Review
The differences in treatment
of hypertriglyceridaemia vs.
hypercholesterolaemia
Sumari Davis, BPharm, Amayeza Info Services
Abstract
Treatment of hyperlipidaemia needs to be tailored to each individual patient, taking into consideration the risk factors for
cardiovascular disease, lipid profile, response to treatment and adverse effects of the drugs. Low-risk patients may benefit from
lifestyle modifications only, while patients at high risk of contracting cardiovascular disease may need immediate pharmacological
treatment, despite only moderate abnormalities in lipid profiles. Since hypertriglyceridaemia is often accompanied by low levels
of high-density lipoprotein (HDL) cholesterol, fibrates may be considered as first-line treatment. Fibrates reduce triglyceride
levels and also increase HDL levels. Statins are first choice in treating hypercholesterolaemia as they have been shown to reduce
mortality, in addition to lowering low-density lipoprotein (LDL) cholesterol levels. Severe or mixed hyperlipidaemias may require
combination therapy. Since the combination of statins with fibrates can lead to myotoxicity or rhabdomyolysis, drugs that lower
the risk for these side-effects should be used. Fenofibrate, in combination with pravastatin or fluvastatin, may be considered.
S Afr Pharm J 2011;78(1):38–41
Introduction
• Low-density lipoprotein (LDL)
The difference in the treatment of hypertriglyceridaemia and
hypercholesterolaemia is based on the difference in these
conditions, as well as the difference in the mechanism of action
of the drugs indicated for these conditions.
• Very low-density lipoprotein (VLDL) and
• Chylomicrons4
VLDL and chylomicrons are larger particles which cannot enter
the blood vessel walls, thus they are not atherogenic. LDL
particles are smaller, can enter the blood vessels easier and
are the main cause of atherosclerosis.4 Higher levels of LDL
increase the risk for atherosclerosis, and ultimately CHD, due
to obstruction, clotting or ischaemic events after dislodging
of plaque from an arterial wall. Although HDL particles are the
smallest of the lipoproteins, higher levels of HDL are preferable,
as these lipoproteins have the ability to remove cholesterol
from blood vessel walls and transport it back to the liver. There
it can be stored as part of the hepatic cholesterol pool, oxidised
to bile acids, excreted unchanged in bile, or entered into VLDL.3,4
The function and effects of cholesterol and
triglycerides in the body
Although an excess of cholesterol and the negative association
with coronary heart disease (CHD) and hardening of the arteries
(atherosclerosis) is well known, cholesterol and triglycerides
have an essential role. Apart from playing an important role in
digestion, cholesterol is necessary for hormone, bile acid and
vitamin D production, and is also essential for cell membrane
maintenance.1 Triglycerides are stored in adipose tissue and are
hydrolysed by lipoprotein lipase (LPL) to release free fatty acids
that serve as a source of energy.2
When cholesterol intake from food is greater than the body’s
ability to process and dispose of it, patients may develop
hypercholesterolaemia. This is also possible if the body
manufactures too much LDL cholesterol.1
Since cholesterol and triglycerides are both fatty molecules
and need to be transported in blood, which consists mainly
of water, they are encapsulated in a “casing” of lipoproteins.3,4
Lipoproteins consist of a hydrophobic core containing
triglycerides or cholesterol esters and a more hydrophilic shell
of free cholesterol and phospholipids.3
Hyperlipidaemias may be classified as either primary (familial
as a result of a genetic defect) or secondary (due to an acquired
condition or certain medication use). Further classification
is based on the lipid profiles, or in terms of lipoprotein
abnormality.5 (See Table I)
There are four basic groups of lipoproteins:
• High-density lipoprotein (HDL)
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Table I: Classification of lipid levels according to the US
National Cholesterol Education Programme expert panel on
detection, evaluation and treatment of high blood cholesterol
in adults.2,6
Table II: Acquired conditions that can cause
hypertriglyceridaemia.2
• Beta blocker use
Triglyceride
• Diabetes mellitus
Normal
< 1.7 mmol/L
• Use of oestrogen replacement and oral contraceptives
Borderline high
1.7 to 2.2 mmol/L
• Hypothyroidism
High
2.2 to 5.6 mmol/L
Very high
≥ 5.6 mmol/L
• Immunosuppressive medication such as cyclosporine and
glucocorticoids
• Nephrotic syndrome
LDL Cholesterol
• Obesity
Optimal
< 2.58 mmol/L
Above optimal
2.58 to 3.33 mmol/L
Borderline high
3.36 to 4.11 mmol/L
High
4.13 to 4.88 mmol/L
Very high
≥4.91 mmol/L
• Tamoxifen use
Highly active antiretroviral treatment (HAART) may manifest as
a syndrome with high triglycerides and low HDL cholesterol.
