancing age in epidemiological
studies.84 The decrease in CHD risk with statin therapy
was evident by the second year of such trials and there is
some suggestion that a decrease in cardiovascular risk can
be achieved in the 6 months immediately after an acute
coronary event.85 The starting of statin treatment at that
time seems to have no adverse effects,86,87 and it is one way
of ensuring that statin treatment is not subsequently
overlooked and its long-term benefit denied.
Whether cholesterol needs to be measured at all is
questioned in making the decision to introduce statin
treatment in patients with CHD or other atherosclerosis.
Measurement might be best avoided if it impedes the
introduction of statin treatment. As for the dose, an
evidence-based dose could be prescribed and left at that,
but measurement of serum cholesterol after the
introduction of a statin is essential to monitor its effect
and to titrate the dose to achieve an LDL-cholesterol
target.
The statin trials are unfortunately confounded as to
what should be the LDL-cholesterol target of statin
treatment. None was designed to establish what the target
should be. Post-hoc analysis comparing patients with
greater and lesser degrees of cholesterol lowering breaks
the randomisation and involves factors other than the
dose and efficacy of the statin. One trial did aim to
compare the effect of achieving the US National
Cholesterol Education Program LDL-cholesterol target of
2·5 mmol/L with normal care among patients with CHD.6
95% of the active intervention group, who received
10–80 mg atorvastatin daily (average 24 mg), achieved
the LDL-cholesterol target, compared with only 3%
receiving normal care. The LDL-cholesterol in the active
intervention group was 41% lower than in the normal care
group, which resulted in a decrease in fatal and non-fatal
new myocardial infarction of 51% and in overall mortality
of 43% during the 3 years of the trial. The decrease in
LDL cholesterol and in CHD risk achieved was greater
than in any previous statin trial.
Whether an absolute LDL-cholesterol concentration
should be the only target of statin treatment or whether
the starting concentration should also be taken into
THE LANCET • Vol 362 • August 30, 2003 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet
SEMINAR
account remains unsettled. Although this consideration
complicates recommendations, it is potentially important.
The trials do seem to show that the percentage decrease in
cholesterol produces a similar percentage decrease in
relative CHD risk, irrespective of the initial LDL
cholesterol concentration—a 1% decrease in LDL
cholesterol produces roughly a 1·25% decrease in CHD
risk (figure 3). Thus in a patient who has an LDL-
cholesterol concentration of 6·0 mmol/L, a 40% decrease
in LDL cholesterol will produce a concentration of
3·6 mmol/L—higher than the absolute target of less than
2·5 mmol/L, but nevertheless a 50% decrease in CHD
risk. In another patient whose LDL cholesterol is only
3·0 mmol/L initially, a reduction in LDL to 2·4 mmol/L,
achieving the absolute target, will result from a 20%
decrease in LDL cholesterol, but represents only a 25%
initial CHD risk to that of the first patient because his
70
susceptibility to cholesterol is increased say by the
presence of other risk factors. Thus, despite achieving a
lower LDL target the second patient will have a poorer
prognosis, unless an LDL target that is lower still were
achieved. Therefore, for a given reduction in CHD risk,
the absolute target can differ between patients.
The issue is further complicated because some trials
suggest that the decrease in CHD risk is not linearly
related to the percentage decrease in LDL cholesterol, but
declines exponentially with no detectable additional
benefit beyond, for example, a decrease of 25%.88 If,
however, the overall results of the statin trials are
considered in relation to the average LDL-cholesterol
reductions they achieved, there does seem to be increased
benefit from greater reduction in LDL cholesterol,
although the CI are wide (figure 3). This analysis,
however, has the advantage that the randomisation within
the individual trials is not disturbed. On the other hand
an additional complication is that different statins were
used in the trials. Thus, some statins might be more
antiatherogenic than others. Currently, therefore, to aim
for at least a 30% decrease in LDL cholesterol or an
absolute concentration of 2·5 mmol/L, whichever is lower,
seems reasonable.
Combined hypercholesterolaemia and
hypertriglyceridaemia
Familial combined hyperlipidaemia
Hypertriglyceridaemia associated with hypercholestero-
laemia is most commonly due to a combined increase
in LDL and VLDL. Combined hyperlipidaemia is a
common disorder, occurring in around 30% of
myocardial-infarction survivors, and may affect as many
as one in 50 of the general population.89,90 The disorder’s
pattern is frequently familial, and is commonly referred to
as familial combined hyperlipidaemia. In family studies,
phenotype has proved variable, and some family members
may have an isolated rise in cholesterol or triglycerides,
whereas in others rises are combined. Originally,
combined hyperlipidaemia was suggested to have a
dominant monogenic mode of inheritance.89 Now it is
thought to result from genetic factors, some predisposing
to high cholesterol and some to hypertriglyceridaemia
running in the same family.91 Thus variants in exons or
promoters of the lipoprotein lipase gene or its activators
and inhibitors, apolipoprotein CII and CIII, or of the
cholesteryl ester transfer protein (CETP) gene or the
genes regulating uptake or release of non-esterified fatty
acid by adipose tissue, such as acylation stimulating
protein or insulin resistance, may, in some families, be
co-inherited with a polygenic tendency for high hepatic
723
SEMINAR
14
Serum cholesterol (mmol/L)
9·0
12 7·5
6·0
Myocardial infarction risk
10
8
6 paraoxonase located on HDL.109
4 Small dense LDL and hyperapobetalipoproteinaemia
2
0 component of LDL.110 Sniderman and colleagues111 were
0 1 2 3 4 5 6 7
Serum triglycerides (mmol/L)
Figure 4: Fatal and non-fatal myocardial infarction risk over next
6 years per 100 men
Risk calculated from reference 95, by use of Spirit 6 calculator for men aged
50 years with no family history of CHD, non-smokers and non-diabetic,
and with systolic blood pressure 140 mm Hg and serum HDL cholesterol
1·4 mmol/L. Plotted as function of serum triglyceride concentration at three
different serum cholesterol concentrations.
VLDL secretion, and thus high concentrations of its
product, LDL. Raised serum triglyceride concentrations
are associated with low HDL partly because they may be
the result of diminished lipoprotein lipase activity, which
not only catabolises triglycerides in the core of
triglyceride-rich lipoproteins, but in doing so generates
HDL components from their surface.
An increased flux of cholesteryl ester from HDL to
triglyceride-rich lipoproteins in hypertriglyceridaemia
causes a further tendency to low HDL-cholesterol
concentrations.92 This process is mediated by cholesteryl
ester transfer protein.93 Hypertriglyceridaemia increases
the risk of atherosclerosis to higher than that which would
be predicted from the cholesterol concentration
(figure 4).94–104 The raised CHD risk seems to stem partly
from the low HDL-cholesterol concentrations and partly
from an increased concentration of cholesterol-depleted
LDL (small dense LDL), the presence of which is not
necessarily appreciated from the serum or LDL
cholesterol concentration, and which is highly
atherogenic.100
The effectiveness of statins to reduce cardiovascular
risk2–10 means that these drugs should be the first-line
treatment for familial combined hyperlipidaemia. Their
triglyceride-lowering effect, which is mainly through an
increase in the hepatic reuptake of VLDL, intermediate-
density lipoprotein, and LDL105 is, however, generally less
than that of fibrate drugs, which increase lipoprotein
lipase activity by a mechanism involving peroxisome
proliferator activator receptors ␣ and ␥.106 Their
cholesterol-lowering effect is, however, smaller than that
of statins and is due mainly to a decrease in VLDL
cholesterol. ␻-3 fatty acids also lower VLDL triglyceride
with little effect on serum cholesterol. Fibrates or ␻-3
fatty acids may thus be combined with statins to lower
triglycerides further, but the former combination increases
the risk of myositis, albeit probably rarely. Nicotinic acid,
although it can lower cholesterol and triglycerides, almost
invariably causes unpleasant flushing in therapeutic
doses.12 There is evidence that all four classes of drugs
decrease activity of cholesteryl ester transfer protein and
724
For personal use. Only reproduce with permission from The Lancet
small dense LDL concentrations.106,107 Interest has been
shown in the development of more specific inhibitors of
cholesteryl ester transfer protein.108 The relation of low
HDL concentrations with CHD risk is the subject of
much interest and is undoubtedly complex. Low HDL
concentrations are potentially associated with heightened
activity of cholesteryl ester transfer protein and small
dense LDL. Attention has also been drawn to the capacity
of HDL to protect LDL against atherogenic oxidative
modification, which seems to reside in the enzyme
Patients with and without diabetes who have high
triglyceride concentrations may, despite apparently
normal serum or LDL cholesterol, have high serum
concentrations of apolipoprotein B, the main protein
8 the first to realise the cause was the presence of
a cholesterol-depleted LDL, and termed the disorder
hyperapobetalipoproteinaemia. Direct measurements of
the cholesterol-depleted LDL subtype, known as LDLIII
or small dense LDL, in epidemiological studies have
shown a strong association with the risk of developing
CHD,101 and experimental studies show it to be more
susceptible to oxidation than more buoyant LDL.98,112,113
Small dense LDL concentrations increase as serum
triglycerides concentrations rise to higher than
1·5 mmol/L.100,114 Small dense LDL is generally also
associated with low HDL-cholesterol concentrations, but
raised concentrations of serum cholesterol or LDL
cholesterol are not necessary for it to be present. Methods
for the direct measurement of small dense LDL are not
currently available in clinical practice, but its presence
undoubtedly explains many of the cases of acute
myocardial infarction occurring in people with low
cholesterol concentrations. More patients with small
dense LDL would be detected, if serum apolipoprotein B
was measured instead of serum cholesterol.115 There is a
strong case for at least monitoring statin treatment in
terms of apolipoprotein B rather than cholesterol
reduction, because concentrations of apolipoprotein B
frequently relate more closely to subsequent CHD event
rates.115,116
Type III hyperlipoproteinaemia
Type III hyperlipoproteinaemia (synonyms: broad
␤ disease, floating ␤ disease, dysbetalipoproteinaemia,
remnant removal disease) results from the presence in the
circulation of large amounts of chylomicron remnants and
intermediate-density lipoprotein (or partly metabolised
VLDL), commonly collectively termed ␤ VLDL. This
disorder is rare and cannot be described in detail here, but
reviews of the disorder are available.12,117,118 Serum
cholesterol and triglyceride concentrations are raised
(table). Striate palmar and tuberoeruptive xanthomata
occur (figure 2). If untreated, the likelihood of CHD and
peripheral arterial disease increase strikingly. The disorder
generally responds to weight reduction and fibrate
treatment.
