CLINICAL PHARMACOLOGY 2003 (PART 27)

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CLINICAL PHARMACOLOGY 2003 (PART 27)

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Correction of blood lipid abnormalities offers scope for a major impact on cardiovascular disease. Drugs play a significant role and have a variety of modes of action. Dietary and lifestyle adjustment are components of overall risk prevention. • Pathophysiology • Primary (inherited) and secondary hyperlipidaemias • Management: risk assessment, secondary and primary prevention, drugs, diet, lifestyle • Drugs used in treatment: statins; fibric acid derivatives; anion-exchange resins; nicotinic acid and derivatives SOME PATHOPHYSIOLOGY The normal function of lipoproteins is to distribute and recycle cholesterol. ...

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25 Hyperlipidaemias SYNOPSIS membranes. Hepatic cholesterol enters the circulation as very-low-density lipoprotein Correction of blood lipid abnormalities offers (VLDL) and is metabolised to remnant scope for a major impact on cardiovascular lipoproteins after lipoprotein lipase removes disease. Drugs play a significant role and have a triglyceride. The remnant lipoproteins are variety of modes of action. Dietary and lifestyle removed by the liver through apolipoprotein adjustment are components of overall risk E-receptors or LDL-receptors (LDL-R) or further prevention. metabolised to LDL and then removed by • Pathophysiology peripheral tissues or the liver by LDL-R. • Primary (inherited) and secondary The quantity of cholesterol transported from the hyperlipidaemias liver to peripheral tissues greatly exceeds its • Management: risk assessment, secondary and catabolism there and mechanisms exist to return primary prevention, drugs, diet, lifestyle cholesterol to the liver. Through this 'reverse • Drugs used in treatment: statins; fibric acid transport', cholesterol is carried by high-density derivatives; anion-exchange resins; nicotinic lipoprotein (HDL) from peripheral cells to the acid and derivatives liver where it is taken up by a process involving hepatic lipase. Cholesterol in the plasma is also recycled to LDL and VLDL by cholesterol-ester transport protein (CETP). SOME PATHOPHYSIOLOGY Cholesterol in the liver is reassembled into The normal function of lipoproteins is to distribute lipoproteins, or secreted in bile then recycled by absorption at the terminal ileum or excreted in and recycle cholesterol. The pathways of lipid metabolism and transport and their primary the faeces. (inherited) disorders appear in Figure 25.1 and can be summarised thus: • Cholesterol is absorbed from the intestine and Lipid disorders transported to the liver by chylomicron remnants, which are taken up by the low-density Disorders of lipid metabolism are manifest by elev- lipoprotein (LDL)-receptor-related protein (LRP). ation of the plasma concentrations of the various • Cholesterol is then transported to peripheral lipid and lipoprotein fractions (total and LDL tissues where, for example, it is converted to cholesterol, VLDL, triglycerides, chylomicrons) and steroid hormones or used to form cell walls and they result, predominantly, in cardiovascular disease. 521
25 H Y P E R L I PI D A E M I AS Fig. 25.1 Pathways of lipid transport. Adapted from Knopp R H 1999 New England Journal of Medicine 341:498-51 I (with permission). This chapter addresses approaches, non-drug as decreased removal, and thus increase of serum well as drug, to correct abnormal lipid profiles and triglyceride; there is increased hepatic secretion diminish vascular disease and its consequences. and thus raised plasma concentration of Deposition of cholesterol in the arterial wall is triglyceride-rich VLDL. Patients are at risk of central to the atherosclerotic process. Carriage of recurrent acute pancreatitis when plasma VLDL, remnant lipoprotein, and LDL to arteries can triglycerides exceed 10 mmol/1, and especially thus be viewed as potentially atherogenic. In the 20 mmol/1. reverse process, HDL carries cholesterol away from Familial combined hyperlipidemia (FCHL) the arterial wall and can be regarded as protective (common and most important) in which there is against atherogenesis. Overproduction of VLDL in increased hepatic secretion of apolipoprotein B the liver raises plasma VLDL, remnant lipoprotein containing VLDL, and conversion to LDL; in and LDL if the capacity to metabolise these consequence plasma LDL and VLDL are raised. lipoproteins is compromised either by a primary Patients exhibit macrovascular disease (coronary (inherited) and/or secondary (environmental) heart, peripheral and cerebral). abnormality. Remnant removal disease (RRD, also called remnant Elevation of LDL-cholesterol is associated