Pharmacotherapy of dyslipidemia

Old + Newer agents for dyslipidemia

1. Pharmacotherapy of Dyslipidemia Dr. Irfan Ahmad Khan Senior Resident

2. Introduction Dyslipidemia – disorders of lipoprotein metabolism. Abnormal plasma cholesterol and/or Triglyceride (TG) concentrations. Major cause of atherosclerosis and related cardiovascular diseases.

3. Lipoprotein

4. Major lipoprotein classes Chylomicron remnants <1.006 Dietary triglycerides and cholesterol TG<CE B-48, E, A-I, A-V, C-I, C-II, C-III Product of Chylomicron metabolism apoE -mediated uptake by liver A-V A-IV, A-V IDL

5. Inhibits LPL activity and lipoprotein binding to receptors

6. Lipoprotein metabolism Transport of Dietary Lipids / Exogenous Pathway Transport of Hepatic Lipids / Endogenous Pathway Reverse Cholesterol Transport

7. + 50% 50% 75% NPC1L1 ACAT-2 ACAT-2 HL

8. Reverse Cholesterol Transport ABCA1 TG HL

9. Hyperlipidemia Primary Secondary Monogenic Polygenic/multifactorial Mutation in apolipoproteins , their receptors , transport mechanism, metabolizing enzyme Diificult to t/t Multiple genetic Dietary P hysical activity related causes DM Nephrotic Syndrome Hypothroidism Alcoholism Drugs (Corticosteroids, oral contraceptives)

10. (I) (III) ( IIa )

11. Polygenic /Multifactorial IIb : Familial Combined (Polygenic)Hyperlipidemia Similar to IIa except VLDL  ed Deficiency of LDL receptors and overproduction of VLDL by liver IV: Familial Hypertriglyceridemia Overproduction and/ or decreased removal of VLDL

12. Treatment strategies 1. Dietary and lifestyle modification (NCEP-ATP 4 guidelines) Aerobic exercise or brisk walking (20-60 min/d for 3-5 days/week) Reduce intake of cholesterol(<30% of total calories) and saturated fats(5-6 % of total calories) Reduce sugary beverage intake (<36 oz / wk ), sweets Cessation of alcohol and smoking 2. Drugs Individualized approach

13. Drugs for dyslipidemia Well established Anti- dyslipidemic therapies HMG-CoA (3-hydroxy-3- methyl glutaryl CoA) reductase inhibitors Fibric acid derivatives Bile acid sequestrants Nicotinic acid Inhibitor of dietary cholesterol uptake B. Newly developed Anti- dyslipidemic therapies Proprotein Convertase Subtilisin / Kexin Type 9(PCSK9) inhibitors Inhibitor of ApoB Synthesis Microsomal Triglyceride Transfer Protein (MTP) inhibitors ApoC -III Synthesis inhibitors Gugulipid and fish oil derivatives

14. Most effective, best-tolerated Agents included Lovastatin Pravastatin Simvastatin Atorvastatin Fluvastatin Rosuvastatin HMG-CoA Reductase Inhibitors (statins)

15. MOA Inhibit HMG-CoA reductase competitively ( HMG- CoA Mevalonic acid) Inhibit biosynthesis of cholesterol Depletion of cholesterol in hepatocytes Activates Scap (SREBP cleavage activating protein) Proteolytic cleavage of SREBP (Sterol regulatory element binding protein) Translocates to nucleus  LDL-R expression on hepatocytes  ed hepatic uptake of LDL, IDL & decrease plasma LDL ( 20-55% ) (Major effect – dose and agent dependent 6 % reduction with doubling of dose)

16. Decrease VLDL by : ↓ hepatic VLDL synthesis d/t ↓ in cholesterol  ↓LDL-C( ~ 25%)  Homozygous familial hypercholesterolemia ( LDLR are absent) Effect on TGs : 1. If TGs >250 mg/ dL - % decrease ~ % decrease in LDL-C 2. If TGs <250 mg/ dL - < 25% decrease in TG levels  in HDL ~15-20 % ( Rosuvastatin )

17. Pleiotropic effects: Improved endothelial function ,  NO Increase plaque stability Reduce lipoprotein oxidation Anti inflammatory role, ↓ CRP Reduce platelet aggregation, profibrinolytic activity

18. Pharmacokinetics Extensive first pass hepatic metabolism (uptake by OATP1B1 ) Simvastatin, Lovastatin : lactone prodrugs t 1/2 -1-4 hrs  taken in evening Atorvastatin , Rosuvastatin (~20 hrs ), Simvastatin (~12 hrs ). Dosing advisable to start each patient on a dose that will achieve the patient's target goal for LDL-C lowering

