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.
STATINS Use
Simvastatin, pravastatin, atorvastatin androsuvastatin are 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.
†
†
†
DRUGSUSED TOTREATDYSLIPIDAEMIA 181
Dietary fat
Bile acid
Fat Muscle
Fat Muscle
FFA FFA
Lipoprotein lipase
Lipoprotein lipase Liver
Chylomicron Remnant VLDL IDL HDL
LDL Tissue
Intestine
Ezetimibe
Resins Fibrates
HMG CoA reductase inhibitors statins
Figure 27.6:Sites of action of lipid-lowering drugs (see Figure 27.3for abbreviations).
Table 27.2:Drugs used in dyslipidaemia
Class/drug Biochemical Effect on Effect on Adverse effects Special situations effect coronary longevity
artery disease
Statin/simvastin, LDLpp pp q(4S,WOSCOPS) Rare: myositisqliver Contraindicated in
pravastatin transaminase pregnancy, caution in
children
Resin/cholestyramine LDLpTGq p NP Constipation, flatulence, Contraindicated in biliary
nausea obstruction
Fibrate/gemfibrozil, TGppLDLp p NP Myocitis; gastro-intestinal Contraindicated in
bezafibrate HDLq symptoms alcoholics, renal/liver
impairment
Nicotinic acid TGppLDLp p NP Flushing (PGD2- Useful in familial
derivatives/high-dose HDLq mediated); diarrhoea; hypercholesterolaemia;
nicotinic acid, urticaria; epigastric pain; PG-related adverse
acipimox hyperuricaemia; effects ameliorated by
hyperglycaemia aspirin before the dose
Fish oil/eicosapentanoic TGp NP NP Belching with a fishy Used in patients with
acid-rich supplements after-taste pancreatitis caused by
raised TG. Contraindicated in patients with familial hypercholesterolaemia, in whom it increases cholesterol levels
Ezetimibe LDLp NP NP Mild GI effects, myalgia Adjunct to statin in
resistant dyslipidaemia LDL, low-density lipoprotein; TG, triglycerides; HDL, high-density lipoprotein; NP, not proven.
Adverse effects and contraindications
Mild and infrequent side effects include nausea, constipation, diarrhoea, flatulence, fatigue, insomnia and rash. More serious adverse events are rare, but include rhabdomyolysis, hepatitis and angioedema. Liver function tests should be performed before starting treatment and at intervals thereafter, and patients should be warned to stop the drug and report at once for determination of creatine kinase if they develop muscle aches. HMG CoA reductase inhibitors should be avoided in alcoholics and patients with active liver disease, and are contraindicated during pregnancy.
Pharmacokinetics
Statins are well absorbed, extracted by the liver (their site of action) and are subject to extensive presystemic metabolism by CYP3A4 or CYP2D6. Simvastatin is an inactive lactone prodrug which is metabolized in the liver to its active form, the corresponding β-hydroxy fatty acid.
Drug interactions
The risk of rhabdomyolysis is increased by concurrent use of a fibrate or inhibitors of statin metabolism, e.g. azoles (Chapter 45), macrolides (Chapter 43). Their potency is increased by concur- rent use of a drug that interferes with cholesterol absorption (see below).
DRUGS THAT REDUCE CHOLESTEROL ABSORPTION
EZETIMIBE Use
Ezetimibe is most often used in combination with diet and statins for severe hypercholesterolaemia; also in occasional patients who cannot tolerate statins or where statins are con- traindicated, and in (rare) cases of homozygous sitosterolaemia.
Mechanism of action
It blocks the NPLC1L sterol transporter in the brush border of enterocytes, preventing cholesterol and plant sterols (phytosterols) transport from the intestinal lumen. This mech- anism is distinct from that of phytosterol and phytostanol esters (present in ‘health’ foods such as Benecol™) which inter- fere with the micellar presentation of sterols to the cell surface, or of resins (see below) which bind bile acids in the gut lumen.
Pharmacokinetics
Ezetimibe is administered by mouth and is absorbed into intestinal epithelial cells, where it localizes to the brush bor- der. It is metabolized, followed by enterohepatic recycling and slow elimination. It enters breast milk.
Adverse effects and contraindications
Diarrhoea, abdominal pain or headaches are occasional prob- lems; rash and angioedema have been reported. It is con- traindicated in breast-feeding.
