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Management of dyslipidaemia

As society becomes increasingly sedentary and obese, the management of dyslipidaemia F J RAAL FCP (SA), FRCP, FRCPC, becomes ever more important for the general MMed, PhD p r a c t i t i o n e r . Professor and Head Ca r d i o vascular disease, pa r ticularly coro- tu r b a n c e , on whether the elevated lipid Division of Endocrinology and na r y arte r y disease (CAD), remains the le v el is prim a r y or secondary, and on the Metabolism leading cause of morbidity and morta l i t y presence of other risk fac t o r s for CAD and Department of wor l d w i d e . Yet , despite compelling epi- absolute ris k . The measurement of serum Medicine de m i o l o g ical and clinical data demonstrat- lipids should therefore form part of a full University of the ing conclusively that dyslipidaemia, p a rt i c- clinical examinati o n . Witwatersrand ularly elevated low-density lipoprotein Johannesburg The following serves as a check list that cholesterol (LDLC) level s , co rr e l a tes with must be considered in each pati e n t : Professor Frederick heightened CAD mortality and that lipid- • Ac c o m p a n ying modifiable risk fac t o r s Raal obtained his M B lo wer ing interventions with either lifestyle for CAD, e. g . hyp e rt e n s i o n , sm o k i n g , BCh degree cum mo d i f i c a tion or drug therapy can reduce laude at the University di a b e t e s , should be sought and treate d . ra tes of cardiovascular even t s , we remain a of the Witwatersrand • Underlying secondary causes of dyslipi- ‘hy p e r c h o l e s t e r o l a e m i c , atherogenic soci- in 1981. After com- da e m i a , e. g . excess alcohol intake, pleting his registrar- et y ’ who are becoming increasingly more hyp o t hy r o i d i s m , should be identified and ship in Internal se d e n t a r y and more obese. Medicine he obtained co rr e c t e d . his MRCP (UK) and • The goal of treatment should be clearly FCP (SA) in 1987, his explained to the patient and the ris k s Master of Medicine in We remain a ‘hyper- co n f e r red by untreated dyslipidaemia 1991, his FRCPC in should be emphasised. 1995 and his PhD in c h o l e s t e r o l a e m i c , 2000. atherogenic society’ who He is particularly NON - PH A RM ACOLOGICA L interested in lipids are becoming increas - and lipid disorders TH ERAP Y (LIFESTYLE and he supervises the ingly more sedentary MODIFICAT I ON) Lipid Clinic at the and more obese. Ep i d e m i o l o g ical and clinical trial evidence Johannesburg Hospital. He is cur- eva l u a ting diet and CAD prevention shows rently researching th a t at least three dietary strate g ies are lipid abnormalities in Although this review will concentrate ef f e c t i ve , namely South African subjects mainly on currently available drug therapy • substituting non-hyd r o g e n a ted unsatu - with familial hyperc- for the management of dyslipidaemia, it ra ted fats (mono- and polyunsatu r at e d holesterolaemia and completed his PhD must be emphasised that non-pharma c o - fats) for satu r a ted and trans-fats thesis based on stud- lo g ical therapy plays a vital role. Ma n y • increasing consumption of omega-3 fatt y ies in these subjects. pa tients with mild or moderate dyslipi- acids from fish and plant sources daemia will be able to achieve optimum • consuming a diet high in frui t s , veg e t a - lipid levels with lifestyle modification alone bl e s , nuts and whole unrefined gra i n s . an d , if they are able to maintain a healthy Such diets, together with regular phys i c a l li f e s t y l e , will not require lifelong lipid- ac t i v i t y , avoidance of smoking, and main- modifying therapy. taining a healthy wei g h t , will probably pre- The management of a patient with dyslipi- vent or at least reduce the prevalence of daemia depends on the type of lipid dis- CA D .

