Hyperlipidemia Drugs and Plasma Expanders PDF

HYPOLIPIDAEMIC DRUGS AND PLASMA EXPANDERS 635 TABLE 45.2 Types of primary hyperlipoproteinaemias Type Disorder Cause Occurrence Elevated Plasma lipids...

HYPOLIPIDAEMIC DRUGS AND PLASMA EXPANDERS 635 TABLE 45.2 Types of primary hyperlipoproteinaemias Type Disorder Cause Occurrence Elevated Plasma lipids plasma lipoprotein CH TG I Familial lipoprotein G Very rare Chylomicron ↑↑ ↑↑↑ lipase deficiency IIa Familial G Less common LDL ↑↑ N hypercholesterolaemia IIb Polygenic MF Commonest LDL ↑ N hypercholesterolaemia III Familial G Rare IDL, Chy. rem. ↑ ↑ dysbetalipoproteinaemia IV Hypertriglyceridaemia MF, G Common VLDL N ↑↑ V Familial combined G Less common VLDL, LDL ↑ ↑ hyperlipidaemia CH—Cholesterol; TG—Triglycerides; G—Genetic; MF—Multifactorial; Chy. rem.—Chylomicron remnants; VLDL—Very low density lipoprotein; IDL—Intermediate density lipoprotein; LDL—Low density lipoprotein. The genetic defect in some of the monogenic disorders is: Type I : absence of lipoprotein lipase—TG in Chy cannot be utilized. Type IIa : deficiency of LDL receptor—LDL and IDL are taken up very slowly by liver and tissues. Type III : the apoprotein in IDL and Chy. rem. (apoE) is abnormal, these particles are cleared at a lower rate. Type IV : this type of hypertriglyceridaemia is both multifactorial and monogenic, the former is more prevalent than the latter. The CHE of LDL is deesterified and used mainly for On the whole, LDL is the primary carrier of plasma cell membrane formation. The CH released into blood from CHE, and VLDL that of TGs. The important degradation of membranes is rapidly incorporated in high density lipoproteins (HDL), esterified with the help of an features of major types of hyperlipoproteinaemias enzyme lecithin: cholesterol acyltransferase (LCAT) and are given in Table 45.2. transferred back to VLDL or IDL, completing the cycle. CLASSIFICATION CHAPTER 45 The excess lipoproteins in plasma are phagocytosed by macrophages for disposal. When too much of lipoproteins have to be degraded in this manner, CH is deposited in 1. HMG-CoA reductase inhibitors (Statins): atheromas (in arterial walls) and xanthomas (in skin and Lovastatin, Simvastatin, Pravastatin, tendons). Raised levels of VLDL, IDL and LDL (rarely Chy Atorvastatin, Rosuvastatin, Pitavastatin and Chy. rem. also) are atherogenic, while HDL may be protective, because HDL facilitates removal of CH from tissues. 2. Bile acid sequestrants (Resins): Cholestyramine, Colestipol Hyperlipoproteinaemias can be: 3. Lipoprotein lipase activators (PPAR α (i) Secondary: associated with diabetes, myxo- activators, Fibrates): Clofibrate, Gemfibrozil, edema, nephrotic syndrome, chronic alcoholism, Bezafibrate, Fenofibrate. drugs (corticosteroids, oral contraceptives, β 4. Lipolysis and triglyceride synthesis blockers) etc. inhibitor: (ii) Primary: due to: Nicotinic acid. (a) A single gene defect: is familial and called 5. Sterol absorption inhibitor: ‘monogenic’ or genetic. Ezetimibe. (b) Multiple genetic, dietary and physical acti- The mechanism of action and profile of lipid vity related causes: ‘polygenic’ or multi- lowering effect of important hypolipidaemic drugs factorial. is summarized in Table 45.3. 636 DRUGS AFFECTING BLOOD AND BLOOD FORMATION TABLE 45.3 Mechanism of action and pattern of lipid lowering effect of important hypolipidaemic drugs Drug (daily dose) Mechanism of action Effect on lipids (%) HMG-CoA reductase inhibitors Lovastatin (10–80 mg) ↓ CH synthesis by inhibition of rate LDL ↓ 20–55 Simvastatin (5–40 mg) limiting HMG-CoA reductase HDL ↑ 5–15 Atorvastatin (10–80 mg) TG ↓ 10–35 Rosuvastatin (5–20 mg) Bile acid sequestrants Cholestyramine (4–16 g) ↓ bile acid absorption, ↑ hepatic LDL ↓ 15–30 Colestipol (5–30 g) conversion of CH to bile acids, HDL ↑ 3–5 ↑ LDL receptors on hepatocytes TG not affected, may ↑ in some Fibric acid derivatives Gemfibrozil (1200 mg) ↑ Activity of lipoprotein lipase, LDL ↓ 5–20* Bezafibrate (600 mg) ↓ release of fatty acids from adipose HDL ↑ 10–20 Fenofibrate (200 mg) tissue TG ↓ 20–50 Nicotinic acid (2–6 g) ↓ Production of VLDL, ↓ lipolysis LDL ↓ 15–25 in adipocytes HDL ↑ 20–35 TG ↓ 20–50 * Gemfibrozil may ↑ LDL-CH when TG levels are high; bezafibrate and fenofibrate not likely to raise LDL-CH HMG-CoA REDUCTASE INHIBITORS 55%. The ceiling effect of lovastatin and (Statins) pravastatin is 30–40% LDL-CH reduction. All Introduced in the 1980s, this class of compounds statins produce peak LDL-CH lowering after are the most efficacious and best tolerated 1–2 weeks therapy. Hepatic synthesis of VLDL hypolipidaemic drugs. They competitively inhibit is concurrently reduced and its removal from conversion of 3-Hydroxy-3-methyl glutaryl plasma is enhanced. coenzyme A (HMG-CoA) to mevalonate (rate A dose-dependent effect is seen with all statins. limiting step in CH synthesis) by the enzyme With lovastatin a mean reduction of LDL-CH by HMG-CoA reductase. Therapeutic doses reduce 25% at 20 mg/day, 32% at 40 mg/day and 40% SECTION 10 CH synthesis by 20–50%. This results in at 80 mg/day has been measured. Atorvastatin compensatory increase in LDL receptor expres- is more potent; the corresponding figures of LDL- sion on liver cells → increased receptor mediated CH reduction are 33% at 10 mg/day, 40% at 20 uptake and catabolism of IDL and LDL. Over mg/day, 45% at 40 mg/day and 50–55% at 80 long-term, feedback induction of HMG-CoA mg/day. A concurrent fall by 10–30% in plasma reductase tends to increase CH synthesis, but a TG level, probably due to reduction of VLDL steady-state is finally attained with a dose- occurs. A modest rise in HDL-CH by 5–15% is dependent lowering of LDL-CH levels. also noted. Simultaneous use of bile salt seques- Different statins differ in their potency and trant augments the LDL lowering effect upto 60% maximal efficacy in reducing LDL-CH. The daily and addition of nicotinic acid to this combination dose for lowering LDL-CH by 30–35% is may boost the effect to 70% reduction in lovastatin 40 mg, pravastatin 40 mg, simvastatin LDL-CH. Statins are effective in secondary 20 mg, atorvastatin 10 mg, rosuvastatin 5 mg hypercholesterolaemias also. The more efficacious and pitavastatin 2 mg. Moreover, at their maximum statins (simvastatin, atorvastatin, rosuvastatin) recommended doses simvastatin (80 mg) causes given at their higher doses effectively reduce TGs 45–50% reduction, while atorvastatin (80 mg) and (by 25% to 35%) when they are moderately raised, rosuvastatin (40 mg) can reduce LDL-CH by upto but not when they are markedly raised.  HYPOLIPIDAEMIC DRUGS AND PLASMA EXPANDERS 637 Because HMG-CoA reductase activity is maxi- Rosuvastatin This is another newer, commonly mum at midnight, all statins are administered at used and potent statin (10 mg rosuvastatin ~ 20 bed time to obtain maximum effectiveness. mg atorvastatin), with a plasma t½ of 18–24 hours. However, this is not necessary for atorvastatin Greater LDL-CH reduction can be obtained in and rosuvastatin, which have long plasma t½. severe hypercholesterolaemia; partly due to its All statins, except rosuvastatin are meta- longer persistence in the plasma. In patients with bolized primarily by CYP3A4. Inhibitors and raised TG levels, rosuvastatin raises HDL-CH by inducers of this isoenzyme respectively increase 15–20% (greater rise than other statins). and decrease statin blood levels. Dose: Start with 5 mg OD, increase if needed upto 20 mg/ day, (max 40 mg/day) Lovastatin It is the first clinically used statin; ROSUVAS, ROSYN 5, 10, 20 mg tabs. is lipophilic and given orally in the precursor Pitavastatin This is the latest and dose-to-dose lactone form. Absorption is incomplete and first the most potent statin. However, no specific pass metabolism is extensive. Metabolites are advantages compared to other statins have been excreted mainly in bile. The t½ is short (1–4 demonstrated, and