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CURRENT STATUS & RECENT
ADVANCES IN DYSLIPIDEMIA
TREATMENT
Dr. Jeffrey Pradeep Raj
Post-graduate
Dept. of Pharmacology – S...
OUTLINE
• Introduction
• Lipid handling in the body
• Pathophysiology of atherosclerosis
• Current Hypolipidaemic drugs
• ...
INTRODUCTION
DYSLIPIDEMIA
• Disorder of Lipid & lipoprotein metabolism
• 3 primary abnormalities
Elevated triglycerides
Elevated LDL ...
PRIMARY DYSLIPIDEMIA
TYPE LIPID LIPOPROTEIN OCCURRENCE
I – Familial lipoprotein lipase
deficiency
TG Chylomicrons Rare
IIa...
SECONDARY DYSLIPIDEMIA
LDL cholesterol Triglycerides HDL cholesterol
Diabetes mellitus
Hypothyroidism
Nephrotic syndrome
O...
LIPID HANDLING IN THE
BODY
LIPID ABSORPTION
• Bile emulsifies fat in
chyme
• P. lipase coverts
Triacyl glyceryl into
FFA + glycerol
• Absorbed into
e...
CHYLOMICRON ASSEMBLY
LIPOPROTEINS
• 5 classes classified
based on the density
• TG transported in
chylomicrons or
VLDLs
• Cholesterol
transport...
LIPOPROTEIN METABOLISM
PATHOPHYSIOLOGY OF
ATHEROSCLEROSIS
MECHANISM OF
ATHEROSCLEROSIS
CURRENT
HYPOLIPIDAEMIC DRUGS
CLASSIFICATION – CURRENT
DRUGS
• HMG – CoA reductase inhibitors
Lovastatin, simvastatin, pravastatin, atorvastatin,
rosuv...
OVERVIEW OF CURRENT DRUGS (1/2)
DRUG CLASS MOA SIDE EFFECTS
HMG CoA reductase
inhibitors
Lovastatin (10-80mg)
Simvastatin ...
OVERVIEW OF CURRENT DRUGS (2/2)
DRUG CLASS MOA SIDE EFFECTS
PPAR alpha activators
Gemfibrozil (1200mg)
Bezafibrate (600mg)...
STATINS (1/3)
Pleotropic effects: Non- lipid lowering, cardioprotective
STATINS (2/3)
• Metabolized by microsomal enzymes except
pravastatin
• CI: pregnancy, lactation
• Potency : rosuvastatin >...
STATINS (3/3)
• Pravastatin: CH lowering effect is less; ↓ plaque
Decrease in fibrinogen level
• Atorvastatin: Long acting...
ASCOT-LLA TRIAL
Sever PS, Dahlöf B, Poulter NR, et al. prevention of coronary and stroke events with
atorvastatin in hyper...
JUPITER TRIAL
Ridker PM, Danielson E, Fonseca FA et al. Rosuvastatin to prevent vascular events in men and
women with elev...
4S TRIAL
Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the
Scandinavian Simvastat...
PROVE-IT
Cannon CP, Braunwald E, McCabe CH et al. Intensive versus moderate lipid lowering with
statins after acute corona...
BILE ACID SEQUESTRANTS
• Secondary effect on cholesterol synthesis actually 
VLDL
• Hyper- TG may limit use
• Used in com...
FIBRATES (1/2)
• Most effective at reducing VLDL (TG); smaller  in
LDL-C ; useful  in HDL-C
• Less favourable effect on ...
FIBRATES (2/2)
• Fenofibrate: prodrug – t ½ 20 hr
Reduce fibrinogen levels
Commonly used in combination with statins (mi...
FIELD TRIAL
Keech A, Simes RJ, Barter P et al. Effects of long-term fenofibrate
therapy on cardiovascular events in 9795 p...
ACCORD TRIAL
Ginsberg HN, Elam MB, Lovato LC et al. Effects of combination lipid
therapy in type 2 diabetes mellitus. N En...
