CURRENT STATUS & RECENT ADVANCES IN

DYSLIPIDEMIA TREATMENT

Dr. Jeffrey Pradeep RajPost-graduate

Dept. of Pharmacology – SJMC02-11-2015

OUTLINE• Introduction • Lipid handling in the body• Pathophysiology of atherosclerosis• Current Hypolipidaemic drugs• Newer Hypolipidaemic drugs• ACC/AHA Clinical guidelines 2013• Pipeline drugs• Summary

INTRODUCTION

DYSLIPIDEMIA• Disorder of Lipid & lipoprotein metabolism• 3 primary abnormalities

Elevated triglycerides Elevated LDL cholesterolReduced HDL cholesterol

• Most important modifiable risk factor for CAD• Causes – Primary / secondary

PRIMARY DYSLIPIDEMIATYPE LIPID LIPOPROTEIN OCCURRENCEI – Familial lipoprotein lipase deficiency

TG Chylomicrons Rare

IIa – Familial Hypercholesterolaemia

C LDL Common

IIb – Polygenic hypercholestrolaemia

C, TG LDL, VLDL Most common

III – Familial dysbetalipoproteinaemia

C,TG IDL Rare

IV – Hypertriglyceridemia TG VLDL CommonV – Familial combined hyperlipidaemia

TG VLDL, chylomicrons

Rare

SECONDARY DYSLIPIDEMIA LDL cholesterol Triglycerides HDL cholesterolDiabetes mellitusHypothyroidismNephrotic syndromeObstructive liver diseaseDrugs Anabolic steroidsProgestinsBeta blockersThiazides

AlcoholismDiabetes mellitusHypothyroidismObesityRenal insufficiencyDrugs Beta blockersBile acid resinsEstrogensTiclopidine

Cigarette smokingDiabetes mellitusHypertriglyceridemiaMenopauseObesityPuberty (in males)UraemiaDrugs Anabolic steroidsBeta blockers

LIPID HANDLING IN THE BODY

LIPID ABSORPTION• Bile emulsifies fat in

chyme• P. lipase coverts

Triacyl glyceryl into FFA + glycerol• Absorbed into

enterocyte rapidly

CHYLOMICRON ASSEMBLY

LIPOPROTEINS• 5 classes classified

based on the density• TG transported in

chylomicrons or VLDLs

• Cholesterol transported as cholesteryl esters in LDLs and HDLs

LIPOPROTEIN METABOLISM

PATHOPHYSIOLOGY OF

ATHEROSCLEROSIS

MECHANISM OF ATHEROSCLEROSIS

CURRENT HYPOLIPIDAEMIC

DRUGS

CLASSIFICATION – CURRENT DRUGS

• HMG – CoA reductase inhibitorsLovastatin, simvastatin, pravastatin, atorvastatin,

rosuvastatin, pitavastatin

• Bile acid sequestrants (resins)Cholestyramine, colestipol

• Lipoprotein lipase activators (PPAR alpha activators)Clofibrate, gemfibrozil, bezafibrate, fenofibrate

• Lipolysis and triglyceride synthesis inhibitorNicotinic acid

• Sterol absorption inhibitorEzetimibe

OVERVIEW OF CURRENT DRUGS (1/2)

DRUG CLASS MOA SIDE EFFECTSHMG CoA reductase inhibitorsLovastatin (10-80mg)Simvastatin (5-40mg)Atorvastatin (10-80mg)Rosuvastatin (5-20mg)

↓ CH synthesis by inhibition of rate limiting HMG-CoA reductase

Myositis, myalgia, Elevated hepatic transaminases, Sleep disturbance, Head ache, nausea

Bile acid sequestrantsCholestyramine (4-16g)Colestipol (5-30g)

↓ bile acid absorption, ↑ hepatic conversion of CH to bile acids, ↑ LDL receptors on hepatocytes

Unpalatability, bloating, constipation, heart burn

OVERVIEW OF CURRENT DRUGS (2/2)

DRUG CLASS MOA SIDE EFFECTSPPAR alpha activatorsGemfibrozil (1200mg)Bezafibrate (600mg)Fenofibrate (200mg)