ANION-EXCHANGE RESINS Use
Colestyramineorcolestipolwere used for hypercholesterol- aemia, but have been almost completely superseded by statins.
Resins retained an important niche as add-in treatment in severe disease (e.g. heterozygous familial hypercholestero- laemia (FH)) which was inadequately responsive to statin monotherapy. This role has now been taken by ezetimibe(see above) which is effective and well tolerated in milligram doses in contrast to resins which are administered in doses of several grams, are unpalatable and commonly cause abdominal bloat- ing and diarrhoea. They retain a highly limited usefulness in children and in breast-feeding women. Completely separate indications include bile salt diarrhoea and pruritus in incom- plete biliary obstruction. (They are ineffective in patients with complete biliary obstruction, in whom there are no bile salts to bind in the gut lumen.) They cause malabsorption of fat solu- ble vitamins and interfere with the absorption of many drugs (Chapter 13).
FIBRATES Use
Bezafibrate, gemfibrozilandfenofibrateare available in the UK and are used mainly for patients with mixed dyslipidaemia with severely raised triglycerides especially if they are poorly responsive to statins. Clofibrate, which was used in a World Health Organization (WHO) trial, is less often used because it increases biliary cholesterol secretion and predisposes to gall- stones. Its use is therefore limited to patients who have had a cholecystectomy. Furthermore, while it reduced the number of myocardial infarctions in the WHO trial, this was offset by an increased number of cancers of various kinds. The meaning of this has been extensively debated, but remains obscure. This issue is clouded by an effect of malignancy of lowering serum cholesterol. The original observations with clofibrate may have been a statistical accident and there is no excess of cancers in patients treated with gemfibrozil in other trials (e.g. the Helsinki Heart Study). These studies have shown that fibrates have a marked effect in lowering plasma triglycerides (TG), with a modest (approximately 10%) reduction in LDL and increase in HDL.Fenofibratehas an additional uricosuric effect.
Mechanism of action
Fibrates are agonists at a nuclear receptor (peroxisome proliferator-activated receptor α(PPARα)) which is present in many tissues including fat. The ensuing effects are incom- pletely understood. They stimulate lipoprotein lipase (hence their marked effect on TG) and increase LDL uptake by the liver. In addition to their effects on plasma lipids, fibrates lower fibrinogen.
Adverse effects
Fibrates can cause myositis (in severe cases rhabdomyolysis with acute renal failure), especially in alcoholics (in whom they should not be used) and in patients with impaired renal func- tion (in whom elimination is prolonged and protein binding 182 PREVENTION OF ATHEROMA:LOWERING PLASMA CHOLESTEROL AND OTHER APPROACHES
reduced). The risk of muscle damage is increased if they are taken with a statin, although lipid specialists sometimes employ this combination. They can cause a variety of gastro- intestinal side effects, but are usually well tolerated.
Contraindications
Fibrates should be used with caution, if at all, in patients with renal or hepatic impairment. They should not be used in patients with gall-bladder disease or with hypoalbu- minaemia. They are contraindicated in pregnancy and in alco- holics (this is particularly important because alcohol excess causes hypertriglyceridaemia; see Table 27.1).
Pharmacokinetics
Bezafibrateandgemfibrozilare completely absorbed when given by mouth, highly protein bound, and excreted mainly by the kidneys.
OTHER DRUGS
Other drugs sometimes used by lipidologists are summarized in Table 27.2. These include nicotinic acidwhich needs to be administered in much larger doses than needed for its effect as a B vitamin (Chapter 35). Its main effects on lipids are distinc- tive, namely to increase HDL, reduce TG and reduce Lp(a).
Unfortunately, it has troublesome adverse effects including flushing (mediated by release of vasodilator prostaglandin D2) which is reduced by giving the dose 30 minutes after a dose of aspirin.