particu- lipaemia, familial dysbetalipoproteinemia) larly with risk of coronary heart disease risk, but (uncommon) in which there is a defect of it is increasingly clear that moderately raised apolipoprotein E. This is the major ligand that triglycerides or VLDL or remnants in the presence of allows internalisation and subsequent low HDL-cholesterol may also be atherogenic. metabolism of remnant particles derived from There are five primary inherited lipoprotein dis- VLDL and chylomicrons. The consequence is orders which disturb lipid matabolism at the points accumulation of VLDL remnants called indicated in Figure 25.1. These are: intermediate density lipoprotein (IDL) with • Familial hypertriglyceridemia (FHTG) cholesterol and triglycerides usually in the range (uncommon), including lipoprotein lipase (LPL) 6-9 mmol/1. Patients experience severe deficiency, in which low LPL activity results in macrovascular disease (as above). 522
M A N A G EM E NT 25 • Familial hypoalphalipoproteinemia (rare) in which glycerides. Nicotinic acid decreases the secretion of the serum concentration of (protective) HDL is VLDL and the formation of LDL and increases the low. Coronary heart and peripheral vascular formation of HDL. disease result. • Familial hypercholesterolemia (FH) (common) is characterised by elevation of total and LDL- cholesterol in plasma. In the more severe heterozygous form, this affects about 1:500 of the Management population (one copy of the LDL-receptor The management of hyperlipidaemias should be protein is absent or defective). LDL-cholesterol is viewed against the background of the following elevated from childhood. Untreated, half the observations. males will be dead by 60 years, females 10 years later. The principal consequence is coronary • Hyperlipidaemias are common; 66% of the adult heart, but occasionally also peripheral and UK population have a plasma cholesterol cerebrovascular disease. concentration in excess of 5.2 mmol/1, the lowest concentration generally associated with Most commonly, patients present with raised total cardiovascular risk (in fact, statistical correlation and LDL-cholesterol of lesser degree which results can be shown with cholesterol concentrations from overproduction of VLDL in the liver due to a well below this value). combination of high dietary fat, obesity and • Investigation of hyperlipidaemia must be individual (inherited) susceptibility; it is thus called directed initially at excluding contributory polygenic, is manifest in adult life, with ather- causes, i.e. secondary hyperlipidaemias (see osclerosis occuring early but not as early as with above). None of these should be assumed to be FH. the sole cause, even if present. Long-term Secondary hyperlipidaemias results from: liver and decisions on management should be initiated biliary disease, obesity, hypothyroidism, diabetes, only on the basis at least two fasting blood diet, alcohol excess, renal disease (nephrotic samples. syndrome) and drugs (including etretinate, HIV • All patients (and their spouses/partners, if protease inhibitors, thiazide diuretics, oral contra- appropriate) should receive advice on lifestyle, ceptive steroids, glucorticosteroids, [3-adrenoceptor diet and weight control, which are important antagonists, ciclosporin). components of overall macrovascular risk The most severe hyperlipidaemias usually occur prevention. Dietary treatment of in patients with concurrent conditions, e.g. diabetes hypercholesterolaemia has a modest effect at mellitus with one of the primary hyperlipidaemias. best but diet and weight reduction are more effective for hypertriglyceridaemia. Total fat, especially saturated fat should be reduced (and SITES OF DRUG ACTION partially replaced with mono- and In general, drugs act to reduce the concentration of polyunsaturated fats); spreads containing plant cholesterol within hepatocytes, causing a compen- sterols and stanols, e.g. Benecol, Flora Proactiv, satory increase in low-density lipoprotein-receptors are useful as they can reduce plasma cholesterol (LDL-R) on their surface, and increased uptake of by up to 10%. In some individuals, especially cholesterol-rich LDL particles from the bloodstream those with mixed hyperlipidaemia (elevated (see Fig. 25.1). Statins decrease the synthesis of cholesterol and triglycerides), successful cholesterol and the secretion of VLDL and increase adherence to dietary advice, and weight loss, the activity of hepatic LDL-receptors. Bile-acid- produces very significant improvements. binding resins deplete the bile acid and thus the Patients with remnant lipaemia (RRD cholesterol pool. Fibrates decrease the secretion of hyperlipidaemia) may respond excellently to VLDL and increase the activity of lipoprotein diet, weight loss (and possibly the addition of a lipase, thereby increasing the removal of tri- fibrate). 523