In the absence of typical xanthomata, type III cannot be
distinguished on simple lipid measurement from type IIb
or V hyperlipoproteinaemia. DNA testing can be used to
identify apolipoprotein E ⑀2 homozygosity present in 90%
of cases. If this test is undertaken, it may show that a
patient is unlikely to have type III hyperlipoproteinaemia,
but provide the unwelcome finding that apolipoprotein E
⑀4 is present. This apolipoprotein has been linked with
Alzheimer’s disease, certainly in its late-onset form and, in
THE LANCET • Vol 362 • August 30, 2003 • www.thelancet.com

some studies, with the early-onset type. Laboratories
should probably report only whether apolipoprotein E ⑀2
homozygosity is present or absent to avoid information
being openly available in medical records without
patients’ consent.119 If the diagnosis of type III hyperlipo-
proteinaemia is deemed still possible when apolipoprotein
E ⑀2 homozygosity is absent, plasma should be sent to a
centre that can provide ultracentrifugation to identify the
presence of ␤ VLDL typical of type III.117 Para-
proteinaemia, which can produce hyperlipoproteinaemia
that can mimic type III, should be excluded.12
Predominant hypertriglyceridaemia
Moderate hypertriglyceridaemia
Patients who have raised fasting triglycerides, whose
serum cholesterol is not raised, have dwindled in numbers
over the years as high serum cholesterol cut-off values
have been revised downwards from 6·5 to 5·0 mmol/L.
Thus, many people formerly deemed to have
hypertriglyceridaemia alone have now become classified
as having combined hyperlipidaemia. Currently, the most
common reason to encounter hypertriglyceridaemia in the
presence of cholesterol concentrations lower than
5·0 mmol/L is in patients with combined hyperlipidaemia
receiving statin treatment who have some persisting
hypertriglyceridaemia. An LDL cholesterol target is
inappropriate in such patients because much of their
serum cholesterol will be in VLDL. The National
Cholesterol Education Program Adult Treatment Panel
III recommendations, partly for this reason, provide a
non-HDL-cholesterol threshold for the introduction of
statin treatment and a non-HDL-cholesterol target.72
Non-HDL cholesterol is the difference between the serum
cholesterol and the HDL cholesterol, and generally
represents the sum of LDL and VLDL cholesterol.
Although not measured routinely, many patients with
increased triglycerides and apparently low LDL
cholesterol actually have increased concentrations of
small dense LDL.96–100 Serum apolipoprotein B, if
available, thus gives a better indication of the
concentration of atherogenic lipoproteins than does non-
HDL cholesterol.115 No trial evidence shows that treating
moderate hypertriglyceridaemia is of benefit in primary
prevention unless cholesterol is also raised. In the three
secondary-prevention trials of fibrate drugs, a significant
decrease in CHD events occurred in only one, all-cause
mortality was reduced in none, and initial serum
triglyceride concentration determined the likelihood
of benefit in only one.120–122 On the other hand, ␻-3 fatty
acids do decrease all-cause mortality, albeit by an
antidysrhythmic mechanism that may not involve
triglycerides,123 and in larger doses can decrease
triglycerides by almost as much as fibrates.124
Severe hypertriglyceridaemia
When fasting triglyceride concentrations higher than
10 mmol/L are encountered, almost invariably chylo-
microns and VLDL are contributing to the hyper-
triglyceridaemia.125 Chylomicronaemia can produce
spectacularly high concentrations of serum triglycerides,
sometimes exceeding 100 mmol/L. Under these
circumstances, because chylomicrons contain cholesterol
from the diet and through synthesis in the gut, and
because VLDL, which also contains cholesterol is also
raised, the accompanying serum cholesterol concentration
may also be increased sometimes by 30 mmol/L or more
with no increase in LDL cholesterol.
In severe hypertriglyceridaemia, chylomicrons and
VLDL are typically increased, because both compete for
THE LANCET • Vol 362 • August 30, 2003 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet
SEMINAR
the same clearance mechanism (lipoprotein lipase). The
lipoprotein phenotype is thus normally type V. This severe
hypertriglyceridaemia generally ensues when an increase
in hepatic VLDL production, either familial or secondary
to, for example, obesity, diabetes, alcohol, or oestrogen
administration, is associated with decreased lipolysis of
VLDL and chylomicrons, which again may be genetic or
acquired, such as in hypothyroidism, ␤ blockade, or
diabetes mellitus (diabetes can cause overproduction of
VLDL and decreased lipoprotein lipase activity). Since
the clearance mechanism is already overloaded with
VLDL, the rise in serum triglyceride concentrations when
chylomicrons enter the circulation after a fatty meal may
be tumultuous and they may spend days rather than hours
in the circulation.12,125 The serum takes on the appearance
of milk (figure 2). Overall the frequency of severe
hypertriglyceridaemia (>10·0 mmol/L) is probably no
more than one in 1000 in adults. The disorder is more
common among people with type 2 diabetes.
Rarely, severe hypertriglyceridaemia is caused by
familial lipoprotein lipase deficiency, a genetic deficiency
in lipoprotein lipase activity. This disorder is inherited as
an autosomal recessive trait. Generally it is due to
mutations in the lipoprotein lipase gene, leading to
defective function or production,125 but occasionally it is
due to a genetic deficiency of apolipoprotein CII, the
activator of lipoprotein lipase.126 In familial lipoprotein
lipase deficiency, severe hypertriglyceridaemia may be
encountered in childhood. Occasionally, in children and
young adults presenting for the first time, type I
hyperlipoproteinaemia arises, in which only serum
chylomicron concentrations are raised. VLDL is not
raised probably because hepatic lipase can catabolise the
lower concentrations of VLDL produced in childhood,
although it is unable to compensate for the absence of
lipoprotein lipase in chylomicron catabolism. With
advancing age VLDL rises to concentrations higher than
those that can be cleared by hepatic lipase. VLDL along
with chylomicrons thus accumulate in the circulation and
type V hyperlipoproteinaemia becomes the rule.127
Eruptive xanthomata are characteristic of extreme
hypertriglyceridaemia. These appear as yellow papules on
the extensor surfaces of the arms and legs, buttocks, and
back (figure 2). Hepatosplenomegaly frequently occurs.
Liver imaging shows the liver to be fatty, and bone-
marrow biopsy may reveal macrophages engorged with
lipid droplets (foam cells).128 Because the triglyceride-rich
lipoproteins can interfere with the measurement of
transaminases, giving spuriously high values, liver disease,
especially alcoholic liver disease, may be difficult to
exclude other than by the prompt resolution of the
syndrome when a low-fat diet is started. Another feature is
lipaemia retinalis (pallor of the optic fundus, in which the
retinal veins and arteries appear white).