In South Africa, with the large HIV population and treatment
being more readily available, increases in the cardiovascular risk
for HIV patients on HAART may be expected.7
Total cholesterol
Desirable
< 5.17 mmol/L
Borderline high
5.17 to 6.18 mmol/L
High
≥ 6.2 mmol/L
Treatment
The decision to treat hypertriglyceridaemia should not be
based on TG levels only. Non-pharmacological treatment is
recommended when TG levels are equal to, or more than,
2.3 mmol/L. However, in patients with additional risk factors
such as the above-mentioned acquired conditions or existing
CHD, the risk may be increased at levels starting from 1.8 to
2.2 mmol/L.2
HDL Cholesterol
Low
< 1.03 mmol/L
High
≥ 1.55 mmol/L
Patients with familial hypercholesterolaemia may present with
cholesterol deposits in the iris of the eye, the loose skin around
the eye, elbow and forearm, and in tendons. These deposits are
called xanthomata. 1,2 Even though triglycerides do not have
a strong atherosclerotic effect, they have been associated
independently with increased CHD risk. Very high levels of
triglycerides may cause hepatosplenomegaly and can also lead
to chylomicronaemia (excess of chylomicrons in the blood).
Patients with this disorder may present with recent memory
loss, dyspnoea, flushing with alcohol consumption, abdominal
pain and/or pancreatitis with nausea and vomiting.2
HYPERTRIGLYCERIDAEMIA
Triglycerides (TG) are carried in VLDL and chylomicrons
and are regulated by lipoprotein lipase (LPL) and other
enzymes and proteins.2 Since VLDL and chylomicrons carry
a relatively small amount of cholesterol, the atherosclerotic
effect of hypertriglyceridaemia seems to be mild to modest.
Hypertriglyceridaemia is often associated with low HDL
cholesterol and high levels of small LDL particles.5
Most patients have familial hypertriglyceridaemia, further
enhanced by certain acquired conditions that may also raise TG
levels. These acquired conditions are listed in Table II.
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In high-risk patients where triglyceride levels are high (1.7 to
2.2 mmol/L), pharmacotherapy may be considered in addition
to non-pharmacological treatment. In addition to lowering LDL
levels, the target in this population is to also increase HDL.2
The initial goal in patients with a very high level of TG is to
prevent pancreatitis. Once TG levels are below 5,6 mmol/L,
attention should be directed to lowering LDL levels.2 Pancreatitis
and chylomicron disorder usually only occur at TG levels of
11.2 mmol/L or higher. 2
Non-pharmacological treatment
Non-pharmacological treatment includes aerobic exercise and
adjustment of diet to promote weight loss in obese patients.
Aerobic exercise, consisting of brisk walking, swimming,
cycling or jogging, can reduce TG and LDL, and increase HDL.
At least two sessions per week of at least 20 minutes each are
recommended.5 Reducing concentrated sugars and fat intake
with the addition of oily fish to increase omega-3 fatty acids
(at least three times per week) may also assist in normalising
triglycerides. In patients with very high TG levels, avoiding
alcohol may also decrease the pancreatitis risk. Non-drug
treatment in low-risk patients should be continued for at least
four to 12 weeks to evaluate outcome, before progressing to the
next treatment step.8 More information on dietary management
is available at www.lassa.org.za/guidelines/NatDietGuide.
