special article managementofhyperlipidaemia: guidelines

Postgrad Med J (1993) 69, 359- 369 i) The Fellowship of Postgraduate Medicine, 1993

Special Article

Management of hyperlipidaemia: guidelines of the BritishHyperlipidaemia Association

D.J. Betteridge, P.M. Dodson', P.N. Durrington2, E.A. Hughes3, M.F. Laker4,D.P. Nicholls5, J.A.E. Rees6, C.A. Seymour7, G.R. Thompson8, A.F. Winder9,P.H. Winocour'° and R. Wray"Department ofMedicine, University College London Medical School London; 'East Birmingham NHSTrust, Birmingham; 2Department ofMedicine, University ofManchester; 3Sandwell District GeneralHospital, West Bromwich; 4Department ofMedicine, University ofNewcastle upon Tyne; 'Royal VictoriaHospital, Belfast; 6University Hospital of Wales, Cardiff; 7St George's Hospital Medical School, London;8MRC Lipoprotein Team, Hammersmith Hospital, London; 9Department ofChemical Pathology, RoyalFree NHS Trust and School ofMedicine, London; '0Department ofMedicine, University ofNewcastle uponTyne; and "'Department ofMedicine, Hastings and RotherNHS Trust, UK

Introduction

There have been considerable advances in theunderstanding of plasma cholesterol and tri-glyceride metabolism and the lipoprotein particleswhich transport these important lipids. Epidemi-ological evidence linking plasma cholesterol tocoronary heart disease (CHD) risk has been streng-thened by the findings ofthe prospective part oftheMultiple Risk Factor Intervention study.' Further-more, the study of populations with plasmacholzsterol concentrations much below those seenin Western industrialized societies has pointed to acontinuous gradient of CHD risk with increasingplasma cholesterol.2 The value of measurement ofindividual plasma lipoproteins in defining CHDrisk more closely is now well established. Lowdensity lipoprotein (LDL) cholesterol, is the majortransporter of plasma cholesterol, and largelyaccounts for the relationship between totalcholesterol and CHD.3 In contrast, high densitylipoprotein (HDL), the other major cholesterol-rich lipoprotein, is inversely related to CHD.4 Therole of plasma triglyceride as an independent riskfactor for CHD remains controversial,' althoughthere is no doubt of the atherogenicity of sometriglyceride-rich lipoproteins, namely chylomicronremnant particles and intermediate density lipo-proteins (IDL). Very high concentrations ofplasma triglycerides, reflecting the accumulation ofchylomicrons which transport exogenous fat fromthe intestine, are associated with risk of pan-creatitis.

Justification for attributing a causal role forLDL cholesterol in atherosclerosis has receivedconsiderable support from the outcome of bothprimary and secondary CHD prevention trialsemploying lipid modifying therapy.6'7 Althoughindirect evidence also points to the benefits ofincreasing plasma HDL concentrations anddecreasing plasma triglyceride concentration, thebulk of evidence implicates LDL as the majoratherogenic particle. Recent angiographic studiessuggest that radical alteration ofplasma lipids andlipoproteins by lifestyle, pharmacological and sur-gical measures can retard the progression ofatherosclerotic lesions, delay the appearance ofnew lesions and in some patients lead to lesionregression8'-2 (Table I).Advances in the cell and molecular biology of

lipoprotein cell interactions have provided newinsights into the mechanisms ofatherosclerosis andmuch is now known about the regulation ofplasmalipoprotein levels. The central role of the liver inthese processes has been identified. The seminalwork of Goldstein and Brown,'3 which identifiedthe LDL receptor pathway, provided the found-ation for major advances in this field. This workhas not only enabled the identification of geneticabnormalities underlying some of the primaryhyperlipidaemias but also has led to an under-standing of the mechanism of action of somelipid-modifying drugs and the logical developmentof new therapeutic agents.

Various consensus committees have reviewedrecent developments and have furnished guidelinesfor optimal lipid and lipoprotein concentrationsfor the population as a whole in an attempt toreduce the burden of CHD.4" 5 In addition,

Correspondence: D.J. Betteridge, B.Sc., Ph.D., M.D.,F.R.C.P., Department of Medicine, University CollegeLondon Medical School, The Middlesex Hospital,Mortimer Street, London WIN 8AA, UK.Accepted: 11 January 1993

copyright. on June 11, 2022 by guest. P

rotected byhttp://pm

j.bmj.com

/P

ostgrad Med J: first published as 10.1136/pgm

j.69.811.359 on 1 May 1993. D

ownloaded from

http://pmj.bmj.com/

360 D.J. BETTERIDGE et al.

Table I Differences between changes in patients in treatment and controlgroups in angiographic trials of lipid-lowering therapy

LDL-C HDL-C Prog RegA% A% A% A%

NHLBIType II8 (Ch) -20 + 6 -17 0

CLAS9Co+NA -36 +35 -22 + 14

FATSI'L+Co -39 + 11 -25 +21NA + Co -25 + 38 -21 + 28

UCSF"Co+NA±L -28 +28 -21 +20

STARS'2Diet - 13 0 - 31 + 34Diet + Ch -33 - 4 -34 + 29

Ch = cholestyramine; Co = colestipol; NA = nicotinic acid; L = lovastatin;NHLBI = National Heart Lung and Blood Institute; CLAS = CholesterolLowering Atherosclerosis Study; FATS = Familial Atherosclerosis TreatmentStudy; UCSF = University College San Francisco; STARS = St Thomas'Atherosclerosis Regression Study; Prog = progression; Reg = regression;LDL-C = LDL cholesterol; HDL-C = HDL cholesterol.Reproduced from Thompson, G.R. Progression and regression of coronaryartery disease. Curr Opinion Lipidol 1992, 4, 263-267, with permission.

guidelines for the identification by screening andtreatment of hyperlipidaemia have been pub-lished.6"7 This review provides the current consen-sus of the views of the British HyperlipidaemiaAssociation, which consists ofphysicians and otherhealth professionals involved in the management oflipid disorders. Hopefully general physicians,whether in hospital or the community, will find it ofbenefit in guiding their own practice.

