LIPID-LOWERING AGENTS

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LIPID-LOWERING AGENTS

• Dr. Lester M. Partlow
• Department of Pharmacology

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NEWSWEEK June 19, 2000
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Steps in Rx of Hyperlipidemia

• Determine lipoprotein profile and degree of
  elevation
• Determine whether the observed lipid elevation
  resulted from a primary (genetic) or a secondary
  cause (Table on page 1)
• Encourage smokers to quit
• Treat hypertension (if present)
• Institute an appropriate diet ? ? ?

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Dietary Therapy for Hyperlipidemia Key Points

• Unlike drugs, there are no toxicities
• Dietary and drug effects are additive
• However, achievable reductions in cholesterol
  from diet are small (4-7 table at top of page
  2)
• Nevertheless, CV benefits can be much greater
  than expected from the degree of LDL reduction
• Diet must be continued as benefits will otherwise
  be lost.
• Functional foods or drugs can be introduced
  after the diet has been established.

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LIPID-LOWERING DRUG CLASSES

1. STATINS SYNTHESIS INHIBITORS
2. CHOLESTEROL ABSORPTION BLOCKER
3. RESINS
4. NICOTINIC ACID
5. FIBRIC ACID DERIVATIVES
6. TRIGLYCERIDE ABSORPTION BLOCKER
7. FUNCTIONAL FOODS

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Class I.HMG CoA Reductase Inhibitors

• HMG CoA 3-Hydroxyl 3-Methyl Glutaryl CoA
• Statins 6 available
• Lovastatin (Mevacor) was the first.
• Atorvastatin (Lipitor) is perhaps the best.
• Simvastatin (Zocor) may be better for combined
  elevations of LDL TGs with low HDL
• Rosuvastatin (Crestor) is newest.
• They all primarily act by inhibiting the
  rate-limiting step in cholesterol biosynthesis.

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HMG CoA Reductase
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Part of each statin molecule is structurally
quite similar to HMG CoA. As a consequence, the
statins attach to the reductase at its HMG CoA
binding site.
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All of the statins have 1000 times greater
affinities for the binding site than HMG CoA. As
a consequence, differences in binding affinity
arent though to be important.
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I.HMG CoA Reductase Inhibitors

• All inhibit the rate-limiting step in cholesterol
  biosynthesis and thereby
• Increase apoB,E receptor activity which increases
  the rate of clearance of LDL.

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HOW DO WE COMPARE STATIN EFFICACY?
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Statin Dose-Response Curves
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Data courtesy of Dr. Paul Hopkins
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Summary of Statin Efficacy

• ?? LDL cholesterol by up to -55
• ?? VLDL-TG by up to -43
• ?? HDL-cholesterol by up to 12

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Clinical Uses of Statins

• Statins have marked demonstrable clinical
  benefits
• ? Regression rate of coronary occlusions
• ? Myocardial Infarct frequency
• ? Angioplasty frequency
• ? CHD death rate
• Used for types IIA and IIB (familial
  hyperchol-esterolemia and combined
  hyperlipidemia)
• Can be used for dysbetalipoproteinemia
  (III)..BUT..
• Simvastatin approved for hypertriglyceridemia
  (type IV)

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Statin Use in At-Risk Patients with Normal or Low
Cholesterol
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Clinical Uses of Statins

• Efficacy questionable for homozygous familial
  hypercholesterolemia
• Most statins should be given immediately before
  bed because
• Most cholesterol synthesis betw 12 3 am
• Most statin half lives are ca 2-3 hr
• But atorvastatin rosuvastatin have half lives
  of ca 20 hr
• Extended release forms of fluvastatin and
  lovastatin are also available

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NEW Possible Uses of Statins

• Aids cardiac transplantation by blocking T-cell
  activation
• Osteoporosis. Statins seem to increase
  osteoblast proliferation
• Alzheimers Disease.
• Two large recent retrospective studies
• Pravastatin lovastatin reduced the likelihood
  of Alzheimers disease by 60-70
• BUT simvastatin didnt reduce AD likelihood ???
• Presumed Mechanism
  ? Plasma
  Cholesterol ? ? Brain Beta Amyloid

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Potential Adverse Effects of Statins

• Generally well tolerated with GI symptoms most
  common (lt10)
• Likelihood of AE is dose-dependent
• Shouldnt use in pregnant women/children
• Insomnia (lovastatin, simvastatin)
• Peripheral neuropathy
  usually reversible, 1/2,200 pt-yrs
• Hepatotoxicity
• Myopathy
• Renal Problems (albumen, hemoglobin only
  rosuvastatin)

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Potential Adverse Effects of Statins

