Subject: Statins and other drugs for cholesterol / lipid (hypercholesterolemia/dyslipidemia/hyperlipidemia) control
last updated: 1-Sep-2008

Statins (a/k/a "HMG-CoA Reductase Inhibitors") include...

First & second generation:
  Lipitor (atorvastatin), from Warner-Lambert and Pfizer/Parke Davis (1996) - current market leader
    www.lipitor.com  Prescribing information: http://www.lipitor.com/pi/
    Plasma half-life 14 hrs, Cmax @1-2 hrs, but "the half-life of inhibitory
    activity for HMG-CoA reductase is 20-30 hours due to the contribution of active
    metabolites."  http://www.pfizer.com/download/uspi_lipitor.pdf
    Available pill sizes are 10, 20, 40 & 80 mg.  Most common dose is 10 mg qd.
    10 mg pills are $2.10 each.  20 mg, 40 mg, and 80 mg pills are all $3.10 each.
    [metabolized via CYP 3A4, beware of +200% potentiation with grapefruit juice]
    Study reported 9/2003 that Lipitor is superior to Pravachol:
      http://www.seniorjournal.com/NEWS/Health/3-11-13lipitor.htm &
      http://www.rxlist.com/rxboard/lipitor.pl?read=3259
    1998 Baylor study says Lipitor better than other 1st & 2nd generation statins:
      http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9514454&dopt=Abstract
    Prescribing information indicates 10 mg qd is almost as effective as higher dose:
      40 mg => -50% LDL-C,   20 mg => -43% LDL-C,   10 mg => -39% LDL-C.
      Consistent with that, Dr. Harold Bays (in Lipids Online) wrote that each
      halving ("titration") of the dose of a statin reduces effectiveness
      only about 5-6% (the so-called "rule of 6"):
      http://www.lipidsonline.org/slides/slide01.cfm?q=rule+of+6  (or here)

  Lescol (fluvastatin), from Novartis (nee Sandoz) (1994)
    http://www.centerwatch.com/patient/drugs/dru648.html
    [metabolized via CYP 2C9]
  Zocor (simvastatin), from Merck (1991) - a synthetic, more potent variant of Mevacor
    [metabolized via CYP 3A4, beware of +1500% potentiation with grapefruit juice]
    The patent on simvastatin has expired in Europe in May 2003, and
    expired in the USA on 23 June 2006.  At of late 2005, Zocor was about
    $2.35 / 10 mg pill, but was predicted to drop to about half that
    for generic simvastatin by the end of 2006.  By late 2007 the
    price of generic simvastatin was under $0.10 / 10mg or 20mg pill
    (in quantity 90) at Sam's Club pharmacy, a 96% drop!  (Strangely, it
    is about 16x that price at Walmart Pharmacy, even though Sam's Club
    and Walmart are the same company.)  As of 9/1/2008, Sam's Club had
    removed simvastatin from their $4/mo prescription drug program,
    but qty 100 of 20mg simvastatin was only $10.44 at Costco pharmacy
    (or a whopping $481 for the same quantity of name-brand Zocor).
  Pravachol (pravastatin), from Bristol-Myers Squibb (1991); and as Mevalotin, from Sankyo
    [not metabolized via P450 (CYP) isoenzyme system]
    Available in 10mg, 20mg, 40mg & 80mg tablets.  Pravachol might be less
    likely than Lipitor, Crestor & Zocor to cause adverse side-effects.
    The U.S. patent on Pravachol expired in April 2006, and generic pravastatin is
    available for $0.13/tablet (10, 20 or 40mg) at Sam's Club & Walmart pharmacies. 
  Mevacor (lovastatin), from Merck (1987);
      and Altocor, an extended-release form of lovastatin, from Andrx.
    [metabolized via CYP 3A4, beware of +1500% potentiation with grapefruit juice]
    The patent has expired, and generic lovastatin is now available for
    $0.13/tablet (10 or 20mg) at Sam's Club & Walmart pharmacies.
  Baycol (a/k/a Baychol or Lipobay) (cerivastatin), from Bayer - withdrawn from market
      because (in combination with gemfibrozil) it caused rhabdomyolysis (muscle
      breakdown) leading to kidney damage, and at least 31 deaths (or 52, or more
      than 100, depending on who you believe).
    Articles:
      http://www.fda.gov/bbs/topics/ANSWERS/2001/ANS01095.html and
      http://www.fda.gov/cder/drug/infopage/baycol/ and
      http://www.injuryboard.com/view.cfm/Topic=797