Screening for hyperlipidaemia

Hyperlipidaemic individuals may be identified byplasma lipid measurements performed becausethey have clinically overt vascular disease. Othersmay have the clinical stigmata of hyperlipidaemia(premature arcus, xanthelasma, xanthomata) andmany will be identified in screening programmes.The question of which individuals should haveplasma lipid measurements performed has led tomuch debate within the profession. Certain coun-tries such as the United States of America haveinstigated well-publicised cholesterol educationprogrammes designed to ensure that every adulthas their cholesterol measured by opportunisticscreening.'7 Although it is possible that othercountries will adopt similar strategies in the future,a strategy of selectively screening only high riskindividuals seems to prevail in the UK. Thepresence of hyperlipidaemia should be sought inindividuals with clinically overt vascular disease;

with the clinical stigmata of hyperlipidaemia; witha strong family history of premature CHD orhyperlipidaemia; and those with other risk factorsfor CHD such as hypertension, diabetes mellitusand obesity. It is recognized that not all individualswith significant hyperlipidaemia will be identifiedby these measures and more general screening maybe appropriate on an opportunistic basis, asresources permit.For general screening purposes a random, non-

fasting plasma cholesterol measurement is appro-priate. If this falls outside our previously publishedguidelines,'8 a full lipid profile including plasmacholesterol, plasma triglyceride and HDL-chol-esterol should be obtained following an overnightfast (12-14 hours). LDL-cholesterol can then becalculated using the Friedewald equation:'9

LDL cholesterol (mmol/l) =Total cholesterol - HDL cholesterol trgl2ceride(applicable when total triglyceride< 4.5 mmol/l).

Measurements are best performed in hospitalchemical pathology departments. Care is requiredin venepuncture techniques as prolonged venousocclusion may increase cholesterol concentrationssignificantly. Posture also affects cholesterol levelswith a significant fall on sitting and a further fall onlying down. It is recommended therefore that bloodshould be taken with minimal venous occlusionafter the subject has been sitting for 10 minutes.Office-based machines employing dry chemistry



j.bmj.com

/P


j.69.811.359 on 1 May 1993. D

ownloaded from

http://pmj.bmj.com/

GUIDELINES IN MANAGEMENT OF HYPERLIPIDAEMIA 361

technology have a role in screening as long as theinstrument operator has received proper trainingand appropriate quality assurance is performed.However, it is inappropriate to make managementdecisions based solely on these tests.

In high risk groups it is advisable to perform afull fasting profile in the first instance as abnor-malities of triglyceride and HDL cholesterol con-centrations may otherwise be missed. Long-termplans should not be made without at least twomeasurements. An important practice point is thatmany intercurrent illnesses, including acutemyocardial infarction and operative procedures,may depress plasma cholesterol levels and lead tofalsely low readings. Some patients with hyper-lipidaemia will require tests beyond the scope ofroutine laboratories. These are available inspecialist lipid centres.20

Diagnosis of hyperlipidaemia

Once significant hyperlipidaemia has beenidentified it is important to diagnose the causewhere possible. It is convenient to determinewhether hyperlipidaemia is secondary to otherconditions or is a primary abnormality. The prin-cipal secondary causes are shown in Table II.Diagnosis will require attention to clinical symp-toms and signs and additional biochemical testssuch as blood glucose, thyroid function, renal andliver function should be performed routinely.

If secondary causes are excluded it is presumedthat a primary hyperlipidaemia is present. Asknowledge of the metabolic and genetic abnor-malities underlying these conditions has accumu-lated it has become possible to classify lipid

disorders by genotype as opposed to laboratoryphenotype. There is no doubt that lipoproteinphenotyping introduced in the early 1970s andadopted by the WHO2' gave a major impetus to theunderstanding of the hyperlipidaemias. However,this was a laboratory classification and has obviousdrawbacks in the sense that it does not point toaetiology; for example, type Ila hyperlipidaemia(increased LDL cholesterol) can be the result ofhypothyroidism or familial hypercholesterolaemia.For convenience the different lipoprotein pheno-types are shown in Table III which lists the morecommon primary hyperlipidaemias. Diagnosisrequires consideration of the clinical symptomsand signs, family history of CHD and hyper-lipidaemia, and laboratory assessment. This diag-nostic process is important as primary disorders areassociated with varying prognoses and differingtreatments.

Treatment

The main aim of treatment in the majority ofhyperlipidaemic patients is to reduce the risk ofdevelopment of premature vascular disease(primary prevention) or the occurrence of furthervascular events in those with clinical vasculardisease (secondary prevention). Treatment isindicated in individuals with severe hypertri-glyceridaemia primarily to prevent pancreatitis.

It cannot be overemphasized that treatment ofhyperlipidaemia in the context ofCHD prevention,either primary or secondary, should be part of themanagement of overall vascular risk. It is wellestablished from prospective studies that risk fac-tors interact to multiply the risk of CHD. It is

Table II Secondary hyperlipidaemias

Hormonalfactors Liver diseasePregnancy Primary biliary cirrhosisDiabetes mellitus Extrahepatic biliary obstructionHypothyroidism

Nutritional factors IatrogenicObesity High dose thiazide diuretics*Anorexia nervosa P-Adrenergic receptor antagonists*

which lack a-blocking effects,intrinsic sympathetic activityor vasodilator properties

Alcohol abuse CorticosteroidsExogenous sex hormones

Renal dysfunction RetinoidsNephrotic syndromeChronic renal failure

*For a short resume of antihypertensive drugs and lipids, see Betteridge, D.J.Questions about cholesterol. 'Lipid-friendly' antihypertensives. Postgrad MedJ 1992, 68: 881-882.