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In a patient consuming a typical se v ere dyslipidaemia and prema- daemia on the South Af r ican mar- Wes t e r n diet who complies wel l ture CAD, together with clinical ke t . with a prudent lipid-lower ing diet ma r k e r s of genetic dyslipidaemia. HMG CoA reductase inhibitors or and achieves and maintains ideal • Se c o n d a r y prev en t i o n . Pati e n t s statins — atorvastatin, fluvastatin, body weight (BMI < 27 kg/m2), th e with manifest CAD, ce r e b r o vas - pravastatin, simvastatin average fall in LDLC could be up cular disease or peripheral vas c u - The HMG CoA reductase to 20% (i.e. a decrease in LDLC of lar disease. Diabetics are at high in h i b i t o r s or ‘s t at i n s ’ ha ve revol u - 1 - 2 mmol/l). There is, ho weve r , ca r d i o vascular risk and type 2 tionised the therapy of dyslipi- considerable individual va ri ation in diabetes is now considered a daemia and are now the drugs of re s p o n s i ve n e s s , and the aver a g e CAD risk equivalent in the USA choice for the management of reduction in LDLC in response to (NCEP III). hyp e r c h o l e s t e r o l a e m i a . Re s u l t s a change in diet is usually more • P ri m a r y prev en t i o n . Su b j e c t s from 6 major clinical trials invol v - mo d e s t . at high risk for CAD (e.g. hyp e r - ing over 30 000 subjects have docu- te n s i v es) in whom the calculate d mented a decrease in both CAD 10 - y ear risk for an acute coronary and total morbidity and morta l i t y , The main indication ev ent is gre a ter than 20% (or reductions in myocardial infar c - more than 30% in young pati e n t s for lipid-modifying ti o n s , re va s c u l a ri s a tion procedures, if their risk is projected to 60 stroke and peripheral vascular dis- medication is to yea r s of age). Recent evidence ea s e . These drugs act by competi- suggests that such high-ris k reduce cardiovascu - ti v ely inhibiting the rate - l i m i t i n g pa tients will benefit from lipid- lar risk. enzyme of cholesterol synthesis — lo wer ing (statin) therapy irre s p e c - HMG CoA reductase. Ch o l e s t e r o l ti v e of baseline LDLC level s . is essential for normal intracellular INDICAT I ONS FOR DRUG No n - c a r d i ov a s c u l a r metabolic processes. Therefore to TH ERAP Y The most serious non-cardiovas c u - co m p e n s a te for the decreased avai l - lar complication of dyslipidaemia is ability of intracellular cholesterol, Ca r d i ov a s c u l a r the development of acute pancreati - the cell increases its LDL receptor The main indication for lipid-modi- ti s . This is seen in subjects with nu m b e r , resulting in increased utili- fying medication is to reduce car- se v ere hyp e rt ri g l y c e ri d a e m i a sa tion of circulating cholesterol and di o vascular ris k . Dr ug therapy (t ri g l y c e r ide (TG) >15 mmol/l). reducing the serum cholesterol should be considered when non- Ideally such patients should be le ve l . ph a rm a c o l o g ical means have fai l e d re f e r red to a lipid specialist. to reduce the lipid levels to within The statins are the most power f u l the target range (Table I). Wh e n The basic principles are to control of the cholesterol-lower ing drug s global risk for the individual is high or rever se possible secondary fac - avai l a b l e . Se r um cholesterol is li p i d - l o wer ing drugs are used.Th i s to r s (e.g. alcohol excess, di a b e t e s ) , reduced by 20 - 45%. LDLC is is al ways in conjunction with ongo- introduction of a ver y low- f at diet decreased by 25 - 55%;TGs are ing lifestyle modificati o n . and lipid-modifying drug therapy. mo d e r a tely reduced by 10 - 30% St a tin therapy is not appropria te for and HDLC is elevated by 5 - 15%. There are 3 main cardiovas c u l a r the treatment of severe hyp e r - It is important to remember that in d i c a tions for lipid-modifying drug tri g l y c e r idaemia and fibrates are the reductions in LDLC are log-linear, th e r a p y : dr ugs of choice. so that with each doubling of the • Se v ere genetic dyslipidaemia , dose of a statin one does not get a e. g . familial hyp e r c h o l e s t e r o - doubling of LDLC reduction. la e m i a , familial combined hyp e r - LI PID- M ODIFYI NG DRUGS Rat h e r , each doubling of the dose lipidaemia and dysbetalipopro- Se v eral drugs are currently avai l - of any statin only results in a fur- te i n a e m i a . These subjects usually able for the treatment of dyslipi ther 6% reduction in LDLC. ha ve a positive family history of Cost effectiveness of the different Table I. Optimal fasted lipid profile st a tins can be determined by com- pa r ing prices of equivalent doses of Total cholesterol £ 5 mmol/l st a tins as shown in Table II. Th e Triglycerides £ 1.5 mmol/l st a tins are equally effective in treat- HDL cholesterol ³ 1.2 mmol/l ing patients with familial and non- LDL cholesterol ³ 3 mmol/l familial hyp e r c h o l e s t e r o l a e m i a .

