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 i...
Do et al. Circulation 2000;102:670-676
Col
In order to transport the steroid through blood,
cholesterol is attached to a s...
Risk factors for CAD
• CVD risk is determined by principally
1. Age
2. Family history
3. Blood pressure
4. Cholesterol lev...
The Role of Lipoproteins in Atherogenesis
HDL
Liver
Oxidative
modification
of LDL
LDL
+
VLDL
Cholesterol
excreted
High pla...
Methods for lipid profile regulation
• Non Pharmacological
Behaviour modification
Diet control
Weight loss programmes, etc...
Therapies to Lower LDL-C
Soluble fiber
Soy protein
Stanol esters
Dietary Adjuncts
Ezetimibe (Zetia)Cholesterol absorption ...
STATINS !!!
Mechanism of Action
Acetyl
CoA
HMG-
CoA
Mevalonate Farnesyl
pyrophosphate
Squalene Cholesterol
Squalene
synthase
Dolichol
...
LDL-R–mediated hepatic
uptake of LDL and VLDL
remnants
Serum VLDL remnants
Serum LDL-C
Cholesterol
synthesis
LDL receptor
...
Major actions of Statins
• Inhibition of :
1. cholesterol biosynthesis
2. Lipoprotein secretion
3. LDL oxidation
4. scaven...
Pleiotropic effects of statins
Liao JK. Am J Cardiol. 2005;96(suppl 1):24F-33F.MMPs = matrix metalloproteinases
 Platelet...
AGENTS
• Atorvastatin
• Fluvastatin
• Lovastatin
• Pravastatin
• Rosuvastatin
• Simvastatin
Current Guidelines for statins use
( ACC/ AHA, 2013 )
• Goal: to formulate recommendations for strong evidence
based found...
METHODOLOGY
• Multicentre ,case-control study conducted in
52 countries, which showed that abnormal
lipid levels accounted...
Four Major Statin Benefit Groups
1) Individuals with clinical ASCVD
2) Individuals with LDL >190
3) Individuals with dm, 4...
Intensity of Statin Therapy in primary
and secondary prevention
Statins Safety recommendations
• Conditions that could predispose patients to
statin side effect:
oImpaired renal or hepat...
• Check baseline ALT prior initiating the statin (Grade B)
• Check LFTs if patient develops Symptoms of hepatic
dysfunctio...
A Review of Perioperative Statin Therapy
• Reduction in postoperative cardiovascular events
such as MI, ACS , cardiac deat...
Perioperative Withdrawal
of Statin Therapy
• There is reasonably good evidence that patients who
are taking statins in the...
SIDE EFFECT PROFILE
Liver toxicity
• Mild increases in hepatic function markers (alanine and
aspartate aminotransferases, bilirubin, gamma-glu...
• In patients with chronic liver disease:
complete abstinence from alcohol ;and
the use of pravastatin at a low dose is re...
Muscle toxicity
• Toxicity ranges from mild myalgia(which includes
muscle symptoms with or without creatine kinase
elevati...
• The risk factors are :
advanced age, female sex, frailty, grapefruit
juice ( CYP 3A4 inhibitor ) and concomitant
treatme...
Management
• Clinical judgment is necessary in interpreting
elevated CK levels in patients on statins.
• Patients with sig...
Renal Dysfunction
• Statins appear to be able to cause proteinuria
through tubular inhibition of active transport of
small...
Neurological dysfunction
A retrospective cohort study in elderly patients
found an association between perioperative
stati...
Drug interaction
• The increase in susceptibility to myopathy is
substantially greater in patients receiving
concurrent th...
• Simvastatin, lovastatin, and to a lesser extent
atorvastatin - CYP3A4
• Fluvastatin-CYP2C9
• Rosuvastatin, Pitavastatin,...
Concomitant Use of Meds
Fibrate
Nicotinic acid (Rarely)
Cyclosporine
Antifungal azoles**
Macrolide antibiotics†
HIV protea...
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 si...
2. GISSI HF Trial ( EJHF, 2004)
THANK YOU !!
Statins : Dr Renuka Joshi Buche
Statins : Dr Renuka Joshi Buche
Statins : Dr Renuka Joshi Buche
Statins : Dr Renuka Joshi Buche
Statins : Dr Renuka Joshi Buche
Statins : Dr Renuka Joshi Buche
Statins : Dr Renuka Joshi Buche
Upcoming SlideShare
Loading in …5
×

Statins : Dr Renuka Joshi Buche

4,502 views

Published on

Published in: Health & Medicine
4 Comments
22 Likes
Statistics
Notes
No Downloads
Views
Total views
4,502
On SlideShare
0
From Embeds
0
Number of Embeds
7
Actions
Shares
0
Downloads
74
Comments
4
Likes
22
Embeds 0
No embeds

No notes for slide

Statins : Dr Renuka Joshi Buche

  1. 1. STATINS ( HMG CoA Inhibitors ) Dr Saurabh Gupta Dr Renuka Joshi
  2. 2. 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
  3. 3. 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
  4. 4. 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
  5. 5. 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
  6. 6. Methods for lipid profile regulation • Non Pharmacological Behaviour modification Diet control Weight loss programmes, etc. • Pharmacological
  7. 7. 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
  8. 8. STATINS !!!
  9. 9. 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
  10. 10. 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
  11. 11. 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
  12. 12. 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
  13. 13. AGENTS • Atorvastatin • Fluvastatin • Lovastatin • Pravastatin • Rosuvastatin • Simvastatin
  14. 14. 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.
  15. 15. 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.
  16. 16. 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%
  17. 17. Intensity of Statin Therapy in primary and secondary prevention
  18. 18. 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
  19. 19. • 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
  20. 20. 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
  21. 21. 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
  22. 22. SIDE EFFECT PROFILE
  23. 23. 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
  24. 24. • 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
  25. 25. 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.
  26. 26. • 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.
  27. 27. 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.
  28. 28. 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).
  29. 29. 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
  30. 30. 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.
  31. 31. • Simvastatin, lovastatin, and to a lesser extent atorvastatin - CYP3A4 • Fluvastatin-CYP2C9 • Rosuvastatin, Pitavastatin, and Pravastatin - non CYP-450 transformations
  32. 32. 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
  33. 33. LANDMARK PAPERS 1. CORONA trial ( EJHF, 2005)
  34. 34. 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.
  35. 35. 2. GISSI HF Trial ( EJHF, 2004)
  36. 36. THANK YOU !!

×