• Hepatotoxicity
• Statins must be discontinued if liver
  aminotransferases are greater than 3X normal in
  serum (1-2)
• Check every 3 months for first 15 mo
• Symptoms flu-like fatigue, weight loss

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Potential Adverse Effects of Statins

• Myopathy
• Cerivastatin (Baycol) was worst it was removed
  from market after 31 US deaths
• Have pts watch for muscle pain, brown urine
• Monitor CPK for muscle breakdown for 15 mo
• NEJM estimates that the likelihood in healthy pts
  not taking other drugs is only 1/10,000 pt-years.
• However, the likelihood is much higher with
• Certain drugs cyclosporine (30), gemfibrozil
  (5 accounts for 12/31 deaths), niacin (2)
• Certain diseases hepatic disease, severe
  infection, renal insufficiency, extreme age

watch for the eagle!!
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• PROTECT YOURSELF FROM THE LEGAL EAGLE!!
• MEASURE LIVER ENZYMES FOR 15 MO
• MEASURE CPK FOR 15 MO
• WATCH FOR DRUG INTERACTIONS
• WATCH FOR TOXICITIES
• ADVISE PATIENTS OF POSSIBLE PROBLEMS

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Drug Interactions

• CYP3A4 inhibitors Only lovastatin simvastatin
  ( atorvastatin to a small degree) are
  metabolized by CYP3A4 so cyclosporine,
  gemfibrozil, some antifungal azoles, grapefruit
  juice, increase their concentrations.
• Rosuvastatin has an unusual dependence on renal
  excretion so its concentration increases in renal
  insufficiency in patients on hemodialysis.
• Antioxidant combos (vitamins C, E, beta carotine
  selenium) block increases in HDL

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Advantages of Atorvastatin (Lipitor)
Rosuvastatin (Crestor)

• They are tied for best for lowering
  LDL-cholesterol
• They are tied for best for lowering triglycerides
• Crestor is better than Lipitor in increasing HDL
  (12.3 vs. 6.5)
• Lowest and 2nd lowest in cost for a single statin

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Price per Month per Percentage Point LDL Reduction Price per Month per Percentage Point LDL Reduction Price per Month per Percentage Point LDL Reduction Price per Month per Percentage Point LDL Reduction Price per Month per Percentage Point LDL Reduction Price per Month per Percentage Point LDL Reduction Price per Month per Percentage Point LDL Reduction
             
Total Daily Dose (mg) Total Daily Dose (mg)
    5 10 20 40 80
Atorvastatin 1.66 2.14 1.88 1.67
Fluvastatin 1.67 2.38 1.85 1.94
Lovastatin (generic) Lovastatin (generic) 0.89 1.15 1.59 2.62
Pravastatin 4.00 3.33 4.02 3.51
Rosuvastatin 1.75 1.55 1.39 1.26
Simvastatin 2.22 2.42 3.72 3.22 2.83
Simvastatin/ezetimibe Simvastatin/ezetimibe   1.63 1.49 1.35 1.26
Data courtesy of Dr. Paul Hopkins, 12/04 Data courtesy of Dr. Paul Hopkins, 12/04 Data courtesy of Dr. Paul Hopkins, 12/04 Data courtesy of Dr. Paul Hopkins, 12/04 Data courtesy of Dr. Paul Hopkins, 12/04 Data courtesy of Dr. Paul Hopkins, 12/04
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Advantages of Atorvastatin (Lipitor)
Rosuvastatin (Crestor)

• Both are best for lowering LDL-cholesterol
• Both are best for lowering triglycerides
• Crestor is better than Lipitor in increasing HDL
• Lowest and 2nd lowest in cost for a single statin
• Neither likely to cause insomnia
• Neither needs to be taken just before bed
• Neither are significantly increased in conc. by
  agents that inhibit CYP3A4
• DRx Rosuvastatin is newest and so not as well
  understood also has more/different side effects

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Class II. Zetia (ezetimibe),
an Inhibitor of Cholesterol Absorption

• Taken once daily at a fixed dose (10 mg) /-
  food.
• Long-acting as metabolized to active glucuronide.
• Acts in brush border of small intestine where it
  selectively inhibits absorption of chol by 54.
• Its maximal efficacy is -19 in LDL, -6
  triglycerides, 1-3 HDL.
• Works in patients with homozygous FH
• No obvious adverse effects or drug interactions.

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Ezetimibe Simvastatin (Vytorin)

• Maximal efficacy -59 reduction of LDL
  cholesterol (80 mg simvastatin / 10 mg ezetimibe)
• How much of an additive effect would you expect?

