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TOPIC:Recent Advances in Dyslipidemia

Dr. Jeetam Singh Rajput MLN Medical college

OutlineIntroduction.Lipid handling in bodyPathophysiology of atherosclerosisCurrent hypolipidemic drugNewer hypolipidemic drugAHA/ACC clinical guidelines

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IntroductionDyslipidemia is a disorder of Lipid & lipoprotein metabolism.Three primary abnormality are thereElevated triglyceride(TG)Elevated LDL cholestrolReduced HDL cholestrolIt is most important modifiable risk factor for CAD.Causes for dyslipidemiaPrimary dyslipidemiaSecondary dyslipidemia

SECONDARY DYSLIPIDEMIAIncreased LDL-CIncreased TGLow HDL-CHypothyroidismHypothyroidismNAFLDRenal disease (Nephrotic syn/CRF)Renal disease(CRF)CRFObstructive liver diseaseDM(1 & 2)DM(1 & 2)Cushing syndromeMetabolic syndromeMetabolis syndromePCOSHIVHIVAnorexia nervosaAnorexia nervosaSmokingDRUG:GaucherGaucherAnabolic steroidPregnancyDRUG:CyclosporinDRUG:ProgestinProgestinEstrogen(OCPS)Beta blockerThiazideBASAnabolic steroidSERMs(Tamoxifen)IsotretinoidsBeta blockerPIs, CorticosteroidThiazide, PIs, Steroids

Lipoprotein

Classified in 7 claases on basis of density1. HDL2. VLDL3. IDL4. LDL5. Chylomicron

TG mainly transported in form of Chylomicron & VLDL.Cholestrol mainly transported as cholestrol ester in LDL & HDL.

LipoproteinMajor surface apolipoproteinChylomicronB-48,E,C-I,C-II,A-I,A-IIChylomicron remnantEVLDLB-100, E, C-I, C-II, IDLB-100, ELDLB-100Lp(a)B-100, (a)HDLA-I, A-II, A-IV, C-I, C-II, D, E

Lipoprotein containing apo-lipoprotein B as cofactor they are atherogenic & which contain apo-lipoprotein A as a cofactor they are non atherogenic.So atherogenic lipoprotein areChylomicronChylomicron remnantVLDLIDLLDLLp(a)Only non atherogenic/antiatherogenic/good cholestrol lipoprotein isHDL

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What does dyslipidemia do:

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Classification of Cholestrol & TG levelLIPIDMg/dlTotal cholestrolDesirable239LDL CholestrolOptimal50 years of age or post menopausal.All patients regardless of age withDiabetes mellitusHypertension Currently smoking cigaretteObesityFamily H/O CAD 500 consider for drug therapy.Individuals with LDLC 190 mg/dL or triglycerides 500 mg/dL should be evaluated for secondary cause of dyslipidemia. AHA blood cholestrol guideline 2013

Treatment goal

191.8% of US positive for antibodiesOrthotopic liver transplantation refers to a procedure in which a failed liver is removed from the patient's body and a healthy donor liver is transplanted into the same location. The procedure is the most common method used to transplant livers.

*For those at moderate risk, additional testing may be considered for some patients to assist with decisions about risk stratification.For patients with diabetes plus 1 major ASCVD risk factor, treating to a nonHDL-C goal of ,100 mg/dL (LDL-C of ,70 mg/dL) is considered a therapeutic option.For patients with chronic kidney disease (CKD) stage 3B stage 4 the lipid lowering therapy is beneficial but, Stage 5 CKD is a very highrisk condition, but results lipid-altering therapies have not provided convincing evidence of reduced ASCVD events in such patients. Therefore, no treatment goals for lipid therapy have been defined for stage 5 CKD.

journal of clinical lipidology 2015/AHA guideline 2013

Major risk factor for ASCVD

Classification of ASCVD(atherosclerotic cardiovascular disease) : Myocardial infarction or other acute coronary syndrome. Coronary or other revascularization procedure. Transient ischemic attack. Ischemic stroke. Atherosclerotic peripheral arterial disease Includes ankle/brachial index of ,0.90 Other documented atherosclerotic diseases such as Coronary atherosclerosis Renal atherosclerosis Aortic aneurysm secondary to atherosclerosis Carotid plaque, $50% stenosis

For patients at low or moderate risk, lifestyle therapy should be given a trial of at least 3 mo before initiation of drug therapy.