NICOTINIC ACID
•  VLDL & fibrinogen; ↑ HDL 30-35%;  TGs ~ 40%
• Usually employed in combination with fibrate, resin
or s...
AIM – HIGH TRIAL
Boden WE, Probstfield JL, Anderson T et al. Niacin in patients with low
HDL cholesterol levels receiving ...
HPS-2 THRIVE TRIAL
Landray MJ, Haynes R, Hopewell JC et al. Effects of extended-release
niacin with laropiprant in high-ri...
EZETIMIBE-STEROL ABSORPTION
INHIBITOR
• Inhibits CH absorption from intestine
• Novel inhibitor of intestinal cholesterol ...
IMPROVE – IT TRIAL
Cannon CP, Blazing MA, Giugliano RP et al. Ezetimibe Added to
Statin Therapy after Acute Coronary Syndr...
NEWER
HYPOLIPIDAEMIC DRUGS
CLASSIFICATION - NEWER DRUGS
• Proprotein convertase subtilisin/kexin type 9
(PCSK9) inhibitors – Evolocumab, bococizumab,...
PCSK9 INHIBITORS
• Inhibit proprotein convertase subtilisn/kexin type 9
• Increases LDLR density on hepatocytes
• Prevents...
PSCK9 - PHYSIOLOGY
PCSK9 ACTION
APPROACHES TO PCSK 9
INHIBITION
• Monoclonal antibodies: RG-7652 and LY3015014
• Peptide mimics - Peptides that mimic the ...
ALIROCUMAB – PRALUENT
• First drug of PCSK9I to be approved (July24, 2015)
• Second line treatment for adults next to diet...
ODYSSEY TRIAL
Robinson JG, Farnier M, Krempf M et al. Efficacy and Safety of
Alirocumab in Reducing Lipids and Cardiovascu...
EVOLOCUMAB - REPHATHA
• PCSK9 inhibitor from Amgen
• FDA approval – 27 Aug 2015 (RUTHERFORD 1, 2 &
GAUSS trials)
• Pts wit...
APO B INHIBITOR – MIPOMERSEN
(KYNAMRO)
• Antisense oligonucleotide binds to mRNA; prevents
translation to form apolipoprot...
MTTP INHIBITOR – LOMITAPIDE
(JUXPID)
• Inhibit TG transfer to apoB-48 or apoB-100 in
intestinal & liver cells respectively...
CETP INHIBITORS
• Inhibit transfer of cholesterol from anti-atherogenic
apolipoprotein A – containing particles to
atherog...
THYROMIMETICS - EPRORITOME
• Thyroid hormone analog with minimal non-hepatic
tissue uptake
• No long term or large studies...
MISCELLANEOUS DRUGS
• Probucol – ↓ LDL-C and HDL-C; facilitate resorption
of cutaneous & tendon xanthomas
• Neomycin – ↓ L...
CLINICAL GUIDELINES
EVOLUTION OF NHBLI SUPPORT
GUIDELINES
Current guidelines ACC/AHA 2013
NCEP ATP III vs ACC/AHA
NCEP ATP III AHA/ACC – ATP IV
Year 2001 (updated in 2004) 2013
Focus Reducing CHD risk Reducing ri...
NCEP ATP III vs ACC/AHA
NCEP ATP III AHA/ACC – ATP IV
Risk
Categories
3 main risk categories:
CHD / CHD risk equivalent (D...
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 l...
MONITORING THERAPY
ACC/AHA COR LOE
1.Creatine Kinase, routinely not needed III (No benefit) A
2.Baseline CK in pts at risk of events IIa C
3....
NIACIN RECOMMENDATIONS
Baseline liver enzymes,
FBS/HBA1c/uric acid
AST/ALT >2-3ULN
Persistent severe cutaneous
symptoms,hy...
BILE ACID
SEQUESTRANTS
Baseline fasting TG
>300 mg/dl
caution if TG 250-299
mg/dl. 4-6 weeks later if TG
>400 -discontinue...