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Data courtesy of Dr. Paul Hopkins, 12/04
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Ezetimibe Simvastatin (Vytorin)

• Maximal efficacy -59 reduction of LDL
  cholesterol (80 mg simvastatin / 10 mg ezetimibe)
• How much of an additive effect would you expect?
• Ezetimibe also works with atorvastatin,
  pravastatin, lovastatin but you have to use
  separate pills.
• Adverse effects of Vytorin like those of statins
  but with more frequent liver enzyme increases

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Vytorin vs. the Single Statins

• As good as or slightly better than Lipitor or
  Crestor alone for lowering LDL-cholesterol (-59
  gt -53/-55)
• Equal to Lipitor Crestor for lowering TG (-35)
• As good as Crestor for raising HDL (12)
• Tied with Crestor for lowest cost (1.26 per 1
  per month at max dose)
• More likely than some to cause insomnia
• Must be taken just before bed
• Concentration of simvastatin is increased by
  agents that inhibit CYP3A4

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Class III.Bile-Acid Binding Resins

• Cholestyramine (Questran), Colestipol (Colestid),
  colesevelam (Welchol) Cl- salts of large
  copolymers
• Administered orally but not absorbed
• Binds bile acids leading to extra excretion of
  bile

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Bile binding liberates Cl- which can cause
hyperchloremic metabolic acidosis.
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Mechanism of Resin Action

• Fecal excretion of bile is greatly increased
• Conversion of cholesterol to bile in the liver is
  increased
• The intracellular level of cholesterol in
  hepatocytes falls
• ApoB,E receptor number on hepatocytes is
  increased
• The rate of LDL clearance is increased and plasma
  LDL level falls by up to 20-35
• BUT triglycerides are increased by up to 20

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Clinical Uses of the Resins

• Only used if LDL cholesterol is elevated
• Primarily used for type IIa but sometimes used
  for type IIb as well even though VLDL can be
  elevated
• Can be used alone or with a statin or niacin
• Must be taken in divided doses with meals

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Adverse Effects of the Resins

• MAJOR PROBLEM Up to half of all patients
  eventually refuse to continue Rx with powdered
  cholestyramine or cholestipol.
• How noxious are the powdered resins?
• In the Coronary Primary Prevention Trial, what
  did they use for the placebo?

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Adverse Effects of the Resins

• Up to half of all patients eventually refuse to
  continue Rx with powdered cholestyramine or
  cholestipol!!
• Cholestipol (Colestid) is available in 1 gm
  tablets up to 16 per day.
• Colesevelam (Welchol) is available in 0.625 gm
  tablets up to 6 per day.
• GI problems include constipation, heartburn,
  nausea, bloating, possible GI impaction
• Give prior to meals with increased fluids with or
  without Metamucil to minimize GI effects
• The older resins (not colesevelam) reduce
  absorption of fats acidic drugs.
• Overall, Colesevelam (Welchol) is probably best.

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Class IV.Nicotinic Acid (Vitamin B3, Niacin)

• A Broad-Spectrum lipid-lowering agent
  everything falls except HDL which tends to
  increase
• Reduces VLDL synthesis increases VLDL clearance
  so that VLDL triglyceride levels fall 30
• Since VLDL is the precursor to LDL, LDL is also
  reduced but only by 10-20
• Niacin resins can cause a fall in LDL
  cholesterol of up to 70.
• Reduces HDL catabolism increases HDL levels
  (esp. in type IV familial hypertriglyceridemia)

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Clinical Uses of Niacin

• An excellent drug that is limited by its
  side effects
• Very good for
• Type IV (familial hypertriglyceridemia)
• Type V (massive hypertriglyceridemia) and
• Patients with low HDL levels (2)
• Good for Type III (dysbetahyperlipidemia)
• Useful for Types IIa IIb, especially with
  resins
• Useful in hypertriglyceridemia as a resin-niacin
  combo because the resin-caused increase in VLDL
  is blocked by niacin.

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Adverse Effects of Niacin

• 15 refuse to take it because of side effects,
  esp. flushing (92), itching (49), rashes
  (20)
• These symptoms can be minimized by
• pretreatment with aspirin,
• taking drug at end of meals, and
• beginning Rx with small dose increasing dose
• use of Niaspan, a sustained-release preparation
• Can cause dizziness fainting if used with
  antihypertensive agents
• gt3 gm/day is no longer used as it can cause
  hepatic / pancreatic dysfunction.