The risk of atheroma in familial lipoprotein lipase
deficiency is uncertain,125 but it does complicate severe
hypertriglyceridaemia, in which there is some lipoprotein
lipase activity, albeit diminished. Precise estimation of the
risk from this hyperlipidaemia per se is difficult because
it is so frequently associated with insulin resistance or
frank diabetes, which are themselves risk factors for
atherosclerosis. If these disorders are included as part of
the syndrome, coronary heart disease and peripheral
arterial disease are common. The reason why the
complete absence of lipoprotein lipase obscures the risk of
atheroma is unclear. It may be because the incidence of
diabetes is not raised in familial lipoprotein lipase
deficiency or because fibrinogen and factor VII activity are
not increased,129 or because the conversion of VLDL and
725
SEMINAR
chylomicrons to the atherogenic IDL, LDL, and remnant
lipoproteins is impaired in the absence of lipoprotein
lipase. Serum LDL and apolipoprotein B concentrations
are frequently normal or low.110
Acute pancreatitis may occur when serum triglyceride
concentrations become higher than 20–30 mmol/L.12
Falsely low serum amylase activities can be encountered
because of interference by triglyceride-rich lipoproteins in
the laboratory method. All laboratories should inspect
serum for milkiness (figure 2) before reporting normal or
only moderately raised serum amylase activity among
patients who have severe abdominal pain to prevent
clinicians from wrongly excluding acute pancreatitis.
Generally the pain subsides within a few hours or days of
starting nasogastric aspiration and intravenous fluids, with
nothing taken by mouth.
Pseudohyponatraemia in extreme hypertriglyceridaemia
may lead to serious consequences, if it is interpreted as
true hyponatraemia. When the serum triglycerides exceed
40–50 mmol/L the concentration of sodium in the
aqueous phase, and thus the serum osmolality, may be
normal. However, spurious serum sodium concentrations
of 120–130 mmol/L are reported because much of the
volume of the serum sample in which sodium is measured
is occupied by lipoproteins as opposed to water.
The treatment of severe hypertriglyceridaemia can be
difficult. Secondary causes should be excluded. The
correct diet is low in all types of fat (to shut off the supply
of chylomicrons), frequently to as little as 20 g per day. If
adhered to, the correct diet is more effective than
pharmacotherapy. Fibrate drugs generally have some
effect. Of the other drugs available, I have not been
impressed by fish oil, which contributes to chylomicrons,
although the more refined ␻-3 fatty acid preparation that
has become available may prove more effective. Medium-
chain triglycerides make matters worse, despite claims to
the contrary, because preparations available contain
quantities of long-chain fatty acids and the medium-chain
triglycerides themselves contribute to hepatic VLDL
synthesis even though they arrive in the portal blood and
bypass chylomicron formation. Bile-acid-sequestrating
Common causes of secondary
hyperlipoproteinaemia
Endocrine
Diabetes mellitus
Hypothyroidism
Pregnancy
Nutritional
Obesity
Alcohol excess
Renal
Nephrotic disease
Chronic renal failure
Hepatic disease
Cholestasis
Heptocellular dysfunction
Immunoglobulin excess
Paraproteinaemia
Gout
Association, rather than a cause
Drugs
␤-adrenoreceptor blockers
Thiazide diuretics
Steroid hormones
Microsomal enzyme-inducing agents
Retinoic-acid derivatives
Protease inhibitors (HIV infection)
726
For personal use. Only reproduce with permission from The Lancet
agents also exacerbate hypertriglyceridaemia. Anecdotally,
when I have been unable to lower triglycerides sufficiently
to prevent recurrent acute pancreatitis, I have been
impressed by the effect of high-dose antioxidant therapy
in preventing attacks, even though this treatment does not
lower triglycerides further.130
Secondary hyperlipidaemia
Secondary hyperlipoproteinaemias are those caused by
another primary disorder that has hyperlipidaemia as a
complication (panel). In societies in which polygenic
hyperlipoproteinaemia is prevalent, secondary hyper-
lipoproteinaemia will have high impact. For example, in
the UK and USA, CHD is the most common cause of
premature death in diabetes mellitus, but in Japan it is
only rarely a complication.73,131 Despite the variety of
secondary disorders, space permits only diabetes mellitus
to be reviewed.
Diabetes mellitus
The dominant hyperlipidaemia in diabetes is
hypertriglyceridaemia,12,132 which is most likely to be
associated with hypercholesterolaemia and with decreased
HDL cholesterol in type 2 diabetes.133 The
hypertriglyceridaemia is associated not simply with an
increase in VLDL, but also in intermediate-density
lipoprotein and small dense LDL.134,135 Since neither of
these lipoproteins contribute greatly to a rise in lipid
concentrations, the term dyslipoproteinaemia is
particularly aptly applied in diabetes. There is also an
increased activity of cholesteryl ester transfer protein.136,137
Additionally, plasma fibrinogen concentration, which is
increased in type 1 and 2 diabetes, relates to serum
50 High cholesterol
High blood pressure
40 High triglyceride
High glucose
Low HDL cholesterol
30
20
10
Percentage rise per quintile
0
0 1 2 3 4 5
Quintiles of body-mass index
50
40
30
20
10
0
0 1 2 3 4 5
Quintiles of serum insulin
Figure 5: Effect of increasing body-mass index and serum insulin
on prevalence of high blood pressure, hypercholesterolaemia,
hypertriglyceridaemia, and high glucose in men
Data from the British Regional Heart Study (reference 143).
THE LANCET • Vol 362 • August 30, 2003 • www.thelancet.com

triglyceride concentrations.138 Lipoprotein abnormalities
in type 1 diabetes may be less frequent than in type 2, but
the risk of coronary heart disease in type 1 diabetes is
more frequently compounded by the presence of
proteinuria. In type 1 diabetes that is uncomplicated by
proteinuria, the risk of coronary heart disease is about two
to three times that of non-diabetic people of a similar age.
Proteinuria increases the risk as much as 40-fold,139 which
may stem partly from hypertension and an exacerbation of
the dyslipoproteinaemia that accompany the development
of proteinuria.140,141 However, the increase in risk is greater
than can be explained in this way and may result because
the proteinuria reflects a generalised increase in the
permeability of arterial endothelium, promoting the entry
of macromolecules into the subintima and thus
accelerating atherogenesis.142
The increased blood glucose concentration in diabetes
mellitus results from insulin resistance, insulin deficiency,
or both. Insulin resistance may be present in non-diabetic,
generally obese, people who are still able to secrete
sufficient insulin to maintain control of blood sugar,
but in such people there is often hypertriglyceridaemia
with low HDL cholesterol and hypercholesterolaemia,
hypertension (figure 5)143 and increased risk of coronary
heart disease. This syndrome is commonly referred to
as the insulin resistance syndrome (syndrome X) or
metabolic syndrome.72,144 Clearly, the disorder has features
in common with familial combined hyperlipidaemia and
with diabetes. Indeed, a substantial proportion of people
who have this syndrome ultimately develop diabetes,145
although sometimes not until after they have already
developed CHD,146 which explains partly why glycaemic
control in diabetes seems to have little impact in
preventing its atheromatous complications.133 Statin
treatment, on the other hand, is effective in preventing
CHD in diabetes5,6,133 and may lessen the excess case
fatality in diabetes associated with acute myocardial
infarction.147 In one report, statin treatment postponed the
development of diabetes.148
Women who have diabetes, particularly those with
type 2 disease, generally have a distribution of adipose
tissue resembling that of obese men around the abdomen
and waist, rather than the more female pattern, which
involves the buttocks and thighs but leaves the waist
relatively small. The protection from CHD that most
women have, even those with familial hyper-
cholesterolaemia, is largely lost by those who have
diabetes, which it is suggested results from this
androgenisation.149 Many women with a similar body
shape, but who have not yet developed diabetes, are
insulin resistant, hypertensive, have hyperlipidaemia, and
have an increased risk of CHD. There is an undoubted
overlap here too with polycystic ovary syndrome.150
Hypolipidaemia
Hypolipidaemia is an increasing clinical problem, since
more cases are being discovered because of population
screening for high cholesterol. People who have had a low
serum cholesterol concentration all their lives seem to
be at no disadvantage unless the decrease is substantial, as
in abetalipoproteinaemia. Indeed, their freedom from
cardiovascular disease may lead to longevity. When the
disorder is discovered for the first time it is frequently
difficult to know whether the low cholesterol is due to
an acquired disease, such as malignant disease (eg,
colonic or prostatic neoplasms, leukaemia, reticulosis, or
myeloma) or malabsorption (eg, due to a short bowel,
blind-loop syndrome, coeliac disease, pancreatic exocrine
insufficiency, or giardiasis).12,151
THE LANCET • Vol 362 • August 30, 2003 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet
SEMINAR
Some people who have serum cholesterol concentrations
around 1·0–3·5 mmol/L will have heterozygous familial
hypobetalipoproteinaemia, an autosomal dominant
disorder in which truncated apolipoprotein B mutations
have been described.152 This hypolipidaemia is benign.