j.bmj.com

/P


j.69.811.359 on 1 May 1993. D

ownloaded from

http://pmj.bmj.com/


co.0 0

Cd Cd m 0(U

I cd cd cuCd 0-0 E

0 0 0Cd x4= IV) +-- cts -4--- Cdcd4-A m cdcd E

rA Cd E r. X=x 0 x 4-bCd Cd cd.0 W., - X 'A E 0 0.

o o rA Cd cd cd-a o 04 0Cr- O 2 E Psd Cd m cdX $20 W

4-W

A 00 04- 4-

04 0 0

> u urACIS

CIS

A:L, C.4C>V V V

as>b 00 Ob Ob Ob Ob Ob Ob C-i C5

A VCd 0 0

rA rA

W,) W') tfj I 0 00-0W" .6 r-: r-: -6 a, Z v

0 0 0 0 0 0 0

u u u u u u u

3t >qJ Cd C13 Cd OZ 0-4 0--4 1-. *_4 >Q, 0--4 P.-O 0

(A0

Cd

CdCd Cd co Cd Cd-,a

rACdCd0 0 Cd

r COW 0 W 0

0tn O.. 0 00 0 Cd 0 W W

x 0 00 04 0. 0

u = 0 0 WW > Cd 0

cd WU. = cdCdO. 0

4-- Cd CdC-d C-d C-d 0 0Cd

0 00 Cd Cd Cd 0 Cd0.4 4-0 WL, "4 04 "O u

therefore mandatory not to regard a particularCHD risk factor in isolation and attention shouldbe given to the modification, where possible, ofother coexisting factors in each patient, particular-ly smoking and raised blood pressure.The treatment of secondary hyperlipidaemia

involves attention to the underlying cause (seeTable II). However, in certain secondary causes ofdyslipidaemia, particularly diabetes mellitus andrenal disease, significant lipid abnormalities maypersist despite best endeavours at management ofthe primary disorder. The risk ofvascular disease ishigh in these individuals and specific lipid-loweringtherapy may be indicated. A detailed discussion ofthe treatment of these patients is beyond the scopeof this article and the reader is referred to recentreviews of the topic.22'23The goals oftherapy in terms ofplasma lipid and

lipoprotein concentrations differ according towhether primary or secondary prevention is theobjective. In the former context a total cholesterol< 5.2 mmol/l and LDL cholesterol < 4.1 mmol/lare appropriate. In patients with clinical vasculardisease data from regression studies suggest thatlower target values are necessary. It has beensuggested and is the view of the authors that in thisimportant patient group the appropriate targetLDL cholesterol concentration should be <3.4mmol/l.`7

Lifestyle measures

The cornerstones of treatment of hyperlipidaemiaare nutritional and other lifestyle measures. Thesemeasures are often successful in individuals withmoderate polygenic hyperlipidaemia where hypo-lipidaemic drug therapy is seldom indicated. Life-style management should include advice on weightreduction in the obese, reduction of excessivealcohol consumption, cessation ofsmoking and theencouragement ofappropriate physical activity. Inaddition to the overall reduction of calories whereappropriate, dietary intake of fat is reduced to nomore than 30% of total calories. Dietary saturatedfat raises plasma cholesterol levels and potentiatesthe hypercholesterolaemic effect of dietary choles-terol. It is therefore important to reduce thesaturated fat content of the diet to less than 10% ofcalories and the dietary intake ofcholesterol below300 mg/day'6 (see Table IV).

Nutritional counselling should be individualizedwhere possible and success is more likely wherecounselling of the patient together with the patient'spartner is undertaken. The provision of adequatedietetic support, particularly in the primary caresituation, remains a problem and the delivery ofappropriate nutritional and lifestyle counsellingwill require optimum use of the limited profes-



j.bmj.com

/P


j.69.811.359 on 1 May 1993. D

ownloaded from

http://pmj.bmj.com/


Table IV Cholesterol-lowering diet

% total calories

Total fat < 30Saturated fat < 10Monosaturated fat 10Polyunsaturated fat 10

Carbohydrate 50-60Protein 10-20Fibre 35 g/dayCholesterol < 300 mg/day

sional dietetic advice available. In primary care asuitably trained practice nurse may help fulfil thisimportant role. The effectiveness of the delivery ofnutritional advice and patient motivation willlargely determine the success of treatment andobviate the inappropriate prescribing of hypo-lipidaemic drugs. Dietary measures should bepursued for at least 3-6 months before contem-plating lipid-lowering drug therapy.

Lipid-modifying drugs

It is convenient to consider these agents under threemain categories; drugs which lower plasmacholesterol alone, drugs which lower both plasmacholesterol and triglyceride, and drugs which lowerplasma triglyceride alone. A detailed review of themechanisms ofaction ofhypolipidaemic agents hasbeen published recently.24

Drugs which lower plasma cholesterol alone

Anion-exchange resins

These compounds which have been available forclinical use for over 20 years are non-absorbablebasic anion-exchange resins which are hydrophilicbut insoluble in water. After oral administrationthe resins bind to bile acids in the intestine preven-ting their reabsorption. In response more bile acidsare synthesized by the liver from cholesterol, whichis acquired from the plasma through increasedLDL receptor activity. Cholesterol synthesis is alsoincreased which partially offsets the cholesterol-lowering effect ofresins. Nevertheless, in compliantpatients these drugs can reduce LDL cholesterollevels by 20-30%, with a slight increase in HDLcholesterol. Plasma triglycerides actually increasewith resin therapy, however.

Currently two resins are available, choles-tyramine and colestipol. They are in granular formand need to be mixed with water or other fluid priorto ingestion. Compliance can be a problem as the

resins are not only inconvenient to take but pro-duce gastrointestinal side effects of bloating,flatulence and constipation. These side effects canbe ameliorated by a low dosage regimen of onesachet twice daily. Resins may interfere with theabsorption of other drugs and there is a theoreticalrisk of malabsorption of fat-soluble vitamins butclinically this is rarely a problem. Folate levelsshould be monitored in pregnant women and inchildren.