For patients at very high risk and selected patients at high risk (those unlikely to reach goal with lifestyle alone), drug therapy may be started concurrently with lifestyle therapy.

Referral to an RDN is recommended to facilitate dietary modification and to an exercise specialist for guided instruction on a suitable exercise program.Recommendation:

After atherogenic cholesterol targets are achieved with lifestyle therapies, responses should continue to be monitored at intervals of 612 mo.Before initiation of atherogenic cholesterollowering drug therapy, the clinician should discuss with the patient the treatment objectives, potential ,adverse effects, possible interactions with other drugs or dietary supplements, lifestyle and medication adherence, and patient preferences as well as convey that alternative agents and regimens are available in the event of side effects.First-line cholesterol-lowering drug therapy, unless contraindicated, is moderate- to high-intensity statin. The statin dosage may be increased or the patient switched to a more efficacious agent, if goal levels of atherogenic cholesterol are not achieved

Nonstatin drug therapy may be considered for patients with contraindications for, or intolerance to, statin therapy.

Combination drug therapy with a statin plus a second (or third) may be considered for patients who have not attained their atherogenic cholesterol levels after the maximum tolerated statin dosage has been reached and for those who have contraindications or are intolerant to statin therapy.

If drug therapy is used, at least a 30% reduction in atherogenic cholesterol should be targeted.Response to therapy should be monitored within 412 mo.

Patients with very high TG (500 mg/dL), the primary objective of therapy is to lower the triglyceride level to ,500 mg/dL to reduce the risk of pancreatitis.

Patients with high TG (200499 mg/dL), the primary objective of therapy is to lower levels of nonHDL-C and LDL-C to reduce risk for an ASCVD event.For the level of TGTG : 200-499= Statins should be use.TG: 500-999= TG lowering agent or Statins may be use.TG: >1000 = TG lowering should be consider.patients with severe hypercholesterolemia, an alternative goal is to lower atherogenic cholesterol levels by at least 50%.LDL apheresis may be considered for selected patients.

Statins:MOA:- HMG CoA inhibitor( rate limiting enzyme in cholestrol synthesis)

DRUGSTARTING DOSEMAXM DOSEBRAND NAMELovastatin20-40 mg daily80 mg dailyStatin,Lostatin,Lovacard,Lochol, LovalipPravastatin40-80 mg daily80 mg dailyPravachol, Pravator, Simvastatin20-40 mg daily80 mg daily Simlip, Starstat Fluvastatin20-40 mg daily80 mg dailyLescol XL 80Atorvastatin20-40 mg daily80 mg daily Atomac, Atorlip, TG-TORXTOR, Avas, Lipikind, AvasRosuvastatin5-20 mg daily 40 mg dailyTurbovas,Lipirose, Rozustat,Roseday,RosulipPitavastatin1-2 mg daily4 mg dailyPivasta, Pitava

Mechanism of action

Pleotropic effect of statin:Reduction in lipoprotein oxidation.Anti inflammatory property.Decrease platelet aggregation & formation of thrombi.Improvement in endothelial function.Antioxidant property.Plaque stability.