↑ Activity of lipoprotein lipase, ↑ VLDL metabolism, ↑ oxidation of FA in muscle & adipose tissue, ↓ TG synthesis in liver

Nausea, skin rash, 1-2% ↑ incidence of gall stones

Nicotinic acid (2-6g) ↓ Production of VLDL, ↓ lipolysis in adipocytes

Flushing, nausea, gluc intolerance, abnormal LFT, hyperuricemia

STATINS (1/3)Pleotropic effects: Non- lipid lowering, cardioprotective

STATINS (2/3)• Metabolized by microsomal enzymes except

pravastatin• CI: pregnancy, lactation• Potency : rosuvastatin > atorvastatin > simvastatin >

pravastatin & lovastatin• Lovastatin: First clinically used statin, prodrug

Extensive first pass metab; excreted in bile• Simvastatin: Greater rise in HDL, prodrug

Extensive first pass metab; Better oral absorption

STATINS (3/3)• Pravastatin: CH lowering effect is less; ↓ plaque

Decrease in fibrinogen level • Atorvastatin: Long acting (t ½ = 18-24 hr)

Highest LDL-C lowering Antioxidant & antiinflammatory

• Rosuvastatin: Most potent Greater LDL-C reduction

• Pitavastatin: Latest; no specific advantage

ASCOT-LLA TRIAL Sever PS, Dahlöf B, Poulter NR, et al. prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower than average cholesterol concentrations in the Anglo-Scandinavian cardiac outcomes trial – lipid Lowering arm (LLA): a multicentre randomised controlled trial. LANCET 2003; 361:1149

Participants 10305 hypertensive patients (aged 40-79 years; at least 3 CV risk factors) in ASCOT trial with non-fasting total cholesterol concentrations 6.5 mmol/L or less

Intervention Atorvastatin 10mg vs placeboEnd point non-fatal myocardial infarction and fatal CHDConclusions 100 events vs 154 in placebo (HR 0.64, p=0.0005).

Strokes, total CV events & coronary events were significantly lowered in statin arm

JUPITER TRIALRidker PM, Danielson E, Fonseca FA et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359(21):2195

Participants 17,802 healthy pts with LDL-C < 130 mg/dl but hs-CRP of 2.0 mg/l or higher

Intervention rosuvastatin, 20 mg daily, or placebo End point Composite end point of MI, stroke, arterial

revascularization, hospitalization for unstable angina, or death from cardiovascular causes

Conclusions ↓ incidence of major CVS events. ↓ LDL-C 50% & ↓hs-CRP 37%

4S TRIALRandomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study. Lancet 1994; 344 (8934): 1383

Participants 4444 patients with angina pectoris or previous MI & serum cholesterol 5.5-8.0 mmol/L on a lipid-lowering diet

Intervention Simvastatin or placeboEnd point Lipid profile improvement and CVD outcomesConclusions mean changes in TC, LDL-C, HDL-C of -25%, -35%, and

+8%, resp. 37% reduction (p<0.00001) in the risk of undergoing myocardial revascularisation procedures. Improved survival in CHD patients

PROVE-ITCannon CP, Braunwald E, McCabe CH et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes N Engl J Med. 2004;350(15):1495

Participants 4162 patients hospitalized for ACS within the preceding 10 days

Intervention 40 mg pravastatin OD (std therapy) vs 80 mg atorvastatin OD (intensive therapy)

End point Composite of death from any cause, MI, documented unstable angina requiring rehospitalization, revascularization (at least 30 days after randomization), & stroke

Conclusions 16% reduction in the hazard ratio in atorvastatin. Intensive lipid-lowering statin regimen greater survival

BILE ACID SEQUESTRANTS• Secondary effect on cholesterol synthesis actually

VLDL • Hyper- TG may limit use• Used in combination with a statin• Important interactions – bind polar drugs such as

warfarin, digoxin, thyroxine and statins • Colesevelam (625mg 3 tab BD) – newer drug; better

tolerated

FIBRATES (1/2)• Most effective at reducing VLDL (TG); smaller in

LDL-C ; useful in HDL-C• Less favourable effect on clinical outcomes• Improvements in microvascular outcomes• Important interactions

