LIPID-LOWERING DRUGS Dr. Arwa Mahmood Fuzi Alsarraf

Objectives  Describe the groups of lipid lowering drugs  Describe the mode of action  Their indication  The clinical use

Indications To prevent cardiovascular disease in all those at high risk of atherosclerosis,include  Those who already have atherosclerotic disease  Diabetics aged over 40 years.  Abnormal lipid concentration  Other risk factors (smoking, blood pressure, impaired glucose tolerance, male sex, age, premature menopause, ethnicity, obesity, triglyceride concentration, and a family history of premature cardiovascular disease). Those with a 10-year risk of cardiovascular disease of 20% or more stand to benefit from drug treatment.

Lowering the concentration of low-density lipoprotein (LDL) cholesterol and raising high-density lipoprotein (HDL) cholesterol slows the progression of atherosclerosis. Lipid-regulating drug treatment must be combined with  Advice on diet and lifestyle measures,  Lowering of raised blood pressure.  Management of diabetes.

For preventing cardiovascular disease events in those at high risk  A target total cholesterol concentration of less than 4 mmol/litre (or a reduction of 25% if that produces a lower concentration) and  A target LDL-cholesterol concentration of less than 2 mmol/litre (or a reduction of 30% if that produces a lower concentration).

Classification Statins Fibrates Ezetimibe Anion-exchange resins Nicotinic acid group Omega -3 fatty acid compounds

STATINS (HMG CoA) reductase inhibitors (Atorvastatin, Fluvastatin, Pravastatin, Rosuvastatin, And Simvastatin) Competitively inhibit 3-hydroxy-3-methylglutaryl coenzyme a (HMG COA) reductase, an enzyme involved in cholesterol synthesis in the liver. More effective than other lipid-regulating drugs at lowering LDL- Cholesterol concentration but they are less effective than the fibrates in reducing triglyceride concentration. However, statins reduce cardiovascular disease events and total mortality irrespective of the initial cholesterol concentration.

Indications  All patients with coronary heart disease (history of angina or acute myocardial infarction ), occlusive arterial disease (peripheral vascular disease, non-haemorrhagic stroke, or transient ischaemic attacks).  For all patients over 40 years with diabetes mellitus  Prevention of cardiovascular disease in asymptomatic individuals at increased risk (10-year cardiovascular disease risk of 20% or more)

Caution  History of liver disease or with a high alcohol intake (should be avoided in active liver disease). Liver-function tests should be carried out before and within 1 – 3 months of starting treatment and thereafter at intervals of 6 months for 1 year  Hypothyroidism should be managed adequately before starting treatment with a statin.  Caution if there is risk for myopathy or rhabdomyolysis  Avoided in porphyria

Contraindication  Active liver disease (or persistently abnormal liver function tests),  In pregnancy (adequate contraception required during treatment and for 1 month afterwards)  Breast-feeding

Side effects  Reversible myositis is a rare but significant side-effect.  Headache  Altered liver-function tests ( rarely, hepatitis)  Paraesthesia  Gastro-intestinal effects (abdominal pain, flatulence, constipation, diarrhoea, nausea and vomiting).  Rash and hypersensitivity reactions (including angioedema and anaphylaxis) rarely

ATORVASTATIN (LIPITOR)  Primary hypercholesterolaemia and combined hyperlipidaemia, 10 mg once daily; increased at intervals of at least 4 weeks to max. 80 mg once daily  Familial hypercholesterolaemia, initially 10 mg daily, increased at intervals of at least 4 weeks to 40 mg once daily; if necessary, further increased to max 80 mg once daily (or 40 mg once daily combined with anion-exchange resin in heterozygous familial hypercholesterolaemia)  Prevention of cardiovascular events in type 2 diabetes, 10 mg once daily

FLUVASTATINE (LESCOL(  Hypercholesterolaemia or combined hyperlipidaemia, initially 20 – 40 mg daily in the evening, adjusted at intervals of at least 4 weeks; up to 80 mg daily  Prevention of progression of coronary atherosclerosis, 40 mg daily in the evening  Following percutaneous coronary intervention, 80 mg daily

ROSUVASTATINE (CRESTOR(  Initially 5 – 10 mg once daily increased if necessary at intervals of at least 4 weeks to 20 mg once daily, increased after further 4 weeks to 40 mg daily ( only in severe hypercholesterolaemia with high cardiovascular risk and under specialist supervision)  Elderly initially 5 mg once daily  Patient of asian origin, initially 5 mg once daily increased if necessary to max. 20 mg daily

SIMVASTATINE (ZOCOR(  Primary hypercholesterolaemia, combined hyperlipidaemia, 10 – 20 mg daily at night, adjusted at intervals of at least 4 weeks; usual range 10 – 80 mg once daily at night  Homozygous familial hypercholesterolaemia, 40 mg daily at night or 80 mg daily in 3 divided doses (with largest dose at night)  Prevention of cardiovascular events, initially 20 – 40 mg once daily at night, adjusted at intervals of at least 4 weeks; max. 80 mg once daily at night

FIBRATES Bezafibrate, Ciprofibrate, Fenofibrate, and Gemfibrozil  Act mainly by decreasing serum triglycerides; they have variable effects on LDL-cholesterol.  Although a fibrate may reduce the risk of coronary heart disease events in those with low HDL-cholesterol or with raised triglycerides, a statin should be used first.  Fibrates may be considered first-line therapy in those whose serum-triglyceride concentration is greater than 10 mmol/litre.