FIBRATES OMEGA 3 FATTY
ACIDS
If used in TG >, evaluate
GI disturbances,
Evaluate GI disturbances
Gemfibrozil + statin ther...
PIPELINE DRUGS
BOCOCIZUMAB (Pfizer)
• PCSK9 inhibitor
• Phase 2b - Monthly or bimonthly injections ↓ LDL-
C at 12 weeks. *
• SPIRE trials...
RG7652 (Roche)
• Monoclonal antibody – PCSK9 inhibitor
• July 2013: Phase II EQUATOR trial completed
(unpublished)
• July ...
LY3015014 (Eli Lilly)
• Monocloncal antibody – PCSK9 inhibitor
• 3 Phase 2 trials completed by June 2014
• No liver / musc...
1D05-IgG2
• Fragment antigen-binding (Fab) protein that mimics
EGFA domain of LDLR
• Current status: Preclinical studies
•...
ALN-PCS02 (Alnylam Pharma)
• siRNA against PCSK9 gene
• Phase 1 trail completed
• IV infusion for 32 patients
• Results of...
PCSK9 VACCINE
• Virus like particle (VLP) – immunogenic carrier of PCSK9
antigenic peptide
• VLP – virus without DNA – no ...
EVACETRAPIB – CETP inhibitor
• ACCELERATE trial – 12095 high risk CVD patients;
stopped prematurely (Oct 2015) for lack of...
ANACETRAPIB – CETP INHIBITOR
• DEFINE – Phase III trial*
1623 pt with CHD or at high risk on statins
100mg anacetrapib v...
IMPLITAPIDE – MTTP INHIBITOR
• Two phase 2 trial terminated (2005)
• 80mg/160 mg doses caused unacceptable rise in
liver e...
OTHER MTTP INHIBITORS
DRUG
(status as
of year)
REMARKS
CP346086
(2003)
Phase 2: 47% ↓total cholesterol, 72% ↓LDL-C,
75% ↓ ...
SUMMARY
• Lipid handling in the body & pathophysiology of
dyslipidemia & atherosclerosis
• Current hypolipidemic drugs – s...
REFERENCES
• Tonkin A, Byrnes A. Treatment of dyslipidemia. F1000Prime
Reports. 2014;6:17
• Robert SR. Lipid lowering with...
• Sahebkar A, Watts GF. New LDL-Cholesterol
Lowering Therapies: Pharmacology, Clinical Trials,
and Relevance to Acute Coro...
Current status & recent advances in dyslipidemia management
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Current status & recent advances in dyslipidemia management

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Current status & recent advances in dyslipidemia management

  1. 1. CURRENT STATUS & RECENT ADVANCES IN DYSLIPIDEMIA TREATMENT Dr. Jeffrey Pradeep Raj Post-graduate Dept. of Pharmacology – SJMC 02-11-2015
  2. 2. OUTLINE • Introduction • Lipid handling in the body • Pathophysiology of atherosclerosis • Current Hypolipidaemic drugs • Newer Hypolipidaemic drugs • ACC/AHA Clinical guidelines 2013 • Pipeline drugs • Summary
  3. 3. INTRODUCTION
  4. 4. DYSLIPIDEMIA • Disorder of Lipid & lipoprotein metabolism • 3 primary abnormalities Elevated triglycerides Elevated LDL cholesterol Reduced HDL cholesterol • Most important modifiable risk factor for CAD • Causes – Primary / secondary
  5. 5. PRIMARY DYSLIPIDEMIA TYPE LIPID LIPOPROTEIN OCCURRENCE I – 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 Common V – Familial combined hyperlipidaemia TG VLDL, chylomicrons Rare
  6. 6. SECONDARY DYSLIPIDEMIA LDL cholesterol Triglycerides HDL cholesterol Diabetes mellitus Hypothyroidism Nephrotic syndrome Obstructive liver disease Drugs Anabolic steroids Progestins Beta blockers Thiazides Alcoholism Diabetes mellitus Hypothyroidism Obesity Renal insufficiency Drugs Beta blockers Bile acid resins Estrogens Ticlopidine Cigarette smoking Diabetes mellitus Hypertriglyceridemia Menopause Obesity Puberty (in males) Uraemia Drugs Anabolic steroids Beta blockers
  7. 7. LIPID HANDLING IN THE BODY
  8. 8. LIPID ABSORPTION • Bile emulsifies fat in chyme • P. lipase coverts Triacyl glyceryl into FFA + glycerol • Absorbed into enterocyte rapidly
  9. 9. CHYLOMICRON ASSEMBLY
  10. 10. LIPOPROTEINS • 5 classes classified based on the density • TG transported in chylomicrons or VLDLs • Cholesterol transported as cholesteryl esters in LDLs and HDLs
  11. 11. LIPOPROTEIN METABOLISM
  12. 12. PATHOPHYSIOLOGY OF ATHEROSCLEROSIS
  13. 13. MECHANISM OF ATHEROSCLEROSIS
  14. 14. CURRENT HYPOLIPIDAEMIC DRUGS
