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Pharmacotherapy of dyslipidemia

This document discusses the pharmacotherapy of dyslipidemia. It begins by defining dyslipidemia as disorders of lipoprotein metabolism that result in abnormal cholesterol and triglyceride levels, and describes lipoproteins. It then discusses the treatment of dyslipidemia, including lifestyle modifications and various drug therapies such as statins, fibrates, bile acid sequestrants, nicotinic acid, ezetimibe, PCSK9 inhibitors, and other newer therapies. It provides details on the mechanisms of action, uses, dosing, and side effects of these different drug classes.

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Pharmacotherapy of Dyslipidemia Dr. Irfan Ahmad Khan Senior Resident
Introduction • Dyslipidemia – disorders of lipoprotein metabolism. – Abnormal plasma cholesterol and/or Triglyceride (TG) concentrations. • Major cause of atherosclerosis and related cardiovascular diseases.
Lipoprotein
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
Inhibits LPL activity and lipoprotein binding to receptors
Lipoprotein metabolism • Transport of Dietary Lipids / Exogenous Pathway • Transport of Hepatic Lipids / Endogenous Pathway • Reverse Cholesterol Transport
+ 50% 50% 75% NPC1L1 ACAT-2 ACAT-2 HL
Reverse Cholesterol Transport ABCA1 TG HL
Hyperlipidemia Primary Secondary Monogenic Polygenic/multifactorial Mutation in apolipoproteins, their receptors, transport mechanism, metabolizing enzyme Diificult to t/t • Multiple genetic • Dietary • Physical activity related causes • DM • Nephrotic Syndrome • Hypothroidism • Alcoholism • Drugs (Corticosteroids, oral contraceptives)
(I) (III) (IIa)
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
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
Drugs for dyslipidemia A. 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
• Most effective, best-tolerated • Agents included • Lovastatin • Pravastatin • Simvastatin • Atorvastatin • Fluvastatin • Rosuvastatin HMG-CoA Reductase Inhibitors (statins)
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)
 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)
Pleiotropic effects: • Improved endothelial function ,  NO • Increase plaque stability • Reduce lipoprotein oxidation • Anti inflammatory role, ↓ CRP • Reduce platelet aggregation, profibrinolytic activity
Pharmacokinetics • Extensive first pass hepatic metabolism(uptake by OATP1B1) • Simvastatin, Lovastatin : lactone prodrugs • t1/2-1-4 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
Statins dose (mg) Required to Achieve Various Reductions in LDL-C from Baseline
Adverse effects • Myopathy: o Myopathy–rhabdomyolysis–myoglobinuria–renal shut down o High dose / Old age/ Perioperative period o Hepatic/ renal dysfunction, Hypothyroidism o Drugs: fibrates, especially gemfibrozil (OATP1B1 inhibition, interferes with glucuronidation), erythromycin, cyclosporine, itraconazole (CYP3A4) o Fluvastatin (2C9) and pravastatin (unchanged) – less risk of myopathy o Niacinenhanced inhibition of skeletal muscle cholesterol synthesis
• 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.
Use • DOC for hypercholesterolemia • Statins + Niacin = ed effectiveness but  risk of myopathy • Statins + resins = 20-30% greater reduction in 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
Activators of PPARα – gene transcription regulator (expressed primarily in liver and brown adipose tissue) !st generation - Gemfibrozil (600-mg BD, 30 minutes before morning and evening meals) 2nd generation - Clofibrate (~500 mg QID) Fenofibrate (~145 mg OD) Bezafibrate( ~200 mg TDS) Fibric Acid Derivatives
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
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
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 • Children & pregnant women • Renal failure
• 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
• 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. • 40 – 60% reduction in LDL-C when used along with statin/ niacin • 4-5% rise in HDL-C.
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 Mixed with water or juice. Ideally, patient should take resins BBF and before supper, starting with one packet twice daily
Adverse effects • Heart burn, dyspepsia, bloating, gritty sensation (suspending powder in liquid several hours before ingestion) • Malabsorption 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.
Niacin (Nicotinic Acid) • Oldest, effective, inexpensive, often used in combination • Best agent available for increasing HDL-C (25-30%) • Lowers TGs (40%), LDL-C (20-25%) in dose of 1.5-3 g/day • Reduces Lp(a) levels significantly.
• LPL activity,  clearance of chylomicrons and VLDL • Inhibit 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.
Therapeutic uses: • Hypertriglyceridemia 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
Side effects • Flushing, warmth (PGD2 & E2) • 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
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
Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) inhibitors • PCSK9: physiological enzyme ligand of LDL-R Low pH Prevents dissociation
• 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
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
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
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
Gugulipid • Developed at CDRI, Lucknow • MOA: inhibits CH biosynthesis and enhances rate of excretion of CH • Dose: 25 mg TDS orally • ADR: Loose stools
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
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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
2. Therapies that HDL – Cholestryl ester transfer protein (CETP) Inhibitors: Dalcetrapib, Torcetrapib, Evacetrapib, Anacetrapib