Caution  Fibrates can cause a myositis-like syndrome, especially if renal function is impaired.  Combination of a fibrate with a statin increases the risk of muscle effects (especially rhabdomyolysis) -gemfibrozil and statins should not be used concomitantly.  Monitoring of liver function and creatinine kinase should be considered

Contraindication  Severe hepatic impairment  Renal impairment  Hypoalbuminaemia  Primary biliary cirrhosis  Gall bladder disease  Nephrotic syndrome  Pregnancy  Breast-feeding

Side effects  Gastro-intestinal disturbances  Rash, pruritus less commonly  headache, fatigue, dizziness, insomnia rarely  Gallstones, hepatomegaly, cholestasis, hypoglycaemia, impotence, anaemia, leucopenia, thrombocytopenia, increased risk of bleeding, alopecia, photosensitivity reactions, raised serum creatinine (unrelated to renal impairment), and myotoxicity

Bezafibrate (bezalip) 200 mg 3 times daily fenofibrate 200 mg 1 capsule daily

Gemfibrazole (lopid( 300 mg cap 600mg tab (0.9 – 1.2 gm/day) Indications  Hyperlipidaemias of types IIa, II b, III, IV and V in patients who have not responded adequately to diet and other appropriate measures Side effects  Gastro-intestinal disturbances  Headache, fatigue, vertigo  Eczema, rash less commonly  Atrial fibrillation Rarely  pancreatitis, appendicitis, disturbances in liver functin, dizziness, paraesthesia, sexual dysfunction, thrombocytopenia, anaemia, leucopenia, eosinophilia, bone- marrow suppression, myalgia, myopathy, myasthenia, myositis, blurred vision, exfoliative dermatitis, alopecia, and photosensitivity

Anion-exchange resins Cholestyramine, Colestipol  Act by binding bile acids, preventing their reabsorption; this promotes hepatic conversion of cholesterol into bile acids; the resultant increased LDL-receptor activity of liver cells increases the clearance of LDL-cholesterol from the plasma  Thus effectively reduce LDL-cholesterol but can aggravate hypertriglyceridaemia.

Caution  Interfere with the absorption of fat-soluble vitamins; supplements of vitamins A, D and K may be required when treatment is prolonged. Side effects  Gastro-intestinal side-effects predominate. Constipation is common, diarrhoea, nausea, vomiting, and gastro-intestinal discomfort.  Hypertriglyceridaemia may be aggravated.  Increased bleeding tendency has been reported due to hypoprothrombinaemia associated with vitamin K deficiency.

Cholestyramine (4 g/sachet )  Hyperlipidaemias, particularly type IIa, in patients who have not responded adequately to diet and other appropriate measures  Pruritus associated with partial biliary obstruction and primary biliary cirrhosis  Diarrhoeal disorders Dose  Lipid reduction 12 – 24 g daily in water, in single or up to 4 divided doses; up to 36 g daily

Ezetimibe Inhibits the intestinal absorption of cholesterol. Ezetrol (10 mg once daily) Indications  Adjunct to dietary manipulation in patients with primary hypercholesterolaemia in combination with a statin or alone  In homozygous familial hypercholesterolaemia in combination with a statin

Caution  Hepatic impairment (avoid if moderate or severe(  Pregnancy  If ezetimibe is used in combination with a statin, there is an increased risk of rhabdomyolysis

Side effect  Gastro-intestinal disturbances  Headache, fatigue, myalgia Rarely  Arthralgia, hypersensitivity reactions including rash and angioedema, hepatitis Very rarely  Pancreatitis, cholelithiasis, cholecystitis, thrombocytopenia, raised creatine kinase, myopathy, and rhabdomyolysis

NICOTINIC ACID (VIT B3) Reduce perepherral fatty acid release lowers both cholesterol and triglyceride increases HDL-cholesterol.  Indicated as adjunct to statin in dyslipidaemia or used alone if statin not tolerated  Dose Initially 100 – 200 mg 3 times daily, gradually increased over 2 – 4 weeks to 1 – 2 g 3 times daily

Cautions Unstable angina, acute myocardial infarction, diabetes mellitus, gout, peptic ulceration\, hepatic impairment, renal impairment, pregnancy Contra-indications Arterial bleeding; active peptic ulcer disease; breast-feeding Side-effects Vasodilatation, flushing, itching, rashes, urticaria, erythema; heartburn, epigastric pain, nausea, diarrhoea, headache, malaise, dry eyes; rarely angioedema, bronchospasm, anaphylaxis

Omega-3 fatty acid compounds  Omega-3 fatty acid compounds may be used to reduce triglycerides, as an alternative to a fibrate and in addition to a statin, in patients with combined (mixed) hyperlipidaemia not adequately controlled with a statin alone.  A triglyceride concentration exceeding 10 mmol/litre is associated with acute pancreatitis and lowering the concentration reduces this risk.

caution haemorrhagic disorders, anticoagulant treatment (bleeding time increased) hepatic impairment. pregnancy Side effects  Gastro-intestinal disturbances  Less commonly taste disturbances, dizziness, and hypersensitivity reactions  Rarely hepatic disorders, headache, hyperglycaemia, acne, and rash