25 H Y P E R L I PI D A E M I AS • Much of the work of lipid clinics is taken up with plasma cholesterol > 5.0 mmol/1 (or LDL attending to multiple interacting risk factors cholesterol > 3.0 mmol/1) who have a history of such as hypertension, diabetes, thyroid disease ischaemic stroke or transient ischaemic attacks, or and smoking, as well as to the lipid abnormality. CHD or diabetes mellitus. • The decision to use lipid-lowering drugs is made More controversial is the extent to which on the basis of the overall absolute CHD risk (see primary prevention (treatment of clinically below and footnote 3), e.g. evidence of existing unaffected patients with moderate elevation of CHD, hypertension, diabetes mellitus, positive cholesterol levels) should include drugs, and family history. The justification is easiest in two whether secondary prevention should ever start cases. Firstly, as primary prevention in the with drugs rather than diet. Dietary treatment can relatively small number of patients who are lower cholesterol levels in committed subjects, and asymptomatic but have significant abnormalities is obviously less costly than drug treatment. of their lipid profiles; patients with FH and Unfortunately numerous studies have shown that remnant lipaemia are at high risk. The decision over any substantial period of time (e.g. one year) to treat is made on the patient's absolute risk as diet has no clinically significant influence on well as the degree of lipid abnormality. Secondly, plasma cholesterol; and the wait for diet to have an as secondary prevention in patients who have effect often results in patients being lost from evidence of CHD (previous myocardial hospital follow-up after their initial myocardial infarction, angina pectoris), cerebrovascular or infarction. Evidence comes from the WOSCOPS peripheral vascular disease or diabetes mellitus. study3 in which pravastatin 40 mg/day and placebo The Scandinavian '4S' Study1 of 4444 patients were compared in 6590 men age 50-70 with LDL with a total cholesterol 5.8-8.0 mmol/1 after a cholesterol 4-6 mmol/1; pravastatin reduced myocardial infarction randomised to receive coronary heart disease (fatal and nonfatal events) simvastatin (median dose 27 mg) or placebo by 31%. The authors estimated that treatment of found that active treatment reduced total 1000 such subjects each year would prevent 20 mortality by 30%, deaths from coronary heart myocardial infarctions. Concerns that primary disease by 42% and recurrent myocardial prevention could have a net adverse outcome (that infarction risk by 34%. The authors estimated cholesterol reduction increased the risk of cancer or that addition of simvastatin to the treatment violent deaths) have been laid to rest by a number regimens of 100 patients with coronary heart of outcome trials. disease would, over 6 years, preserve the lives of The decision to offer a patient primary prophylaxis 4 out of 9 patients who would otherwise die and is influenced by the absolute risk for the individual, would prevent a nonfatal myocardial infarction the potential risks from the statin therapy and costs in 7 of an expected 21 cases. to the health provider. As statins so far have an • Consensus minimum targets for primary and excellent safety record, costs will escalate with a secondary prevention of CHD with statins are a decision to treat lower and lower levels of absolute total plasma cholesterol of < 5 mmol/1 (or a risk. Current UK recommendations suggest treating reduction of 20-25% if the result is lower) or a patients with a CHD risk of at least 30% over LDL-cholesterol of < 3 mmol/1 (or a reduction of 10 years, and an aspiration to treat those with a 15% 30% if that is lower).2 These may be revised in the light of the Heart Protection Study (see p. 486). 2 Wood D et al 1998 Joint British recommendations on • There is evidence that statins protect against prevention of coronary heart disease in clinical practice. stroke. The benefit is seen in patients with Heart 80(Suppl): Sl-29. (British Cardiac Society, British Hyperlipidaemia Association, British Hypertension Society, British Diabetic Association). 1 3 Scandinavian Simvastatin Survival Study Group 1994 WOSCOPS = West of Scotland Coronary Prevention Study. Randomised trial of cholesterol lowering in 4444 patients Shepherd J et al 1995 Prevention of coronary heart disease with coronary heart disease: the Scandinavian Simvastatin with pravastatin in men with hypercholesterolemia. New Survival Study (4S). Lancet 344:1383-1389. England Journal of Medicine 333:1301-1307. 524