2011 Vol 78 No 1
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Optimal management of the acquired conditions in table II may
also contribute towards reducing triglyceride levels.2
The Framingham CHD predictor was shown to perform well for
both white, as well as black, men and women.6 In South Africa,
the decision to treat is based on the existence of cardiovascular
disease, and in the absence thereof, calculation of the risk for
myocardial infarction over 10 years.10
Pharmacological treatment
Pharmacological treatment of hypertriglyceridaemia is
indicated in patients with a strong family history of CHD,
multiple cardiac risk factors and overt CHD. Fibrates
(bezafibrate, fenofibrate and gemfibrozil) and nicotinic acid
are most effective in reducing triglycerides and also have a
positive effect on HDL levels.9 In isolated hypertriglyceridaemia,
fibrates are the first treatment choice. Nicotinic acid is often
not well tolerated due to vasodilatory adverse effects. Fish oil
supplements (> 3 g per day) is recommended only in patients
with very high triglyceride levels in some refractory cases, but
gastrointestinal and metabolic adverse effects may restrict use.
There are also concerns that omega-3 fatty acids may increase
LDL cholesterol.2
When interpreting lipid profiles, measurement of HDL in
addition to TC is recommended. Since a high level of HDL is
preferable, two patients with the same TC levels may have
different risk levels for CHD. Patients with higher HDL levels
may not be at risk, whilst the patient with the same TC level, but
lower HDL levels, may be at risk. Thus, the higher the ratio of TC
to HDL, the higher the risk for CHD.1 Other indicators such as
non-HDL cholesterol and LDL particle number to HDL particle
number ratio have also been used to determine risk and to
identify when to start treatment.6
Treatment
Very high levels of triglycerides may be reduced by up to 70%
with the introduction of gemfibrozil therapy. Gemfibrozil may
potentiate muscle toxicity if used in combination with statins.
In the event that combination therapy is required (see below),
fenofibrate is a safer choice as it does not increase statin levels.
If gemfibrozil has to be used, it is safer to combine this fibrate
with pravastatin or fluvastatin to reduce the risk of muscle
toxicity. Bile acid sequestrants (cholestyramine) should be
avoided until hypertriglyceridaemia has been normalised.
These products can increase the production of VLDL and lead
to hypertriglyceridaemia.2
Non-pharmacological treatment
As with hypertriglyceridaemia, lifestyle adjustment is the
first step in reducing cholesterol levels, and the same
recommendations mentioned above should also be introduced
to these patients. The adjustment of diet alone can reduce TC
and/or LDL cholesterol from anything between 5% up to 30%
(in patients with poor baseline diets.) However, there is limited
evidence that lifestyle modifications can improve cardiovascular
outcome on their own. 11
Pharmacological treatment
Finally, the addition of orlistat, to reduce the uptake of fat and
production of intestinal chylomicrons, may be of benefit in
patients who do not respond sufficiently to other treatment
options.2
Once again, the decision to start pharmacological treatment
is based on overall risk, rather than on lipid levels only. In
asymptomatic, apparently healthy patients, the goal is to
maintain TC levels below 5 mmol/L and LDL cholesterol
levels below 3 mmol/L. In patients at high risk of contracting
cardiovascular disease, the goal is to obtain and maintain
TC levels below 4.5 mmol/L and LDL cholesterol levels below
2.5 mmol/L.10
Since lipoproteins that carry triglycerides often also
transport cholesterol, some patients may also have hyper­
cholesterolaemia.2
HYPERCHOLESTEROLAEMIA
Several drugs are available, but statins are the first line of drug
therapy as they are the only group to have shown improvement
in mortality, in addition to substantial lowering of LDL
cholesterol. The effect of statins is also synergistic to the effects
of dietary modifications.12
As with hypertriglyceridaemia, the decision to treat hyper­
cholesterolaemia should not be based on the lipid profile only,
but should also consider other risk factors for CHD. These risks
include:6
•
•
•
•
•
•
•
•
•
Abdominal aortic aneurysm
Age
Cigarette smoking
Diabetes
Family history of premature CHD
Hypertension
Low HDL levels
Peripheral arterial disease
Symptomatic carotid arterial disease
Rosuvastatin is the most potent statin with the ability to lower
cholesterol, as well as triglycerides, in patients with high levels
of both these lipids. In addition, rosuvastatin also has a positive
effect in raising HDL cholesterol. 12 Patients taking atorvastatin
may experience the same benefits, although atorvastatin is
not as effective in raising HDL cholesterol. Fluvastatin is not
as effective, but has a lower risk of producing myalgia. Since
myalgia can be aggravated by combining statins with fibrates,
fluvastatin or pravastatin may be the first choice statins when
used in combination with a fibrate. Treatment with a statin
should lower cholesterol by at least 25%.10
The risk for CHD in combination with the lipid profile is used to
identify patients that need to start treatment. Treatment goals
for different risk groups are also defined by the risk category.