DyspepsiaHeadache FatigueMuscle & joint painMyopathy, RhabdomyolysisNote: Myopathy is precipitated by older age, renal failure, drug interfere with metabolism of statins. In the event of muscle symotoms Plasma CK level should be measure.Elevation of ALT & ASTNote: Checked before starting the therapy & after 2-3 mnth of start of therapy then anually. Change in therapy should be consider when level of enzyme > 3times normal.Associated with risk of diabetes mellitus.Side effect of statins

Contraindication:PregnancyLactation

Potency: Rosuvastatin ( 39-45% LDL reduction)>Atorvastatin (39-42%)>Simvastatin(35-41%)>Fluvastatin (25-35%) >Pravastatin(34%)> Pitvastatin(32%)>Lovastatin(31%)

Some important point regarding individual statin:Atorvastatin: Long acting, highest LDL-C lowering, antioxidant, antinflamatory.Lovastatin: First clinically used statin, prodrug, extensive FPM.Simvastatin: Prodrug, Extensive FPM, greater rise in HDL.Pravastatin: CH lowering effect is less,decrease plaque,decrease fibrinogen.Rosuvastatin: Most potent, greater reduction in LDL-C.Pitvastatin: Latest, no specific advantage.

High-Mod-Low intensity statin therapy

AHA/ACC guidelines 2013

MOA: Increase bile acid excretion , increase LDL receptor.EXAMPLE:

Bile acid sequestrants:DRUGSTARTING DOSEMAXM DOSEBRAND NAMECholestyramine4 gm daily32 gm dailyCholtran,Choltran sachet, QuestranColestipol5 gm daily40 gm dailyColestidColesevelam3750 mg daily4375 mg dailyWelchol625

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SIDE EFFECT:BloatingConstipationElevated TG

Some important point :2nd DOC for dyslipidemia, for statins intolerant patients.DOC in children, lactating, pregnant, or could become pregnant women(b/c do not absorb systemically).Used in combination with a statins.Hyper-TG limit use.Secondary effect on CH synthesis increase VLDL.

NOTE: Usually employed in combination with fibrate, statins.Most effctive HDL-C raising pharmacological agent.MOA: dec VLDL & fibrinogen & TG(40%), Inc HDL.INDICATION : Elevated LDL-C, & TG.SIDE EFFECT:Cutaneous flushing.GI upsetElevated glucose, uric acid , LFTPREPARATION:

Nicotinic acid:PREPARATIONSTARTING DOSE MAXM DOSEBRANDImmidiate release100 mg tid1 gm tidNiaspan100Sustained/Extended release250 mg bid1.5 gm bidNialip250/375

MOA: Increase LPL, decrease VLDL synthesis.INDICATION: Elevated TG.SIDE EFFECT:DyspepsiaMyalgiaGall stone , Elevated transaminases.EXAMPLE:

Fibric acid derivatives:DRUGSTARTING DOSEMAXM DOSEBRAND NAMEGemfibrozil600 mg bid600 mg bidGempar300Triglyd600, Normolip300Fenofibrate145 mg qd145 mg qdTG Chek160, Trichek, FenolipBezafibrate200 mg bid200 mg bidBeza XL 400

NOTE:Less favourable effect on clinical outcome, improvement in microvascular outcome.FENOFIBRATE:Reduce fibrinogrn level.Commonly used in combination with statins(myopathy).

GEMFIBROGIL: Increase risk of myopathy with statin.

BEZAFIBRATE: No myopathy.INTERACTION:Increase risk of myositis on statins.Reduction dose(30%) requirement for patients on warfarin.

EZETIMIBE:TRADE NAME: Ezetib10mg, Ezitimide 10mg, Ezedoc 10mg.DOSE: 10 mg daily. Inhibit CH absorption from intestine by binding to NPC1L1 transporter in intestine.Indicated for elevated LDL-C.Unlike resin it causes fall in TG.Causes elevation in transaminases.Cholestrol absorption inhibitor:

Omega-3 fatty acid :Causes increase catabolism of TG.Indicated in elevated TG.

SIDE EFFECT: Dyspepsia Fishy odor to breath.

DRUG STARTING DOSEMAXM DOSEBRAND NAMEOmega-3 acid ethyl ester4 gm daily4 gm dailyMAX-OMEGA300/200Multivite FM Omega

Icosapent ethyl4 gm daily 4 gm dailyVascepa 1gm

PCSK9 INHIBITOR:Inhibit proprotein convertase subtilisin/kexin type 9.Increase LDL receptor density on hepatocyte.Prevent LDL receptor degredation.

