Pharmacotherapy of Dyslipidemia

Dr. Irfan Ahmad KhanSenior 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

ABCA1TG HL

Hyperlipidemia

Primary

Secondary

Monogenic Polygenic/multifactorialMutation 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)

MOAInhibit HMG-CoA reductase competitively

(HMG-CoAMevalonic 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 dependent6% 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 downo High dose / Old age/ Perioperative periodo Hepatic/ renal dysfunction, Hypothyroidismo Drugs: fibrates, especially gemfibrozil (OATP1B1 inhibition,

interferes with glucuronidation), erythromycin, cyclosporine, itraconazole (CYP3A4)

o Fluvastatin (2C9) and pravastatin (unchanged) – less risk of myopathy

o Niacinenhanced 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 ezetimibeshould 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 lipoproteinsTG

• 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

Thank you

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