S Afr Pharm J
Bile acid sequestrants, such as cholestyramine, bind to bile acid
in the gut, reducing reabsorption of bile acids, thus increasing
40
2011 Vol 78 No 1
Review
the need for cholesterol to form more bile acid.5,13 They can be
used effectively in combination with a statin or nicotinic acid to
reduce cholesterol in patients with high LDL cholesterol.12 Their
use is often limited by the side-effects which are mainly gastrointestinal, such as constipation.5 Since cholestyramine also
affects absorption of other drugs, it should be taken at least one
hour after, or four to six hours before, any other medication.12
Ezetimibe prevents the absorption of cholesterol in the
intestines. Side-effects are mostly gastrointestinal. Nicotinic
acid decreases LDL cholesterol, as well as triglycerides in the
liver, and also increases HDL cholesterol.12
Although fibrates are the first line of treatment in hyper­
triglyceridaemia, they are also valuable in treatment of
moderate hypercholesterolaemia, especially if accompanied by
low HDL cholesterol and hypertriglyceridaemia. As mentioned
previously, care should be exercised when combining fibrates
with statins due to possible myotoxicity. Gemfibrozil, in
combination with a statin, may cause rhabdomyolysis. When
choosing a fibrate to combine with a statin, fenofibrate should
be the first choice as there appears to be a lower incidence
of myopathy in patients taking fenofibrate with or without a
statin.7
Conclusion
In South Africa, 59% of ischaemic heart disease and 29% of
ischaemic strokes are is attributable to high cholesterol levels.
Since in future these statistics may be negatively affected
due to the need to treat HIV patients with HAART and other
antiretrovirals,7 the pharmacist has an important role to play in
lowering the risk for CHD. In addition to counselling patients
on lifestyle modification, the pharmacist, as custodian of
medication, needs to monitor patients for possible adverse
effects and interactions to optimise patient compliance and
reduce overall morbidity and mortality due to lipid disturbances.
References:
1. Ohlsen S, Rogers D. Significance of lipid measures. The Pharmaceutical Journal. Vol.
272. 2004.
2. Rosenson, RS. Approach to the patient with hypertriglyceridaemia. UpToDate.
2010.
3. Dale M M, Haylett D G. Pharmacology condensed. Churchill Livingstone. Elsevier
Limited. 2004.
4. Neal M J. Medical pharmacology at a glance. Fourth Edition. Blackwell Science.
2002.
5. Ohlsen S, Rogers D. Reducing hyperlipidaemia and CHD. The Pharmaceutical
Journal. Vol 273. 2004.
6. Rosenoson R S. ATP III guidelines for treatment of high blood cholesterol.
UpToDate. 2010.
7. Norman R, Bradshaw D, Steyn K, Gaziano T. The South African Comparative Risk
Assessment Collaborating Group. Estimating the burden of disease attributable to
high cholesterol in South Africa. SAMJ. Vol. 97, No. 8. 2007.
8. Wolmarans P. South African Medical Association Dyslipidaemia Nutrition Working
Group. Dietary Management of Dyslipidaemia clinical guideline. www.lassa.org.
za/guidelines/NatDietGuide. Cited 24 August 2010.
9. Rosenson R S. Lipid lowering with fibric acid derivatives. UpToDate. 2010.
10. Van Schoor J. South African Cholesterol Guidelines Compared. SA Pharmaceutical
Journal. 2010.
11. Pignone M. Treatment of lipids (including hypercholesterolaemia) in primary
prevention. UpToDate. 2010.
12. Rosenson R S. Treatment of lipids (including hypercholesterolaemia) in secondary
prevention. UpToDate. 2010.
13. Rossiter, D, editor. South African Medicines Formulary. Ninth edition. Health and
Medical Publishing Group. 2010.
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