experience with its use is hours). limited. A ceiling response of 40% LDL-CH Dose: 10–40 mg/day (max. 80 mg). reduction with the maximum recommended daily ROVACOR, AZTATIN, LOVAMEG 10, 20 mg tabs. dose of 4 mg is noted. The plasma t½ is 12 hours. Simvastatin It is twice as potent as lovastatin; Use of pitavastatin in combination with gemfibrozil also more efficacious. A greater rise in HDL- should be avoided, as the latter decreases its CH (when low) has been noted with simvastatin clearance. than lovastatin or pravastatin. Like lovastatin, it Dose: 1–4 mg per day; FLOVAS 1.0, 2.0 mg tabs. is lipophilic and given in the lactone precursor Adverse effects All statins are remarkably form. Oral absorption is better and first pass well tolerated; overall incidence of side effects not metabolism extensive; t½ is 2–3 hr. differing from placebo. Notable side effects are: Dose: 5–20 mg/day (max. 80 mg) Gastrointestinal complaints and headache are SIMVOTIN, SIMCARD, ZOSTA 5, 10, 20 mg tabs. usually mild. Rashes and sleep disturbances are Pravastatin It is hydrophilic and given in the uncommon. Rise in serum transaminase can occur, active form. At low doses it is equipotent to but liver damage is rare. Monitoring of liver CHAPTER 45 lovastatin, but at higher dose (40 mg/day), CH function is recommended. lowering effect is less. It can be employed when Muscle aches are the commonest (10%) side reduction of LDL-CH by < 25% is contemplated. effect. Rise in CPK levels occurs infrequently. An additional action of decrease in plasma fibrino- Myopathy is the only serious reaction, but is rare gen level has been observed. The t½ is 1–3 hours. (< 1 per 1000). Few fatalities due to rhabdo- PRAVATOR 10, 20 mg tabs. myolysis are on record. Myopathy is more common when nicotinic acid/gemfibrozil or Atorvastatin This newer and most popular statin CYP3A4 inhibitor—ketoconazole/ erythromycin/ is more potent and appears to have the highest cyclosporine/HIV protease inhibitor is given LDL-CH lowering efficacy at maximal daily dose concurrently. Gemfibrozil inhibits the hepatic of 80 mg. At this dose a greater reduction in uptake of statins by the organic anion transporter TGs is noted if the same was raised at baseline. OATP2. Fenofibrate interferes the least with statin Atorvastatin has a much longer plasma t½ of 18– uptake/metabolism and should be preferred for 24 hr than other statins, and has additional combining with them. A lower dose of statin is antioxidant property. advisable when a fibrate is given concurrently. Dose: 10-40 mg/day (max. 80 mg) Statins should not be given to pregnant women, AZTOR, ATORVA, ATORLIP 5, 10, 20 mg tabs. since there is no data on their safety. 638 DRUGS AFFECTING BLOOD AND BLOOD FORMATION Use Statins are the first choice drugs for primary for dyslipidaemia in diabetics. Statin therapy is hyperlipidaemias with raised LDL and total CH continued indefinitely, unless adverse effects levels, with or without raised TG levels (Type occur. IIa, IIb, V), as well as for secondary (diabetes, nephrotic syndrome) hypercholesterolaemia. BILE ACID SEQUESTRANTS (Resins) Cholestyramine and Colestipol These are basic ion Efficacy of statins in reducing raised LDL- exchange resins supplied in the chloride form. They are neither CH associated mortality and morbidity is now digested nor absorbed in the gut: bind bile acids in the intestine well established. Since the dose-response relation- interrupting their enterohepatic circulation. Faecal excretion ship of each statin is quite well documented, the of bile salts and CH (which is absorbed with the help of bile salts) is increased. This indirectly leads to enhanced initial dose of selected statin should aim to bring hepatic metabolism of CH to bile acids. More LDL receptors down the LDL-CH to the target level. It should are expressed on liver cells: clearance of plasma IDL, LDL then be adjusted by LDL-CH measurements every and indirectly that of VLDL is increased. 