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Ag e , ge n d e r , or body weight do not Bile acid sequestrants (or anion (9 % ) . More rarely diarrh o e a , st e a t- influence the response to the stati n s exchange resins) — cholestyra- orr h o e a , intestinal obstruction and si g n i f i c a n t l y . Tolerance does not mi n e hyperchloraemic acidosis can de ve l o p , and the response is main- This is a wel l - t r ied drug that is oc c u r . tained indefinitely during therapy. widely used in the treatment of These agents also interfere with The statins are mainly hepati c a l l y familial hyp e r c h o l e s t e r o l a e m i a . ab s o r ption of anionic drug s , e. g . excreted and doses therefore do not Cholestyramine is not absorbed wa r fa ri n , thy r o xine and lipid-solu- ha ve to be decreased in renal fai l - and its function is to reduce intesti- ble vitamins. Antacids can amelio- ur e . The drugs are easily adminis- nal reabsorbtion of bile acids. ra te the dyspepsia, while increasing tered and are ver y well tolerate d . Increased production of bile acids fluid intake and a high-fibre diet or They are best giv en at bedtime. by the liver therefore ensues, stool softener can help counteract Ho weve r , ato r vas t a tin can be depleting liver cells of cholesterol, co n s t i p at i o n . administered at any time of the day thereby inducing increased LDL because of its long half-life. receptor activity on the liver cells. Nicotinic acid (niacin) As a result LDL catabolism is Nicotinic acid, or niacin, a B-gro u p He p at o t o xicity (transient 3%, pe r - increased and plasma LDLC level s vi t a m i n , is a potent lipid-lowe ri n g sistent 0.5%) and myop at h y fall by 15 - 30%. agent which decreases LDL and (< 0.5%) are the two major side- VLDL production. Ni c o t i n a m i d e effects of the stati n s . The incidence HDLC may increase by 3 - 5%. is not effective in lower ing serum of myop at h y is increased in the Because of increased hepati c cholesterol (SC) and cannot substi- el d e r l y , in the presence of liver or lipoprotein synthesis stimulated by tute for nicotinic acid. Ni c o t i n i c renal disease, or with the concomi- resin therapy, tri g l y c e r ides may acid appears to act by inhibiting tant administration of other drug s ho wev er increase moderate l y . lipolysis and by reducing the flux of such as cyc l o s p o ri n e , fi b r at e s , er y- Resins are therefore contraindicat- free fatty acids to the liver , li m i t i n g th r o m ycin and nicotinic acid. ed as monotherapy in persons with VLDL and LDL production. hyp e rt ri g l y c e ri d a e m i a . Fatal rhabdomyolysis is howev er a Nicotinic acid may also reduce ver y rare event with an incidence of The sequestrants are not absorbed he p a tic synthesis of apoB10 0 , an less than one death per million pre- from the gastrointestinal tract and essential component of VL D L . Th e sc ri p t i o n s . Frequently rhabdomyol - therefore lack systemic toxi c i t y . reduced hepatic synthesis of these ysis is the result of a potentially They are particularly suitable for lipoproteins leads to a reduction of avoidable drug interaction. tr e a ting younger pati e n t s , es p e c i a l l y the plasma concentrations of ch i l d r e n , and women considerin g tri g l y c e ri d e , and to a lesser extent St a tins are therefore remarkably pr e g n a n c y. cholesterol (as LDL is derive d safe drug s . The ratio betwee n mainly from VL D L ) . Se r um cho- sa ved and lost lives among stati n - Un f o rt u n a tely these agents are lesterol levels decrease by 20 - 30% tr e a ted patients over 10 yea r s of use un p a l at a b l e , leading to poor pati e n t and TGs by 20 - 60%. HDLC can can be estimated at about co m p l i a n c e . Common side-effects increase by 20 - 30%.The dose 100 000 to 1 — undoubtedly justi- include constipation (> 30 % ) , ga s - needed is 2 - 6 g/day (100 mg tabs fying lifelong clinical use of stati n s trointestinal (GIT) discomfort only are available in South Af ri c a , in those who war rant it. (2 0 % ) , nausea (8%) and bloating therefore one would require 20 - 60 ta b s / d a y in divided doses). Si d e -

Table II. Comparative efficacy of currently available statins (mg/day)

% reduction Atorvastatin Simvastatin Pravastatin Fluvastatin TC LDLC

10 20 40 22 27 10 20 40 80* 27 34 20 40 32 41 40 80 37 48 80 42 55

TC = total cholesterol; LD LC = low-density lipoprotein cholesterol. *Extended release.