Probucol

Probucol is a lipophilic bis-phenol compoundstructurally unrelated to the other lipid-loweringdrugs. It produces moderate reductions in plasmacholesterol (15%) and its maximal effect maytake up to 3 months to occur. Probucol reducesHDL cholesterol as well as LDL cholesterol andfor this reason has not been considered as first-linetherapy. However, clinically, probucol isassociated with mobilization of tissue cholesterolfrom skin and tendon xanthomata.

There is increasing interest in the role ofoxidizedLDL in atherogenesis. Probucol has antioxidanteffects which in vitro and in animal studies inhibitLDL oxidation and atherogenesis.25 However,there is as yet no evidence in man of an anti-atherogenic effect of the drug.Probucol is generally well tolerated. Prolonga-

tion of the Q-T interval on the electrocardiogramhas been described but the clinical significance ofthis is unclear. The drug accumulates in adiposetissue and may persist for many weeks after the lastdose. For this reason the drug should be stopped inwomen at least 6 months prior to attemptedconception.

Drugs which lower plasma cholesterol andtriglyceride

Fibric acid derivatives

Several fibrates are available for clinical use inBritain: bezafibrate, ciprofibrate, fenofibrate andgemfibrozil. On the whole these agents are moreeffective than the parent compound, clofibrate,which is now obsolete owing to the associatedincreased risk of gallstones. The exact mode(s) ofaction of the fibrates remain to be determined butthe main effect is to stimulate clearance oftriglyceride-rich lipoproteins.The major effect of fibrate drugs is to reduce

plasma triglyceride levels (; 50%). HDLcholesterol levels increase (t 15-20%) withtherapy but effects on plasma cholesterol and LDLcholesterol vary depending on the type of hyper-lipidaemia. In patients with isolated hyper-



j.bmj.com

/P


j.69.811.359 on 1 May 1993. D

ownloaded from

http://pmj.bmj.com/


cholesterolaemia or mixed hyperlipidaemia fibratetherapy is associated with reductions of plasmaLDL cholesterol of 10-25%. On the other hand, inpatients with isolated hypertriglyceridaemia (typeIV), where LDL concentrations tend to be low,LDL cholesterol may increase with fibrate therapy.Apart from minor gastrointestinal symptoms the

fibrates are generally well tolerated and moreserious side effects are rare. Occasionally, abnor-malities of liver function occur and myopathy hasbeen reported especially in subjects with impairedrenal function. The fibrates interact withanticoagulants increasing anticoagulant activity.The long-term safety of fibrates has been ques-

tioned following the findings of the WHO primaryprevention trial of cholesterol-lowering in the1970s which used clofibrate.26 The mortality ratefrom non-cardiac causes was increased in theclofibrate-treated group due to an increasedincidence of malignancy and gallstone relateddisorders, including cholecystectomy. Such effectswere not observed in the Helsinki Heart Studywhere the drug used was gemfibrozil."

Nicotinic acid

In pharmacological doses nicotinic acid (3-6 g/day) lowers plasma cholesterol and plasma tri-glyceride and increases HDL cholesterol. Themechanism of action of the drug is not fullyunderstood. It is unlikely that the well-demonstrated inhibition of the breakdown ofadipose tissue triglyceride fully explains its effect.

Nicotinic acid is poorly tolerated because offlushing and gastrointestinal symptoms; these canbe overcome to a certain extent by starting the drugin low dosage. Tachyphylaxis to the flush developsbut is lost ifa dose is missed. The flush appears to beprostaglandin mediated as it is partly blocked byaspirin. Other side effects include a pruritic rashand hyperpigmentation. Nicotinic acid mayexacerbate gout and glucose intolerance and pro-duce abnormalities of liver function. Two nicotinicacid analogues, acipimox and nicofuranole,Bradilan, are available for clinical use in the UK.These agents are generally better tolerated thannicotinic acid, both in terms of symptoms andmetabolic side effects, and acipimox does notimpair glucose tolerance. The analogues are not aseffective in modifying plasma lipid levels asnicotinic acid itself.28

HMG-CoA reductase inhibitors

The introduction ofthis new, exciting class ofdrugsinto clinical practice represents a major advance inthe therapy of hyperlipidaemia.29 There are cur-rently two members of this class available in theUK, pravastatin and simvastatin. These agents are

specific competitive inhibitors of the microsomalenzyme HMG-CoA reductase which catalyses theconversion of HMG-CoA to mevalonate, a majorrate-determining step in cholesterol synthesis. Theyare very potent inhibitors of the enzyme with K,values ranging from 0.2 to 2.2 x 10-9 M comparedto the Km of the natural substrate which is4 x 1O0-M. The liver is the major organ forcatabolism of LDL and the activity of specifichepatic receptors which bind and take up LDLlargely determines plasma LDL concentrations.The inhibition of hepatic cholesterol synthesis bythese drugs stimulates the expression of LDLreceptors resulting in increased uptake ofLDL anda reduction in its plasma concentration. LDLproduction is also decreased. Very low densitylipoprotein (VLDL) is catabolised by the enzymelipoprotein lipase resulting in VLDL remnantswhich can either be taken up by hepatic LDLreceptors or further catabolised to LDL. IncreasedLDL receptor activity as a result of HMG-CoAreductase inhibition will therefore result in in-creased direct hepatic uptake of VLDL remnantsand consequent decreased conversion to LDL.As expected from their mode of action, these

drugs have a major impact on plasma cholesterollevels through the reduction of LDL cholesterol.This effect is dose-dependent and maximal after 4weeks of therapy. Reductions of 30-40% inplasma LDL cholesterol are commonly achieved.M'odest reductions in plasma triglycerides(10-20%) are also observed together with a smallincrease in HDL. The reduction in LDLcholesterolis paralleled by a reduction in apoprotein B, themajor protein component of LDL.The HMG-CoA reductase inhibitors are con-