  15. 15. CLASSIFICATION – CURRENT DRUGS • HMG – CoA reductase inhibitors Lovastatin, 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 inhibitor Nicotinic acid • Sterol absorption inhibitor Ezetimibe
  16. 16. OVERVIEW OF CURRENT DRUGS (1/2) DRUG CLASS MOA SIDE EFFECTS HMG CoA reductase inhibitors Lovastatin (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 sequestrants Cholestyramine (4-16g) Colestipol (5-30g) ↓ bile acid absorption, ↑ hepatic conversion of CH to bile acids, ↑ LDL receptors on hepatocytes Unpalatability, bloating, constipation, heart burn
  17. 17. OVERVIEW OF CURRENT DRUGS (2/2) DRUG CLASS MOA SIDE EFFECTS PPAR alpha activators Gemfibrozil (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
  18. 18. STATINS (1/3) Pleotropic effects: Non- lipid lowering, cardioprotective
  19. 19. 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
  20. 20. 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
  21. 21. 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 placebo End point non-fatal myocardial infarction and fatal CHD Conclusions 100 events vs 154 in placebo (HR 0.64, p=0.0005). Strokes, total CV events & coronary events were significantly lowered in statin arm
  22. 22. JUPITER TRIAL Ridker 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%
  23. 23. 4S TRIAL Randomised 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 placebo End point Lipid profile improvement and CVD outcomes Conclusions 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
  24. 24. PROVE-IT Cannon 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
  25. 25. 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
  26. 26. 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 statin reduction in dose requirements (~30%) for patients on warfarin
  27. 27. FIBRATES (2/2) • Fenofibrate: prodrug – t ½ 20 hr Reduce fibrinogen levels Commonly used in combination with statins (minimally affects statin metab & ↓ myopathy) • Gemfibrozil: Reduces TG & CH Increased risk of myopathy with statin • Bezafibrate: No myopathy
  28. 28. FIELD TRIAL Keech 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, 366:1849-61 Participants 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 Placebo End 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
  29. 29. ACCORD TRIAL Ginsberg HN, Elam MB, Lovato LC et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med 2010, 362:1563-74 Participants 5518 pts - type 2 diabetes on simvastatin treatment Intervention 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
  30. 30. 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
  31. 31. AIM – HIGH TRIAL Boden WE, Probstfield JL, Anderson T et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med 2011; 365:2255-2267 Participants 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/d End 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
  32. 32. HPS-2 THRIVE TRIAL Landray MJ, Haynes R, Hopewell JC et al. Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med 2014; 371:203-212 Participants 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 placebo End 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
  33. 33. 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
  34. 34. IMPROVE – IT TRIAL Cannon CP, Blazing MA, Giugliano RP et al. Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. N Engl J Med. 2015;372(25):2387 Participants 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
  35. 35. NEWER HYPOLIPIDAEMIC DRUGS
  36. 36. 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
  37. 37. PCSK9 INHIBITORS • Inhibit proprotein convertase subtilisn/kexin type 9 • Increases LDLR density on hepatocytes • Prevents LDLR degradation
  38. 38. PSCK9 - PHYSIOLOGY
  39. 39. PCSK9 ACTION
  40. 40. 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 mRNA RNA interference (ALN PCS02) • Naturally occurring inhibitors: Plant alkaloid berberine & endogenous Annexin A2
  41. 41. 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 irritation Injection site reactions and bruising Flu-like symptoms Diarrhoea Bronchitis and cough Muscle pain, soreness, and spasms