However, the much rarer homozygous hypobeta-
lipoproteinaemia and abetalipoproteinaemia (inherited
as autosomal recessive), which produce more severe
hypocholesterolaemia, are associated with retinitis
pigmentosa, steatorrhoea, fatty liver, abnormally shaped
erythrocytes (acanthocytes), and a syndrome that
resembles Friedreich’s ataxia, and is preventable with
fat-soluble vitamin administration. Mutation of the
microsomal triglyceride transfer protein (MTP) gene
necessary for VLDL assembly rather than of the APOB
gene is associated with apobetalipoproteinaemia.
Analphalipoproteinaemia (Tangier disease) is a very
rare disorder with virtually absent HDL because of rapid
clearance, and reduced LDL cholesteryl ester, but
increased tissue cholesteryl ester deposition throughout
the body. This deposition leads to enlarged orange-yellow
tonsils and adenoids, lymph-node enlargement, hepato-
splenomegaly, bone-marrow infiltration (thrombo-
cytopenia), orange-brown spots on the rectal mucosa,
neuropathy, and corneal cloudiness.153 The disorder has
been ascribed to mutation of the ABCA1 gene encoding
the cholesterol efflux regulatory protein.154
Low HDL-cholesterol (hypoalphalipoproteinaemia) has
been defined as concentrations lower than 1·0 mmol/L.
This definition would make it a common disorder,
affecting as many as 25% of adults in the USA.155 Only
rarely could it be caused by a single-gene disorder, such
as heterozygous APOAI or ABCA1 mutation. More
frequently it is the result of similar factors to those leading
to hypertriglyceridaemia, and is associated with obesity
and the metabolic syndrome or frank diabetes (figure 5).
Low HDL cholesterol is a common finding in patients
who have CHD, and frequently precedes this disease by
many years.156 Measurement of HDL cholesterol is,
therefore, essential in CHD risk prediction.157 However,
low HDL-cholesterol concentrations cannot be effectively
raised by pharmacological means or lifestyle changes of
raising.72 A 20% increase in HDL cholesterol would be
more than could be expected in most patients, but with an
initial concentration of, for example, 0·9 mmol/L, even
this improvement would be hardly appreciable in the
clinic. Therefore, particular attention to achieving LDL-
cholesterol or non-HDL-cholesterol targets in patients
with low HDL cholesterol is recommended,72 which in
higher-risk patients will generally require statin treatment.
Further research is required to find out whether more
precise diagnosis of the causes of low HDL-cholesterol
can identify people at particular CHD risk and allow the
development of more specific interventions.
Conflict of interest statement
None declared.
Acknowledgment
I thank C Price for the preparation of this manuscript.
References
1 Thompson GR. The proving of the lipid hypothesis.
Curr Opin Lipidol 1999; 10: 201–05.
2 Scandinavian Simvastatin Survival Study Group. Randomised trial of
cholesterol lowering in 4444 patients with coronary heart disease: the
Scandinavian Survival Study. Lancet 1994; 344: 1383–89.
3 Sacks FM, Pfeffer MA, Moye LA, et al, for the Cholesterol and
Recurrent Events Trial Investigators. The effect of pravastatin on
coronary events after myocardial infarction in patients with average
cholesterol levels. N Engl J Med 1996; 335: 1001–09.
727
SEMINAR
4 The Long-Term Intervention with Pravastatin in Ischemic Disease
(LIPID) Study Group. Prevention of cardiovascular events and death
with pravastatin in patients with coronary heart disease and a broad
range of initial cholesterol levels. N Engl J Med 1998; 339: 1349–57.
5 Heart Protection Study Collaborative Group MRC/BHF Heart
Protection Study of cholesterol lowering with simvastatin in 20 536
high-risk individuals: a randomised placebo-controlled trial, Lancet
2002; 360: 7–22.
6 Athyros VG, Papageorgiou AA, Mercouris BR, et al. Treatment with
atorvastatin to the ‘National Cholesterol Educational Program Goal’
versus ‘usual’ care in secondary coronary heart disease prevention:
the GREek Atorvastatin and Coronary heart-disease Evaluation
(GREACE) Study. Curr Med Res Opin 2002; 18: 220–28.
7 Shepherd J, Cobbe SM, Ford I, et al, for the West of Scotland
Coronary Prevention Study Group. Prevention of coronary heart
disease with pravastatin in men with hypercholesterolaemia.
N Engl J Med 1995; 333: 1301–07.
8 Downs GR, Clearfield M, Weiss S, et al. Primary prevention of acute
coronary events with lovastatin in men and women with average
cholesterol levels: results of the AFCAPS/TEXCAPS (Air
Force/Texas Coronary Atherosclerosis Prevention Study). JAMA
1998; 279: 1615–22.
9 Hebert PR, Gaziano JM, Chan KS, Hennekens CH. Cholesterol
lowering with statin drugs, risk of stroke, and total mortality: an
overview of randomised trials. JAMA 1997; 278: 313–21.
10 Gordon DJ. Cholesterol lowering reduces mortality. In: Grundy SM,
ed. Cholesterol lowering therapy: evaluation of clinical trial evidence.
New York: Marcel Dekker, 2000: 299–311.
11 Goldstein JL, Hobbs HH, Brown MS. Familial hypercholesterolemia.
In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The metabolic
and molecular bases of inherited disease, 7th edn. Columbus, OH:
McGraw-Hill Information Service Company, 1995: 1981–2030.
12 Durrington PN. Hyperlipidaemia: diagnosis and management,
2nd edn. Oxford: Butterworth Heinemann, 1995.
13 Durrington PN. Rigorous detection and rigorous treatment of
familial hypercholesterolaemia. Lancet 2001; 357: 574–75.
14 Slack J. Risk of ischaemic heart disease in familial
hyperlipoproteinaemic states. Lancet 1969; 2: 1380–82.
15 Scientific Steering Committee of the Simon Broome Register Group.
Risk of fatal coronary heart disease in familial hypercholesterolaemia.
BMJ 1991; 303: 893–96.
16 Goldstein JL, Brown MS. The low-density lipoprotein pathway
and its relation to atherosclerosis. Annu Rev Biochem 1977; 46:
897–927.
17 Myant NB. Disorders of cholesterol metabolism: the
hyperlipoproteinaemias. In: The biology of cholesterol and related
steroids. London: Heinemann Medical, 1981; 689–772
18 Heath KE, Gahan M, Whittall RA, Humphries SE. Low-density
lipoprotein receptor gene (LDLR) world-wide website in familial
hypercholesterolaemia: update, new features and mutation analysis.
Atherosclerosis 2001; 154: 243–46.
19 Steyn K, Goldberg YP, Kotze MJ, et al. Estimation of the prevalence
of familial hypercholesterolaemia in a rural Afrikaner community by
direct screening for three Afrikaner founder low density lipoprotein
receptor gene mutations. Hum Genet 1996; 98: 479–84.
20 Hayden MR, De Braekeleer M, Henderson HE, Kostelein J.
Molecular geography of inherited disorders of lipoprotein
metabolism: lipoprotein lipase deficiency and familial
hypercholesterolaemia. In: Lusis AJ, Rolter JI, Sparkes RS, eds.
Molecular genetics of coronary heart disease, candidate genes and
processes in atheorsclerosis Basle: Karger, 1992: 350–62.
21 Myant NB, Slack J. Type II hyperlipoproteinaemia.
Clin Endocrinol Metab 1973; 2: 81–109.
22 Durrington PN. Normal lipid and lipoprotein levels in childhood and
adolescence. In: Hyperlipidaemia in childhood. Neil A, Rees A,
Taylor C, eds. London: Royal College of Physicians of London,
1996: 9–16.
23 Leonard JV, Whitelow AG, Wolff OH, Lloyd JK, Slack J. Diagnosing
familial hypercholesterolaemia in childhood by measuring serum
cholesterol. BMJ 1977; 1: 1566–68
24 Pimstone SN, Sun X-M, Du Souich C, Frohlich JJ, Hayden MR,
Soutar AK. Phenotypic variation in heterozygous familial
hypercholesterolaemia: a comparison of Chinese patients with the
same or similar mutations in the LDL-receptor gene living in China
or Canada. Artheroscler Thromb Vasc Biol 1998; 18: 209–15.