venient to take as once-daily dosage and aregenerally well tolerated with few adverse effects.Unlike triparanol, an inhibitor of cholesterol syn-thesis on trial in the 1960s, there is no evidence ofany deleterious effects ofthe HMG-CoA inhibitorson the lens. Rarely, elevated liver transaminases areobserved but these abnormalities are rapidly rever-sible when the drugs are discontinued. Potentiallythe most important side effect is myositis withmarked elevation of plasma creatine kinase. Mostof the reported cases have been in patients takingthe drugs with other agents particularly cyclo-sporine, nicotinic acid and gemfibrozil or inpatients with significant hepatic disease. The fre-quency of myositis is very rare.

There is no evidence of clinically significanteffects of the drugs on other products of thecholesterol synthetic pathway such as steroid hor-mones, ubiquinones and dolichols.



j.bmj.com

/P


j.69.811.359 on 1 May 1993. D

ownloaded from

http://pmj.bmj.com/


Drugs which lower plasma triglyceride alone

Omega-3fatty acids

Omega-3 fatty acids when taken in large amountsappear to reduce hepatic VLDL synthesis. Maxepa(a preparation containing eicosapentaenoic acidand decosahexaenoic acid) is licenced in the UKand is useful for the treatment of severe hypertri-glyceridaemia. In the recommended dosage (10 g/day) Maxepa does not reduce plasma cholesterolconcentrations and in more modest hypertrigly-ceridaemia LDL concentrations may even increasewith treatment.

When to use drugs and which drugs to use

Lipid-lowering drug therapy should not be under-taken lightly as therapy is usually lifelong and itsrisk/benefit ratio should be carefully considered.The important clinical question is does theanticipated benefit of drug therapy in terms ofreduction ofCHD risk outweigh the imposition oflong-term drug therapy with the potential forunpredicted adverse effects? Drug therapy shouldbe reserved for those patients at high risk wherelifestyle measures have failed to result in acceptableplasma lipid levels. In general terms, those patientswith clinical vascular disease, those with severehyperlipidaemias (familial hypercholesterolaemia,familial combined hyperlipidaemia and remnantparticle disease) and those with other major riskfactors are more likely to require drug therapy. Aguide to priorities for therapy is given in Table V.

The choice of hypolipidaemic drug will dependmainly upon the nature and severity of the lipiddisorder to be treated, as shown in Table VI. Forisolated moderate hypercholesterolaemia first lineagents would be the anion exchange resins. In thissituation relatively small doses of the resins will beeffective. Fibrates can be tried if patients areintolerant of resins. In severe hypercholestero-laemia due to increased LDL cholesterol, as seen infamilial hypercholesterolaemia, the HMG-CoAreductase inhibitors are effective first line agents.Despite their excellent efficacy in reducing LDLcholesterol (Z 30-40%) the LDL concentrationmay not reach acceptable levels because of the veryhigh pretreatment value. In this situation con-comitant low dose resin therapy will have addi-tional benefit.

In children and women of child-bearing ageresins are very useful agents because they are notabsorbed. Women treated with other lipid-lowering drugs should be advised to stop themedication prior to conception. More informationis required on pharmacological therapy of childrenwith heterozygous familial hypercholesterolaemia.Until more is known, resins remain the drugs ofchoice in this situation.

In the patient with raised cholesterol and tri-glycerides where the predominant abnormality ishypercholesterolaemia, the fibrates can be used asfirst line agents. In some patients cholesterol mayremain high despite a satisfactory reduction inplasma triglyceride. The addition of low dose resintherapy is a useful option here. The HMG-CoAreductase inhibitors are also useful in these patientsas single therapy. However, plasma triglycerides

Table V Priorities and action limits for lipid-lowering drug therapy in diet-resistantsubjects*

Total cholesterol LDL cholesterolPriority Subject category (mmol/l) (mmol/l)

First Patients with existing CHD, >5.2 >3.4or post-CABG, angioplastyor cardiac transplant

Second Patients with multiple risk > 6.5 > 5.0factors or genetically determinedhyperlipidaemia, e.g. FH

Third Males with asymptomatic > 7.8 > 6.0hypercholesterolaemia

Fourth Postmenopausal females > 7.8 > 6.0with asymptomatic and HDL ratiohypercholesterolaemia < 0.2*

*Aim of cholesterol lowering should be an LDL cholesterol < 3.4 mmol/l in the presence ofCHD and < 4.1 mmol/l in the absence of CHD.



j.bmj.com

/P


j.69.811.359 on 1 May 1993. D

ownloaded from

http://pmj.bmj.com/


Table VI Drug therapy of hyperlipidaemia

Lipid LDL Degree of Drug regimenabnormality cholesterol hyperlipidaemia 1st choice 2nd choice

Type IlaCholesterol + 4 Moderate Resin Fibrate

Severe Statin ProbucolResin + statin

Type IIbCholesterol + 4 Moderate Fibrate NATriglyceride t

Severe Resin + fibrateor statin

Type IIICholesterol 4 N or 4, Usually severe Fibrate StatinTriglyceride 4

Type IVTriglyceride 4 N Moderate Fibrate NACholesterol Nor 4 Severe Fibrate + NA

Type VTriglyceride 4 N Always severe Fibrate + NA Fish oilCholesterol 4

Severe hyperlipidaemia is defined as a serum cholesterol > 7.8 or fasting triglyceride >4.5 mmol/l,especially if they occur together or are accompanied by an HDL cholesterol < I mmol/l.Resin = cholestyramine or colestipol; Fibrate = bezafibrate, ciprofibrate, fenofibrate,gemfibrozil; Statin (HMG-CoA reductase inhibitor) = pravastatin, simvastatin; NA (nicotinicacid or derivative) = acipimox; N = normal.

may remain high. The addition of a fibrate ornicotinic acid to a statin to reduce plasma tri-glycerides in these patients cannot be generallyrecommended because of the potential for adversereactions, particularly myositis.