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Class V. Fibric Acids (Fenofibrate Tricor
Gemfibrozil Lopid )

• They alter transcription of LPL other enzymes
  involved in lipid metabolism.
• While the mechanism is different, the effects are
  very similar to those of niacin
• Decreased VLDL production and increased clearance
  so that VLDL falls by 40-50
• Modestly decreased LDL cholesterol (ca 10)
• Increased HDL production (10-23)

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Clinical Uses of Fibric Acids

• They are good for lowering LDL-cholesterol
  VLDL-triglycerides.
• Almost as good as niacin for types III
  (dysbetalipoproteinemia) and IV (familial
  hypertriglyceridemia) and is better tolerated
• 1 for Rx of low HDL levels

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Adverse Effects of Fibric Acids

• Generally well tolerated except for GI distress
  should be taken with food.
• Also, possible skin rash, blurred vision, anemia,
  gallstones.
• Liver function (ALT, AST) should be monitored
  periodically (discontinue gt3x).
• In combination with a statin, use fenofibrate
  (Tricor) because it is much less likely lt0.1
  to cause rhabdomyolysis than gemfibrozil 5

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Class VI. Triglyceride Absorption Blocker
Xenical (Orlistat)

• Approved for obesity if BMIgt30 kg/m2 or gt27 kg/m2
  if hypertensive, diabetic, or dyslipidemic
• A reversible inhibitor of stomach/intestinal
  lipases undigested TGs arent absorbed.
• TG absorption is reduced by 30
• Taken 3x per day with (or right after) meals

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Clinical Uses of Xenical

• When used with a weight-loss diet, it causes
  5-15 more weight loss than with diet alone.
• Xenical must be continued or lost weight will be
  slowly regained.

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Xenicals Side Effects

• Decreases absorption of fat-soluble vitamins so
  pt needs supplementation.
• Untoward GI events caused by Xenical
• Often during 1st year but less frequently later.
• They occur much more often following meals with
  high fat so a low-fat diet is really a must.
• (Think of it as Antabuse for fatty foods!!)
• Effects include abdominal pain, nausea, diarrhea,
  flatus, fecal urgency, fatty/oily stool, oily
  spotting, and fecal incontinence.
• Frequency of SE can be reduced from 71 to 29 by
  simultaneous use of Metamucil

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Class VII.Food Supplements (Functional Foods)
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Phytosterol-containing Foods

• Take Control margarine Benecol margarine,
  salad dressings and snack bars.
• Like Zetia, phytosterols reduce absorption of
  cholesterol by 10-14.
• Must be taken with every cholesterol-containing
  meal as phytosterols must be present.
• These FFs taste fine can be used for cooking,
  toast, potatoes, etc. but cost a lot.

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Fiber Foodsand Drugs
1997 The first federally sanctioned health claim
for a food!
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Fiber Preparations

• Dietary supplementation with soluble fiber can ?
  LDL cholesterol by 5-10.
• The beta-glucan in soluble fiber binds to
  promotes loss of bile works like the resins.
• Both soluble insoluble fiber are in cereals,
  fruits, vegetables, and metamucil (psyllium).
• Only soluble fiber is in Benefiber which is more
  palatable but more expensive.

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Omega-3 Polyunsaturated Fatty Acids

• Attracted attention because of the inverse
  relationship between intake of omega-3 PUFA
  frequency of CHD in Eskimos, others
• Present in high conc in fish oil as
  eicosa-pentaenoic acid (EPA) docosahexaenoic
  acid (DHA).
• Lowers triglyceride levels by 30 with 3 gm/day
  or 50 with 9 gm/day.
• Useful food alternative for hypertriglyceridemia.
• Recommended by AHA for pts with CHD at 1 gm/day.
  ?? cardiac death by 20-48

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Adverse Effects of Omega-3 Fatty Acids

• Contaminants Side effects
• Mercury
• Toxic fat-soluble organic compounds (e.g.,
  dioxin, insecticides)
• Fishy taste and burping
• Solution to problems Use purified, concentrated
  fish oil
• Omacor (Reliant 85 pure omega 3s NEW FDA
  approved 135/mo)
• SeeYourselfWell or Dr. Sears Omega 3 preps
  (gt60 25/mo)
• (Hg lt10 ppb Dioxin lt1 ppt PCBs lt45 ppb)
• Variable Concentration of EPA DHA in different
  preparations affects needed dose for 1 gm per
  day
• 5 capsules of cod liver oil/day (dont do it!)
• 3 capsules of standard fish body oil (not
  recommended)
• 2 capsules of purified, concentrated fish oil/day
• 1 capsule of Omacor

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In closing, let us briefly return to Humpty
Dumpty and our opening slide.
WAS HE PUSHED?
DID HE JUMP?
OR WAS HIS DEATH IN SOME WAY RELATED TO ELEVATED
CHOLESTEROL?????
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