Agents used in dyslipidemia: DGK

1. Drugs u sed in Dyslipidemia  Dr. Divya Krishnan Calicut medical college

2. CONTENTS  Introduction Lipid physiology and lipid metabolism Classification of drugs for dyslipidemias Salient features of different drugs Principles of treatment of dyslipidemias Recent advances Summary

3. What are Dyslipidemias? Disorders of lipoprotein metabolism resulting in abnormal plasma concentration of lipoproteins/lipids . Hyperlipidemias/ Low HDL levels Hypercholesterolemias ( total cholesterol/ LDL/ Triglycerides )

4. Dyslipidemias Primary Secondary Diabetes Monogenic Polygenic Myxoedema Nephrotic syndrome Alcoholism Drug induced

5. Drugs for dyslipidemias Modify lipid levels in blood. Can we call these drugs “HYPOLIPIDEMICS”????

6. Growing interest in drugs for dyslipidemias…..??? Dyslipidemias are important risk factors for atherosclerosis. Drugs have potential to retard accelerated atherosclerotic process and decrease morbidity and mortality associated with atherosclerosis .

7. LIPID PHYSIOLOGY Heterogenous group of compounds related to fatty acids insoluble in water but soluble in non polar solvents. Simple lipids compound lipids Neutral lipids Triglycerides C holesteryl esters

8. LIPOPROTEINS Macromolecular complexes of lipid and proteins apoproteins - provide structural stability -ligands for receptors -activate enzymes unesterified cholesterol core (TG , cholesteryl esters) phospholipids

9. Classification of lipoproteins Lipoprotein type Density (g/ml) diameter (nm) Lipid core Apoprotein Source Function Chylomicron 0.93 100-500 TG>>CHE ApoB48, Apo E diet Dietary lipid transport VLDL 0.93-1.006 40-80 TG>>CHE Apo B100 Apo E liver Endogenous lipid transport IDL 1.006-1.019 30-35 CHE>>TG Apo B100 Apo E VLDL Lipid transport to liver Source of LDL LDL 1.019-1.063 20-25 CHE Apo B100 IDL cholesterol transport to tissues & liver HDL 1.05-1.120 5-10 CHE ApoA Ι , ApoA п tissues Removal of cholesterol from tissues Lipoprotein A /LP(a) : Similar to LDL but with an additional Apo A. Linked to risk of atherosclerosis

10. LIPOPROTEIN TRANSPORT Exogenous pathway Endogenous pathway

11. LIPOPROTEIN TRANSPORT

12. Drugs used in Dyslipidemias Part 2

13. Dyslipidemias Hypercholesterolemias Hypertriglyceridemias Combined hyperlipidemias ##low HDL is also part of dyslipidemia

14. Classification of drugs First line agents : Lower LDL levels (mainly) - HMG-CoA reductase inhibitors(statins) - Bile acid binding resins - Inhibitors of intestinal cholesterol absorption Second line agents : Lower VLDL levels - LPL activators (fibrates) -VLDL secretion inhibitors(Niacin) Miscellaneous : Gugulipid ,Fish oils

15. HMGCoA reductase inhibitors(Statins ) - Most effective & best tolerated drugs History - First isolated from Penicillium citrinum mould (1972) - Compactin ( Mevastatin ) - first to be studied in man Lovastatin (from Aspergillus terreus ) - first to be approved for use in humans Pravastatin , Simvastatin chemically modified derivatives Atorvastatin , Fluvastatin , Rosuvastatin , Pitavastatin - synthetic products

16. Mechanism of action of statins Acetyl Co A 3Hydroxy 3 methyl glutaryl C oA HMG CoA reductase cholesterol mevalonate STATINS

17. Statins (MOA) contd …………………

18. Statins—effect on plasma lipoprotein levels LDL levels

19. TG Levels - 10 – 35% decrease HDL Levels – 5 -15 % increase

20. Pleiotropic effects of statins Improves endothelial function Decreases vascular inflammation(lowers CRP) Decreases lipoprotein oxidation Stabilisation of atheromatous plaque Decreases platelet aggregation Decreases fibrinogen levels Enhances fibrinolysis Neovascularisation of ischemic tissue Protection from sepsis Immune suppression Inhibition of primordial germ cell migration Beneficial effects Antiatherogenic Alzheimers disease Prostate cancer Harmful effects Contraindication in pregnancy

21. Statins-pharmacokinetics Variable absorption Extensive first pass hepatic uptake (OATP1B1) Lovastatin Pravastatin Simvastatin A torvastatin Rosuvastatin prodrug active prodrug active active High PPB 50% PPB High PPB High PPB High PPB Lipophilic hydrophilic lipophilic hydrophilic hydrophilic T1/2=1-4hrs 1-3hrs 2-3hrs 18-24hrs 18-24hrs CYP3A4 Sulfate conjugation CYP3A4 CYP3A4 CYP2C9

22. Statins-ADR Headache N ausea & bowel upset Rashes Insomnia (lipophilic drugs) Increase in serum transaminases Muscle tenderness & rise in CPK Myopathy & rhabdomyolysis (rare) Contraindication -pregnancy / lactation / children / elderly / liver & kidney disease