25 Gagné C, Moorjani S, Brun DToussaint M, Lupien PJ.
Heterozygous familial hypercholesterolaemia: relationship between
plasma lipids, lipoproteins, clinical manifestations and ischaemic
heart disease in men and women. Atherosclerosis 1979; 34:
13–24.
26 Thompson GR, Seed M, Niththyananthan S, McCarthy S,
Thorogood M. Genotypic and phenotypic variation in familial
hypercholesterolemic. Arteriosclerosis 1989; 9: 175–80.
728
For personal use. Only reproduce with permission from The Lancet
27 Bhatnagar D, Morgan J, Siddiq S, Mackness MI, Miller JP,
Durrington PN. Outcome of case finding among relatives of patients
with known heterozygous familial hypercholesterolaemia. BMJ 2000;
321: 1497–500.
28 Marks D, Thorogood M, Neil HAW, Humphries SE. A review on
the diagnosis, natural history, and treatment of familial
hypercholesterolaemia. Atherosclerosis 2003; 168: 1–14.
29 Sijbrands EJG, Westendorp RGJ, Defesche JC, de Meier PHEM,
Smelt, AHM, Kastelein JJP. Mortality over two centuries in large
pedigree with familial hypercholesterolaemia: family tree mortality
study. BMJ 2001; 322: 1019–23.
30 Heiberg A, Slack J. Family similarities in the age at coronary death in
familial hypercholesterolaemia. BMJ 1977; 2: 493–95.
31 Hill JS, Hayden MR, Frohlich J, Pritchard PH. Genetic and
environmental factors affecting the incidence of coronary artery
disease in heterozygous familial hypercholesterolemia.
Arterioscler Thromb 1991; 11: 290–97.
32 Sun X-M, Patel DD, Knight BL, Soutar AK, and the Familial
Hypercholesterolaemia Regression Study Group. Influence of
genotype at the low density lipoprotein (LDL) receptor gene locus
on the clinical phenotype and response to lipid-lowering drug
therapy in heterozygous familial hypercholesterolaemia.
Atherosclerosis 1998; 136: 175–85.
33 Moorjani S, Gagne C, Lupien PJ, Brunn D. Plasma triglyceride
related decrease in high-density lipoprotein cholesterol and its
association with myocardial infarction in heterozygous familial
hypercholesterolaemia. Metabolism 1986; 35: 311–16.
34 Streja D, Steiner G, Kwiterovich P. Plasma high-density lipoproteins
and ischaemic heart disease: studies in a large kindred with familial
hypercholesterolaemia. Ann Intern Med 1978; 89: 871–880.
35 Miettinen TH, Gytling H. Mortality and cholesterol metabolism in
familial hypercholesterolaemia: long-term follow-up of 96 patients.
Arteriosclerosis 988; 8: 163–67
36 MBewu AD, Bhatnagar D, Durrington PN, et al. Serum lipoprotein
(a) in patients heterozygous for familial hypercholesterolaemia, their
relatives, and unrelated control populations. Arterioscler Thromb 1991;
11: 940–46.
37 Danesh J, Collins R, Peto R. Lipoprotein (a) and coronary heart
disease: meta-analysis of prospective studies. Circulation 2000; 102:
1082–85.
38 Rallidis L, Naoumova RP, Thompson GR, Nihoyannopoulos P.
Extent and severity of atherosclerotic involvement of the aortic valve
and root in familial hypercholesterolaemia. Heart 1998; 80: 583–90.
39 Rajamannen NM, Subramanium M, Sprigett M, et al. Atorvastatin
inhibits hypercholesterolemia-induced cellular proliferation and bone
matrix production in the rabbit aortic valve. Circulation 2002; 105:
2660–65.
40 Marks D, Wonderling D, Thorogood M, Lambert H, Humphries SE,
Neil HAW. Screening for hypercholesterolaemia versus case finding
for familial hypercholesterolaemia: a systematic review and cost-
effectiveness analysis. Health Technol Assess 2000; 4: 1–123.
41 Umans-Eckenhausen MAW, Defesche JC, Sijbrands EJG, Scheerder
RLJM, Kastelein JJP. Review of the first five years of screening for
familial hypercholesterolaemia in the Netherlands. Lancet 2001; 357:
165–68.
42 Scientific Steering Committee on behalf of the Simon Broome
Register Group. Mortality in treated heterozygous familial
hypercholesterolaemia: implications for clinical management.
Atherosclerosis 1999; 142: 105–12.
43 Smilde TJ, van Wissen S, Wollersheim H, Trip MD, Kastellein JJP,
Stallenhoef AFH. Effect of aggressive versus conventional lipid
lowering on atherosclerosis progression hypercholesterolaemia
(ASAP): a prospective, randomised, double-blind trial. Lancet 2001;
357: 577–81.
44 Buchwald H, Varco RL, Matts JP, et al. Effect of partial ileal bypass
surgery on mortality and morbidity from coronary heart disease in
patients with hypercholesterolaemia: report of the program on the
surgical control of hyperlipidaemia (POSCH). N Engl J Med 1990;
323: 946–55.
45 de Jongh S, Ose L, Szamosi T, et al. Efficacy and safety of statin
therapy in children with familial hypercholesterolaemia: a
randomised, double-blind, placebo-controlled trial with simvastatin.
Circulation 2002; 16: 2231–37.
46 West RJ, Lloyd JK, Leonard JV. Long-term follow-up of children
with familial hypercholesterolaemia treated with cholestyramine.
Lancet 1980; 2: 873–75.
47 Gagne C, Gaudet D, Bruckert E. Efficacy and safety of ezetimibe
co-administered with atorvastatin or simvastatin in patients with
homozygous familial hypercholesterolaemia. Circulation 2002; 105:
2469–75.
48 Thompson GR, Miller JP, Breslow JL. Improved survival of patients
with homozygous familial hypercholesterolaemia treated with plasma
exchange. BMJ 1985; 295: 1671–73.
THE LANCET • Vol 362 • August 30, 2003 • www.thelancet.com

49 Kajinami K, Mabuchi H. Therapeutic effects of LDL apheresis in the
prevention of atherosclerosis. Curr Opin Lipidol 1999; 10: 401–06.
50 Stangl MJ, Beuers U, Schauer R, et al. Die allogene
Lebertrasplantationeine: Form der ‘Gentherapie’ bei metabolischen
Erkrankungen—Munchener Ergebnisse und Ubersicht. Chirurg 2000;
71: 808–19.
51 Ishibashi S, Brown MS, Goldstein JL, Gerard RD, Hammer RE,
Herz J. Hypercholesterolemia in low density lipoprotein receptor
knockout mice and its reversal by adenovirus-mediated gene delivery.
J Clin Invest 1993; 92: 883–93.
52 Myant N. Familial defective apolipoprotein B-100: a review,
including some comparisons with familial hypercholesterolaemia.
Atherosclerosis 1993; 104: 1–18.
53 Talmud P, Tybjaerg-Hansen A, Bhatnagar D, et al. Screening for
specific mutations in patients with a clinical diagnosis of familial
hypercholesterolaemia. Atherosclerosis 1991; 89: 137–42.
54 Heath KE, Gudneson V, Humpheries SE, Seed M. The type of
mutation in the low density lipoprotein receptor gene influences the
cholesterol-lowering response of HMG-CoA reductase inhibitor
simvastatin in patients with heterozygous familial
hypercholesterolaemia. Atherosclerosis 1999; 143: 41–54.
55 Arca M, Zuliani G, Wilund K, et al. Autosomal recessive
hypercholesterolaemia in Sardinia, Italy, and mutations in ARH: a
clinical and molecular genetic analysis Lancet 2002; 359: 841–47.
56 Norman D, Sun X-M, Bowbon M, Knight BL, Naoumova RP,
Soutar A. Characterisation of a novel cellular defect in patients with
phenotypic homozygous familial hypercholesterolemia. J Clin Invest
1999; 104: 619–28.
57 Kane JP, Havel RJ. Disorders of the biogenesis and secretion of
lipoproteins containing the B apolipoproteins. In: Scriver CR, Beaudet
AL, Sly WS, Valle D, eds. The metabolic and molecular bases of
inherited disease, 7th edn. New York: McGraw-Hill, 1995; 1853–85.
58 Keys A. Coronary heart disease: the global picture. Atherosclerosis
1975; 22: 149–92.
59 Simons LA. Interrelations of lipids and lipoproteins with coronary
artery disease mortality in 19 countries. Am J Cardiol 1986; 57:
5G–10G.