Third generation ("superstatins"):
  Crestor (rosuvastatin, nee visastatin, nee ZD4522), from Shionogi and AstraZeneca (2003)
    Available pill sizes are 5, 10, 20, & 40 mg.  Usual starting dose is 10 mg qd.
    5, 10, 20, and 40 mg pills are all priced at $2.25 ea.
    Half-life 20 hrs, Cmax @3-5 hrs.  [partially metabolized by CYP 2C9, CYP 2C19]
    Articles:
      circa 8/2003: http://www.astrazeneca.com/pressrelease/590.aspx
      circa 4/2003: http://www.astrazeneca.com/pressrelease/485.aspx
      circa 2003: http://www.future-drugs.com/summery.asp?articleid=1052&submit=txt2
      circa 2000: http://www.ims-global.com/insight/news_story/news_story_000316a.htm
      Contrary view: leftist Public Citizen website, worstpills.org, worries about
        safety: http://www.worstpills.org/public/crestor.cfm.  However, just because
        they are leftist (stupid), that doesn't mean they are always wrong.  Even
        smart people are sometimes wrong, and stupid people are sometimes right.
      This article http://www.eohsi.rutgers.edu/internal/classes/biochemical_toxicology/SM%20Huang%20D1.pdf
        indicates that Crestor is effective even in very tiny doses.  On p. 26 it
        reports that 40 mg qd reduced LDL-C by 62%, 10 mg reduced LDL-C by 50%,
        2.5 mg reduced LDL-C by 40% and even 1 mg reduced LDL-C by 33%.
  Pitava (pitavastatin, NK-104, itavastatin, nisvastatin), from Kowa/Novartis - investigational


Non-Statin drugs (can be used with statins):
  Zetia (ezetimibe), a/k/a Ezetrol, from Merck/Schering-Plough
    "The first clinically approved cholesterol absorption inhibitor."
    10 mg pills (the only size available) are about $2.35 each.
    See www.zetia.com and full prescribing information.
    Zetia is often prescribed for use in combination with a statin, such as Lipitor,
    Pravachol or Zocor.  (Vytorin is a combination of Zetia & Zocor.)
    Like statins, ezetimibe's effectiveness is only mildly dependent on dose.  The
    standard 10 mg/day dose typically results in about an 18% reduction (improvement)
    in LDL cholesterol, about 4% increase (improvement) in HDL cholesterol, and
    about 3-6% decrease (improvement) in triglycerides.  Halving it to 5 mg is only
    slightly less effective, typically reducing LDL-C by 15-16% instead of 18%, and even
    0.25 mg/day (1/40th of the usual dose) typically reduces LDL-C by about 10%:
    http://www.lipidsonline.org/slides/slide01.cfm?q=ezetimibe+efficacy&dpg=1  (or here)
    However, a 2006 study of 720 patients failed to find that Zetia+simvastatin
    (Vytorin) reduced growth of arterial plaque by more than simvastatin alone;
    other studies are ongoing.
  Niacin (nicotinic acid, a/k/a vitamin B3), to lower triglycerides & increase HDL-C.
    Very inexpensive OTC, except for a pricey extended release prescription form called
    Niaspan.  However, niacin is dangerous.  The theraputic dose of niacin is similar to
    the toxic dose, and it should never be used for lipid improvement except under the
    close supervision of a physician.  Doses of 1000 mg/day or more are generally needed
    for substantial lipid improvement, but abnormal liver function has been reported in
    patients taking daily doses as low as 500 mg/day.  Studies indicate that extended-
    release forms of niacin may be more dangerous than regular niacin.  Niacin is
    discussed in this article: http://www.well-connected.com/report.cgi/000023_9.htm
  WelChol (colesevelam HCl), from Sankyo/GelTex - nonsystemic/non-absorbed
    Requires huge dose: six 625 mg solid tablets / day
    This article http://www.sankyopharma.com/headlines/index.cfm?article_ID=19 says:
      "WelChol works by binding to bile acids in the intestine and taking those
      bile acids with it as it leaves the body. The body responds naturally by
      drawing cholesterol from the bloodstream to replenish the supply."
  Torcetrapib (nee CP-529414) - http://www.medscape.com/viewarticle/471969 - investigational
    Torcetrapib is described as a "cholesteryl ester transferase protein (CETP) inhibitor"
    which greatly increases HDL-C ("good cholesterol") with little effect on LDL-C.
    It is currently in phase III clinical trials.  See article.
    Pfizer hopes to sell it in a combined pill with Lipitor, probably in 2009.
  JTT-705, from Japan Tobacco Inc. http://www.google.com/search?q=JTT-705 - investigational
    Raises HDL-C (apparently similar to Torcetrapib)
  Avasimibe (CI 1011), from Pfizer http://www.google.com/search?q=Avasimibe - investigational
  Implitapide (BAY 13-9952), from PPD/MRLI and Bayer http://www.google.com/search?q=Implitapide - investigational
  Esperion/Pfizer's ETC-216 (apolipoprotein A-I / Apo-I Milano complex / "Super-HDL")
    "Like Drano For the Arteries" - investigational
    http://www.healthandage.com/Home/gm=0!gc=39!gid2=2756  (or here)
    http://pharmexec.com/pharmexec/content/printContentPopup.jsp?id=109681  (or here)
  Lorelco (Panavir) (probucol) - not available in the USA
    Article: http://content.nejm.org/cgi/content/abstract/337/6/365
    Lowers total cholesterol, but unfortunately also lowers HDL-C
  AGI-1067, from AtheroGenics & AstraZeneca http://www.google.com/search?q=AGI-1067
    Designed to reduce cardiac inflammation - investigational.


