Dyslipidaemia

Therapuetics I
College of pharmacy
Fifth stage
Dr. Mohammed Hamzah Ibadi
[Link]. Pharmacy, [Link]., Ph.D., Pharma
&Therapeutics

• Disorders of lipoprotein metabolism that result in elevated serum

concentrations of total cholesterol (TC) and low-density lipoprotein
cholesterol (LDL-C) increase the risk of development of
cardiovascular disease (CVD).
• high-density lipoprotein cholesterol (HDL-C) confers protection
against CVD, with the risk reducing as HDL-C increases.
 Triglycerides
• The role of hypertriglyceridaemia as an independent risk factor for
atherosclerotic CVD is unclear because triglyceride levels are confounded
by an association with low HDL-C, hypertension, diabetes and obesity, and
a synergistic effect with LDL-C and/ or low HDL-C.

• An isolated elevation of triglyceride may be the consequence of a primary

disorder of lipid metabolism; it may be secondary to the use of medicines
such as oestrogens, protease inhibitors, retinoids, corticosteroids, some
immunosuppressants and some antipsychotic.
• or it may be a component of the metabolic syndrome or type 2 diabetes
mellitus.
• Many individuals have a mixed dyslipidaemia that includes elevated levels
of triglycerides and LDL-C, but a reduction of LDL-C normally remains the
primary focus of treatment.
• Primary dyslipidaemia
• the primary hypercholesterolaemias such as familial
hypercholesterolaemias (FHs) in which LDL-C is raised;

• • the primary mixed (combined) hyperlipidaemias in which both

LDL-C and triglycerides are raised; or

• • the primary hypertriglyceridaemias such as type III

hyperlipoproteinaemia, familial lipoprotein lipase deiciency and
familial apoC-II deiciency.
• Familial hypercholesterolaemia
• Familial combined hyperlipidaemia
• Familial type III hyperlipoproteinaemia
• Familial lipoprotein lipase deficiency
• Familial apolipoprotein C-II deficiency
 Cardiovascular risk assessment
Primary prevention
• It is recommended that CV risk assessment is carried out
every 5 years for all adults from the age of 40 years, with
no history of CVD or diabetes, and not receiving treatment
for raised blood pressure or dyslipidaemia. A number of
CVD risk calculators are available, including
• QRisk (UK and recommended by NICE;
[Link]
• SCORE (Europe; [Link]
org/Education/Practice-Tools/CVD-prevention-
toolbox/SCORERisk- Charts#),
• Joint British Socities-3 (JBS-3; [Link] [Link])
and
• ASSIGN (Scotland; [Link]
• QRisk2
• QRisk2 is based on a database, established in 2003, of anonymised UK primary
care patients. The following parameters, with any missing values calculated by a
complex averaging procedure, are used to calculate a patient’s CV risk,
• • patient age (35–84 years)
• • patient sex
• • smoking status
• • family history of heart disease aged less than 60 years
• • existing treatment with blood pressure agent
• • postcode (postcode is linked to Townsend score measure of deprivation)
• • body mass index (BMI) (height and weight)
• • systolic blood pressure (use current, not pretreatment, value)
• • TC and HDL-C
• • self-assigned ethnicity (not nationality)
• • rheumatoid arthritis
• • chronic kidney disease
• • atrial fibrillation

• The QRisk2 risk assessment tool should be used to

assess CVD risk of the primary prevention of CVD
in people up to and including age 84 years.
• Patients with a CV risk ≥10% over 10 years are
considered to be at suficient risk to warrant lipid-
lowering therapy according to NICE (2014)
guidelines.
• It should be noted that although NICE (2014)
recommends using the tool for people with type 2
diabetes, it does not recommend using it for
patients with type 1 diabete
 Lipid profile
• Serum concentrations of triglycerides increase after the
ingestion of a meal and, therefore, if a full lipid profile is
to be obtained, patients must fast for 12–15 hours before
they can be measured.
• Patients must also be seated for at least 5 minutes before
drawing a blood sample.
• TC level and HDL are little affected by food intake, and this is,
therefore, not a consideration if only these are to be
measured.
 • Treatment
• Body weight and waist measurement
• It is useful to classify the extent to which an
individual is overweight by calculating their BMI.
The BMI (kg/m2) in all but the most muscular
individual gives a clinical measure of adiposity.
• • BMI 18.5: underweight
• • BMI 18.6–24.9: ideal
• • BMI 25–29.9: overweight
• • BMI 30–40: obese
• • BMI >40: morbidly obese
 • Diabetes mellitus
• Premature atherosclerotic disease is the main cause of
reduced life expectancy in patients with diabetes.
• The atherosclerotic disease is often widespread, and
complications such as plaque rupture and thrombotic
occlusion occur more often and at a younger age.
• The prevalence of CHD is up to four times higher
among patients with diabetes, with more than 80%
likely to die of a CV event .
• LDL levels are a stronger predictor of CV risk in
patients with diabetes than blood glucose control or
blood pressure.