Increased risk of myositis on a statinreduction in dose requirements (~30%) for patients on

warfarin

FIBRATES (2/2)• Fenofibrate: prodrug – t ½ 20 hr

Reduce fibrinogen levelsCommonly used in combination with statins (minimally

affects statin metab & ↓ myopathy)

• Gemfibrozil: Reduces TG & CHIncreased risk of myopathy with statin

• Bezafibrate: No myopathy

FIELD TRIALKeech A, Simes RJ, Barter P et al. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet 2005, 366:1849-61Participants 9795 pts (2131 with previous CVD & 7664 without)

aged 50-75 years, with type 2 diabetes mellitus not taking statin therapy

Intervention Micronised fenofibrate 200 mg OD vs PlaceboEnd point Coronary events (CHD death or non-fatal MI). For

subgroup analysis - Total cardiovascular events (CVD death, MI, stroke, coronary & carotid revascularisation)

Conclusions Significant reduction in TGs. Reduction in total CV events. No significant reduction in coronary events

ACCORD TRIALGinsberg HN, Elam MB, Lovato LC et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med 2010, 362:1563-74Participants 5518 pts - type 2 diabetes on simvastatin treatmentIntervention Fenofibrate vs placebo. End point First occurrence of nonfatal MI, nonfatal stroke, or

death from CV causes.Conclusions Combination therapy did not reduce the rate of fatal

CV events, nonfatal MI, or nonfatal stroke. 30% ↓ in TG. ↓ progression in Retinopathy

NICOTINIC ACID• VLDL & fibrinogen; ↑ HDL 30-35%; TGs ~ 40%• Usually employed in combination with fibrate, resin

or statin – this avoids side effects of higher doses

AIM – HIGH TRIALBoden WE, Probstfield JL, Anderson T et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med 2011; 365:2255-2267Participants 3414 established CVD, low HDL-C, high TG Intervention ER niacin 1.5 – 2.0g vs placebo. All patients received

simvastatin 40-80mg/d ± ezetimibe 10mg/dEnd point 1st event of the composite of death from CHD,

nonfatal MI, ischemic stroke, hospitalization for ACS or symptom-driven coronary or cerebral revascularization

conclusions Among ASCVD pts with LDL <70mg/dl – no benefit despite Improvements in HDL-C and TG

HPS-2 THRIVE TRIALLandray MJ, Haynes R, Hopewell JC et al. Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med 2014; 371:203-212Participants 25,673 adults with vascular disease.

Prerandomization run-in phase to standardize the background statin-based LDL-C lowering therapy

Intervention ER Niacin 2g + 40mg Laropiprant vs placeboEnd point First major vascular event (nonfatal MI, death from

coronary causes, stroke, or arterial revascularization)Conclusions In ASCVD, no significant reduction in major vascular

events but increased serious ADE

EZETIMIBE-STEROL ABSORPTION INHIBITOR

• Inhibits CH absorption from intestine• Novel inhibitor of intestinal cholesterol transporter

(NPC1C1)• No important adverse effects or significant drug

interactions• Statins decrease liver CH synthesis but increase

intestinal absorption. Ezetimibe vice versa (synergistic)• Unlike resins, it causes fall in TG

IMPROVE – IT TRIALCannon CP, Blazing MA, Giugliano RP et al. Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. N Engl J Med. 2015;372(25):2387Participants 18,144 pts hospitalized for ACS in last 10 days

LDL-C 50-100mg/dl if receiving lipid-lowering therapy or 50-125mg/dl if not receiving

Intervention Simvastatin 40 mg + ezetimibe 10 mg vs simvastatin 40 mg + placebo

End point Composite of CVD, nonfatal MI, unstable angina requiring rehospitalization, coronary revascularization, or nonfatal stroke

