A Textbook of Clinical Pharmacology and Therapeutics

Mechanism of action

HMG CoA reductase is the rate-limiting step in cholesterol

biosynthesis. Statins inhibit this enzyme, lowering cytoplasmic

cholesterol. Hepatocytes respond by increasing the synthesis

of LDL receptors. This increases hepatic LDL uptake from the

plasma, further reducing the plasma LDL concentration.

180 PREVENTION OF ATHEROMA:LOWERING PLASMA CHOLESTEROL AND OTHER APPROACHES

0.03

0.02

0.01

0

No. at risk

Oestrogen and progestin

Placebo

8506 8506 8375

8102 8005 7912

8277

8102

8353

7999

8248

7899

8133

7789

7004

6639

4251

3948

2085

1756

814

523

8155 7032 4272

3960

2088

1760

814

78046659 524

HR, 1.41

HR, 1.29

Coronary heart disease Stroke

Time (years) Time (years)

Cumulative hazard

Figure 27.4:Kaplan–Meier plots of cumulative hazards for coronary heart disease and stroke in the Women’s Health Initiative study, in
healthy postmenopausal women taking hormone replacement therapy or placebo. Blue line, oestrogen and progestin; black line,
placebo. (Redrawn with permission from Writing Group for the Women’s Health Initiative Investigators, Journal of the American
Medical Association2002; 288: 321–33.)

Table 27.1:Secondary dyslipidaemia

Disorder Main lipid disturbance

Diabetes Mixed

Hypothyroidism Cholesterol

Ethanol excess Triglyceride

Nephrotic syndrome Cholesterol

Renal failure Mixed

Primary biliary cirrhosis Cholesterol

Figure 27.5:Risk thresholds and targets for blood cholesterol

in asymptomatic people without cardiovascular disease (CVD).

(Source: JBS 2. Joint British Societies’ guidelines on prevention

of cardiovascular disease in clinical practice. Heart2005;

91(Suppl. 5): v1–v52. Reproduced with permission from the BMJ

Publishing Group.)

DRUGS USED TO TREAT DYSLIPIDAEMIA

The three main classes of drugs used to treat dyslipidaemia are
the statins (HMG CoA reductase inhibitors), drugs that block
cholesterol absorption and fibrates (Figure 27.6). Additional
drugs (see Table 27.2) are useful in special situations.

STAT I N S

Use

Simvastatin,pravastatin,atorvastatinandrosuvastatinare
available in the UK. Randomized controlled trials have shown
thatsimvastatin,atorvastatinandpravastatinreduce cardiac
events and prolong life, and are safe. Pravastatinis distrib-
uted selectively to the liver and is tolerated even by some indi-
viduals who develop mylagia on other statins, but is less
potent.Rosuvastatinlacks clinical end-point data, but is more
potent. Another highly potent statin, cerivastatin, was with-
drawn because of rhabdomyolysis and drug interactions.

Measure random (non-fasting) total cholesterol

and HDL cholesterol as part of a CVD

risk assessment

Lifestyle advice,

monitor blood lipids and

treat to target:

total cholesterol 4 mmol/L

and

LDL cholesterol 2 mmol/L

Total CVD risk20%

Measure fasting total cholesterol,

HDL cholesterol and

triglycerides

Calculate LDL cholesterol

Total CVD risk 20% and

no cardiovascular complications

and no diabetes

Lifestyle advice and follow up,

ideally within 5 years,

to repeat cardiovascular risk

assessment

Assessed with CVD risk chart.

Statins are first line drugs for reducing total and LDL cholesterol. Other

classes of lipid lowering drugs (fibrates, bile acid sequestrants, cholesterol

absorption inhibitors, nicotinic acid, omega-3 (n-3) fatty acids) should be

considered in addition to a statin if the total and LDL cholesterol targets

have not been achieved, or if other lipid parameters such as HDL

cholesterol or triglycerides need to be addressed.

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