• Type 1 diabetes.
• In patients with type 1 diabetes, HDL-C may appear high, but for
reasons which are unclear it does not impart the same degree of
protection against CVD as in those without diabetes.
• It is, therefore, not appropriate to use CV risk prediction charts
that utilise the TC:HDL-C ratio in patients with type 1 diabetes.
• Patients with type 1 diabetes have a two fold to
threefold increased risk of development of CVD.
• NICE (2014) recommends that people with type 1
diabetes should be considered for treatment with a
statin if they are more than 40 years old or have had
type 1 diabetes for more than 10 years, or have
evidence of kidney disease or other CVD risk factors
• Type 2 diabetes.
• Patients with type 2 diabetes typically have increased triglycerides
and decreased HDL-C. Levels of TC may be similar to those found
in individuals without diabetes, but the patient with type 2
diabetes often has increased levels of highly atherogenic small,
dense LDL particles.
• Individuals with type 2 diabetes and older than 40 years, but
without CVD, are often considered to have the same CV risk as
patients without diabetes who have survived an MI.
• In previous NICE (2008b) guidance, the criteria for at risk was age
older than 40 years but with one other risk factor present, for
example, hypertension, obesity, smoker, etc.
• NICE (2014) now recommends CV risk assessment using QRisk2
for individuals with type 2 diabetes to assess whether a statin
should be considered

• Drugs
• If an individual is found to be at risk of CVD
(primary prevention), including people with type
2 diabetes, then all other modifable risk factors
should be addressed, including dietary and
lifestyle changes, before statin therapy is offered.

• CV risk assessment should then be repeated using

QRisk2, and if the CV risk remains high, drug
therapy in the form of a statin should be offered.
 • Primary prevention
• dyslipidaemia should not be treated in isolation,
and management must be embarked upon with
clear goals.

• In patients without evidence of arterial disease,

statin treatment must be considered if the risk of
CVD is ≥10% over 10 years (NICE, 2014).

• • a lipid-lowering agent such as atorvastatin 20 mg/day

(or alternative) with an aim of a 40% decline in non-HDL-
C from baseline to indicate adherence to treatment
(NICE, 2014)

• • personalised information on modifiable risk factors

including physical activity, diet, alcohol intake, weight and
tight control of diabetes

• • advice to stop smoking; and

• • advice (and treatment if appropriate) to achieve blood

pressure below 140 mmHg systolic and 90 mmHg
diastolic
• For primary prevention in patients with type 1
diabetes who are more than 40 years old or have had
type 1 diabetes for more than 10 years or have
established nephropathy or other CVD risk factors,
atorvastatin 20 mg daily should be offered and
lifestyle modiications made (NICE, 2014).

• Patients with type 2 diabetes who have a risk of CVD

of ≥10% over 10 years should be offered atorvastatin
20 mg daily for primary prevention (NICE, 2014).
 • Secondary prevention
• In individuals diagnosed with CVD or other occlusive arterial disease,
treatment should include:
• 1. a lipid-lowering agent such as atorvastatin 80 mg/day (or alternative)
with an aim of a 40% decline in non-HDL-C from baseline to indicate
adherence to treatment (NICE, 2014);
• 2. advice to stop smoking;
• 3. personalised information on modiiable risk factors including physical
activity, diet, alcohol intake, weight and diabetes;
• [Link] and treatment to achieve blood pressure at least below 140
mmHg systolic and 90 mmHg diastolic;
• 5. tight control of blood pressure and glucose in those with diabetes;
• 6. low-dose aspirin (75 mg daily) or clopidogrel (75 mg daily);
• 7. ACE inhibitors in selected groups, speciically those with left
ventricular dysfunction, diabetes, chronic kidney disease or
nephropathy;
• 8. β-blocker for those who have had an MI and in those with heart
failure; and
• 9. anticoagulant therapy for those with atrial fibrillation and additional
stroke risk factors.
 • Lipid-lowering therapy
• Five well-established classes of lipid-lowering
agents are available:
• • statins
• • cholesterol absorption inhibitors
• • fibrates
• • bile acid binding agents
• • nicotinic acid and derivatives