3–4 weeks. Resins have been shown to retard atherosclerosis, but In the ‘Scandinavian Simvastatin Survival Study’ (4S are not popular clinically because they are unpalatable, study, 1994), patients with history of MI (80%) or angina inconvenient, have to be taken in large doses, cause flatulence (20%) and raised serum CH level (> 212 mg/dl) were treated and other g.i. symptoms, interfere with absorption of many with simvastatin or placebo. Simvastatin reduced total CH drugs and have poor patient acceptability. by 25%, LDL-CH by 35%, raised HDL-CH by 8%. Over a period of 6 years coronary artery disease (CAD) mortality LIPOPROTEIN-LIPASE ACTIVATORS was less by 42%, overall mortality by 30% and cerebrovascular (Fibrates) events by 30% in the simvastatin group. Similar results have been obtained with other statins, e.g. the West of Scotland The fibrates (isobutyric acid derivatives) primarily Coronary Prevention Study (WOSCOPS) in men with no activate lipoprotein lipase which is a key enzyme history of MI has found pravastatin to lower risk of MI in the degradation of VLDL resulting in lowering by 31% and all cause mortality by 22%. of circulating TGs. This effect is exerted through Subsequent studies like Long-term intervention with peroxisome proliferator-activated receptor α pravastatin in ischaemic disease (LIPID-1998), Airforce/Texas coronary atherosclerosis prevention study (AFCAPS/ (PPARα) that is a gene transcription regulating TexCAPS-1998), Cholesterol and recurrent events (CARE- receptor expressed in liver, fat and muscles. 1998), and trials conducted by Heart Protection Study Activation of PPARα enhances lipoprotein lipase Collaborative Group (2002, 2004) in over 20,000 patients synthesis and fatty acid oxidation. PPARα may have confirmed the mortality and morbidity benefits of statins, also mediate enhanced LDL receptor expression including stroke prevention. in liver seen particularly with second generation SECTION 10 Beneficial effects in subjects who have raised fibrates like bezafibrate, fenofibrate. Fibrates CH levels but no evidence of CAD may relate decrease hepatic TG synthesis as well. A peri- to improved coronary artery compliance and athe- pheral effect reducing circulating free fatty acids romatous plaque stabilization due to suppression has also been shown. of macrophage mediated inflammation, reducing Drugs in this class primarily lower TG levels chances of plaque rupture and thrombus formation. by 20–50%, generally accompanied by 10–15% Improvement in endothelial function due to decrease in LDL-CH and a 10–15% increase in increased NO production and reduction in LDL HDL-CH. In some patients with hypertriglyceri- oxidation are proposed as additional mechanisms daemia LDL-CH may rise, partly because of by which statins may exert antiatherosclerotic inability of LDL receptor to clear the excess number action. Recently, a reduction in venous of LDL particles generated by enhanced VLDL thromboembolism has also been observed with catabolism. The increase in HDL-CH is at least rosuvastatin. On the basis of these results as well in part due to transfer of surface lipid components as the excellent patient acceptability, the statins from catabolized VLDL to HDL, and partly due are being increasingly used for primary and to increased production of HDL apoproteins (apo secondary hypercholesterolaemia with or without A-I, apo A-II) by liver. Gemfibrozil also appears raised TG levels. They are the first choice drugs to reduce VLDL secretion by liver.  