  42. 42. ODYSSEY TRIAL Robinson JG, Farnier M, Krempf M et al. Efficacy and Safety of Alirocumab in Reducing Lipids and Cardiovascular Events Participants 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
  43. 43. 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 / flu Back pain Injection site reactions • Ongoing trials GAUSS – 2,3 in Statin Intolerant & FOURIER
  44. 44. 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, and hepatic steatosis with elevated liver enzymes in up to 15% of patients • Approved for homozygous familial hypercholesterolemia, minimising apheresis need
  45. 45. 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.
  46. 46. CETP INHIBITORS • Inhibit transfer of cholesterol from anti-atherogenic apolipoprotein A – containing particles to atherogenic apolipoprotein B particles DRUG NAME TRIAL REMARKS Torcetrapib (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)
  47. 47. 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
  48. 48. 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
  49. 49. CLINICAL GUIDELINES
  50. 50. EVOLUTION OF NHBLI SUPPORT GUIDELINES Current guidelines ACC/AHA 2013
  51. 51. NCEP ATP III vs ACC/AHA NCEP 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
  52. 52. NCEP ATP III vs ACC/AHA NCEP 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 ASCVD Primary LDL-C elevations ≥190 mg/dl DM without clinical ASCVD No 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 therapy High intensity statin therapy (LDL-C reduction ≥50%) recommended for most patients in 4 statin benefit groups Rx recommen dations Statin (or bile acid sequestrants or nicotinic acid) to achieve LDL-C goal Maximally tolerated statin first-line to reduce risk of ASCVD events
  53. 53. CLASS OF RECOMMENDATION LEVEL OF EVIDENCE
  54. 54. AHA/ACC GUIDELINE 2013 (1/2)
  55. 55. AHA/ACC GUIDELINE 2013 (2/2)
  56. 56. CV RISK CALCULATOR
  57. 57. 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 mg Fluvastatin XL 80 mg * Only one RCT Fluvastatin 40 mg bid Pitavastatin 2-4 mg STATIN THERAPY
  58. 58. MONITORING THERAPY
  59. 59. ACC/AHA COR LOE 1.Creatine Kinase, routinely not needed III (No benefit) A 2.Baseline CK in pts at risk of events IIa C 3.Baseline ALT before initiating statins I B 4.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) A 6.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
  60. 60. 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
  61. 61. 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
  62. 62. 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
  63. 63. PIPELINE DRUGS
  64. 64. 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 statins Hereditary heterozygous hypercholesterolemia Primary 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.
  65. 65. 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)
  66. 66. 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)
  67. 67. 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
  68. 68. 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
  69. 69. 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
  70. 70. 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
  71. 71. ANACETRAPIB – CETP INHIBITOR • DEFINE – Phase III trial* 1623 pt with CHD or at high risk on statins 100mg anacetrapib vs placebo ↑ HDL 138.1%, ↓LDL-C 36%, ↓Lp(a) 36.4% in comparison with placebo by 24 weeks No change in BP, Electrolyte or aldosterone by 76w No ↑ 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
  72. 72. 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
  73. 73. OTHER MTTP INHIBITORS DRUG (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
  74. 74. 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
  75. 75. 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)
  76. 76. • 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)

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