Ueda2016 new horizon in the management of dyslipidemia - diaa ewais
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Transcript of Ueda2016 new horizon in the management of dyslipidemia - diaa ewais
DR: DIAA EWAIS M.D.Consultant Int Med
Saudi German Hospital
New Horizon In The Management Of
Dyslipidemia
Atherosclerotic Cardiovascular Disease (CVD) is common in the general population, affecting the majority of adults
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New ACC/AHA cholesterol treatment guideline published November 2013
6AHA, American Heart Association
ACC, American College of Cardiology
To lower LDL-C intensify statin ,add ezitamibe - PCSK9i
• Despite these impressive results of optimal use of statin,
there remains a substantial residual risk of cardiovascular (CV) events
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• Research has shown that up to 46% of patients prescribed statins for hypercholesterolemia Do Not Adhere to therapy
• In fact, one in ten CVD events is directly linked to non adherence.
• In addition, while in randomised, placebo-controlled trials, statins are extremely well tolerated and Adverse Events are recorded particularly myalgia
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Today’s challenge is, therefore, to establish whether it is
possible to improve CV outcomes by additional therapies
which enable lower levels of cholesterol
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Thus, there is a real need for alternative lipid-lowering therapies that are not only effective, but also well tolerated.
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PCSK9 (Proprotein Convertase Subtilisin Kexin type 9) and inhibitors of PCSK9
• Humanised monoclonal antibodies
(Evolocumab, Alirocumab, Bococizumab) have been developed
that increase LDL-R by ~2-fold and lower LDL-C by up to 75 %
PCSK9 inhibitors
Not designed to replace statins
This effect is synergistic to that of statins
Mechanism of action
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Removal
Production
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Dadu, R. T. & Ballantyne, C. M. (2014) Lipid lowering with PCSK9 inhibitors
Nat. Rev. Cardiol. doi:10.1038/nrcardio.2014.84
Ongoing phase III clinical trials of PCSK9 inhibitors
July 24, 2015
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Efficacy and Safety of Alirocumab in Reducing Lipids
ODYSSEY Program
ODYSSEY Program
• The program includes 14 global Phase 3 trials evaluating more than 23,500 patients.
The primary efficacy end point in all of the studies was the mean
percent reduction from baseline in LDL cholesterol
at week 24 compared to placebo
(maximally tolerated statin therapy)
Alirocumab
April 16, 2015 Vol. 372 No. 16
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Efficacy and Safety of Alirocumab in Reducing Lipids and
Cardiovascular Events
ODYSSEY Long Term
FDA approved Evolocumab on Aug 27, 2015
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Efficacy and Safety of Evolocumab in Reducing Lipids
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April 16, 2015 Vol. 372 No. 16
Efficacy and Safety of Evolocumab in Reducing Lipids and Cardiovascular Events
(OSLER-1 and OSLER-2)
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OSLER-1 and OSLER-2
During approximately 1 year of therapy, the use of evolocumab plus
standard therapy, as compared with standard therapy alone, reduced
LDL Cholesterol levels and reduced the incidence of cardiovascular events
OSLER-1 and OSLER-2
Conclusion
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PCSK9 Inhibitors
• Subcutaneously administered
• Dosing is every 2 or every 4 weeks
• Reduces LDL-C by about 60-70%
• Has been shown to lower LDL-C in statin intolerant patients, patients with FH
• Patients will receive pre-filled syringes that they can easily administer at home
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• In August 2013, the European Atherosclerosis Society (EAS) published a consensus statement for screening and treatment of heterozygous FH.[5, 6] The recommendations for screening for heterozygous FH include patients with[5, 6] :
• A family member presenting with diagnosed FH;
• Plasma cholesterol in an adult ≥8mmol/L (≥310 mg/dL);
• Plasma cholesterol in a child ≥6mmol/L (≥230 mg/dL);
• Premature CHD;
• Tendon xanthomas; or
• Sudden premature cardiac death.
• The LDL-receptor on the surface of hepatocytes plays a central role in cholesterol homeostasis.
• Circulating LDL-cholesterol binds to the LDL-receptor and the complex is internalised in the hepatocyte in Clathrin-Coated vesicles, the contents of which undergo lysosomal degradation
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The LDL-receptor is, recycled to the cell surface where it can bind with more LDL-cholesterol molecules
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• PCSK9 is a protein synthesised by the hepatocytes, which binds to the LDL-receptor component of the LDL-receptor/LDL-cholesterol complex.
• The resultant lysosomal degradation does not permit the LDL-receptor to be recycled to the cell membrane
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• Thus, the number of LDL-receptors on the surface of the hepatocytes is reduced and serum levels of LDL-cholesterol increase.
• The more PCSK9 produced by the liver, the higher the LDL-cholesterol level
• Removal
• Production
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Monoclonal antibodies have been developed that bind PCSK9 and prevent its interaction with the LDL-receptor
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PCSK9 binds to the epidermal growth factor-like repeat A (EGF-A) domain of the low-density lipoprotein receptor (LDLR), inducing LDLR degradation.
Reduced LDLR levels result in decreased metabolism of LDL-C, which could lead to hypercholeseroleia.
To lower LDL-C intensify statin ,add ezitamibe - PCSK9