380 C M E July 2003 Vol.21 No.7 MAIN TOPIC effects at the doses needed to be Fibrates — fenofibrate, bezafi- the treatment of dyslipidaemia are ef f e c t i v e are significant and the brate, gemfibrozil sh o wn in Tables III and IV. dr ug can often not be tolerate d . These drugs appear to work mainly Combination therapy The adver se effects include flushing by increasing the activity of In patients with severe dyslipi- (> 95 % ) , p ru ri t u s , ra s h , ac a n t h o s i s lipoprotein lipase (thereby increas- daemia single drug therapy in com- ni g ric a n s , to xic amblyop i a , di z z i - ing VLDL clearance) and may also bi n a tion with diet may fail to ne s s , GIT discomfort, hy p e ru ri- decrease VLDL production. Th e y ac h i e v e an adequate reduction in caemia with acute gout, im p a i r e d act by stimulating the nuclear tran- the lipid level s . In these situati o n s glucose tolerance and increased sc r iption factor peroxisome prolif- co m b i n a tion therapy may be war - li v er enzymes. er at o r - a c t i v ated receptor-alpha ra n t e d . (P PA R - a ). Their main effect is on The incidence of side-effects can be plasma trig l y c e r ides which can In patients with predominant decreased by taking the tablets with decrease by 20 - 50%. HDLC can hypercholesterolaemia the most meals and by starting with small increase by 10 - 35%. SC can ef f e c t i v e combination curre n t l y doses increasing the dose gra d u a l l y ho wev er also be decreased due to available is a statin plus a resin. over a 3 - 4-week perio d . Pati e n t s decreased VLDL synthesis and With this combinati o n , a gre at e r must be encouraged not to take the increased LDL clearance. LD L C up r e g u l a tion of LDL receptors tablets intermittently as this aggra - is usually decreased modestly by oc c u r s as a result of both a vates the side-effects. As p i r in taken 5 - 20%. decrease in cholesterol synthesis ap p r ox i m a tely an hour before can and an increase in cholesterol elim- also ameliorate side-effects. Ove r The fibrates are well tolerated and in at i o n . Reductions in LDLC are 40% of patients are unable to side-effects are uncommon (< 3% therefore gre a ter than with either remain on therapy due to side- of pati e n t s ) . Side-effects include agent alone.This combination can ef f e c t s . Sustained-release prepara- na u s e a , abdominal pain and rarely decrease serum LDLC by 50 - tions of nicotinic acid have been myop at h y, im p o t e n c e , raised liver 60 % . The triple combination of used which cause fewer side-effects, function tests (LFTs) and alopecia. an HMG CoA reductase inhibitor but are unfortu n a tely also less These drugs are renally excreted + resin + nicotinic acid can reduce ef f e c t i v e in lipid reduction. Ra r e and therefore impaired renal func- LDLC by up to 70%. cases of fulminant hepatitis have tion is a relati v e contraindication to also been reported with sustained- fi b r a te drug s . Gemfibrozil is least In patients with mixed hyp e r l i p i - release preparati o n s . reliant on the kidney for its excre- daemia or predominant hyp e r - tion but its limiting effect on glu- tri g l y c e ri d a e m i a , a combination of Co n t r a i n d i c a tions to the use of cu r o n i d a tion is thought to be the a statin plus a fibrate or nicotinic nicotinic acid include peptic ulcera- reason for its interaction with acid may be more effective. ti o n , he p a tic disease and gouty st a tins to promote rhabdomyol i s i s . a rt h ri t i s. It is also necessary to While combination drug therapy monitor blood glucose, li v er func- A summary of the lipid-modifying ma y prove essential to achieve tion and uric acid levels durin g effects of the different drugs as wel l desirable lipid level s , it must be th e r a p y . as the present drugs of choice for remembered that side-effects are

Table III. Summary of the effects of the major lipid-lowering agents

% % decrease decrease % increase % change Reduced Long-term TC LDLC HDLC TG CHD risk safety

HMG CoA 15 - 45% 25 - 55% 5 - 15% ¯10 - 30% Yes Yes reductase inhibitors Bile acid 10 - 25% 15 - 30% 3 - 5% • 0 - 10% Yes Yes resins Nicotinic 5 - 20% 5 - 25% 15 - 35% ¯20 - 50% Yes Yes acid Fibrates 0 - 15% 5 - 20% 10 - 35% ¯20 - 50% Yes Yes

TC = total cholesterol; LD LC = low-density lipoprotein cholesterol; TG = triglycerides; CHD = coronary heart disease; HDLC = high-density lipopro- tein cholesterol.