DRUGS USED IN TREATMENT 25 10-year risk if resources allow. The large number of (above) together with a fibrate; nicotinic acid additional patients involved by treating at the may be added. lower level raises issues of funding and resources • Familial combined hyperlipidaemia should be (but not the cost-effectiveness of the treatment, treated with dietary modification and weight which is clear). reduction (above) together with a statin; The absolute CHD risk is computed using risk nicotinic acid and/or a fibrate may be added equations based on the Framingham cohort;4 in in resistant cases. reality this means consulting a simple colour-coded • Remnant removal disease (remnant lipaemia) chart armed with data about the patient including responds to dietary modification and weight age, sex, smoking status, pretreatment blood pressure reduction (above) and a fibrate; nicotinic acid and plasma total and LDL cholesterol, and presence and/or a statin may be added where there is or absence of diabetes.4 failure to respond. • Familial or polygenic hypercholesterolaemia Management may proceed as follows: is treated by dietary modification and a statin; 1. Any medical disorder that may be causing an anion-exchange resin and/or a fibrate hyperlipidaemia, e.g. diabetes, hypothyroidism, and/or nicotinic acid may be added. should be treated first. • Familial hypoalphalipoproteinaemia may 2. Dietary adjustment. The following applies to all respond to exercise, weight loss, and nicotinic patients: acid; a fibrate and/or a statin may be added for a small HDL-raising effect but primarily to • Those who are overweight should reduce lower triglycerides and LDL. their total caloric intake, ideally until they have returned to the weight that is appropriate for their height (i.e. body mass index) but realistically with an initial aim of reducing body weight by 10% (see Appetite Drugs used in treatment control p. 696); this automatically assumes reduced intake of alcohol and total (especially STATINS animal) fat. Elevated triglyceride These agents block the rate-limiting enzyme for concentrations may respond particularly well endogenous cholesterol synthesis, hydroxy-methyl- to alcohol withdrawal. glutaryl coenzyme A (HMG CoA) reductase. This • Those who fail to achieve adequate weight results in increased synthesis of LDL-receptors (up- reduction or who are already at their ideal regulation) in the liver and increased clearance of weight should reduce their total fat intake; LDL from the circulation; plasma total cholesterol poly- and monounsaturated fats or oils may and LDL-cholesterol fall to attain a maximum effect be taken partially to substitute for the 1 month after commencing therapy. All statins reduction in animal fats. Reduction in dietary cause a dose-dependent reduction in total and LDL- cholesterol is a much less important element cholesterol although there are differences in their of the diet, but excess egg yolks should be therapeutic efficacy: for example, at their starting avoided. Benecol or Flora Proactiv should be doses LDL-cholesterol falls by average of 17% with added. fluvastatin (20 mg/d), 28% with simvastatin 3. Specific types of hyperlipidaemia are treated thus: (10 mg/d) and 38% with atorvastatin (10 mg/d). At • Familial hypertriglyceridaemia responds best higher doses, e.g. atorvastatin 80 mg/d or possibly to dietary modification and weight reduction simvastatin 80 mg/d, a 50% reduction in LDL- cholesterol is possible. The effects of pravastatin are 4 similar. There is no tolerance to continued admin- The cardiac risk program (actually an Excel spreadsheet) and risk assessment charts can be downloaded from the BHS istration of a statin, and because of a circadian website at http://www.hyp.ac.uk/bhsinfo. They may also rhythm to LDL-receptor synthesis, statins are a little be found in the British National Formulary. more effective if given in the evening rather than in 525
25 H Y P E R L I PI D A E M I AS the morning. Their efficacy in both primary and cholesterolaemia, alone or with anion exchange secondary prophylaxis of hypercholesterolaemia resins or (with care) with statins. There is evidence is probably a class effect, although long-term of varying efficacy among the drugs both in outcome studies may in time differentiate between cholesterol-lowering and in additional beneficial the drugs. On current information, with no clear effects, such as reduction in blood fibrinogen and advantages or disadvantages between the different urate concentration; the clinical significance of statins, the choice of agent to achieve the suggested these differences is not yet known. total or LDL-cholesterol levels3 is heavily influenced Fibric acid derivatives are well absorbed from by their relative cost, and the dose likely to achieve the gastrointestinal tract, extensively bound to the target. (See also the Heart Protection Study, p. 486.) plasma