An Update on Lipid Management

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An Update on Lipid Management

• ? ? ? ??
• 92.12.25

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• Statins are highly effective and well tolerated
  for the treatment of dyslipidemia.
• Decrease cardiovascular and all-cause mortality
  as primary or secondary prevention
• To reduce LDL and triglyceride levels, increase
  HDL level slightly, and decrease clinical events
• Not all patients can tolerate the statins or
  achieve their treatment goal with these drugs
• Clinical events still occur

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Occurrence of Cardiovasculer Events Despite
Treatment with Statins in Five Primary and
Secondary Prevention Trials
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• Statin produced a significant overall reduction
  in the relative risk for clinical events, 63-78
  of events were not prevented.
• Limitation of available statin only a small
  increase in HDL levels, not very effective for
  markedly elevated TG level.
• Both HDL and TG are independent risk factors for
  coronary heart disease (CHD).
• VA-HIT Every 1 increase in HDL level produce a
  3 reduction in death or MI.
• The important of HDL and TG is reflected in ATP
  III guideline for lipid management.

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New Therapeutic Agents

• Statin
• Bile Acid Sequestrants
• Selective Cholesterol Absorption Inhibitors
• Lovastatin plus Niacin

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Statin Rosuvastain (Crestor)

• A potent HMG-CoA reductase inhibitor
• Treatment of primary hypercholesterolemia, mixed
  dyslipidemia, hypertriglyceridemia, and
  homozygous familial hypercholesterolemia.
• Rosuvastatin, a new statin that reduce LDL levels
  and increases HDL levels at least more
  effectively than atovastatin.

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Rosuvastain (Crestor)

• Manufactured in the US by AstraZeneca
• Dated Approved by FDA Aug 12, 2003
• Supplied 5, 10, 20, 40 mg/tab.
• Dosage 5 to 40 mg orally once daily
• With or without food, at any time of day
• Initial Response Within 2 weeks
• Structure hydrophilicity
• - containing a polar methane sulfonamide group

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Rosuvastain (Crestor)

• Pharmacokinetics
• Absorption Bioavailability 20
• Distribution 88 bound to plasma proteins
• Metabolism Liver (10), CYP2C9 and 2C19
• Excretion Renal excretion (10), feces (90)
• Half-life 13-20 hrs
• Special population
• Severe renal impairment (CCrlt30 ml/min)
• - starting dose 5 mg/d with titration not to
  exceed 10 mg/d
• - chronic hemodialysis dose reduction (Css?50)
• Hepatic insufficiency
• - mild to moderate no dose adjustments
• - liver disease related to chronic alcohol use
  Cp mod. ?
• Pregnancy Category X

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Dose-response effect of rosuvastatin and
atovastatin on LDL-c and HDL-c
Rosuvastatin (mg)
Atorvastatin (mg)
Linear regression model
LDL-c
HDL-c
1. Olsson AG. Am J Cardiol 200188504-8 2.
Olsson AG. Am J Cardiol 200187B33-6
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Effects of Rosuva- (5 or 10 mg/d) VS Atorva-
(10mg/d) on the serum lipid profile of patients
at 12 weeks










P lt 0.05
Davidson MH et al. J Am Coll Cardiol
200137(suppl A)292A
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Effects of Rosuva- (5 or 10 mg/d) vs Prava-
(20mg/d) and Simva- (20mg/d) on the serum lipid
profile of patients at 12 weeks






P lt 0.05
Paoletti R et al. J Am Coll Cardiol 200137(suppl
A)291A
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Characteristics of Statins
Knopp RH. N Engl J Med 1999341498-511
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Adverse Events of Rosuvastain (Crestor)
NDA approval letter 08/2003
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The risk factor of drug induced myopathy

• High dose of statin
• Renal insufficiency (Scr gt2.0 mg/dl)
• Combination with fibrate and
• cytochrome P-450 inhibitor
• Age gt 70 y/o