Conclusions Lowering of LDL-C and improved CV outcomes

NEWER HYPOLIPIDAEMIC

DRUGS

CLASSIFICATION - NEWER DRUGS

• Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors – Evolocumab, bococizumab, Alirocumab• Apolipoprotein B synthesis inhibitor – Mipomersen • Microsomal triglyceride transfer protein (MTTP)

inhibitor – Lopitamide • Thyromimetic – Eprotirome • Cholestryl ester transfer protein (CETP) inhibitors –

Torcetrapib, dalcetrapib

PCSK9 INHIBITORS• Inhibit proprotein convertase subtilisn/kexin type 9• Increases LDLR density on hepatocytes• Prevents LDLR degradation

PSCK9 - PHYSIOLOGY

PCSK9 ACTION

APPROACHES TO PCSK 9 INHIBITION

• Monoclonal antibodies: RG-7652 and LY3015014• Peptide mimics - Peptides that mimic the EGFA

domain of the LDLR that binds to PCSK9 (1D05-IgG2 )• Gene silencing:

PCSK9 antisense oligonucleotide, increases expression of the LDLR

Locked nucleic acid – reduced PCSK9 mRNARNA interference (ALN PCS02)

• Naturally occurring inhibitors: Plant alkaloid berberine & endogenous Annexin A2

ALIROCUMAB – PRALUENT• First drug of PCSK9I to be approved (July24, 2015)• Second line treatment for adults next to diet &

statin for clinical ASCVD & FH• Side effects -

Nose & throat irritationInjection site reactions and bruisingFlu-like symptomsDiarrhoeaBronchitis and coughMuscle pain, soreness, and spasms

ODYSSEY TRIALRobinson JG, Farnier M, Krempf M et al. Efficacy and Safety of Alirocumab in Reducing Lipids and Cardiovascular EventsParticipants 2341 patients at high risk for CVD. LDL-C of 70 mg/dl or

more + receiving rx with statins at the maximum tolerated dose, +/- other lipid-lowering therapy

Intervention Patients randomly assigned in a 2:1 ratio to receive alirocumab (150 mg) or placebo as a 1-ml S/C every 2 weeks for 78 weeks

End point Percentage change in calculated LDL cholesterol level from baseline to week 24

Conclusions At 24 weeks % change from baseline was 64% (p<0.001) Over 78 weeks significant ↓ LDL-C. In a post hoc analysis, evidence of ↓cardiovascular events

EVOLOCUMAB - REPHATHA • PCSK9 inhibitor from Amgen• FDA approval – 27 Aug 2015 (RUTHERFORD 1, 2 &

GAUSS trials)• Pts with uncontrolled LDL-C on current Rx options• Side effects:

Nasopharyngitis / URTI / fluBack painInjection site reactions

• Ongoing trials GAUSS – 2,3 in Statin Intolerant & FOURIER

APO B INHIBITOR – MIPOMERSEN (KYNAMRO)• Antisense oligonucleotide binds to mRNA; prevents translation

to form apolipoprotein-B • Decreased formation of apoB-containing lipoproteins,

including LDL cholesterol (40-50%). • Also decrease Lp(a) concentrations.• Side effects:

Injection-site reactions in almost all Influenza-like illness in many, andhepatic steatosis with elevated liver enzymes in up to 15% of

patients

• Approved for homozygous familial hypercholesterolemia, minimising apheresis need

MTTP INHIBITOR – LOMITAPIDE (JUXPID)

• Inhibit TG transfer to apoB-48 or apoB-100 in intestinal & liver cells respectively; decrease formation of chylomicrons & VLDL. • VLDL inhibition leads to LDL inhibition.• Side effects: Increased stool frequency, hepatic

steatosis & increase in serum transaminase levels. • FDA approval in Dec 2012 for homozygous familial

hypercholesterolemia.