proteins and excreted mainly by the kidney Statins are well absorbed after administration as unchanged drug or metabolites. They are contra- orally, and are metabolised in the liver. They are indicated where hepatic or renal function is severely well tolerated, the commonest adverse effect being impaired (but gemfibrozil has been used in uraemic transient, and usually minor abnormality of liver and nephrotic patients without aggravating de- function tests in some 1% of patients. Asympto- terioration in kidney function). Rarely, fibric acid matic elevation of muscle enzymes (creatine phos- derivatives may induce a myositis-like syndrome; phokinase, CPK) and myositis (with a generalised the risk is greater in patients with poor renal muscle discomfort) occur more rarely,5 but is more function, and in those who are also receiving a statin. frequent when statins are combined with other anti- Fibrates enhance the effect of co-administered oral hyperlidaemic drugs such as fibrates and nicotinic anticoagulants. acid; patients should be counseled about myositis when these drugs are co-administered. Myositis is also more likely with co-administered anti-HIV protease inhibitors, and with drugs that interfere Anion-exchange resins with metabolism of some statins, e.g. ciclosporin. (bile acid sequestrants) FIBRIC ACID DERIVATIVES (FIBRATES) Colestyramine is an oral anion-exchange resin,8 which binds bile acids in the intestine. Bile acids are The class includes bezafibrate, ciprofibrate, fenofibrate formed from cholesterol in the liver, pass into the and gemfibrozil; the original fibrate, clofibrate, is gut in the bile and are largely reabsorbed at the obsolete. The drugs partly resemble short-chain terminal ileum. The total bile acid pool is only 3-5 g fatty acids and increase the oxidation of these acids but, because such enterohepatic recycling takes place in both liver and muscle. In the liver, secretion of 5-10 times a day, on average 20-30 g of bile acid are triglyceride-rich lipoproteins falls, and in muscle delivered into the intestine every 24 hours. Bile the activity of lipoprotein lipase and fatty acid acids bound to colestyramine are lost in the faeces uptake from plasma are both increased. Fibrates act and the depletion of the bile acid pool stimulates through a nuclear transcription factor (PPARa) conversion of cholesterol to bile acid: the result is a which up-regulates expression of LDL-cholesterol and apolipoprotein A-l genes, and down-regulates expression of the apolipoprotein C-ll gene. The 5 result is that plasma triglyceride declines by In 30 641 patients in 5 major statin trials, myositis (serum creatinine kinase x 10 normal) occurred in 30 (control 29) and 20-30% and cholesterol by 10-15%; associated with rhabdomyolysis in 2 (control 2). Farmer J A 2001 Lancet 358: this is a rise in the 'protective' HDL-cholesterol. The 1383-1385. 6 latter effect may have contributed to the reduction Frick M H et al 1987 New England Journal of Medicine 317: in nonfatal myocardial infarction with gemfibrozil 1237-1245. 7 in both the Helsinki Heart Study6 and more recent Rubins H B et al 1999 New England Journal of Medicine 341:410-418. VA-HIT trials.7 They are the drugs of choice for 8 The resins consist of aggregations of large molecules mixed hyperlipidaemia (elevated cholesterol plus carrying a fixed positive charge which therefore bind triglycerides) but may be used in hyper- negatively charged ions (anions). 526
NICOTINIC ACID AND DERIVATIVES 25 fall in intracellular cholesterol in hepatocytes, and levels of Lp(a), the modest reduction of which an increase (up-regulation) in both LDL-receptors (achieved by nicotinic acid) may contribute to overall and cholesterol synthesis. The former has the protection against the complications of atheroma. predominant influence on plasma LDL-cholesterol, which falls by 20-25%. In many patients there is OTHER DRUGS some compensatory increase in hepatic triglyceride output. Anion exchange resins therefore may be Alpha-tocopherol acetate (vitamin E) has no effect used first line for hypercholesterolaemia but not when on lipid levels but is a powerful antioxidant. Con- there is significant hypertriglyceridaemia, which siderable evidence points to oxidation of LDL as an may be aggravated in such patients. The powder is essential step in the development of atheroma, and taken mixed with water or orange juice and shaken therefore interest has centred on the role of either in a closed container. endogenous or therapeutic vitamin E in prevention About half the patients who take colestyramine of atheroma. Reduced concentrations of vitamin E experience constipation and some complain of in both blood and fat (vitamin E is a fat soluble anorexia, abdominal fullness and occasionally