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Clinically Reported Drug Interactions With
Statins Associated With Rhabdomyolysis
Arch Intern Med. 2003163553-64 FDA
approval letter 08/2003
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Fluvastatin (Lescol?)
Lovastatin (Mevacor?)
Atovastatin (Lipitor?)
Simvastatin (Zocor?)
Rosuvastain (Crestor)
Pravastatin (Mevalotin?)
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Physical Properties and Structures

• Hydrophobic and hydrophilic
• Hydrophobic agents
• Simvastatin (Zocor?) Lovastatin (Mevacor?)
• Atovastatin (Lipitor?)
• Hydrophilic agents
• Rosuvastatin (Crestor?) Pravastatin (Mevalotin?)
  Fluvastatin (Lescol?)
• Chemical structure
• Derive from fungi
• Lovastatin (Mevacor?) Pravastatin (Mevalotin?)
• Simvastatin (Zocor?)
• Synthetic
• Rosuvastatin (Crestor?) Fluvastatin (Lescol?)
• Atovastatin (Lipitor?)

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Alternative therapy?

• Combination with Cytochrome P-450 inhibitor
• Pravastatin (Mevalotin?)
• Incidence of myopathy
• Pravastatin (Mevalotin?), Rosuvastatin (Crestor?)
  lt Lovastatin (Mevacor?), Simvastatin (Zocor?)
• If Pravastatin --gt myopathy
• suggest switching to Atovastatin (Lipitor?) or
  Rosuvastatin (Crestor?), not chemically similar
  agents, such as Simvastatin (Zocor?) or
  Lovastatin (Mevacor?)

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Steps to minimize the risk of muscle toxicity
with statin therapy

• Use statin alone .
• Keep the dose of the statin and fibrate low
• Avoid (or cautiously use) combination therapy in
  renal impairment
• Assure no interaction
• Teach the patient to recognize muscle symptom

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Steps to minimize the risk of muscle toxicity
with statin therapy

• 6. Discontinue therapy if muscle symptom are
• present and CPK is gt 10 times the upper
  limit or
• normal.
• 7. If CPK is increase butlt 3 times and the
  patient
• is Asymptomatic? CPK reassessment in 2 weeks
• 8. If myalgias are due to the treatment, even if
  CK is not increased ? prefer not re-administer
  the
• same treatment

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Bile Acid Sequestrants

• The sole precursor of bile acids is cholesterol.
• Bile Acid sequestrants are nonabsorbable polymers
  that act by binding bile acids in the intestine,
  preventing the reabsorption of bile acids.
• Decrease in hepatic cholesterol concentrations
  produces an upregulation of LDL receptors,
  increased LDL clearance from the plasma

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Intestinal Cholesterol Absorption
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Bile Acid Sequestrants

• Colesevelam (WelChol?) is a new bile Acid
  sequestrants that differ from earlier agents in
  that it has multiple hydrophobic side chains
  extending from polymers backbone.
• The bile acid binding sites are located at the
  base of these side chain.
• The primary limitation of colestyramine and
  colestipol is GI intolerance, as constipation.

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Colesevelam (WelChol?) 625
mg/tab

• Manufactured by Sankyo
• Dated Approved by FDA May 26, 2000
• Supplied 625 mg/tab.
• Colesevelam have several advantage over bile acid
  sequestrants such as cholestyramine and
  colestipol.
• Given simultaneously with statins, the lack of
  drug interaction,high potency, a decreased
  frequency of GI adverse events, and a tablet
  formulation.
• The primarily disadvantage is that attenuates the
  TG reduction produced by statins alone.

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Effect of Colesevelam on LDL-c
Davidson MH et al. Expert Opin Investig Drug
200092663-71
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Effect of colesevelam plus statins on lipid
parameters
Hunninghake D et al. Atherosclerosis
2001158407-16 Knapp HH. Am J Med
2001110352-60
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Clinical Features of BARs

• Products available
• Cholestyramine (Questran), 4-16 g/d
• Colestipol (Colestid), 5-20 g/d
• Colesevelam (WelChol), 625 mg/tab., 6-7 tab./d
• Adverse effects
• GI intolerance constipation, bloating, abdominal
  pain, flatulence
• Lack systemic toxicity
• Drug interactions (colestipol and cholestyramine)
• Bind other negatively charged drugs
• Impede the absorption of drugs and/or fat-solube
  vitamines
• Must give other drugs 1 hour before or 4-6 hours
  after

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Selective Cholesterol Absorption Inhibitors-
Ezetimibe (Zetia?)