Fibrates remain the treatment of first choice inremnant particle disease (type III). In addition,there are favourable reports of the use of HMG-CoA reductase inhibitors in this condition. Resinsaggravate the hypertriglyceridaemia and are contra-indicated.

Pharmacological treatment of isolated moderatehypertriglyceridaemia remains controversial.However, some patient groups may be consideredfor drug therapy if lifestyle measures are ineffective,including patients with known CHD, familial com-bined hyperlipidaemia, familial hypertri-glyceridaemia, a family history of CHD, remnantparticle disease, diabetes mellitus and a low HDL-cholesterol.30 Fibrates and nicotinic acid or itsderivatives are the drugs of choice for isolatedhypertriglyceridaemia. LDL cholesterol tends to below in these subjects and may rise with fibratetherapy in some individuals. For this reason, LDLconcentrations should be monitored.

Fibrates are the first line treatment for severehypertriglyceridaemia with chylomicronaemia.Omega-3 fatty acids may also be useful in thissituation and can be used in conjunction withfibrates. Nicotinic acid or its derivatives can also beusefully added to fibrate therapy.

In chylomicronaemia of childhood due to lipo-protein lipase deficiency or apoprotein C-IIdeficiency, no pharmacological treatment isavailable. However, the very low fat diet necessaryin these individuals may be supplemented bymedium chain triglycerides to improve tolerability.

Monitoring drug therapy

The response to lipid-lowering drug therapy is notalways predictable and plasma lipid and lipo-protein concentrations should be monitored toensure adequate response. If one fibrate isineffective another member of the fibrate class canbe tried. The response to HMG-CoA reductaseinhibitors is more predictable and the majority ofpatients will show the expected response. Failure torespond to resins usually indicates poor com-pliance.



j.bmj.com

/P


j.69.811.359 on 1 May 1993. D

ownloaded from

http://pmj.bmj.com/


Patients should be questioned with regard topossible side effects of the drugs and intermittentmeasurements of liver function tests are indicatedduring therapy with fibrates and HMG-CoAreductase inhibitors. If patients develop musclepain then measurement of creatine kinase isindicated. Myositis is more likely to occur whenHMG-CoA reductase inhibitors are combinedwith fibrates or nicotinic acid and when other drugsare used concurrently such as cyclosporine. Verycareful monitoring is required in these patients.Patients taking nicotinic acid need screening forpotential metabolic effects including liver functiontests, uric acid and plasma glucose. Ophthal-mological surveillance is also required in patientstaking nicotinic acid as a reversible macularoedema may occur rarely. Initial concerns aboutcataracts with the HMG-CoA reductase inhibitorshave not materialized and there is no need forroutine ophthalmological surveillance.

Non-pharmacological therapy

Surgicalprocedures

Partial ileal bypass3' involving the terminal onethird of the ileum has been performed in the past inheterozygous familial hypercholesterolaemic indi-viduals intolerant of resin therapy. Reductions inLDL cholesterol ofabout 30% have been achieved.Postoperative diarrhoea, mild steatorrhoea and theneed for vitamin B12 replacement are disadvantagesof this procedure. The advent of the HMG-CoAreductase inhibitors means that few patients willnow be candidates for this operation despite recentevidence of its effectiveness in decreasing coronarymortality and morbidity.32

In homozygous familial hypercholesterolaemia,liver transplantation is the most definitive treat-ment providing a source of LDL receptor activitybut at the cost of life-long immunosuppression. Acombined heart/liver transplant was originally per-formed in 1984 in a 7-year-old patient. Thecholesterol fell from a preoperative concentrationof 25 mmol/l to 7 mmol/1.33

Plasma exchange and related techniques

Plasma exchange was first used in 1974 for thetreatment of homozygous familial hyperchol-esterolaemia.34 Regular exchanges (weekly or bi-weekly) led to regression of xanthomata and slow-ing of progression of atherosclerosis. Recentlymore selective procedures have been developedincluding LDL apheresis with disposable affinitycolumns. These columns remove apoprotein Bcontaining lipoproteins including Lp(a), but HDLis conserved.35 An alternative technique involves

the precipitation of LDL with heparin - theHeparin Extracorporal LDL Precipitation (HELP)system.36

Controversial issues

Overall mortality

It is generally accepted that primary preventiontrials of cholesterol-lowering reduce the risk ofnon-fatal and fatal CHD.37 However, concern hasbeen expressed in some quarters that these trialshave failed to show a reduction in total mortality.Further, the potential adverse effects of lipid-lowering therapy in increasing non-cardiac deathshas been emphasized by some authors.38'39 It shouldbe remembered that these trials have not had thestatistical power to answer the question as towhether or not cholesterol-lowering alters totalmortality. It is highly unlikely that a trial with suchstatistical power will ever be carried out because ofthe cost. For the time being the apparent increase innon-cardiovascular mortality observed in somedrug trials remains unexplained and needs to beinvestigated further before its clinical significancecan be assessed. The variety of drugs used, some ofthem now obsolete, the very wide range ofcauses ofnon-CHD death and the lack of increase in thelatter when cholesterol was lowered in diet trialsrenders a single causal mechanism most unlikely.In the meantime responsible use of cholesterol-lowering drugs in diet-resistant patients with CHDor at high risk of developing CHD remains goodclinical practice.

The elderly

The gradient of risk between plasma cholesterollevels and CHD risk is less steep in the elderly.However, the number of CHD events is muchgreater and the risk attributable to cholesterol istherefore high. Currently there is a view thatprimary prevention with hypolipidaemic agentsshould not be undertaken after the age of 65. Trialsbeginning in the United States of lipid-lowering inthe elderly will help to clarify the position withregard to this increasing sector of the population.

