Statins : Dr Renuka Joshi Buche
Upcoming SlideShare
Loading in...5
×
 

Statins : Dr Renuka Joshi Buche

on

  • 269 views

 

Statistics

Views

Total Views
269
Views on SlideShare
269
Embed Views
0

Actions

Likes
0
Downloads
40
Comments
0

0 Embeds 0

No embeds

Accessibility

Categories

Upload Details

Uploaded via as Microsoft PowerPoint

Usage Rights

© All Rights Reserved

Report content

Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel
  • Full Name Full Name Comment goes here.
    Are you sure you want to
    Your message goes here
    Processing…
Post Comment
Edit your comment

Statins : Dr Renuka Joshi Buche Statins : Dr Renuka Joshi Buche Presentation Transcript

  • STATINS ( HMG CoA Inhibitors ) Dr Saurabh Gupta Dr Renuka Joshi
  • Physiology of Lipids • Cholesterol is a fatty steroid made primarily in the liver of most animals and humans. • It is an integral component in the synthesis of hormones, can also be found in cell walls of animals and humans. H O Cholesterol
  • Do et al. Circulation 2000;102:670-676 Col In order to transport the steroid through blood, cholesterol is attached to a set of proteins called lipoproteins 1995;15:1987-1994 HDLLDLChylomicrons, VLDL, and their catabolic remnants > 30 nm 20–22 nm Potentially pro-inflammatory 9–15 nm Potentially anti-inflammatory Lipoprotein Classes
  • Risk factors for CAD • CVD risk is determined by principally 1. Age 2. Family history 3. Blood pressure 4. Cholesterol level 5. Smoking • The interaction between these risk factors is complex but only 3,4 and 5 are amenable to intervention • Lowering cholesterol alone reduces risk in all groups
  • The Role of Lipoproteins in Atherogenesis HDL Liver Oxidative modification of LDL LDL + VLDL Cholesterol excreted High plasma LDL LDL infiltration into intima + Macrophages Foam cells Fatty streak Advanced fibrocalcific lesion Endothelial injury Adherence of platelets Release of PDGF Other growth factors LCAT APO-A1 APO-A1=Apolipoprotein A1, HDL=High density lipoprotein, LCAT=Lecithin cholesterol acyltransferase, LDL=Low density lipoprotein, PDGF=Platelet-derived growth factor, VLDL=Very low density lipoprotein
  • Methods for lipid profile regulation • Non Pharmacological Behaviour modification Diet control Weight loss programmes, etc. • Pharmacological
  • Therapies to Lower LDL-C Soluble fiber Soy protein Stanol esters Dietary Adjuncts Ezetimibe (Zetia)Cholesterol absorption inhibitor Cholestyramine (generic and Questran) Colesevelam (Welchol) Colestipol (Colestid) Bile acid sequestrants Atorvastatin (Lipitor) Fluvastatin (Lescol XL) Lovastatin (generic and Mevacor) Pravastatin (Pravachol) Rosuvastatin (Crestor) Simvastatin (Zocor) 3-Hydroxy-3-Methylglutaryl Coenzyme A (HMG-CoA) reductase inhibitors [Statins] Drug(s)Class Nicotinic acid Niacin
  • STATINS !!!
  • Mechanism of Action Acetyl CoA HMG- CoA Mevalonate Farnesyl pyrophosphate Squalene Cholesterol Squalene synthase Dolichol Farnesyl- transferase Farnesylated proteins E,E,E-Geranylgeranyl pyrophosphate Geranylgeranylated proteins Ubiquinones HMG-CoA Reductase Inhibition of the Cholesterol Biosynthetic Pathway
  • LDL-R–mediated hepatic uptake of LDL and VLDL remnants Serum VLDL remnants Serum LDL-C Cholesterol synthesis LDL receptor (B–E receptor) synthesis Intracellular Cholesterol Apo B Apo E Apo B Systemic CirculationHepatocyte • The reduction in hepatic cholesterol synthesis lowers intracellular cholesterol, which stimulates upregulation of the LDL receptor and increases uptake of non-HDL particles from the systemic circulation LDL Serum IDL VLDLR VLDL Mechanism of Action
  • Major actions of Statins • Inhibition of : 1. cholesterol biosynthesis 2. Lipoprotein secretion 3. LDL oxidation 4. scavenger receptors expression • Reduction of the accumulation of esterified cholesterol into macrophages. • Increase endothelial NO synthetase • Reduction of the inflammatory process • Increased stability of the atherosclerotic plaques • Reduction of plaques
  • Pleiotropic effects of statins Liao JK. Am J Cardiol. 2005;96(suppl 1):24F-33F.MMPs = matrix metalloproteinases  Platelet activation  Coagulation  Endothelial progenitor cells  Effects on collagen  MMPs  AT1 receptor  VSMC proliferation  Endothelin  Macrophages  Inflammation  Immunomodulation  Endothelial function  Reactive oxygen species  NO bioactivity Statins 12
  • AGENTS • Atorvastatin • Fluvastatin • Lovastatin • Pravastatin • Rosuvastatin • Simvastatin
  • Current Guidelines for statins use ( ACC/ AHA, 2013 ) • Goal: to formulate recommendations for strong evidence based foundation for treatment of cholesterol for the primary and secondary prevention of ASCVD.
  • METHODOLOGY • Multicentre ,case-control study conducted in 52 countries, which showed that abnormal lipid levels accounted for approximately 50% of the attributable risk for myocardial infarction (MI) • mortality benefits in CHD were : 1% - 5% with primary prevention 9% to the use of statins by patients with stable coronary artery disease.
  • Four Major Statin Benefit Groups 1) Individuals with clinical ASCVD 2) Individuals with LDL >190 3) Individuals with dm, 40-75 yrwith LDL 70-189 and without clinical ASCVD 4) Individuals without clinical ASCVD or dm with LDL 70-189 and estimated 10-year ASCVD risk >7.5%
  • Intensity of Statin Therapy in primary and secondary prevention