23. Statins-Drug interactions OATPIBI inhibitors( gemfibrozil ) increase statin toxicity CYP3A4 inhibitors increase toxicity of Lovastatin , Atorvastatin & Simvastatin CYP2C9 inhibitors increase toxicity of Rosuvastatin & Fluvastatin Warfarin toxicity with Rosuvastatin (CYP2C9)

24. Indications for use First choice drugs for 1 ° & 2 ° hypercholester-olemias with or without raised TG levels Drug combinations used in severe / combined dyslipidemias. 1 ° prevention of arterial disease in patients with hypercholesterolemias 2 ° prevention of MI/stroke (initiated soon after an event irrespective of lipid levels) Tried in Alzheimers disease , prostate cancer

25. Bile acid binding resins Oldest & safest MOA----explained with the fig Cholestyramine , Colestipol , Colesevelam - lower LDL levels (15-25%) -3-5% rise in HDL -Increase TG levels -induces HMGCoA reductase activity

26. Bile acid binding resins contd ….. Adverse drug reactions (mild ) - unpalatable , unpleasant - bloating , dyspepsia - constipation Drug interactions -interferes with absorption of :- fat soluble vitamins thiazides , frusemide digoxin , warfarin , statins , tetracycline , thyroxine Colesevelam has less side effects & is devoid of interactions

27. Bile acid binding resins contd … Indications for use - Primary hypercholesterolemias.~20% fall in LDL levels. Monotherapy less popular.Used in combinations for better control of hypercholesterolemias - Relief of pruritus (cholestasis) - Bile acid diarrhoea - Digitalis toxicity

28. Intestinal cholesterol absorption inhibitors Inhibit absorption of dietary & biliary cholesterol absorption from intestine- reduced hepatic cholesterol-LDL receptor expression & increased uptake of LDL from plasma. Plant sterols & stanols Sitostanol competes with cholesterol for NPC1L1 Sitosterol interferes with cholesterol transfer in the enterocyte Ezetimibe Inhibits NPC1L1 & inhibits absorption of cholesterol&phytosterol

29. EZETIMIBE…………… Pharmacokinetics -Poorly absorbed -Conjugated form gets absorbed & undergoes enterohepatic circulation. -T1/2=22hrs.Dose -10mg/day -Excreted in feces ADR - Diarrhoea / abd pain/headache -Allergic rxn ,hepatic dysfunction,myositis (rare) -Contraindicated in pregnancy

30. Ezetimibe contd …………… Drug interactions -Bile acid sequestrants inhibit ezetimibe absorption Indications Mild hypercholesterolemia when statin is contraindicated/not tolerated.(~15-20% decrease in LDL otherwise monotherapy less efficient than statin Adjunct to statin in hypercholesterolemia Additive reduction in LDL levels occurs.

31. Second line agents Marked reduction in VLDL (TG) Modest fall in LDL & modest rise in HDL Includes :- Activators of LPL (Fibrates) Inhibitors of VLDL secretion (Niacin)

32. Fibrates ( Clofibrate ) , Gemfibrozil , Fenofibrate , Bezafibrate , Ciprofibrate MOA : Activate PPAR α resulting in:- Increase in LPL activity Decrease in Apo C Ш FFA oxidation Decreased VLDL synthesis Increased hepatic SREBP Increased Apo A Ι , Apo A Ц Fall in VLDL (20-50%) Fall in LDL (10-15%) HDL rise (10-15%)

33. Fibrates Additional effects ( antiatherogenic ) Decrease fibrinogen levels , factor V Ц Increases fibrinolysis Decrease CRP & vascular inflammation Inhibit vascular smooth muscle proliferation I mproves glucose tolerance Pharmacokinetics Well absorbed High PPB(95%) T1/2—Varies Excreted by kidney

34. Fibrates ADR GI distress , headache Rash , urticaria Myalgia , fatigue Hair loss , impotence Minor elevations in AST , ALP Myopathy—more when combined with statins Lithogenicity of bile Contraindication Pregnancy , children , kidney disease

35. Fibrates Drug interactions Myopathy risk with statins (OATP1B1 inhibition & interference with statin metabolism) Toxicity of oral anticoagulants (displacement from plasma protein binding sites)

36. Fibrates………………… Clofibrate - Abandoned - Doesn’t prevent atherosclerosis - R isk of gallstones Gemfibrozil - Higher risk of myopathy with statin Short t1/2 Bezafibrate - More LDL lowering than gemfibrozil - Less risk of myopathy with statin Fenofibrate - More LDL lowering & more HDL - Raising effect than gemfibrozil - Less risk of myopathy with statin - U ricosuric action

37. Fibrates Indications for use - Drug of choice for 1 °& 2° severe hyper- triglyceridemia -Mixed dyslipidaemia ( Bezafibrate / fenofibrate ) -Combined with other drugs like statins for resistant dyslipidaemias ( fenofibrate preferred)

38. Nicotinic acid(Niacin) B group vitamin at higher doses reduces plasma lipids MOA Inhibits lipolysis in adipose tissue decreased FFA for TG & VLDL synthesis in liver Decreases VLDL(20-50%),LDL (15-25%) Raises HDL (20-35%) & reduces lipoprotein A & has antiatherogenic properties