CETP INHIBITORS• Inhibit transfer of cholesterol from anti-atherogenic

apolipoprotein A – containing particles to atherogenic apolipoprotein B particles

DRUG NAME TRIAL REMARKSTorcetrapib(with statins, ↑ HDL 60%, ↓ LDL 25%)

ILLUMINATE (Terminated - ADR )

↑ all-cause mortality & cardiovascular events, ↑ Sys BP by 5-6 mm Hg, ↑ aldosterone & cortisol, ↑ endothelial NO synthase & endothelin I

Dalcetrapib(↑ HDL 30%, LDL no effect)

Dal-OUTCOMES (Terminated - futility)

↑ Sys BP , smaller but significant↑ CRP (inflammation)

THYROMIMETICS - EPRORITOME

• Thyroid hormone analog with minimal non-hepatic tissue uptake• No long term or large studies done so far• No clinical hyper/hypo-thyroidism• Side effect: elevated transaminases

MISCELLANEOUS DRUGS• Probucol – ↓ LDL-C and HDL-C; facilitate resorption

of cutaneous & tendon xanthomas• Neomycin – ↓ LDL-C & Lp(a) 25%; similar in action

to bile acid sequestrants• Oestrogen Replacement therapy in post-

menopausal women - ↓ LDL-C ↑ HDL-C• Tamoxifen - ↓ LDL-C & tot. CH. No effect on HDL

CLINICAL GUIDELINES

EVOLUTION OF NHBLI SUPPORT GUIDELINES

Current guidelines ACC/AHA 2013

NCEP ATP III vs ACC/AHANCEP ATP III AHA/ACC – ATP IV

Year 2001 (updated in 2004) 2013

Focus Reducing CHD risk Reducing risk of atherosclerotic CV disease (ASCVD) – includes CHD + TIA/stroke, PAD or revascularisation

Risk assessment

Framingham 10 yr risk score (CHD death + non fatal MI

Pooled cohort equations* (fatal & nonfatal CHD + fatal & nonfatal stroke

*Developed by the Risk Assessment Work Group to estimate the 10-year ASCVD risk (defined as first-occurrence nonfatal and fatal MI and nonfatal and fatal stroke) for the identification of candidates for statin therapy

NCEP ATP III vs ACC/AHANCEP ATP III AHA/ACC – ATP IV

Risk Categories

3 main risk categories:CHD / CHD risk equivalent (DM, Clinical CHD, symptomatic CAD, PAD)2+ risk factors & 10-yr risk ≤ 20%0-1 risk factors & 10-yr risk <10%

4 statin benefit groups: Clinical ASCVDPrimary LDL-C elevations ≥190 mg/dlDM without clinical ASCVDNo DM/CVD with 10-yr ASCVD risk ≥7.5%

Rx targets LDL-C primary target<100mg/dl<130mg/dl (<100 if risk 10-20%)<160mg/dl(in the order of categories mentioned above)

Intensity of statin therapyHigh intensity statin therapy (LDL-C reduction ≥50%) recommended for most patients in 4 statin benefit groups

Rx recommendations

Statin (or bile acid sequestrants or nicotinic acid) to achieve LDL-C goal

Maximally tolerated statin first-line to reduce risk of ASCVD events

CLASS OF RECOMMENDATION LEVEL OF EVIDENCE

AHA/ACC GUIDELINE 2013 (1/2)

AHA/ACC GUIDELINE 2013 (2/2)

CV RISK CALCULATOR

HIGH INTENSITY THERAPY

MODERATE INTENSITY THERAPY

LOW INTENSITY THERAPY

Daily dose lowers LDL-C on avg ~ ≥50%

Daily dose lowers LDL –C on avg ~ 30-50%

Daily dose lowers LDL –C <30%

Atorvastatin (40*) 80 mg

Atorvastatin 10 (20) mg

Simvastatin 10 mg

Rosuvastatin 20 (40) mg

Rosuvastatin (5) 10 mg

Pravastatin 10-20 mg

Simvastatin 20-40 mg

Lovastatin 20 mg

Pravastatin 40 (80) mg

Fluvastatin 20-40 mg

Lovastatin 40 mg Pitavastatin 1 mgFluvastatin XL 80 mg

* Only one RCT Fluvastatin 40 mg bidPitavastatin 2-4 mg

STATIN THERAPY

MONITORING THERAPY

ACC/AHA COR LOE1.Creatine Kinase, routinely not needed III (No benefit) A2.Baseline CK in pts at risk of events IIa C3.Baseline ALT before initiating statins I B4.Decreasing the statin dose, if 2 consecutive values of LDL-C <40 mg/dl.