  • Statins Safety recommendations • Conditions that could predispose patients to statin side effect: oImpaired renal or hepatic function oHistory of previous statin intolerance or muscle disorder oAge >75 oUnexplained ALT elevation > 3x ULN oHistory of hemorrhagic stroke oAsian ancestry
  • • Check baseline ALT prior initiating the statin (Grade B) • Check LFTs if patient develops Symptoms of hepatic dysfunction (Grade E) • If 2 consecutive LDL <40, Consider decreasing the statin dose (Grade C, weak recommendation) • It may be harmful to initiate simvastatin 80mg, or increase the dose of simvastatin to 80mg (Grade B) Statins Safety recommendations
  • A Review of Perioperative Statin Therapy • Reduction in postoperative cardiovascular events such as MI, ACS , cardiac death • Reduction in postop Atrial arrythmias • Statins have been shown to reduce acute deterioration in renal function in patients undergoing CABG and other vascular surgery requiring aortic clamping
  • Perioperative Withdrawal of Statin Therapy • There is reasonably good evidence that patients who are taking statins in the preoperative period may have worse outcomes if their statin is discontinued. • the interruption of statins is a result of the inability to take oral medications. • Patients who are post-ACS and whose statins are stopped are at greatest risk for cardiovascular event
  • SIDE EFFECT PROFILE
  • Liver toxicity • Mild increases in hepatic function markers (alanine and aspartate aminotransferases, bilirubin, gamma-glutammyl- transferase, alkaline phosphatase) However, whether these findings represent a real liver injury or are an expression of some hepatic response to lipid-lowering drugs is a matter for debate. Despite the excess risk of abnormal liver tests, no serious adverse liver effects (hepatitis or liver failure)were observed
  • • In patients with chronic liver disease: complete abstinence from alcohol ;and the use of pravastatin at a low dose is recommended • If the LDL-C remains elevated, combined therapy with a bile acid sequestrant can be used. • Statins are contraindicated in patients with progressive liver disease
  • Muscle toxicity • Toxicity ranges from mild myalgia(which includes muscle symptoms with or without creatine kinase elevations) to rhabdomyolysis (marked increase in CK with renal dysfunction). • Exact cause is not known . • Statins decrease the synthesis of coenzyme Q10 (CoQ10, ubiquinone), which plays an important role in muscle cell energy production.
  • • The risk factors are : advanced age, female sex, frailty, grapefruit juice ( CYP 3A4 inhibitor ) and concomitant treatment (fibrates, cyclosporine, certain antifungals, macrolides). • The contributing factor in clinical practice is the presence of myopathy in patients with hypothyroidism,congenital myopathies and neuromuscular disorder.
  • Management • Clinical judgment is necessary in interpreting elevated CK levels in patients on statins. • Patients with significant muscle toxicity from a statin should discontinue therapy • large quantities of fluids to facilitate renal excretion of myoglobin. • Pravastatin and fluvastatin appear to have much less intrinsic muscle toxicity than other statins. Vit D and CoQ10 are under trial.
  • Renal Dysfunction • Statins appear to be able to cause proteinuria through tubular inhibition of active transport of small molecular weight proteins . • Benign and no evidence of renal failure is found. • Atorvastatin and fluvastatin do not require dose adjustment and are the statins of choice in patients with severe renal impairment. • Dose adjustment is warranted with other statins in patients with severe kidney disease (CrCl less than 30 mL/min).
  • Neurological dysfunction A retrospective cohort study in elderly patients found an association between perioperative statin use and postoperative delirium and neuropathy. But no causal association is found. Decrease in cholesterol in mylin , synapses and depletion of CoQ10 is found to be responsible
  • Drug interaction • The increase in susceptibility to myopathy is substantially greater in patients receiving concurrent therapy with a number of drugs, particularly CYP3A4 inhibitors and fibrates. • The uptake, metabolism, and clearance of each statin differs, and therefore each statin is subject to different types of drug interactions.
  • • Simvastatin, lovastatin, and to a lesser extent atorvastatin - CYP3A4 • Fluvastatin-CYP2C9 • Rosuvastatin, Pitavastatin, and Pravastatin - non CYP-450 transformations
  • Concomitant Use of Meds Fibrate Nicotinic acid (Rarely) Cyclosporine Antifungal azoles** Macrolide antibiotics† HIV protease inhibitors Nefazadone Verapamil, Amiodarone STATINS : DRUG INTERACTIONS Pasternak RC et al. Circulation 2002;106:1024-1028 *General term to describe diseases of muscles **Itraconazole, Ketoconazole †Erythromycin, Clarithromycin ‡Chronic renal insufficiency, especially from diabetes mellitus
  • LANDMARK PAPERS 1. CORONA trial ( EJHF, 2005)
  • Conclusion of CORONA trial 1. Treatment with rosuvastatin did not reduce the composite outcome of death. 2. There was a significant reduction in secondary end point of hospitalization due to CV causes 3. A post hoc analysis focusing on definite ischemic end points of non fatal or fatal MI or stroke demonstrated a significant 16 % relative risk reduction in these end points with rosuvastatin.
  • 2. GISSI HF Trial ( EJHF, 2004)
  • THANK YOU !!