• First agent in a new class that selectively
  inhibits absorption of cholesterol at brush
  border of the small intestine.
• Manufactured in the US by Merck/Schering.
• Date Approved by the FDA October 25, 2002
• Supplied 10 mg/tab.
• The action results in decreased cholesterol
  delivery to the liver.
• Ezetimibe is indicated for monotherapy or in
  combination with statins.

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Ezetimibe (Zetia?) Mechanism of Action

• Selectively inhibits intestinal cholesterol
  absorption
• ?intestinal delivery of cholesterol to the liver
• ?expression of hepatic LDL receptors
• ?cholesterol content of atherogenic particles
• Ezetimibe and its active glucuronide metabolite
  circulate enterohepatically
• Delivers agent back to the site of action
• Limits systemic exposure
• Moderate reductions in LDL (lt20), Apo-B, TG, and
  increase HDL.

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Ezetimibe (Zetia?) Dosage and Administration

• Dose 10 mg once day alone or with statin, any
  time of day, with or without food.
• Elderly, mild hepatic or renal insufficiency
  dosage adjustment is not necessary
• Not recommended in treatment of children younger
  than 10 years of age.
• Adverse effect
• GI diarrhea, abdominal pain
• Musculoskeletal back pain, arthralgia
• Respiratory sinusitis, coughing, pharyngitis
• Miscellaneous fatigue, viral infection

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Ezetimibe (Zetia?) - Pharmacokinetics

• Onset
• Initial response within 1 week
• Peak response 2 to 4 weeks
• Total protein binding greater than 90
• Metabolism
• Intestine, extensive Liver, glucuronide
  conjugation
• Metabolite Glucuronide (active)
• Excretion
• Renal 11 (9 active metabolite in the urine)
• Faces extensive, 78 (69 unchanged drug)
• Elimination half-life approximately 22 to 24
  hours

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Ezetimibe (Zetia?) - Metabolism

• Ezetimibe undergoes glucuronidation in the
  intestinal wall and is then metabolized to its
  active glucuronide metabolite in the liver and
  delivered back to the intestine for enterohepatic
  recirculation
• The enterohepatic recirculation helps account for
  ezetimibes 22 hour half-life
• Ezetimibe is not an inducer or inhibitor of
  cytochrome P450 enzymes, reducing the risk for
  potential drug interactions with many common
  drugs enzymatically affected by cytochrome P450
  enzymes

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Ezetimibe (Zetia?) Drug Interaction

• Statins No significant pharmacokinetic
  interaction.
• Cholestyramine Decreased the mean AUC of total
  ezetimibe concentration by 50. Ezetimibe should
  be administered ?2 hours before or ?4 hours after
  a resin.
• Fibrate Not currently recommended in combination
  with ezetimibe, as safety and efficacy has not
  yet been established by clinical trials.
• Cyclosporin May substantially increase ezetimibe
  levels
• No significant pharmacokinetic interactions with
  antacids, cimetidine, warafrin, digoxin, ethinyl
  estradiol, glipizide, tolbutamide.

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Ezetimibe (Zetia?) Cautions

• Contraindication
• Prior hypersensitivity to ezetimibe
• Precautions
• Hepatic dysfunction (moderate to severe) or
  biliary obstruction
• Pregnancy (human data unavailable)
• Breastfeeding period (human data unavailable)
• Statin is contraindicated in pregnant.