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Table IV. Present drugs of choice for the treatment FURTH ER READ ING of dyslipidaemia SA MA and Lipid and Atheros c l e ro s i s Society of Southern Africa Wor k i n g Predominant hypercholesterolaemia Gr oup. Diagnosis, management and Statin* pr evention of the common dyslipi- Resin daemias in South Africa. — Clinical Fibrate Guideline. S Afr Med J 20 0 0 ; Nicotinic acid 90 : 161 - 1 6 8 . Combined hyperlipidaemia Executive summary of the Thi r d Statin or fibrate* Rep o r t of the National Choleste ro l Nicotinic acid Ed u c ation Program (NCEP) Exp e r t Predominant hyperglyceridaemia Panel on Detection, Evaluation and Treatment of High Blood Choleste ro l Fibrate* in Adults. JAM A 20 0 1; 28 5 : 24 8 6 - Nicotinic acid 24 9 6 . Statin (only effective in mild to moderate hypertriglyceridaemia) He a r t Protection Study Collaboration *First choice. Gr oup. MRC/ BHF Heart Prot e c t i o n Study of choleste r ol lowering with more likely and that costs become th a t potently and selectively inhibit si m v a s tatin in 20,536 high risk indi- su b s t a n t i a l . di e t a r y cholesterol absorption at viduals in a randomized placebo con- the brush border of the intestinal tr olled trial. La n c e t 2002; 36 0 : 7-2 2 . Hu FB, Willett WU. Optimal diets for epithelium without affecting the OTH ER AGENT S pr evention of coron a r y heart disease. absorbtion of trig l y c e r ide or fat- s o l - Plant stanol/sterols JAM A 2002; 2 88 : 25 6 9 - 2 5 78. uble vitamins. Unlike resins, GI T These act to lower cholesterol side-effects are uncommon. absorbtion by interfering with cho- Ezetimibe at a dose of 10 mg/day lesterol assimilation in micelles in can reduce LDLC by 15 - 25%. the gut. They are added to mar- When used in combination with ga r ines and at a dose of 2 - 3 g/day st at i n s , ezetimibe produces signifi- can lower LDLC by 6 - 15% with cant additional reductions in IN A NUTSHELL little or no change in HDLC or TG LDLC (±20%) with no increase in Dyslipidaemia, particularly an ele- le ve l s . ad ve r se even t s . vated LDL-cholesterol level, is the major risk factor for cardiovascular Pol i c o s a n o l disease. Policosanol is a mixture of higher CONCLUSIONS Lifestyle modification is essential p ri m a ry aliphatic alcohols isolate d Management of dyslipidaemia and must be applied to all patients from sugar cane wax ; its main com- requires appropria te lifestyle modi- with dyslipidaemia. ponent is octacosanol. The exact fi c a tion and, where indicate d , li p i d - Patients with genetic dyslipidaemia, mechanism of action of policosanol modifying drug therapy. Safe and established cardiovascular disease, is unknown but at doses of 10 - 20 ef f e c t i v e drug therapy is now avai l - diabetes, and those at high cardio- mg / d a y it can lower LDLC by 15 - vascular risk warrant lipid-modify- able for the management of most 29 % . Da ta on efficacy determi n e d ing drug therapy. dy s l i p i d a e m i a s . by clinical end-points such as car- Appropriately prescribed lipid-mod- diac mortality are howev er lacking. There is now substantial evidence ifying drug therapy can lower car- to show that appropria tely pre- diovascular morbidity and mortality and improve overall survival. WH A T’S ON THE HORI- sc r ibed lipid-modifying drug thera- py can lower morbidity and morta l - Statins are the most effective ZON ? ity from CAD and improve over a l l agents for the treatment of pre- More potent statins su rv i va l , both in subjects with dominant hypercholesterolaemia. Two new stati n s , ro s u va s t a tin and established cardiovascular disease Fibrates are more effective for the pi t a vas t at i n , are being devel o p e d . and in those at high risk for devel - treatment of hypertriglyceridaemia. In clinical studies with rosuvas t at i n oping cardiovascular disease. Combination therapy may be reductions in LDLC of 45 - 70% required for the treatment of ha ve been achieved . severe dyslipidaemia but side- ACKNOWL E DGEMENT effects are more likely and costs Eze t i m i b e Barby Head is thanked for her become substantial. Ezetimibe is the first in a new class ex p e r t secretarial assistance. of cholesterol absorbtion inhibitors

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