39. Niacin ADR Cutaneous flushing , itching , heat Dyspepsia , vomiting , diarrhoea , activation of peptic ulcer Dryness , hyperpigmentation of skin Liver dysfunction Precipitation of diabetes Hyperuricemia Atrial arrhythmias Contraindication Pregnancy , peptic ulcer , diabetes , gout .liver disease

40. Niacin Drug interactions -Postural hypotension with antihypertensives -Myopathy risk with statins Indications -Severe h ypertriglyceridemias -Adjunctive drug to statins / fibrates in severe dyslipidaemia -Combined dyslipidemias - Shown to decrease recurrence of MI

41. Miscellaneous agents Gugulipid : Ayurvedic prep -Inhibits synthesis & increases excretion of cholesterol Modest lowering of LDL , TG & rise in HDL Fish oils -lower TG levels but raise LDL - Antiatherogenic property due to production of 3 series Prostanoids & 5 series LTs

42. Overview of drugs Total cholesterol LDL HDL TG Statin Resins - - Ezetimibe - - Fibrates Niacin

43. Treatment of hyperlipidemias Treatment modalities Lifestyle modifications Pharmacotherapy Treatment plan decided on the basis of :- lipid profile risk assessment for CAD

44. Plasma lipid levels (NCEP-2001) mg/dl Total cholesterol LDL HDL TG Optimal <200 <100 <70(CAD) >40(M) >50(F) <150 Borderline high 200-239 130-159 - 150-199 high ≥240 160-189 >60 200-499 Very high - ≥190 - ≥500

45. Risk factors for CAD Men >45, Women>55yrs Family h/o MI/sudden cardiac death before 55yrs in men & 65yrs in women in first degree relative Smoking HTN High LDL (>160mg/dl) or total cholesterol(>240mg/dl) Low HDL (<40 in men , <50 in women) Obesity ##CAD equivalent : DM / PVD /abdominal aortic aneurysm / symptomatic carotid artery disease

46. Patient stratification Low risk : 0-1 CAD risk factor Moderate risk : ≥2 CAD risk factors + 10yr CAD risk < 10% Moderately high risk : ≥2 CAD risk factors + 10 yr CAD risk 10- 20 % High risk : CAD / CAD equivalent Very high risk : CAD/CAD equivalent + 1 of the below ≥2CAD risk factors Single uncontrolled CAD risk factor DM Metabolic syndrome Acute coronary syndrome

47. NCEP-ATP Ш Guidelines Risk category LDL goal (Mg/dl) Lifestyle Drug Very high risk < 70 all subjects All subjects High risk < 100 All subjects All subjects Moderately high risk < 130 (or < 100) ≥ 100 ≥ 130 Moderate risk < 130 ≥ 130 ≥ 160 Low risk < 160 ≥ 160 ≥ 190

48. Drug treatment Low dose statin(as per target LDL level & cost effectiveness) Double the dose every six weeks till max dose if inadequate response with low dose Add another drug ( ezetimibe / fibrate /niacin) if needed

49. Treatment of raised TG levels TG < 150mg/dl – No TG lowering needed .Treat as per LDL levels TG 200-499 mg/dl ( High) -lifestyle modification -treatment of cause if identified -statin therapy to achieve goal LDL level -TG lowering drug (fibrate/niacin) considered if:--CAD present/family h/o premature CAD/non HDL ≥190/HDL<40/ 1°hypertriglyceridemias TG > 500mg/dl (Very high) -vigorous measures including TG lowering drugs indicated

50. Treatment of low HDL -Total cholesterol: HDL < 3.5 desirable -Statin therapy targeted at LDL lowers the ratio -Treatment of metabolic syndrome helps -Niacin can be added 2 statin therapy

51. Combined Drug Therapy Combined drug therapy is useful when : LDL or VLDL levels are not normalized with a single agent LDL and VLDL levels are both elevated initially VLDL levels are significantly increased during treatment of hypercholesterolemia with a resin. An elevated level of Lp (a) or an HDL deficiency coexists with other hyperlipidemias.

52. Combined Drug Therapy Statins & Resins synergistic combination in the treatment of hypercholesterolemia. Niacin & Resins Effective in familial hypercholesterolemia/combined hyperlipidemias.Resin neutralises acid production by niacin Statins & Niacin More effective than either agent alone in treating hypercholesterolemia & combined hyperlipidemia

53. Combined Drug Therapy Statins & Ezetimibe Is highly synergistic in hypercholesterolemia. Statins & Fenofibrate Fenofibrate with certain statins is useful in combined hyperlipidemias The combination of fenofibrate with rosuvastatin is particularly effective.

54. Current status

55. Future Drugs CETP inhibitors ( anacetrapib & dalcetrapib ) lower LDL while increasing HDL to an extent not possible with existing HDL-raising therapies. Darapladib inhibits lipoprotein associated phospholipase A2 (enzyme produced by inflammatory cells & involved in atherosclerosis) Mipomerson (antisense drug ) directed against Apo B (present in LDL)

56. Thank you