60 Shepherd J, Blauw GJ, Murphy MB, et al. Pravastatin in elderly
individuals at risk of vascular disease (PROSPER): a randomised
controlled trial. Lancet 2002; 360: 1623–30.
61 Law MR, Wald NJ, Thompson SG. By how much and how quickly
does reduction in serum cholesterol concentration lower risk of
ischaemic heart disease? BMJ 1994; 308: 367–73.
62 Chen Z, Peto R, Collins R, McMahon S, Lu J, Li W. Serum
cholesterol concentration and coronary heart disease in a population
with low cholesterol concentrations. BMJ 1991; 303: 276–82.
63 Castelli WP. Epidemiology of coronary heart disease: the
Framingham Study. Am J Med 1984; 76 (suppl 2A): 4–12.
64 Pekkanen J, Linn S, Heiss G, et al. Ten-year mortality from
cardiovascular disease in relation to cholesterol level among men with
and without pre-existing cardiovascular disease. N Engl J Med 1990;
322: 1700–07.
65 Shaper AG, Pocock SJ, Phillips AN, Walker M. Identifying men at
high risk of heart attacks: strategy for use in general practice. BMJ
1986; 293: 474–79.
66 West of Scotland Coronary Prevention Group. West of Scotland
Coronary Prevention Study: identification of high-risk groups and
comparison with other cardiovascular intervention trials. Lancet 1996;
348: 1339–42.
67 Anderson KM, Wilson PWF, Odell PM, Kannel WB. An updated
coronary risk profile. A statement for health professionals. Circulation
1991; 83: 356–62.
68 Dyslipidaemia Advisory Group, on behalf of the Scientific
Committee of the National Heart Foundation of New Zealand. 1996
National Heart Foundation Guidelines for the Assessment and
Management of Dyslipidaemia. N Z Med J 1996; 109: 224–32.
69 Wood D, Durrington PN, Poulter N, McInnes G, Rees A, Wray R.
Joint British recommendations on prevention of coronary heart
disease in clinical practice. Heart 1998; 80 (suppl 2): S1–29.
70 British Cardiac Society, British Hyperlipidaemia Association, British
Hypertension Society, British Diabetic Association. Joint British
guidelines on prevention of coronary heart disease in clinical practice:
summary. BMJ 2000; 320: 705–08.
71 Wood D, De Backer G, Faergeman O, Graham I, Mancia G,
Pyörälä K, with members of the Task Force. Prevention of coronary
heart disease in clinical practice: recommendations of the Second
Joint Task Force of European and other Societies on Coronary
Prevention. Atherosclerosis 1998; 140: 199–270.
72 Expert Panel on Detection, Evaluation and Treatment of High Blood
Cholesterol in Adults. Executive summary of the third report of the
National Cholesterol Education Program (NCEP) Expert Panel on
Detection, Evaluation and Treatment of High Blood Cholesterol in
Adults (Adult Treatment Panel III) JAMA 2001; 285: 2486–97.
THE LANCET • Vol 362 • August 30, 2003 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet
SEMINAR
73 Jarrett RJ, Keen H, Chakrabarti R. Diabetes, hyperglycaemia and
arterial disease. In: Keen H, Jarrett R, eds. Complications of
diabetes, 2nd edn. London: Edward Arnold, 1982: 179–204.
74 Robertson TL, Kato H, Rhoads GG, et al. Epidemiologic studies of
coronary disease and stroke in Japanese men living in Japan, Hawaii
and California. Am J Cardiol 1977; 39: 239–49.
75 Witztum JL, Steinberg D. Role of oxidized low density lipoprotein in
atherogenesis. J Clin Invest 1991; 88: 1785–92.
76 Thelle DS, Shaper AG, Whitehead TP, et al. Blood lipids in middle-
aged British men. Br Heart J 1983; 49: 205–13.
77 Grundy SM. Dietary therapy of hyperlipidaemia.
Baillière Clin Endocrinol Metab 1987; 1: 667–98.
78 McKeigue PM, Miller GJ, Marmot MG. Coronary heart disease in
south Asians overseas: a review. J Clin Epidemiol 1989; 42: 597–609.
79 Bhatnagar D, Anand S, Durrington PN, et al Coronary risk factors in
people from Indian subcontinent living in West London and their
siblings in India. Lancet 1995; 345: 405–09.
80 Dowse G, Zimmet P. The thrifty genotype in NIDDM: the
hypothesis survives. BMJ 1993; 306: 532–33.
81 Neil HAW, Roe L, Godlee RJP, et al. Randomised trial of lipid
lowering dietary advice in general practice: the effects on lipids,
lipoproteins and antioxidants. BMJ 1995; 310: 569–73.
82 Napoli C, Glass CK, WitztumJ, Deutsch R, D’Amiento FP,
Palinski W. Influence of maternal hypercholesterolaemia during
pregnancy on progression of early atherosclerotic lesions in
childhood: Fate of Early Lesions in Children (FELIC) study.
Lancet 1999; 354: 1235–41.
83 The ALLHAT Officers and Co-ordinators for the ALLHAT
Collaborative Research Group. Major outcomes in moderately
hypercholesterolemic, hypertensive patients randomised to
pravastatin vs usual care: the Antihypertensive and Lipid-Lowering
Treatment to Prevent Heart Attack Trial (ALLHAT-LLT). JAMA
2002; 288: 2998–3007.
84 Kannel WB, Castelli WP, Gordon T, McNamara PM. Serum
cholesterol, lipoproteins, and the risk of coronary heart disease.
Ann Intern Med 1971; 74: 1–12.
85 Schwartz GG, Olsson AG, Ezekowitz MD, et al. Effects of
atorvastatin on early recurrent ischemic events in acute coronary
syndromes: the MIRACL study—a randomised controlled trial.
JAMA 2001; 285: 1711–18.
86 Olsson AG, Schwartz GG. Early initiation of treatment with statins in
acute coronary syndromes. Ann Med 2002; 34: 37–41.
87 Newby LK, Kristinsson A, Bhapkar MV, et al. Early statin initiation
and outcomes in patients with acute coronary syndromes. JAMA
2002; 287: 3087–95.
88 West of Scotland Coronary Prevention Group. Influence of
pravastatin and plasma lipids on clinical events in the West of
Scotland Coronary Prevention Study (WOSCOPS). Circulation 1998;
97: 1440–45.
89 Goldstein JL, Hazzard WR, Schrott AG, Bierman EL, Motulsky AG.
Hyperlipidaemia in coronary heart disease: lipid levels in 500
survivors of myocardial infarction. J Clin Invest 1973, 52: 1544–68.
90 Nikkila EA, Aro A. Family study of serum lipids and lipoproteins in
coronary heart disease. Lancet 1973, 1: 954–58.
91 de Graaf J, Stalenhoef AFH. Defects of lipoprotein metabolism in
familial combined hyperlipidaemia. Curr Opin Lipidol 1998; 9:
189–96.
92 Mann CJ, Yen FT, Grant AM, Bihain BE. Mechanism of plasma
cholesteryl ester transfer in hypertriglyceridaemia. J Clin Invest 1991;
88: 2059–66
93 Barter PJ, Rye K-A. Cholesteryl ester transfer protein, high density
lipoprotein and arterial disease. Curr Opin Lipidol 2001; 12: 377–82.
94 Sniderman AD, Wolfson C, Teng B, Franklin FA, Bachorik PS,
Kwiterovich PO. Association of hyperapobetalipoproteinemia with
endogenous hypertriglyceridaemia and atherosclerosis.
Ann Intern Med 1982; 97: 833–39.
95 Assmann G, Schulte H. Relation of HDL-cholesterol and
triglycerides to incidence of atherosclerotic coronary artery disease
(The PROCAM experience). Am J Cardiol 1992; 70: 733–37.
96 Austin MA, King M-C, Vranizan KM, Krauss RM. The atherogenic
lipoprotein phenotype (ALP): a proposed genetic marker for coronary
heart disease risk. Circulation 1990; 82: 495–506.
97 Hokanson JE, Austin MA. Plasma triglyceride level is a risk factor for
cardiovascular disease independent of high-density lipoprotein
cholesterol level: a meta-analysis of population-based prospective
studies. J Cardiovasc Risk 1996; 3: 213–19.
98 Dejager S, Bruckert E, Chapman MJ. Dense low density lipoprotein
subspecies with diminished oxidative resistance predominate in
combined hyperlipidaemia. J Lipid Res 1993; 34: 295–308.
99 Reaven GM, Chen Y-DI, Jeppesen J, Maheux P, Krauss RM. Insulin
resistance and hyperinsulinaemia in individuals with small dense low
density lipoprotein particle. J Clin Invest 1993; 92: 141–49.