HYPOLIPIDAEMIC DRUGS AND PLASMA EXPANDERS 639 LDL composition may be altered. Gemfibrozil naemia and severe hypertriglyceridaemia. It is and bezafibrate have been shown to shift small most effective in type III hyperlipoproteinaemia; dense LDL particles (believed to be more athero- also beneficial in type IV and type V disease. genic) to larger less dense particles. Patients with raised TG and low HDL-CH levels Clofibrate It was a widely used hypolipidaemic drug, but (as is the case with metabolic syndrome, type later evidence showed that it does not prevent atherosclerosis, 2 diabetes) are the most suitable to be treated therefore has gone out of use. with fibrates. Fibrates may also be used to supplement statins. Gemfibrozil This fibric acid derivative effecti- vely lowers plasma TG level by enhancing Bezafibrate This second generation fibric breakdown and suppressing hepatic synthesis of acid derivative is an alternative to gemfibrozil TGs. Besides high efficacy in type III hyperlipo- in mixed hyperlipidaemias (type III, IV and V). proteinemia, gemfibrozil has shown action in Though it has also been indicated in hypercholes- subjects with raised blood CH in addition. In the terolaemia (type II), it is inferior to statins and ‘Helsinki Heart Study’ men without known CAD resins. Bezafibrate has not shown propensity to treated with gemfibrozil had a 34% reduction in increase LDL-CH in hypertriglyceridaemic fatal and nonfatal MI, though overall mortality patients and appears to have greater LDL-CH was not affected. That these benefits extend to lowering action than gemfibrozil. Circulating secondary prevention of coronary events in men fibrinogen and glucose levels may decrease. The with existing CAD and low HDL-CH, has been 5 year ‘Bezafibrate Coronary Atherosclerosis demonstrated in another trial. Additional actions Intervention Trial’ (BECAIT) in young male post- to decrease the level of clotting factor VII-phos- MI subjects showed an atherosclerosis slowing pholipid complex and promotion of fibrinolysis effect and reduction in coronary events. The have been observed, which may contribute to the Bezafibrate Infarction Prevention (BIP) registry antiatherosclerotic effect. has also noted reduction in coronary events in subjects with high TG and low HDL-CH levels. Pharmacokinetics Gemfibrozil is completely Adverse effects and contraindications are absorbed orally, metabolized by glucuronidation similar to other fibrates. Main side effects are and undergoes some enterohepatic circulation. It g.i. upset, myalgia, rashes. Dose reduction is is excreted in urine; elimination t½ is 1–2 hr. needed in elderly and in renal insufficiency. Action CHAPTER 45 Adverse effects Common side effects are of oral anticoagulants may be enhanced. epigastric distress, loose motions. In contrast to gemfibrozil, combination of Skin rashes, body ache, eosinophilia, impotence, bezafibrate with a statin has not so far been found headache and blurred vision have been reported. to increase the incidence of rhabdomyolysis. Myopathy is uncommon. Gemfibrozil + statin Dose: 200 mg TDS with meals. BEZALIP 200, 400 mg tab. increases risk of myopathy. Incidence of gallstone is not increased as was Fenofibrate Another 2nd generation prodrug seen with clofibrate. fibric acid derivative which has greater HDL– It is contraindicated during pregnancy. CH raising and greater LDL-CH lowering action GEMPAR, NORMOLIP 300 mg cap. LOPID 300 mg cap, 600 than other fibrates: may be more appropriate as mg and 900 mg tabs. an adjunctive drug in subjects with raised LDL- Use In a dose of 600 mg BD taken before meals, CH levels in addition to raised TG levels. No gemfibrozil is a first line drug for patients with rise in LDL-CH has been observed in patients markedly raised TG levels, whether or not CH with high TG levels. Its t½ is 20 hr. Adverse levels are also raised. Episodes of acute pancrea- effects are myalgia, hepatitis, rashes. Cholelithiasis titis are prevented in patients with chylomicro- and rhabdomyolysis are rare. Fenofibrate appears 640 DRUGS AFFECTING BLOOD AND BLOOD FORMATION to be the most suitable fibrate for combining with the blush area) occur after every dose. This is statins, because statin metabolism is minimally associated with release of PGD2 in the skin, and affected and enhancement of statin myopathy risk can be minimized by starting with a low dose