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Ezetimibe (Zetia?) Laboratory Safety Monitoring

• Laboratory parameters
• Liver function tests periodically when ezetimibe
  is co-administered with an HMG-CoA reductase
  inhibitor
• Physical examination
• Signs/symptoms of toxicity, including GI
  symptoms, headache, sensitivity (eg, rash)

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Ezetimibe (Zetia?) Efficacy Mean percentage
change (Week 12 )
Bays HE et al. Clin Ther 2001231209-30
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Ezetimibe (Zetia?) Efficacy Added On to
Ongoing Statin Therapy
Patients on ongoing stable statin therapy not
reaching NCEP ATP II LDL-c goal
RANDOMIZATION
Open-lable statin ezetimibe
(n379, mean LDL-c138 mg/dl)
Open-lable statin placebo
(n390, mean LDL-c139 mg/dl)
40 on atorvastatin (weighted mean baseline dose
34 mg) 31 simvastatin (37 mg) and 29 others
combined (pravastatin 20 mg, fluvastatin 35 mg,
lovastatin 26 mg, cerivastatin 0.4mg)
Gogne C et al. Am J Cardiol 2002901084-91
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Ezetimibe (Zetia?) Efficacy Added On Study
Gogne C et al. Am J Cardiol 2002901084-91
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Ezetimibe (Zetia?) Efficacy (10 10 80)
Mean percentage change in LDL-c
Zetia Atorva-10
Atorvastatin
Ballantyne CM et al. Circulation 20031072409-15
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Statin and Complementary GI-Acting Drugs vs
Statin Titration
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Niacin Extended Release Lovastatin (Advicor?)

• Manufactured by Kos Pharmaceuticals, Inc.
• Date Approved by the FDA Nov. 04, 2003
• Supplied 500 mg/20 mg 750 mg/20 mg 1000 mg/20
  mg
• Once-daily extended-release niacin and
  lovastatin.
• Niacin markedly reduces triglyceride levels and
  increases HDL levels, smaller effects on lowering
  LDL levels.
• Niacin monotherapy is used infrequently to lower
  LDL-C level, primarily because it is poorly
  tolerated at high doses required for monotherapy.

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Advicor? Dosage and Administration

• Fixed-dose combination formulation primary
  hypercholesterolemia and mixed dyslipidemia.
• Usual effective doses 1000 mg extended-release
  niacin/20 mg lovastatin to 2000/40 mg once daily.
• Severe renal impairmentshould not be exceeded
  fixed-dose of 500 to 1000/20 mg daily.
• Liver dysfunction, particularly active/severe
  liver disease, unexplained transaminase
  elevations Should be avoided.
• Elderly Dosage adjustment is not necessary

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Niacin Extended Release Lovastatin (Advicor?)

• Augment reductions in LDL-C and triglycerides and
  increases in HDL-C.
• Treatment primary hypercholesterolemia and mixed
  dyslipidemia.
• Myopathy 2
• Rhabdomyolysis has not been reported.
• Adverse events flushing episodes (warmth,
  redness, itching, and/or tingling) 5383.

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Niacin ER/L (Advicor?) vs Monotherapy with
Atorvastatin or Simvastatin






Niacin ER/L 1000/40
Atorvastatin 10
- Week 8
Niacin ER/L 1000/40
Simvastatin 20
- Week 12
P lt 0.01 vs simvastatin
Bays H et al. Am J Cardiol 200391667-72
P lt 0.001 vs simvastatin and atorvastatin
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Advicor? Pharmacokinetics

• Onset Peak response4 weeks
• Absorption Bioavailability (niacin) 30
• Total protein binding Niacin 20 L greater
  than 95
• Metabolism Liver, extensive,active metabolites
• Excretion
• Renal at least 50 (niacin) 10 (lovastatin)
• Faces about 80 (lovastatin)
• Elimination half-life L-4.5 hours Niacin-20-48
  min

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Advicor? Contraindications

• Prior hypersensitivity to niacin or to lovastatin
  or other HMG-CoA reductase inhibitors
• Pregnancy
• Breastfeeding period
• Active peptic ulcer disease (exacerbation)
• Active liver disease or unexplained persistent
  transaminase elevations (exacerbation)
• Arterial bleeding (exacerbation niacin component)

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Advicor? Laboratory Safety Monitoring (1)