19. Statins dose (mg) Required to Achieve Various Reductions in LDL-C from Baseline

20. Adverse effects Myopathy: Myopathy – rhabdomyolysis – myoglobinuria –renal shut down High dose / Old age/ Perioperative period Hepatic / renal dysfunction, Hypothyroidism Drugs : fibrates, especially gemfibrozil (OATP1B1 inhibition, interferes with glucuronidation ), erythromycin, cyclosporine, itraconazole ( CYP3A4) Fluvastatin (2C9) and pravastatin (unchanged) – less risk of myopathy Niacin  enhanced inhibition of skeletal muscle cholesterol synthesis

21. Hepatotoxicity : Elevation of transaminases. Severe hepatitis rare Monitoring recommended before starting therapy and at 2-3 months, then annually. C/I : pregnancy & lactation . Pravastatin in children >8 yrs. Atorvastatin, Simvastatin and Lovastatin >11 yrs .

22. Use DOC for hypercholesterolemia Statins + Niacin =  ed effectiveness but  risk of myopathy Statins + resins = 20-30% greater reduction i n LDL-C Statins + fibrates = useful when  LDL associated with  TG Atorvastatin and Rosuvastatin : max TG lowering effect Statin + resins + Niacin = 70% reduction in LDL- C Simvastatin + Ezetimibe = 60 % reduction in LDL-C

23. Activators of PPAR α – gene transcription regulator (expressed primarily in liver and brown adipose tissue) ! st generation - Gemfibrozil (600 -mg BD, 30 minutes before morning and evening meals) 2 nd generation - Clofibrate (~500 mg QID) Fenofibrate (~145 mg OD) Bezafibrate ( ~200 mg TDS) Fibric Acid Derivatives

24. MOA  LPL synthesis :  clearance of TG- rich lipoproteins Reduce expression of apoC - III (an inhibitor of lipolytic processing and R- mediated clearance) thereby  clearance of VLDL Reduce TGs ( upto 50% ) by stimulation of fatty acid oxidation  in HDL- C(~15%): stimulation of apoA -I & apoA -II expression Misc. effect : inhibition of coagulation and  fibrinolysis

25. Therapeutic Uses DOC Type III familial dysbetalipoproteinemia Severe hypertriglyceridemia Chylomicronemia syndrome Familial hypercholesterolemia type IIa Familial combined hypercholesterolemia type IIb  triglycerides and low HDL-C levels associated with the metabolic syndrome or type 2 diabetes mellitus

26. Adverse effects Abdominal discomfort/ Diarrhea/ Nausea. Increased risk of gallstones ( clofibrate ). Prolonged prothrombin time Myopathy : high risk when combined with statins (followed at 3 months). Gemfibrozil : highest incidence. Fenofibrate safer: glucuronidated by enzymes that are not involved in statin glucuronidation C/ I C hildren & pregnant women Renal failure

27. Safest as not absorbed from intestine Cholestyramine, colestipol, colesevelam MOA: Highly positively charged molecules that bind negatively charged bile acids Due to large size, resins are not absorbed and bound bile acids are excreted in stool Pool of bile acids is depleted Bile Acid Sequestrants

28. The resin- induced decrease in BA is a/w  in hepatic TG synthesis. Monitoring ( every 1-2 weeks) of fasting TG levels is needed or their use in such patients should be avoided. 12-18% reduction in LDL-C. 4 – 60% reduction in LDL-C when used along with statin/ niacin 4 -5% rise in HDL-C .

29. Therapeutic Uses: Heterozygous familial hypercholesterolemia Drug of choice for children and females in reproductive age group. Dose : Cholestyramine 4g packet Colestipol 5g packet / 1g tab. Colesevelam 1.875 g packet/ 625 mg tab. (3 tab.)  BD with meal C /I- Hypertriglyceridemia M ixed with water or juice . Ideally, patient should take resins BBF and before supper, starting with one packet twice daily

30. Adverse effects Heart burn, dyspepsia , bloating, gritty sensation (suspending powder in liquid several hours before ingestion) M alabsorption of Vitamin K, folic acid etc. Constipation (adequate water intake and psyllium ) Rarely can cause hyperchloremic acidosis. D/I: Binds to digoxin, warfarin, thyroxine , some statins, furosemide , thiazides; prevents absorption  1 hr before or 3-4 hrs after bile acid sequestrants .

31. Niacin (Nicotinic Acid) Oldest, effective , inexpensive, often used in combination B est agent available for increasing HDL-C (25-30%) L owers TGs ( 40 %), LDL-C (20-25%) in dose of 1.5-3 g/day Reduces Lp(a) levels significantly.