is lower. Indications of fenofibrate are similar taken with meals and gradually increasing as to that of gemfibrozil. tolerance develops. Use of sustained release (SR/ Dose: 200 mg OD with meals. ER) tablet also subdues flushing. Aspirin taken FENOLIP, LIPICARD 200 mg cap. before niacin substantially attenuates flushing by inhibiting PG synthesis. Laropiprant is a specific LIPOLYSIS AND TRIGLYCERIDE antiflushing drug with no hypolipidaemic action SYNTHESIS INHIBITOR of its own, that has been combined with nicotinic Nicotinic Acid (Niacin) acid to minimize flushing. An ER tablet containing 1.0 g nicotinic acid and 20 mg laropiprant is used It is a B group vitamin (see Ch. 67) which in in UK and Europe. much higher doses reduces plasma lipids. This Dyspepsia is very common; vomiting and action is unrelated to its vitamin activity and not diarrhoea occur when full doses are given. Peptic present in nicotinamide. When nicotinic acid is ulcer may be activated. given, TGs and VLDL decrease rapidly, followed Dryness and hyperpigmentation of skin can be by a modest fall in LDL-CH and total CH. A troublesome. Other long-term effects are: 20–50% reduction in plasma TGs and 15–25% Liver dysfunction and jaundice. Serious liver reduction in CH levels has been recorded. damage is the most important risk. Nicotinic acid is the most effective drug to raise Hyperglycaemia, precipitation of diabetes (should HDL-CH, probably by decreasing rate of HDL not be used in diabetics). destruction; a 20–35% increase is generally Hyperuricaemia and gout, atrial arrhythmias. obtained. Relatively lower dose suffices to raise It is contraindicated during pregnancy and in HDL–CH. It also reduces lipoprotein Lp (a), which children. is considered more atherogenic. Nicotinic acid reduces production of VLDL Interaction Postural hypotension may occur in in liver by inhibiting TG synthesis. Indirectly the patients on antihypertensives when they take VLDL degradation products IDL and LDL are nicotinic acid. Risk of myopathy due to statins is increased. SECTION 10 also reduced. No direct effect on CH and bile acid metabolism has been found. It inhibits intra- Dose: Start with 100 mg TDS, gradually increase to cellular lipolysis in adipose tissue and increases 2–4 g per day in divided doses. It should be taken just after food to minimize flushing and itching. the activity of lipoprotein lipase that clears TGs. NIALIP, NEASYN-SR 375, 500 mg tabs. A cell surface Gi-protein coupled receptor which negatively regulates adipocyte adenylyl cyclase has been found Use Nicotinic acid is a wide spectrum hypo- to selectively bind nicotinic acid, and has been called ‘niacin lipidaemic drug. It is highly efficacious in receptor’. Nicotinic acid appears to inhibit lipolysis in adipose tissue by decreasing hormone stimulated intracellular cAMP hypertriglyceridaemia (type III, IV, V) whether formation through this receptor. Hepatic VLDL production associated with raised CH level or not. It is mostly is believed to be decreased due to reduced flow of fatty used to lower VLDL and raise HDL levels, and acids from adipose tissue to liver. as an adjunctive drug to statins/fibrates. Adverse effects The large doses needed for Nicotinic acid is the most effective drug in hypolipidaemic action are poorly tolerated. Only reducing plasma TG levels. Its most important about half of the patients are able to take the indication is to control pancreatitis associated with full doses. severe hypertriglyceridaemia, mostly in genetic Nicotinic acid is a cutaneous vasodilator: type IV and type V disorders. Long-term use marked flushing, heat and itching (especially in prevents further attacks of pancreatitis. Given over  HYPOLIPIDAEMIC DRUGS AND PLASMA EXPANDERS 641 long-term in post-MI patients, it has been found Another study has found statin + niacin to cause to reduce recurrences of MI and overall mortality. greater reduction in IMT of carotid than statin However, doses