• Laboratory parameters
• Liver function tests (pretherapy and every 6 to
  12 weeks for the first 6 months, then
  periodically)
• Creatine kinase and urine myoglobin in patients
  presenting with symptoms of muscle pain,
  weakness, or tenderness a level exceeding 10
  times the upper limit of normal indicates
  myopathy in patients
• Renal function tests before and periodically
  during therapy (renal insufficiency is a risk
  factor for rhabdomyolysis) renal function should
  be determined in patients with symptoms
  suggestive of myopathy
• Periodic during therapy serum phosphorus,
  platelet counts, prothrombin time, blood glucose
  (frequently in diabetics or prediabetics), serum
  uric acid

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Advicor? Laboratory Safety Monitoring (2)

• Physical examination
• Symptoms of myopathy (eg, muscle pain, weakness)
  particularly during the first month of treatment
  or during upward dose adjustment
• Signs/symptoms of other toxicity, including GI
  symptoms (persistent nausea dictates ALT/AST
  determinations), flushing severity/persistence,
  headache, and dermatologic symptoms (eg, rash)

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Conclusion

• Improvements in the evaluation and treatment of
  hyperlipidemia have been dramatic, but the
  management of the condition continues to evolve
  and improve.
• ATP III guideline increased appreciation of the
  absolute risk of CHD and the need to treat
  patients aggressively with lipid therapy base on
  their overall risk.
• Statin are firstline agents for many lipid
  problems, but some patients do not achieve their
  goals with theses agents, and CHD events may
  occur despite aggressive statin therapy.

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Conclusion

• Additional lipid-lowering agents and technique
  have been approved recently or in the late stages
  of clinical trial.
• New bile acid sequestrants, statin-niacin
  combination products, new statin, and selective
  cholesterol inhibitors.
• Rationale for combination therapy is to alter
  lipid parameters by complementary pathways.
• Most desirable regimen Combination therapy or
  monotherapy, should optimize all the major lipid
  parameters (I.e. LDL, HDL, TG) and be documented
  to reduce clinical events.

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Q1 What antilipidemic should not be used to
lower triglycerides?

• A. atorvastatin.
• B. Cholestyramine.
• C. Niacin.
• D. Ezetimibe.

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Q2 Selective cholesterol absorption inhibitors
such as ezetimibe

• A. Decrease dietary and biliary cholesterol
  absorption
• through interference with intestinal
  cholesterol transport .
• B. Complete with dietary and biliary cholesterol
  for inclusion into micells in the GI tract,
  disrupting cholesterol and fat absorption.
• C. Prevent the reabsorption of bile acids, the
  precursor of cholesterol.
• D. Inhibit lipolysis, decreasing the availability
  of free fatty acids in circulation.

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Q3 Ezetimibe inhibits absorption of fat soluble
vitamins.

• A.True
• B. False

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• Q4
• R.E. is a 32-year-old white man with
  dyslipidemia, CHD, a history of MI at age 30,
  hypertension, and gastroesophageal reflux
  disease. He presents to the clinic for follow-up
  of dyslipidemia. R.E. reported that he has been
  suffering from significant myalgias, particularly
  during his work hours (he works for a local food
  distributor and loads trucks all day long).

His current drugs are HCTZ 25 mg
QD, Metoprolol 50 mg BID Lisinopril 40 mg/day
Pravastatin 20 mg at bedtime Niaspan 1000 mg at
bedtime NTG sublingual 0.4 mg as needed.
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Lab Values
Niaspan added
Pravastatin added
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Which one of the following is the best way to
handle the adverse drug reaction?

• Discontinue niaspan and add gemifibrozil.
• Switch from pravastatin to simvastatin.
• Switch from pravastatin to fluvastatin.
• Discontinue pravastatin and add fish oil.

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Fluvastatin (Lescol?)
Lovastatin (Mevacor?)
Atovastatin (Lipitor?)
Simvastatin (Zocor?)
Rosuvastain (Crestor)
Pravastatin (Mevalotin?)
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Thank You for Your Attention and Opinion