729
SEMINAR
100 Griffin BA, Freeman DJ, Tait G, et al. Role of plasma triglyceride in
the regulation of plasma low density lipoprotein (LDL) subfractions:
relative contribution of small dense LDL to coronary heart disease
risk. Atherosclerosis 1994; 106: 241–49.
101 Lamarche B, Tchernof A, Dagenais GR, Cantin B, Lupien PJ,
Després JP. Small, dense LDL particle and the risk of ischemic heart
disease: prospective results from the Quebec Cardiovascular Study.
Circulation 1997; 95: 69–75.
102 Durrington PN. Triglycerides are more important in atherosclerosis
than epidemiology has suggested. Atherosclerosis 1998; 141 (suppl 1):
S57–62.
103 Egger M, Davey Smith G, Pfluger D, Altpeter E, Elwood PC.
Triglyceride as a risk factor for ischaemic heart disease in British
men: effect of adjusting for measurement error. Atherosclerosis 1999;
143: 275–84.
104 Austin MA, McKnight B, Edwards KL, Bradley CM,
McNeely MJ, Psaty BM, et al. Cardiovascular disease mortality in
familial forms of hypertriglyceridemia: a 20 year prospective study.
Circulation 2000; 101: 2777–82.
105 Forster LF, Stewart G, Bedford D, et al. Influence of atorvastatin
and simvastatin on apolipoprotein B metabolism in moderate
combined hyperlipidemic subjects with low VLDL and LDL
fractional clearance rates. Atherosclerosis 2002; 164: 129–145.
106 Guerin M, Bruckert E, Dolphin PJ, Turpin G, Chapman MJ.
Fenofibrate reduces plasma cholesteryl ester transfer from HDL to
VLDL and normalises the atherogenic, dense LDL profile in combined
hyperlipidemia. Arterioscler Thromb Vasc Biol 1996; 16: 763–72.
107 Guerin M, Egger P, Soudant C, et al. Dose-dependent action of
atorvastatin in type IIb hyperlipidaemia: preferential and progressive
reduction of atherogenic apo B-containing lipoprotein subclasses
(VLDL-2, IDL, small dense LDL) and stimulation of cellular
cholesterol efflux. Atherosclerosis 2002; 163: 287–96.
108 Okamoto H, Yonemori F, Wakitani K, Minowa T, Maeda K,
Shinkai H. A cholesteryl ester transfer protein inhibitor attenuates
atherosclerosis in rabbits. Nature 2000; 406: 203–07.
109 Durrington PN, Mackness B, Mackness MI. Paraoxonase and
Atherosclerosis. Arterioscler Thromb Vasc Biol 2001; 21: 473–80.
110 Durrington PN, Bolton CH, Hartog M. Serum and lipoprotein
apolipoprotein B levels in normal subjects and patients with
hyperlipoproteinaemia. Clin Chim Acta 1978; 82: 151–60.
111 Sniderman A, Shapiro S, Marpole D, Skinner B, Teng B,
Kwiterovich POJ. Association of coronary atherosclerosis with
hyperapobetalipoproteinaemia (increased protein but normal
cholesterol levels in human plasma low density (beta) lipoproteins).
Proc Natl Acad Sci USA 1980; 77: 604–08.
112 Chait A, Brazg R, Tribble D, Krauss R. Susceptibility of small,
dense, low-density lipoproteins to oxidative modification in subjects
with the atherogenic lipoprotein phenotype, pattern B.
Am J Med 1993; 94: 350–56.
113 De Graaf J, Hak-Lemmers H, Hectors M, Demacker P, Hendriks J,
Statenhof AFH. Enhanced susceptibility to in vitro oxidation of the
dense low density lipoprotein sub-fraction in healthy subjects
Arterioscler Thromb 1991; 11: 298–306.
114 Griffin BA, Minihane AM, Furlonger N, et al. Inter-relationships
between small, dense low-density lipoprotein (LDL), plasma
triacylglycerol and LDL apoprotein B in an atherogenic lipoprotein
phenotype in free-living subjects. Clin Sci 1999; 97: 267–76.
115 Miremadi S, Sniderman A, Frohlich J. Can measurement of serum
apolipoprotein B replace the lipid profile monitoring of patients with
lipoprotein disorders? Clin Chem 2002; 48: 484–88.
116 Durrington PN. Can measurement of apolipoprotein B replace the
lipid profile in the follow-up of patients with lipoprotein disorders?
Clin Chem 2002; 48: 401–02.
117 Morganroth J, Levy RI, Fredrickson DS. The biochemical, clinical
and genetic features of type III hyperlipoproteinaemia.
Ann Intern Med 1975; 82: 158–74.
118 Mahley RW, Rall SC. Type III hyperlipoproteinemia (dysbeta-
lipoproteinemia): the role of apolipoprotein E in normal and
abnormal lipoprotein metabolism. In: Scriver CR, Beaudet AL,
Sly WS, Valle D, eds. The metabolic and molecular bases of
inherited disease, 7th edn. New York: McGraw Hill, 1995: 1953–80.
119 Humphries S, Betteridge DJ, Durrington PN, Galton DJ, Nicholls P.
Apolipoprotein E genotyping in Alzheimer’s disease. Lancet 1996;
347: 1776.
120 Rubins HB, Robins SJ, Collins D, et al, for the Veterans Affairs
High-Density Lipoprotein Cholesterol Intervention Trial Study
Group. Gemfibrozil for the secondary prevention of coronary heart
disease in men with low levels of high-density lipoprotein cholesterol.
N Engl J Med 1999; 341: 410–18.
121 The BIP Study Group. Secondary prevention by raising HDL
cholesterol and reducing triglycerides in patients with coronary artery
disease: the Bezafibrate Infarction Prevention (BIP) Study.
Circulation 2000, 102: 21–27.
730
For personal use. Only reproduce with permission from The Lancet
122 Meade T, Zuhrie R, Cook C, Cooper J, on behalf of MRC General
Practice Research Framework. Bezafibrate in men with lower
extremity arterial disease: randomised controlled trial. BMJ 2002;
325: 1139–41.
123 Marchioli R, Barzi F, Bomba E, et al. Early protection against
sudden death by n-3 polyunsaturated fatty acids after myocardial
infarction: time course analysis of the results of the Gruppo Italiano
per lo Studio della Sopravvivenza nell’Infarto Miocardico (GISSI)-
Prevenzione. Circulation 2002; 105: 1897–903.
124 Durrington PN, Bhatnagar D, Mackness MI, et al. The effect of an
omega-3 polyunsaturated fatty acid concentrate administered for one
year to simvastatin treated patients with established coronary heart
disease and persisting hypertriglyceridaemia. Heart 2001; 85: 544–48.
125 Brunzell JD. Familial lipoprotein lipase deficiency and other causes of
the chylomicronemia syndrome. In: Scriver CR, Beaudet AL,
Sly WS, Valle D, eds. The metabolic and molecular bases of
inherited disease, 7th edn. New York: McGraw Hill, 1995: 1913–32.
126 Breckenridge WC, Little JA, Steiner G, Chow A, Poapst M.
Hypertriglyceridaemia associated with deficiency of apolipoprotein
C-II. N Engl J Med 1978; 298: 1265–73.
127 Demant T, Gaw A, Watts GF, et al. Metabolism of apo B100-
containing lipoproteins in familial hyperchylomicronemia.
J Lipid Res 1993; 34: 147–56.
128 Durrington PN, MacIver JE, Holdsworth G, Galton DJ. Severe
hypertriglyceridaemia associated with pancytopenia and lipoprotein
lipase deficiency. Ann Intern Med 1981; 94: 211–14.
129 Mitropoulos KA, Miller GJ, Watts GF, Durrington PN. Lipolysis
of triglyceride-rich lipoproteins activates coagulant factor XII: a study
in familial lipoprotein lipase deficiency. Atherosclerosis 1992; 95:
119–25.
130 Heaney AP, Sharer N, Rameh B, Braganza JM, Durrington PN.
Prevention of recurrent pancreatitis in familial lipoprotein lipase
deficiency with high dose antioxidant therapy. J Clin Endocrinol Metab
1999; 84: 1203–05.
131 Matsumota T, Ohashi Y, Yamada N, Kibuchi M. Coronary heart
disease mortality is actually low in Japanese by direct comparison
with the Joslin cohort. Diabetes Care 1994; 17: 1062–63.
132 Malmström R, Packard CJ, Caslake M, et al. Defective regulation of
triglyceride metabolism by insulin in the liver in non-insulin-
dependent diabetes mellitus. Diabetologia 1997; 40: 454–62.
133 Durrington PN. Diabetic dyslipidaemia.
Bailliere’s Clin Endocrinol Metab 2000; 13: 265–78.