32.  LPL activity ,  clearance of chylomicrons and VLDL I nhibit a rate-limiting enzyme of TG synthesis, Diacyl Glycerol Acyl Transferase-2 Inhibits lipolysis of TGs by HS Lipases by inhibiting adipocyte adenylyl cyclase Decrease fractional clearance of Stimulates expression of SR-CD36 & ABCA1 1. 2. 3. 4.

33. Therapeutic uses: H ypertriglyceridemia and high LDL-C associated with low HDL DOC for Familial combined hypertriglyceridemia Familial dysbetalipoproteinemia (type 3) Severe mixed hypertriglyceridemia(type 4) Heterozygous familial hypercholesterolemia (+ resins/statins) Niacin Starting Dose Maximal Dose Immediate release 100 mg TDS 1 g TDS Sustained release 250 mg BD 1.5 g BD Extended release 500 mg HS 2 g HS

34. Side effects Flushing , warmth ( PGD 2 & E 2 ) Pruritus, rashes Dyspepsia Skin dryness Acanthosis nigricans Liver dysfunction (flu like fatigue) Hyperglycemia, Hyperuricemia Risk of myopathy if combined with statins. (dose not >25% of maximum) C/I Peptic ulcer disease Gout DM Pregnancy

35. Ezetimibe Inhibition of cholesterol absorption by jejunal enterocytes (NPC1L1 transport protein)  decrease in hepatic cholesterol  upregulation of LDL-R. Lowers LDL -C by 15-20 %  HDL-C by ~2% and decrease TGs by ~5% 10 mg tablet/day with statins Bile-acid sequestrants inhibit absorption of ezetimibe  should not be co-administered ADRs: rare allergic reactions

36. Proprotein Convertase Subtilisin / Kexin Type 9 (PCSK9) inhibitors PCSK9: physiological enzyme ligand of LDL-R Low pH Prevents dissociation

37. Alirocumab & Evolocumab (Approved in 2015) Heterozygous FH Lower LDL-C by 50-72% ( effect persists for 2-4 weeks after single S.C. injection) Lower PCSK9 activity upto 80%; Reduce Lp (a) Alirocumab : 75 mg SC q2weeks; If the LDL-C lowering response is inadequate, may increase to 150 mg SC q2weeks Evolocumab : 140 mg SC q2weeks Bococizumab (Phase III) PCSK9 also involved in degradation of many receptors that are also receptors for viruses (human rhinovirus and hepatitis C virus)  viral infections need to be monitored in patients on PCSK9 inhibitors

38. Inhibitor of ApoB Synthesis: Mipomersen Antisense oligonucleotide that inhibits ApoB-100 synthesis in liver  decrease VLDL & LDL-C Useful in heterozygous and homozygous FH who lack LDL-R 200 mg SC weekly: reduces apoB (33-54%), LDL-C(34-52%), Lp (a)(24%) ADRs: severe injection site reaction, flu-like reactions, headache, hepatotoxicity Approved for t/t of homozygous FH with restriction due to hepatotoxicity available through restricted Risk Evaluation & Mitigation Strategy(REMS) program

39. Microsomal Triglyceride Transfer Protein (MTP) inhibitors: Lomitapide Bind and inhibit MTP from transferring TG to apoB in liver  decrease in VLDL & LDL-C Useful in homozygous FH who lack LDL-R Reduces LDL-C (42-50%) Dose: Initially orally 5mg/day 10, 20 40 upto 60 mg Approved for t/t of homozygous FH with restriction  hepatotoxicity available through restricted Risk Evaluation & Mitigation Strategy(REMS) program

40. ApoC -III Synthesis inhibitors: Volanesorsen ApoC -III  inhibits LPL reduced lipolysis of TG rich lipoproteins  TG ApoC - III  Inhibits hepatic lipase reduced catabolism and uptake of TG rich lipoprotein remnants Phase 3 : hypertriglyceridemia, familial chylomicronemia syndrome

41. Gugulipid Developed at CDRI, Lucknow MOA: inhibits CH biosynthesis and enhances rate of excretion of CH Dose: 25 mg TDS orally ADR: Loose stools

42. Fish oil derivatives (Omega-3 Fatty Acids) Contains PUFAs: eicosa penta-enoic acid (EPA) and docosa hexa -enoic acid (DHA )  TG catabolism, membrane stabilizing and anti-oxidant action 4g/day

43. Thank you

44. Disorders of reduced HDL-C Gene deletion in APO A5-A1-C3-A4 locus and coding mutation in APOA1 Tangier Disease (ABCA1 deficiency) Familial LCAT deficiency

45. 2. Therapies that HDL Cholestryl ester transfer protein (CETP) Inhibitors: Dalcetrapib , Torcetrapib , Evacetrapib , Anace trapib