IIb C

5.Simvastatin at 80 mg daily harmful III (Harm) A6.New onset diabetes on statin therapy, continue statins & lifestyle management

I B

7.If muscle symptoms develop, discontinue, use again

II a C

8.Confusional state, evaluate non-statin causes II b C

SAFETY RECOMMENDATION OF

STATINS

NIACIN RECOMMENDATIONS

Baseline liver enzymes, FBS/HBA1c/uric acid

AST/ALT >2-3ULN

Persistent severe cutaneous symptoms,hyperglycemia,

acute gout

New onset AF,weight loss

Start at low dose

Take niacin with food or aspirin 325mg ½ hr BF

Uptitrate 500 mg ER to 2000mgER over 4-8 weeks

(or)Plain niacin 100mg TID to

3g/day

BILE ACID SEQUESTRANTS

Baseline fasting TG>300 mg/dl

caution if TG 250-299 mg/dl. 4-6 weeks later if TG >400 -discontinue

STEROL ABSORPTION INHIBITORS

Baseline hepatic transaminases

Discontinue if ALT>3 times occur

FIBRATES OMEGA 3 FATTY ACIDS

If used in TG >, evaluate GI disturbances,

Evaluate GI disturbances

Gemfibrozil + statin therapy (causes muscle

symptoms)

If TG>500mg/dl and benefit>risks -Fenofib

GFR<30 ml/min

PIPELINE DRUGS

BOCOCIZUMAB (Pfizer) • PCSK9 inhibitor• Phase 2b - Monthly or bimonthly injections ↓ LDL-

C at 12 weeks. *• SPIRE trials (Phase 3) - plans to enrol 17,000 pts.

Intolerant to statinsHereditary heterozygous hypercholesterolemiaPrimary hyperlipidemia/mixed dyslipidemia (3 trials)At highrisk CVD (2 trials)

* Ballantyne CM, Neutel J, Cropp A et al. Results of Bococizumab, A Monoclonal Antibody Against Proprotein Convertase Subtilisin/Kexin Type 9, from a Randomized, Placebo-Controlled, Dose-Ranging Study in Statin-Treated Subjects With Hypercholesterolemia. Am J Cardiol. 2015 May 1;115(9):1212-21.

RG7652 (Roche)• Monoclonal antibody – PCSK9 inhibitor• July 2013: Phase II EQUATOR trial completed

(unpublished)• July 2014:

Discontinued - Phase-I; Metabolic disorders (Switzerland)

Discontinued - Phase-II; Coronary disorders & Hyperlipidaemia (USA, Canada, Czech Republic, Germany, Hungary, New Zealand, Norway, Slovakia and South Africa)

LY3015014 (Eli Lilly)• Monocloncal antibody – PCSK9 inhibitor• 3 Phase 2 trials completed by June 2014 • No liver / muscle safety issues• Upto 51% ↓ in LDL-C, significant ↓ non-HDL-C,

ApoB and Lp(a)*

* Kastelein J, Nissen S; Rader D et al. Safety and Efficacy of LY3015014, a New Monoclonal Antibody to Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) with an Inherently Longer Duration of Action, in Patients with Primary Hypercholesterolemia: A Randomized, PlaceboControlled, Dose-Ranging, Phase 2 Study. J Am Coll Cardiol. 2015;65(10_S)

1D05-IgG2• Fragment antigen-binding (Fab) protein that mimics

EGFA domain of LDLR• Current status: Preclinical studies• Ts mouse model LDL-C ↓ 40% & ↑ hepatic LDLR

protein levels 5 fold. • In healthy rhesus monkeys, LDL cholesterol ↓

20%–50% for over 2 weeks

*Ni YG, Di Marco S, Condra JH et al. A PCSK9-binding antibody that structurally mimics the EGF(A) domain of LDL-receptor reduces LDL cholesterol in vivo. J Lipid Res. 2011 Jan;52(1):78-86

