The reports released in the NEJM on 2 Sept 2008 on the SEAS trial , and the cumulative analysis with the other two current ezetimibe trials- IMPROVE-IT and SHARP, and the accompanying editorial Ezetimibe and Cancer — An Uncertain Association, do not discuss the issue of the possible pathogenesis of increased cancer in the SEAS trial.
What these papers ignore is the long-known destabilizing effects (eg Muldoon 1997) on neuroimmunoendocrinology from driving LDLC too low, as we reviewed on line on 30 August 2008 below : In the recent Hong Kong study (Yang, Chan ea 2008), the cancer and death rates rose progressively when LDLC levels fell below a mean of 3.28mmol/L .
in the 2008 Baltimore statin metaanalysis in people from 60yrs upwards, cancer increased by 6%.
The reports on the ezetimibe ( IMPROVE-IT and SHARP) trials now under way do not disclose the mean baseline and interim LDLC levels during these trials- but these trials have run respectively only a mean of 1 and 2.7years , nowhere near the mean duration of 4.3years in the SEAS trial. In the latter, the approximate 50% increase in cancer (7.5% placebo, vs 11.16% with ezetimibe) and 67% in cancer deaths (2.5% on placebo vs 4.1%) associated with +- 50% decrease in mean LDL cholesterol from 3.6 +-1 mmol/L to 1.36mmol/L..
Overall there was no significant improvement in survival with ezetimibe in the SEAS trial.
Wikipedia sums up: “common adverse drug reactions (≥1% of patients) associated with ezetimibe therapy include: headache and/or diarrhoea. Infrequent effects (0.1–1% of patients) include: myalgia and/or serious liver damage. Rarely (<0.1% of patients), hypersensitivity reactions (rash, angioedema) or myopathy may occur. … Clinical trial controversy: In January 2008, ENHANCE- a clinical trial of Zetia -showed that the drug resulted in growth (not lessening) of fatty plaques. Merck and Schering-Plough completed the clinical trial in April 2006 and had initially planned to release the findings no later than March 2007. The companies missed several self-imposed deadlines, and in December 2007, finally agreed to publish the results “soon” after the delays were publicized in news reports. .. A March 2008 meeting of the ACC resulted in negative press for drugs like Zetia as Yale University Cardiologist Harlan Krumholz et al questioned the efficacy of such drugs, that such pharmaceuticals should not be the first or even second option for prescribing doctors. ”
In short, the SEAS and ENHANCE trials confirm the probability that such drastic lowering of LDLC has no overall benefit; but increases the risk of cancer, and statin-related muscle, liver, kidney and lung damage. If there wa a trend in the SEAS trial to a particular cancer with hypocholesterolemia, it was to prostate, gastric and skin cancer; whereas in the Hong Kong study it was to “cancers of the digestive organs and peritoneum, genitourinary organs, and lymphatic and hematopoietic tissues”
The Womens’ Health Initiative and therefore the WISDOM prempro trials were terminated in 2002 in people in the same age bracket for far lower increase in cancer.
Hence, on strong published evidence, the ezetimibe (SHORT and IMPROVE-IT) trials, and the promotion of ever-lower cholesterol bloodlevels, should be stopped now on the basis of no likelihood of gain except in increased cancer and neuroimmunoendocrine destabilization..
Merck should rather stick to promoting it’s slow release metformin (Glucophage SR) , the only true proven panacea drug ever invented and patented (1922) , as this column points out regularly.
But major journals and the FDA and their chief funder Big Pharma do not lightly back off on a drug registered without longterm evidence of need let alone overall benefit and safety that has already grossed some $5billions…