• Statins
• Their primary site of action is the inhibition of
HMGCoA reductase in the liver and the subsequent
inhibition of the formation of mevalonic acid, the rate-
limiting step in the biosynthesis of cholesterol.
• This results in a reduction in intracellular levels of
cholesterol, an increase in expression of hepatic LDL
receptor, and enhanced receptor-mediated catabolism
and clearance of LDL-C from serum. Production of
VLDL-C, the precursor of LDL-C, is also reduced.
• The overall effect is a reduction in TC, LDL-C, VLDL-C
andand triglycerides with an increase in HDL-C.
• There is much debate around the statin of choice.
Atorvastatin is currently the preferred agent because of
its low cost, safety profile and evidence of efficacy.
• Rosuvastatin is the most potent of the statins, with
evidence of impact on morbidity and mortality. It is
normally reserved for those individuals who have had an
inadequate response to their first-line statin or failure to
tolerate other statins.
• There remains concern about its safety profile,
rhabdomyolysis in particular, when used at the higher
dosage of 40 mg/day.
• It is recommended that this dosage should be used only
under specialist supervision in individuals with severe FH
and at high CV risk.
• Myopathy (unexplained muscle soreness or weakness) leading to
myoglobulinuria secondary to rhabdomyolysis is also a rare but
serious potential adverse effect.
• The risk of myopathy is increased:
• 1. when there are underlying muscle disorders, a family history of
muscle disorders, renal impairment, untreated hypothyroidism,
alcohol abuse, or the recipient is aged over 65 years or female;
• 2. where statins are co-prescribed with other lipid-lowering drugs,
for example, fibrates or nicotinic acid.
• 3. when there is a history of myopathy with another lipid-lowering
drug or statin; or
• 4. where there is co-prescription of simvastatin or atorvastatin
with drugs that inhibit cytochrome P450 3A4 (CYP3A4).
• The statins are a heterogeneous group metabolised by different
cytochrome P450 (CYP450) isoenzymes.

Pleiotropic properties
• plaque stabilisation,
• inhibition of thrombus formation,
• reduced serum viscosity,
• and anti-inflammatory and
• antioxidant activity
 • Cholesterol absorption inhibitors
• Ezetimibe is a 2-azetidinone derivative that
interacts with a putative cholesterol transporter in
the intestinal brush-border membrane and
thereby blocks cholesterol re-absorption from the
gastro-intestinal tract. It can reduce LDL-C by 15–
20% when added to diet.
• Ezetimibe also brings about a small increase in
HDL-C and a reduction in triglycerides. When
added to a statin, ezetimibe lowers LDL-C by
approximately 20% over and above that achieved
by statin therapy alone

• Fibrates
• Members of this group include bezaifbrate, ciprofibrate,
fenofibrate and gemfibrozil.
• They are thought to act by binding to peroxisome proliferator-
activated receptor α on hepatocytes. This then leads to changes in
the expression of genes involved in lipoprotein metabolism.
• fibrates reduce triglyceride and, to a lesser extent, LDL-C levels,
while increasing HDL-C.
• Fibrates take 2–5 days to have a measurable effect on VLDL-C, with
their optimum effect present after 4 weeks
• the fibrates may also have a beneifcial effect on the fibrinolytic and
clotting mechanisms.
• The fibrates also produce an improvement in glucose tolerance
• Bile acid binding agents
• colestyramine, colestipol and colesevelam. Both colestyramine and
colestipol were formerly considered first-line agents in the
management of patients with FH but now have limited use.
• Each of the bile acid binding agents reduce TC and increase
triglyceride levels.
• There is little evidence that bile acid binders reduce the risk of CV
events, and therefore they are not recommended for use for
primary or secondary prevention of CVD (NICE, 2014).
• Colesevelam is up to six times as potent as the other bile acid
binding agents, probably because of a greater binding to glycocholic
acid..

Adverse effects
• Bloating, flatulence, heartburn and constipation are common
complaints. Constipation is the major subjective side effect
• Colestyramine, colestipol and colesevelam are known to
interact with many drugs primarily by interfering with
absorption
• Long-term use of bile acid binding agents may also interfere
with the absorption of fat-soluble vitamins, and
supplementation with vitamins A, D and K is recommended
• Proprotein convertase subtilisin/kexin type 9
inhibitors.

• Mr AJ, a 75-year-old patient receiving

warfarin to prevent DVT, comes to the
clinic with an INR of 12, despite taking
the same dose of the drug. There is no
evidence of bleeding. He was previously
well controlled on warfarin.
• What should be done?