DRUGSUSED TOTREATDYSLIPIDAEMIA 183
Case history
A 36-year-old male primary-school teacher was seen because of hypertension at the request of the surgeons following bilateral femoral artery bypass surgery. His father had died at the age of 32 years of a myocardial infarct, but his other relatives, including his two children, were healthy. He did not smoke or drink alcohol. He had been diagnosed as hypertensive six years previously, since which time he had been treated with slow-release nifedipine, but his serum cholesterol level had never been measured. He had been disabled by claudication for the past few years, relieved temporarily by angioplasty one year previously. There were no stigmata of dyslipidaemia, his blood pressure was 150/100 mmHg and the only abnormal findings were those relating to the peripheral vascular disease and vascular sur- gery in his legs. Serum total cholesterol was 12.6 mmol/L, triglyceride was 1.5 mmol/L and HDL was 0.9 mmol/L. Serum creatinine and electrolytes were normal. The patient was given dietary advice and seen in clinic four weeks after dis- charge from hospital. He had been able to run on the games field for the first time in a year, but this had been limited by the new onset of chest pain on exertion. His cholesterol level on the diet had improved to 8.0 mmol/L. He was readmitted.
Questions
Decide whether each of the following statements is true or false.
(a) This patient should receive a statin.
(b) Coronary angiography is indicated.
(c) Renal artery stenosis should be considered.
(d) The target for total cholesterol should be 6.0 mmol/L.
(e) Ezetimibe would be contraindicated.
(f) Anα1-blocker for his hypertension could coincidentally improve his dyslipidaemia.
(g) His children should be screened for dyslipidaemia and cardiovascular disease.
Answer (a) True.
(b) True.
(c) True.
(d) False.
(e) False.
(f) True.
(g) True.
Comment
It was unfortunate that this young man’s dyslipidaemia was not recognized earlier. Coronary angiography revealed severe inoperable triple-vessel disease. The target total cholesterol level should be 5.0 mmol/L and was achieved with a combination of diet, a statin at night and ezetimibe in the morning. Renal artery stenosis is common in the setting of peripheral vascular disease, but renal angiography was nega- tive. This patient’s relatively mild hypertension was treated with doxazosin (a long-acting α1-blocker, see Chapter 28) which increases HDL, as well as lowering blood pressure. He probably has heterozygous monogenic familial hypercholes- terolaemia and his children should be screened. One of his sons is hypercholesterolaemic and is currently being treated with a combination of diet and a statin.
FURTHER READING
Durrington PN. Dyslipidaemia. Lancet2003;362: 717–31.
Durrington PN. Hyperlipidaemia: diagnosis and management, 3rd edn.
London: Hodder Arnold, 2005.
Key points
Treatment of dyslipidaemia
• Treatment goals must be individualized according to absolute risk. Patients with established disease need treatment irrespective of LDL.
• Dietary measures involve maintaining ideal body weight (by caloric restriction if necessary) and reducing consumption of saturated fat – both animal (e.g. red meat, dairy products) and vegetable (e.g. coconut oil) – as well as cholesterol (e.g. egg yolk).
• Drug treatment is usually with a statin (taken once daily at night) which is effective, well tolerated and reduces mortality. Consider the possibility of secondary dyslipidaemia.
• Ezetimibe is well tolerated. It is a useful adjunct to a statin in severely dyslipidaemic patients who show an inadequate response to a statin alone, and has almost completely replaced bile acid binding resins for this indication.
• Fibrates are useful as a first-line treatment in patients with primary mixed dyslipidaemias with high triglyceride concentrations, as well as high LDL (and often low HDL). Avoid in alcoholics.
• Other reversible risk factors for atheroma (e.g.
smoking, hypertension) should be sought and treated.
• Consideration should be given to adjunctive use of aspirin as an antiplatelet/antithrombotic drug.
Feher MD, Richmond W. Lipids and lipid disorders. London: Gower Medical Publishing, 1991.
Hansson GK. Mechanisms of disease: inflammation, atherosclerosis, and coronary artery disease. New England Journal of Medicine2005;
352: 1685–95.
Kosoglou T, Statkevich P, Johnson-Levonas AO et al. Ezetimibe – A review of its metabolism, pharmacokinetics and drug interactions.
Clinical Pharmacokinetics2005;44: 467–94.
Ross R. Atherosclerosis – an inflammatory disease. New England Journal of Medicine1999;340: 115–26.
Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease:
the Scandinavian Simvastatin Survival Study (4S). Lancet 1994;
344: 1383–9.
Shepherd J, Cobbe SM, Ford I et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia.
New England Journal of Medicine1995;333: 1301–7.
184 PREVENTION OF ATHEROMA:LOWERING PLASMA CHOLESTEROL AND OTHER APPROACHES
●Introduction 185
●Pathophysiology and sites of drug action 185
●General principles of managing essential