Combinations are a hot topic of study, but note that the combination of Baycol
(cerivastatin) and Lopid (gemfibrozil) proved deadly:
  Vytorin (Zetia+Zocor) (ezetimibe+simvastatin), from Merck/Schering-Plough
    Approved by FDA on July 23, 2004.
    Articles: 3/8/2004 lycos story  (or here), and 11/23/2003 press release,
              7/28/2004 TheDoctorsLounge.net article  (or here),
              1/15/08 WebMD story about a disappointing study.
      See Zetia in the "Non-Statin" category, above.
  Advicor (nee Nicostatin) (niacin+lovastatin)  www.advicor.com
  torcetrapib+atorvastatin (torcetrapib+Lipitor), from Pfizer - investigational
    Articles: http://www.medscape.com/viewarticle/473217 and
              http://content.nejm.org/cgi/content/short/350/15/1505
  Benicar+Pravachol (olmesartan+pravastatin) (CS-866MB) - investigational
  Norvasc+Lipitor (amlodipine+atorvastatin) - investigational
  JTT-705+pravastatin - investigational

Here's an excellent lecture (slides and notes) by Dr. Harold Bays, in Lipids Online,
on the subject of combination lipid-altering drug therapies:
http://www.lipidsonline.org//slides/talk_cme_activity.cfm?tk=33&shownotes=1 (or here)


Some earlier (non-statin) cholesterol-lowering drugs are less effective than
statins or Zetia (ezetimibe).  They include:
  Lopid (gemfibrozil), from Warner Lambert - most common "fibrate"
    Other fibrates include Tricor (fenofibrate), and Bezalip (bezafibrate)
  Questran (cholestylramine), from Bristol Myers


General safety concerns about statins:
  "The primary safety concern with statins has involved an uncommon condition
  called myopathy, which can cause muscle damage and in some cases, muscle
  and joint pain.  The risk for myopathy is highest at higher doses and in
  older people, those who are small or frail, people who abuse alcohol, and
  those who are hypothyroid.  There is also a higher risk if statins are
  used before surgery, and if people are taking multiple medications. ...
  In the past, there have been a few reports of a specific myopathy called
  rhabdomyolysis that can lead to kidney failure. Of note, fatal events from
  rhabdomyolysis occurred in less than 1 out of a million prescriptions and
  nearly always with the statin cerivastatin (Baycol), particularly at high
  doses and in combination with fibrates. ... Patients should tell their
  physicians about any unusual muscle discomfort or weakness and if their
  urine becomes brown-colored. ...
  Statins also can effect the liver, particularly at higher doses, so
  periodic liver function tests should be administered. Statins should not
  be taken by anyone with liver problems or by women during pregnancy or
  breast-feeding.
  -quoted from this very comprehensive article:
  http://www.well-connected.com/report.cgi/000023_9.htm


Here are three somewhat conflicting articles about the effects of cholesterol
and statins on the brain:
  http://www.ucdmc.ucdavis.edu/ucdhs/health/a-z/23Cholesterol/doc23braineffect.html
  http://www.xagena.it/news/medicinenews_net_news/e29b722e35040b88678e25a1ec032a21.html
  http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15329062
  There are also reports of two different adverse neurological symptoms
  which are (occasionally) associated with statins: vivid or abnormal
  dreams, and memory loss.  It is unclear whether these two symptoms are
  correlated.  Abnormal or vivid dreams have been associated with Lipitor
  and perhaps other statins, in a small percentage of patients.  Of greater
  concern are reports of statin-associated memory loss among patients taking
  Lipitor, and occasionally patients taking Zocor or Crestor.  The problem
  seems to be rare.  This article www.medscape.com/viewarticle/458867_4 says
  that the problem appears to be less common with Pravachol than with either
  Lipitor or Zocor.

An interesting article about the market battle between these products:
  http://www-personal.umich.edu/~afuah/cases/case11.html

An interesting C&E News article about the generic drug industry:
  http://pubs.acs.org/cen/coverstory/8038/8038biogenerics.html

A.D.A.M.'s quite comprehensive information about Cholesterol and other Lipids:
  http://www.well-connected.com/report.cgi/fr000023.html

MedicineNet's quite comprehensive article about Cholesterol and related topics:
  http://www.medicinenet.com/cholesterol/article.htm

But what about Dr. Russell Blaylock (who says statins are bad)?:
  http://www.burtonsys.com/blaylock_v_statins.html



Here's a web page similar to this one, but about bisphosphonates (drugs for
osteoporosis / bone recalcification): http://www.burtonsys.com/osteoporosis.html