of vitamin) are found in inhabitants of countries with diarrhoea; these effects are dose-related but may a high prevalence of ischaemic heart disease, and limit or prevent its use. Because the drug binds (within these countries) in patients who develop anions, drugs such as warfarin, digoxin, thiazide ischaemic heart disease. A high dose reduced by diuretics, phenobarbitone and thyroid hormones half the risk of myocardial infarction in 2000 patients should be taken 1 h before or 4 h after colesty- with angina and positive coronary angiogram.9 ramine to avoid impairment of their absorption. However most other studies have failed to confirm Colestipol is similar to colestyramine. this finding and there is no indication at present for routine prescribing of oc-tocopherol in the treatment or prevention of atherosclerosis. Nicotinic acid and derivatives The commonest and most important hyperlipidaemia Nicotinic acid acts as an antilipolytic agent in is hypercholesterolaemia, which is one of the major adipose tissue, reducing the supply of free fatty risk factors for coronary heart disease. acids and hence the availability of substrate for Most treatment works by reducing the intracellular hepatic triglyceride synthesis and the secretion of concentration of cholesterol in hepatocytes, leading to compensatory increase in low density lipoprotein VLDL. Nicotinic acid lowers plasma triglyceride (LDL) receptors on their surface, and increased and cholesterol concentrations, and raises HDL- uptake of cholesterol-rich LDL particles from the cholesterol. Flushing of the skin (preventable by bloodstream. low-dose aspirin) and gastrointestinal upset com- The most effective drugs are the statins, which inhibit monly occur; the unpleasantness may be dimin- the rate-limiting step in cholesterol synthesis. ished by gradually building up the oral dose over Additional agents may be required for mixed or 6 weeks and in time tolerance develops. Rarely severe hyperlipidaemia. In outcome trials with these drugs, reductions in there is major disturbance of liver function. blood cholesterol by 25-35% is associated with a 35—45% reduction in risk of coronary heart disease. Acipimox is better tolerated than nicotinic acid, The main indications for their use are in patients with has a longer duration of action but is less effective. even slight elevations of cholesterol (> 5mmol/l) after Unlike nicotinic acid, it does not reduce circulating a myocardial infarction or any other macrovascular event, in patients with familial hypercholesterolaemia, and in patients with a significant absolute CHD risk, 9 Stephens N G et al 1996 Randomised controlled trial of especially where there is a family history of premature vitamin E in patients with coronary disease: Cambridge CHD. heart antioxidant study. Lancet 347: 781-786. 527
25 H Y P E R L I P I DAEM IAS Omega-3 marine triglycerides (Maxepa) contain Hooper L et al 2001 Dietary fat intake and prevention the triglyceride precursors of two polyunsaturated of cardiovascular disease: systematic review. fatty acids (eicosapentaenoic acid and docosa- British Medical Journal 322: 757-763 hexaenoic acid) derived from oily fish. They have Jonsson B 2001 Economics of drug treatment: for no place in treating hypercholesterolaemia. Some which patients is it cost-effective to lower patients with moderate to severe hypertrigly- cholesterol? Lancet 358:1251 ceridaemia may respond to oral use, although LDL- Knopp R H 1999 Drug treatment of lipid disorders. cholesterol may rise. There is an associated New England Journal of Medicine 341: 498-511 90 calorie per day energy load. Mansell P, Reckless J P D 1991 Garlic. British Medical Journal 303: 379 Orlistat, a weight-reducing agent, lowers the Oliver M F 2000 Cholesterol and strokes. British glycaemia of diabetes mellitus to a degree that Medical Journal 320: 459^60 accords with the weight loss, and improves Primatesta P, Poulter N 2000 Lipid concentrations and hyperlipidaemia to an extent greater than would be the use of lipid lowering drugs: evidence from a expected (see p. 696). Since it is a lipase inhibitor national cross sectional study. British Medical there is a risk of steatorrhoea and malabsorption of Journal 321:1322-3125 fat-soluble vitamins A, D and E. Sacks F M, Pfeffer M A, Moye L A et al 1996 The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. New England Journal of Medicine 335: GUIDETO FURTHER READING 1001-1009 Caro J et al 1997 The West of Scotland coronary White H D et al 2000 Pravastatin therapy and the risk prevention study: economic benefit analysis of of stroke. New England Journal of Medicine 343: primary prevention with pravastatin. British 317-326 Medical Journal 315:1577-1582. 528

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