above 2 g/day are poorly tolera- + ezetimibe. ted; should seldom be exceeded for maintenance No specific adverse effect, except reversible purposes. Because of potential toxicity, use of hepatic dysfunction and rarely myositis has been nicotinic acid is restricted to high-risk cases only. noted with ezetimibe. Dose: 10 mg OD; ZETICA, EZEDOC 10 mg tab. STEROL ABSORPTION INHIBITOR BITORVA, LIPIVAS-EZ, LIPONORM-EZ: Atorvastatin 10 mg + ezetimibe 10 mg tab; SIMVAS-EZ, STARSTAT- Ezetimibe It is a novel drug that acts by EZ: Simvastatin 10 mg + ezetimibe 10 mg tabs. inhibiting intestinal absorption of cholesterol and CETP-INHIBITORS phytosterols. It interferes with a specific CH The cholesteryl ester transfer protein (CETP) facilitates transport protein NPC1L1 in the intestinal mucosa exchange of CHEs with TGs between HDL particles and and reduces absorption of both dietary and biliary chylomicrons, VLDL, LDL, etc. It plays an important role CH. There is compensatory increase in hepatic in the disposal of HDL-associated CH. Inhibitors of this protein, torcetrapib, anacetrapib, etc. markedly raise HDL- CH synthesis, but LDL-CH level is lowered by CH and lower LDL. They were presumed to have 15–20%. The enhanced CH synthesis can be antiatherosclerotic action. However, during a large randomized blocked by statins, and the two drugs have clinical trial, torcetrapib was found to increase cardiovascular synergistic LDL-CH lowering effect. events like angina, MI, heart failure and death. The trial and further development of the drug was stopped in 2007. Due to very poor aqueous solubility, ezetimibe Whether other CETP inhibitors will have therapeutic value is not absorbed as such. A fraction is absorbed is being investigated, but appears doubtful. after getting conjugated with glucuronic acid in the intestinal mucosa. This is secreted in bile and Summary guidelines on the use of undergoes enterohepatic circulation to be mainly hypolipidaemic drugs excreted in faeces. A plasma t½ of 22 hours has Raised plasma CH is a major risk factor for been calculated. coronary artery disease (CAD); higher the CH Used alone, ezetimibe is a weak hypocholes- level, greater is the risk of CAD. Abundant terolaemic drug; LDL-CH lowering beyond data has confirmed that lowering the level of 15–20% is not obtained by increasing the dose. LDL-CH, when the same is high, results in Though it may be used alone in mild hypercho- CHAPTER 45 lowering of cardiovascular mortality and lesterolaemia when a statin is contraindicated/not tolerated, its main value is to supplement statins morbidity. More recent evidence (HPS, 2002; without increasing their dose. The combination ASCOT-LLA, 2003 studies) has indicated that of ezetimibe + low dose of a statin is as effective prophylactic use of a statin in CAD/hypertensive in lowering LDL-CH as high dose of statin alone. patients even with average or lower than average Upto 60% decrease in LDL-CH level has been CH levels lowers coronary and stroke events. With obtained with a combination of simvastatin + the availability of effective, well tolerated and ezetimibe. The ENHANCE trial has found that safe hypolipidaemic drugs, it has become a though addition of ezetimibe to simvastatin further standard practice to prescribe statin therapy after decreased LDL-CH, it caused little reduction in an acute coronary event irrespective of lipid levels. carotid artery intima : media thickness (IMT) ratio, Evidence that elevated plasma TG level or low a measure of subintimal CH deposition. While plasma HDL-CH level poses independent high this could be due to the fact that the subjects risk of CAD and stroke is also quite strong now. were on long-term statin therapy and had relatively Whereas raised LDL-CH is atherogenic, a low basal IMT ratio, the actual clinical benefit higher HDL-CH level is either itself protective of adding ezetimibe to a statin needs confirmation. or indicates a low atherogenic state.