ALN-PCS02 (Alnylam Pharma)

• siRNA against PCSK9 gene• Phase 1 trail completed• IV infusion for 32 patients• Results officially not published • However, significant impact on lipid management

PCSK9 VACCINE• Virus like particle (VLP) – immunogenic carrier of PCSK9

antigenic peptide• VLP – virus without DNA – no replication. External

structure – antigen display• Animal studies showed high titre IgG antibodies• Significant ↓ total cholesterol, TG & PL

* Crossey E, Amar MJ, Sampson M, Peabody J, Schiller JT, Chackerian B, Remaley AT (2015). "A cholesterol-lowering VLP vaccine that targets PCSK9". Vaccine 33(43): 5747–55

EVACETRAPIB – CETP inhibitor

• ACCELERATE trial – 12095 high risk CVD patients; stopped prematurely (Oct 2015) for lack of efficacy• ACCENTUATE trial – pts with hyperlipidemia or DM

ANACETRAPIB – CETP INHIBITOR

• DEFINE – Phase III trial*1623 pt with CHD or at high risk on statins100mg anacetrapib vs placebo↑ HDL 138.1%, ↓LDL-C 36%, ↓Lp(a) 36.4% in

comparison with placebo by 24 weeksNo change in BP, Electrolyte or aldosterone by 76wNo ↑ in CVD events

• REVEAL – Phase III trial (ongoing) 30,000 pts with occlusive arterial disease

* Cannon P, Shah S, Dansky HM et al. Safety of Anacetrapib in Patients with or at High Risk for Coronary Heart Disease. NEJM 2010; 363:2406-2415

IMPLITAPIDE – MTTP INHIBITOR

• Two phase 2 trial terminated (2005)• 80mg/160 mg doses caused unacceptable rise in liver

enzymes & GI disturbances *• Trials with lower doses suggested• No further details obtainable

*Dam MV, Farmer M, Stein EA et al. Efficacy an d safety of implitapide (bayy 13-9952), a microsomal triglyceridee transfer protein inhibitor,, in patients with primary hypercholesterolemia-accessed on 1/11/15 from http://dare.uva.nl/document/2/14716

OTHER MTTP INHIBITORSDRUG (status as of year)

REMARKS

CP346086(2003)

Phase 2: 47% ↓total cholesterol, 72% ↓LDL-C, 75% ↓ TG

AEGR733 ↓LDL-C by 51% from baseline at the highest dose. ↑ Liver aminotransferase & hepatic fat accumulation

JTT130 Animal study: 25% ↓ LDL-C & 30% ↓ TG & No hepatic steatosis. Current status – phase 2 trials

SUMMARY• Lipid handling in the body & pathophysiology of

dyslipidemia & atherosclerosis• Current hypolipidemic drugs – statins, BAS, fibrates

niacin, sterol absorption inhibitors• Newer agents – PCSK9 inhibitors, MTTP inhibitors,

apo B inhibitor, CETP inhibitor, thyromimetics• ACC/AHA 2013 guidelines - LDL-C targets are not

absolute as in ATPIII• Drugs in the making

REFERENCES• Tonkin A, Byrnes A. Treatment of dyslipidemia. F1000Prime Reports.

2014;6:17• Robert SR. Lipid lowering with drugs other than statins and fibrates

(accessed on 15/09/2015) http://www.uptodate.com/contents/lipid-lowering-with-drugs-other-than-statins-and-fibrates

• Robert SR. Lipid lowering with fibric acid derivatives. (accessed on 15/09/2015) http://www.uptodate.com/content/lipid-lowering-with-fibric-acid-derivatives

• 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. (accessed on 22/10/2015)

• Sahebkar A, Watts GF. New LDL-Cholesterol Lowering Therapies: Pharmacology, Clinical Trials, and Relevance to Acute Coronary Syndromes. Clin Ther. 2013 Aug;35(8):1082-98• For pipeline drugs status

(http://adisinsight.springer.com/drugs )• For various trial details (https://clinicaltrials.gov)