Women

Premenopausal women are at lower risk of CHDthan men and the major trials of lipid-loweringtherapy have been confined to men. More researchis needed in more clearly defining individual risk inwomen, particularly as caution is required with theprescription of most hypolipidaemic drugs if preg-nancy is likely.

In postmenopausal women the risk of CHD



j.bmj.com

/P


j.69.811.359 on 1 May 1993. D

ownloaded from

http://pmj.bmj.com/


increases steeply, possibly related to increasingplasma LDL cholesterol levels. Changes in plasmalipoprotein concentrations are ameliorated by hor-mone replacement therapy. More information isrequired on the effects of combined hormonetherapy (progestogen and oestrogen) on vascularrisk and on whether the progestogen, necessary forthe prevention of endometrial hyperplasia, reducesthe benefit conferred by the oestrogen.

Children

Children from families carrying the gene forfamilial hypercholesterolaemia (FH) should bescreened for the presence ofhypercholesterolaemiaat an early age. It is generally accepted that alow-fat, low-cholesterol diet can be prescribed afterthe age of 5 years. However, more information isneeded on the safety of systemically activehypolipidaemic drug therapy in children. In FHfamilies where the clinical onset ofCHD is early itmay be necessary to prescribe drug therapy inchildren but most physicians would wait until afterpuberty.

Summary

There is considerable evidence to suggest that theidentification and treatment of dyslipidaemia will

reduce the risk of premature CHD, i.e. before theage of 65. Diagnosis of the cause of raised plasmalipid levels will enable appropriate decisions to betaken with regard to management. The cornerstoneof treatment is nutritional counselling and atten-tion to other major risk factors for CHD, partic-ularly smoking and hypertension. For a smallpercentage of patients with severe hyperlipidaemiadrug therapy is indicated. Appropriate drugchoices need to be made based on the particularlipid abnormality to be treated. In general thosepatients with clinical vascular disease are treatedmore aggressively than those where the aim isprimary prevention.More research is needed to determine individual

risk more precisely and to allow proper targeting oftherapy. Genetic factors, qualitative changes inlipoproteins, lipoprotein (a), fibrinogen, and othercoagulation and thrombotic factors are likely to beimportant in individual risk assessment.

There is no doubt that more information isneeded from prospective studies of lipid-loweringtherapy in terms of risk benefit for affected individ-uals. Hopefully the major studies currently under-way will fill some of the gaps in our knowledge.Until then aggressive therapy with drugs should bereserved for those at highest risk where the benefitis likely to be greatest.

References

1. Martin, M.J., Hulley, S.B., Browner, W.S., Kuller, L.H. &Wentworth, D. Serum cholesterol, blood pressure and mor-tality: implications from a cohort of 361,662 men. Lancet1986, ii: 933-936.

2. Chen, Z., Peto, R., Collins, R., MacMahon, S., Lu, J. & Li,W. Serum cholesterol concentration and coronary heartdisease in population with low cholesterol concentrations. BrMed J 1991, 303: 276-282.

3. Kannel, W.B., Gordon, T. & Castelli, W.P. Role of lipid andlipoprotein fractions in assessing atherogenesis. The Fram-ingham Study. Progr Lipid Res 1981, 20: 339-348.

4. Castelli, W.P., Garrison, R.J., Wilson, P.W.F., Abbott, R.D.,Kalousdian, S. & Kennel, W.B. Incidence of coronary heartdisease and lipoprotein cholesterol levels. JAMA 1986, 256:2835-2838.

5. Hulley, S.B. & Avins, A.L. Asymptomatic hypertri-glyceridaemia. Br Med J 1992, 304: 394-396.

6. Rossouw, J.E. & Rifkind, B.M. Does lowering serumcholesterol levels lower coronary heart disease risk? In:LaRosa, J.C. (ed) Endocrinology and Metabolism Clinics ofNorth America. Lipid Disorders, Vol. 19, no. 2. W.B.Saunders, Philadelphia, 1990, pp. 279-297.

7. Rossouw, J.E., Lewis, B. & Rifkind, B.M. The value oflowering cholesterol after myocardial infarction. N Engl JMed 1990, 323: 1112-1119.

8. Levy, R.I., Brensike, J.F., Epstein, S.E. et al. The influence ofchanges in lipid values induced by cholestyramine and diet onprogression ofcoronary artery disease: results of the NHLBItype II coronary intervention study. Circulation 1984, 69:325-337.

9. Blankenhorn, D.H., Nessim, S.A., Johnson, R.L., Sanmarco,M.E., Azen, S.P. & Cashin-Hemphill, L. Beneficial effects ofcombined colestipol-niacin therapy on coronary atherosc-lerosis and coronary venous bypass grafts. JAMA 1987, 257:3233-3240.

10. Brown, G., Albers, J.J. & Fisher, L.D. Regression ofcoronary artery disease as a result of intensive lipid loweringtherapy in men with high levels of apolipoprotein B. N EnglJMed 1990, 323: 1289-1298.

11. Kane, J.P., Malloy, M.J., Ports, T.A., Phillips, N.R., Diehl,J.C. & Havel, R.J. Regression of coronary atherosclerosisduring treatment of familial hypercholesterolaemia withcombined drug regimens. JAMA 1990, 264: 3007-3012.

12. Watts, G.F., Lewis, B., Brunt, J.N.H. et al. Effects oncoronary artery disease of lipid-lowering diet, or diet pluscholestyramine, in the St. Thomas' Atherosclerosis Regres-sion Study (STARS). Lancet 1992, 339: 563-569.