134 Duell PB. Diabetes mellitus. In: Betteridge DJ, Illingworth DR,
Shepherd J, eds. Lipoproteins in heart and disease. London: Arnold,
1999: 897–929.
135 Tan KCB, Cooper MB, Ling KLE. et al. Fasting and postprandial
determinants for the occurrence of small dense LDL species in non-
insulin-dependent diabetic patients with and without
hypertriglyceridaemia: the involvement of insulin, insulin precursor
species and insulin resistance. Atherosclerosis 1995; 113: 273–87.
136 Bhatnagar D, Durrington PN, Kumar S, Mackness MI,
Boulton AJM. Plasma lipoprotein composition and cholesteryl ester
transfer from high density lipoproteins to very low density and low
density lipoproteins in patients with non-insulin dependent diabetes
mellitus. Diabet Med 1992; 13: 139–44.
137 Bagdade JD, Ritter MC, Subbaiah PV. Accelerated cholesterol
ester transfer in patients with insulin dependent diabetes mellitus.
Eur J Clin Invest 1991; 21: 161–67.
138 Lee AJ, Lowe GDO, Woodward M. Fibrinogen in relation to
personal history of prevalent hypertension, diabetes, stroke
intermittent claudication, coronary heart disease and family history:
the Scottish Heart Health Study. Br Heart J 1993; 69: 338–42.
139 Borsch-Johnsen K, Kreiner S. Proteinuria: value as a predictor of
cardiovascular mortality in insulin dependent diabetes mellitus. BMJ
1987; 294: 1651–54.
140 Winocour PH, Durrington PN, Ishola M, Anderson DC, Cohen H.
Influence of proteinuria on vascular disease, blood pressure and
lipoproteins in insulin-dependent diabetes mellitus. BMJ 1987; 294:
1648–51.
141 Winocour PH, Durrington PN, Bhatnagar D, Ishola M,
Mackness MI, Arrol S. Influence of early diabetic nephropathy on
very low density lipoprotein, intermediate density lipoprotein and low
density lipoprotein composition. Atherosclerosis 1991; 89: 49–57.
142 Kornerup K, Nordestgaard BG, Feldt-Rasmussen B,
Borch-Johnsen K, Jensen KS, Jensen JS. Transvascular low-density
lipoprotein transport in patients with diabetes mellitus (type 2): a
non-invasive in vivo isotope technique. Arterioscler Thromb Vasc Biol
2002; 22: 1168–74.
143 Wannamethee SG, Shaper AG, Durrington PN, Perry IJ.
Hypertension, serum insulin, obesity and the metabolic syndrome.
J Hum Hypertens 1998; 12: 735–41.
144 Reaven GM. The role of insulin resistance and hyperinsulinemia in
coronary heart disease. Metabolism 1992; 41: 16–19.
THE LANCET • Vol 362 • August 30, 2003 • www.thelancet.com

145 Haffner SM, Stern MP, Hazuda HP, Mitchell BD, Patterson JK.
Cardiovascular risk factors in confirmed prediabetic individuals: does
the clock for coronary disease start ticking before the onset of clinical
diabetes. JAMA 1990; 263: 2893–98.
146 Farrer M, Fulcher G, Albers CJ, Neil HAW, Adams PC,
Alberti KGMM. Patients undergoing coronary artery bypass surgery
are at a high risk of impaired glucose tolerance and diabetes mellitus
during the first post-operative year. Metabolism 1995; 44: 1016–27.
147 Londahl M, Katzman P, Nilsson A, Ljungdahl L, Prutz KG.
Cardiovascular prevention before admission reduces mortality
following acute myocardial infarction in patients with diabetes.
J Intern Med 2002; 251: 325–30.
148 Freeman DJ, Norrie J, Sattar N, et al. Pravastatin and the
development of diabetes mellitus: evidence for a protective treatment
effect in the West of Scotland Coronary Prevention Study. Circulation
2001; 103: 357–62.
149 Barrett-Connor EL, Cohn BA, Wingaard DL, Edelstein SL. Why is
diabetes mellitus a stronger risk factor for fatal ischaemic heart
disease in women than in men? The Rancho Benardo Study. JAMA
1991; 265: 627–31.
150 Durrington PN. Gender and coronary heart disease. In:
Mackness MI, Miller JP, Rees A, eds. Yearbook in dyslipidaemia
2003. Oxford: Clinical Publishing Services, 2003; 297–306.
Uses of error
Errors: Incompetence, ineptitude or failure
Lionel H Opie
Errors are of most interest if they reflect overt
incompetence or ineptitude (my first example) or failure
to do what should have been done (my second example).
In about 1973, I was doing a student teaching ward
round certain that I knew most of internal medicine and
all of cardiology. During a teaching ward round the
patient, an elderly gentleman of about 76 years of age
with a cerebrovascular accident thought to be on the
basis of atrial fibrillation, developed another stroke, the
direct result of my ward round. Why? I wanted to
explain to the students that carotid sinus massage was no
therapy for atrial fibrillation, though an excellent self-
help remedy in younger patients with supraventricular
tachycardia. By way of demonstration, totally
unnecessary for the health of the patient, I proceeded to
massage the right carotid sinus, and within seconds he
went pale. I was totally surprised and did not know what
to do. There were no resuscitation trolleys on the ward.
Instead of thumping or pumping the chest, I just stood
there, paralysed. I slowly came to realise that he had had
carotid sinus syncope that precipitated another stroke.
Why this happened is still not clear. On the background
of increased carotid sinus sensitivity of the elderly,
increased conduction block probably induced severe
bradycardia with reduced cerebral blood flow. Great
care is needed to protect the patient’s interests during
teaching ward rounds.
Hatter Institute, Faculty of Health Sciences, University of Cape Town, Observatory 7925, South Africa (L H Opie MD)
THE LANCET • Vol 362 • August 30, 2003 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet
SEMINAR
151 Lloyd JK. Lipoprotein deficiency disorders. Clin Endocrinol Metab
1973; 2: 127–47.
152 Kane JP, Havel RJ. Disorders of the biogenesis and secretion of
lipoproteins containing the B apolipoproteins. In: Scriver CR,
Beaudet AL, Sly WS, Valle D, eds. The metabolic and molecular
bases of inherited disease, 7th edn. New York: McGraw-Hill, 1995:
1853–85 .
153 Assmann G, von Eckardstein A, Brewer HB. Familial high density
lipoprotein deficiency: Tangier disease. In: Scriver CR, Beaudet AL,
Sly WS, Valle D, eds. The metabolic and molecular bases of
inherited disease, 7th edn. New York: McGraw-Hill, 1995: 2053–72.
154 Oram JF. ATP-binding cassette transporter A1 and cholesterol
trafficking. Curr Opin Lipidol 2002; 13: 373–81.
155 Sacks FM, for the Expert Group on HDL Cholesterol. The role of
high-density lipoprotein (HDL) cholesterol in the prevention and
treatment of coronary heart disease: expert group recommendations.
Am J Cardiol 2002; 90: 139–43.
156 Goldbourt U, Yaari S, Medalie JH. Isolated low HDL cholesterol as
a risk factor for coronary heart disease mortality: a 21-year follow-up
of 8000 men. Arterioscler Thromb Vasc Biol 1997; 17: 107–13.
157 Durrington PN, Prais H, Bhatnagar D, et al. Indications for
cholesterol-lowering medication: comparison of risk-assessment
methods. Lancet 1999; 353: 278–81.
My other major error occurred only a few weeks
before writing this piece. In a meta-analysis of calcium
channel blockers (CCBs), my co-worker and I found
that CCB therapy for hypertension reduced stroke but
increased myocardial infarction, while leaving
cardiovascular and total mortality unchanged relative to
conventional therapy by diuretics or ␤ blockers. In view
of the continuing controversy about the safety of CCBs,
it was my hope that this article and the other recent
meta-analyses published, would help settle the issue.
But, to cut a long story short, we made a calculation
error in the rate of reduction of non-fatal stroke, which
we claimed was the very high rate of 25%. We
incorrectly emphasised stroke reduction as being
statistically more robust than increased non-fatal
myocardial infarction. In fact, stroke reduction just
about exactly balanced myocardial infarct increase.
Although the overall results are still intact, any error in
this contentious area is serious. Published errors are very
difficult to correct. What should we have done to avoid
the error? Simple addition of the numbers for non-fatal
stroke would have shown up the error. Ironically, there
have been other addition errors in previous meta-
analyses that I had picked up and criticised. So I should
have been ultra careful. Thus, before publication, apply
commonsense checks to statistics. It is not the job of the
referees to pick up statistical errors.
731