1. ALIROCUMABBrand name PraluentDose 1. starting dose : 75 mg s/c twice weekly. 2. maxm dose : 150 mg s/c twice weekly.INDICATION:Adjunct to diet & maximally tolerated statin therapy.Adult with hetrozygous familial hypercholestrolemia.Clinical ASCVD.Who require additional lowering of LDL-C.

SIDE EFFECT:Nose throat irritationInjection site reaction & bruisingFlue like symptomsDiarrhoea, muscle pain NOTE: Alirocumab is first PCSK9I to be approved in july 2015

2. EVOLOCUMAB:Brand name : RepathaDose: 420 mg s/c once monthly.FDA approval in 27 aug 2015.Indication & side effects are same as that of Alirocumab.

3. BOCOCIZUMAB: Yet not approved by FDA.

Brand name: Kynamro.DOSE: 200 mg s/c weekly.Decrease formation of apo-B containing lipoprotein including LDL-C(40-50%)Also decrease Lp(a) concentration.Approved for homozygous familial hypercholestrolemia & minimising need lipid apheresis.SIDE EFFECT: 1. Influenza like illness. 2. Injection site reaction . 3. Hepatic steatosis.

Apo B Inhibitor- MIPOMERSEN

MTTP Inhibitor- LOMITAPIDEBrand name: JuxpidDose: 5 mg daily to 60 mg daily.Inhibit TG transfer to Apo-B48 & Apo B100 in intestine & liver cells respectively.Lead to decrease formation chylomicron & VLDL, decrease VLDL lead to decrease level of LDL.FDA approval in 2012 for homozygous familial hypercholestrolemia.SIDE EFFECT: 1. Increased stool frequency. 2. Hepatic steatosis, elevated tranaminases.

Thyroid hormone analog with minimal non hepatic tissue uptake.No long term or large study done so far.No clinical hyper/hypo thyroidism.S/E: Elevated liver enzyme.

Thyromimetic- EPRORITOME

Lipid apheresis:

Selective removal of LDL, VLDL, Lp(a).Little pr no effect on other plasma component( HDL, alb,IgG)Indication: Familial hypercholestrolemia

Note:- After diet and maximum tolerated drug therapy for 6month 1)LDL level >200 with CAD 2)LDLlevel >300 without CAD then Lipid apheresis/LDL apheresis is indicated.

Best predictor for future risk of cardiovascular events among following is:hsCRPLipoprotein aHomocysteineInterleukin 6

Ans; A hsCRPCRP when measure d by high senstivity assay strongly and indepenly predict risk of MI, Stroke, PAD, hsCRP+ TC:HDL-C > hsCRP > TC:HDL-C > Apo B > S. Amyloid A > LDL-C > TC > IL-6 > Homocysteine > lip(a)

2. The protein which has structural homologywith plasminogen and is responsible for MI & strokeHDLLp(a)LDLHomocysteine

Ans : B Lp(a)It is an LDL like plasma lipoprotein consisting of a cholestrol rich LDL particle with one molecule of Apo-B 100 and an additional protein Apo(a) apolipoprotein.It has structural homology to plasminogen but lack any fibrinolytic activity.

3.Which of the following increases the susceptibility to coronary artery disease:Type V HyperlipoproteinemiaVon willebrands diseaseNephrotic syndromeSLE

Ans. C Nephrotic syndrome

Hyperlipidemia in nephrotic syndrome is a consequences of increased hepatic lipoprotein synthesis LDL & Cholestrol increased in majority of patients ,this hyper lipidemia may accelerate atherosclerosis and progression of renal disease .harrisionsHyperlipidemia type V not associated with increased LDL This disorder does not appear to increase risk of CHD either because large TG rich lipoporotein are not atherogenic or because only normal amount of LDL can be generated .harrisons

4. All of the following are diatery goal are recommended for patient with high risk of CHD exceptSaturated fat < 7% of total calTotal cholestrol < 250 mg/dPolyunsaturated fat upto 10% of total calorie Salt intake < 6 gm/d

Ans. B. Total cholestrol