13. Brown, M.S. & Goldstein, J.L. Receptor-mediated control ofcholesterol metabolism. Science 1986, 191: 150-154.

14. Consensus Conference. Lowering blood cholesterol to pre-vent heart disease. JAMA 1985, 253: 2080-2086.

15. Study Group of the European Atherosclerosis Society.Strategies for the prevention of coronary heart disease, apolicy statement of the European Atherosclerosis Society.Eur Heart J 1987, 8: 77-88.

16. Study Group of the European Atherosclerosis Society. Therecognition and management of hyperlipidaemia in adults: apolicy statement of the European Atherosclerosis Society.Eur Heart J 1988, 9: 571-600.



j.bmj.com

/P


j.69.811.359 on 1 May 1993. D

ownloaded from

http://pmj.bmj.com/


17. Report of the National Cholesterol Education ProgramExpert Panel on Detection, Evaluation and Treatment ofHigh Blood Cholesterol in Adults. Arch Intern Med 1988,148:36-69.

18. Shepherd, J., Betteridge, D.J., Durrington, P.N. et al.Strategies for reducing coronary heart disease and desirablelimits for blood lipid concentrations: guidelines of the BritishHyperlipidaemia Association. Br Med J 1987, 295:1245-1246.

19. Friedewald, W.T., Levy, R.I. & Fredrickson, D.S. Estimationof the concentration of low density lipoprotein cholesterol inplasma, without use of the preparative ultracentrifuge. ClinChem 1972, 18: 499-502.

20. Laker, M.F., Reckless, J.P.D., Betteridge, D.J. et al.Laboratory facilities for investigating lipid disorders in theUnited Kingdom: results of the British HyperlipidaemiaAssociation Survey. J Clin Pathol 1992, 45: 102-105.

21. Beaumont, J.L., Carlson, L.A., Cooper, G.R., Fejfar, Z.,Fredrickson, D.S. & Strasser, T. Classification of hyper-lipidaemias and hyperlipoproteinaemias. Bull World HealthOrganisation 1970, 43: 891-915.

22. Betteridge, D.J. Lipids, diabetes and vascular disease: thetime to act. Diabet Med 1989, 6: 195-218.

23. Short, C.D. & Durrington, P.N. Hyperlipidaemia and renaldisease. In: Betteridge, D.J. (ed) Clinical Endocrinology andMetabolism. Lipid and Lipoprotein Disorders, Vol. 4, no. 4,Bailliere Tindall, London, 1990, pp. 777-806.

24. O'Connor, P., Feely, J. & Shepherd, J. Lipid lowering drugs.Br Med J 1990, 300, 667-672.

25. Kita, T., Nagano, Y., Yokode, M. et al. Probucol prevents theprogession of atherosclerosis in Watanabe heritable hyper-lipidaemic rabbit, an animal model for familial hyper-cholesterolaemia. Proc Natl Acad Sci USA 1987, 84:5928-5231.

26. Report from the Committee of Principal Investigators. Acooperative trial in the primary prevention ofischaemic heartdisease using clofibrate. Br Heart J 1978, 40: 1069-1118.

27. Frick, M.H., Elo, O., Haapa, K. et al. Helsinki Heart Study:primary prevention trial with gemfibrozil in middle-aged menwith dyslipidaemia. N Engl J Med 1987, 317: 1237-1245.

28. O'Kane, M.J., Trinick, T.R., Tynan, M.B., Trimble, E.R. &Nicholls, D.P. A comparison of acipimox and nicotonic acidin type 2b hyperlipidaemia. Br J Clin Pharmac 1992, 33:451-453.

29. Grundy, S.M. HMG-CoA reductase inhibitors for treatmentof hypercholesterolaemia. N Engl J Med 1988, 319: 24-33.

30. Assmann, G., Betteridge, D.J., Gotto, A.M. & Stainer, G.Management of hypertriglyceridaemic patients. Treatmentclassifications and goals. Am J Cardiol 1991, 68: 30A-34A.

31. Buchwald, H. Lowering of cholesterol absorption and bloodlevels by ileal exclusion. Circulation 1964, 29: 713-720.

32. Buchwald, H., Varco, R.L., Matts, J.P. et al. Effect of partialileal bypass surgery on mortality and morbidity from cor-onary heart disease in patients with hypercholesterolaemia.Report of the Program on the Surgical Control of theHyperlipidaemias (POSCH). N Engl J Med 1990, 323:946-955.

33. Starzl, T.E., Bilheimer, D.W., Bahnson, H.T. et al.Heart-liver transplantation in a patient with familial hyper-cholesterolaemia. Lancet 1984, i: 1382-1383.

34. Thompson, G.R., Lowenthal, R. & Myant, N.B. Plasmaexchange in the management of homozygous familial hyper-cholesterolaemia. Lancet 1975, 1: 1208-1211.

35. Yokoyama, S., Hayashi, R., Santani, M. & Yamamoto, A.Selective removal of low density lipoprotein by plas-mapheresis in familial hypercholesterolaemia. Arterio-sclerosis 1985, 5: 613-622.

36. Fuchs, C., Windisch, M., Wieland, H. et al. Selectivecontinuous extracorporeal elimination of low density lipo-proteins from plasma by heparin precipitation withoutcations. In: Plasma Separation and Plasma Fractionation.Karger, Basel, 1983, pp. 272-280.

37. Holme, I. An analysis of randomized trials evaluating theeffect ofcholesterol reduction on total mortality and coronaryheart disease incidence. Circulation 1990, 82: 1916-1924.

38. Muldoon, M.F., Manuck, S.B. & Matthews, K.A. Loweringcholesterol concentrations and mortality: a quantitativereview of primary prevention trials. Br Med J 1990, 301:309-314.

39. Smith, G.D. & Pekkanen, J. Should there be a moratorium onthe use of cholesterol lowering drugs? Br Med J 1992, 304:431-434.



j.bmj.com

/P


j.69.811.359 on 1 May 1993. D

ownloaded from

http://pmj.bmj.com/

special article managementofhyperlipidaemia: guidelines

Documents