2 responses to “FDA Finds It Unlikely That Vytorin Or Zetia Increases Risk Of Cancer, But Such A Link Is Possible”

1. 

   David K. Cundiff, MD

   December 30, 2009

   Vytorin and Zetia Responsible for > 50,000 Cancer Deaths?
   In the case of Zetia (ezetimibe, a novel type of cholesterol lowering drug), the Food and Drug Agency (FDA) failed in its duty to protect the public again ineffective and/or unsafe medications. In 2002, the FDA approved Zetia for patients to lower blood cholesterol levels. In 2004, Schering-Plough in partnership with Merck and Co. launched Vytorin (Zetia plus Zocor or simvastatin, a cholesterol lowering drug in the statin class). None of the published studies used to justify the approvals of Zetia or Vytorin show any significant clinical benefit of the drug in reducing deaths or heart attacks. Prescribing information in the Zetia package insert and in the Physician’s Desk Reference state, “The effect of Zetia on cardiovascular morbidity and mortality has not been determined.”1 Proof of clinical efficacy should have been required for FDA approval in the first place—not merely laboratory confirmation of reduced cholesterol. Despite the lack of proven effectiveness of Zetia, sales and profits have been high. Zetia was named the cardiovascular compound of the year at 2004 Pharmaceutical Achievement Awards.2
   Since FDA approval of Zetia, a major study (The Enhance Trial) suggested that Vytorin (Zetia plus Zocor) may increase adverse cardiovascular events compared with Zocor alone.3 After the Enhance Trial results were published about two years ago, Dr. Steven Nissen, the chairman of cardiology at the Cleveland Clinic, said “This is as bad a result for the drug as anybody could have feared.” Dr. Nissen lamented that millions of patients may be taking a drug that has no benefits for them.4 Last month, another study showed the paradoxical result that the greater the decrease in the low density lipoprotein cholesterol (the bad cholesterol) with Zetia the more atherosclerotic plaque is deposited on the wall of arteries of patients.5 This consistent pattern of lack of effectiveness findings should have been enough for the FDA to pull the drug off the market.
   Over a year ago, a large Zetia trial (SEAS or the Simvastatin and Ezetimibe in Aortic Stenosis trial), showed a highly significant increase in the development of cancers and of cancer deaths with Vytorin compared with placebo. The other finding of the SEAS trial was that Zetia was ineffective in aortic stenosis.6 The FDA downplayed the cancer finding based on a review of data from two large ongoing trials and is endorsing the continued use of Vytorin and Zetia by patients. Before making a definitive determination of the possible increased risk of cancer from Zetia, FDA officials call for waiting for the results of two more large trials (n = 20,617 patients) that are expected to be published in 2011 and 2012. The FDA contends that that Zetia probably does not cause cancer despite the SEAS trial data, because preliminary safety data from the two large ongoing Zetia trials (SHARP: Study of Heart and Renal Protection and IMPROVE-IT: Examining Outcomes in Subjects With Acute Coronary Syndrome: Vytorin vs Zocor alone) do not show a significant increase in cancer deaths. However, patients from the ongoing trials were only on study for less than two years on average. In the SEAS trial, the strong cancer risk signal did not appear until after three years on study. This is consistent with the biology of cancer and carcinogenesis. It generally takes several years for cancers caused by carcinogens to manifest clinically. Disturbingly, even the preliminary analysis from the two large ongoing studies show 97 cancer-related deaths in the Vytorin groups compared to 72 deaths in the control groups. While this 35% increase in cancer deaths is not statistically significant (i.e., less than 1 in 20 chance of being related to random variation), it is in line with the 67% increased chance of cancer deaths in the SEAS trial which had an average follow-up of about 4 1/3 years (39/944 cancer deaths with Vytorin versus 23/929 with placebo). Since the two large ongoing trials had data for less than two years on average, a greater increase in cancer death risk would be expected in the later years of these trials if Zetia is a carcinogen.
   If Zetia causes a 67% increase in cancer deaths in patients taking Vytorin or Zetia alone for 4 1/3 years as suggested by the SEAS trial, then this translates into Zetia causing 38 people in 10,000 per year to die of cancer. Since about 2.4 million Americans take Zetia either alone or as Vytorin, over 9,000 people would be expected to die of cancer per year due to Zetia while we are waiting for the more conclusive data from ongoing trials (38 excess cancer deaths / 10,000 patients of Zetia / year x 2.4 million Americans taking Zetia = 9,120 excess cancer deaths per year). This would also mean that over 50,000 Americans have died of cancer due to Zetia or Vytorin since FDA approval in 2002. Since approval by the FDA, Zetia and Vytorin have grossed at least $15 billion for Merck and Co. and Schering Plough ($3.23 per day for Zetia with > 2.5 million users on average for 5 years).
   The FDA is increasingly lacking in credibility as the protector of the public. The time to withdraw Zetia from the market is now.
   1. Zetia (ezetimibe) prescribing information. Merck Shering Plough Pharmaceuticals. 2002. Available at: http://www.zetia.com. Accessed April 11, 2003.
   2. ZETIA (ezetimibe) Named Cardiovascular Compound of the Year at 2004 Pharmaceutical Achievement Awards. Schering-Plough Pharmaceuticals, Inc. August 13, 2004. Available at: http://www.schering-plough.com/schering_plough/news/release.jsp?releaseID=604017. Accessed August 23, 2004.
   3. Kastelein JJP, Akdim F, Stroes ESG, et al. Simvastatin with or without Ezetimibe in Familial Hypercholesterolemia. 10.1056/NEJMoa0800742. N Engl J Med. April 3, 2008;358(14):1431-1443.
   4. Berenson A. Drug Has No Benefit in Trial, Makers Say. NY Times. http://www.nytimes.com/2008/01/14/business/14cnd-drug.html?_r=1&hp&oref=slogin. January 14, 2008.
   5. Taylor AJ, Villines TC, Stanek EJ, et al. Extended-Release Niacin or Ezetimibe and Carotid Intima-Media Thickness. 10.1056/NEJMoa0907569. N Engl J Med. November 26, 2009;361(22):2113-2122.
   6. Rossebo AB, Pedersen TR, Boman K, et al. Intensive Lipid Lowering with Simvastatin and Ezetimibe in Aortic Stenosis. 10.1056/NEJMoa0804602. N Engl J Med. September 25, 2008;359(13):1343-1356.

   Reply
2. 

   Tom Lamb

   December 31, 2009

   Dr. Cundiff:
   Thank you for taking the time to present this medical research information to us.
   In the benefit versus risk analysis, besides cancer — which seems sufficient cause for the withdrawl of Zetia from the market — numerous cases of drug-induced liver injury have been associated with Byetta.
   Thanks, again, for the Comment, and I hope you will continue to read Drug Injury Watch.
   Tom Lamb

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