Statins Do Not Protect Against and May Increase Risk for Colorectal Adenomas

From Medscape Medical News
Nick Mulcahy

April 22, 2010 (Washington, DC) — Statins do not protect patients against colorectal adenomas, the benign precursors of colorectal cancer, and might increase the risk of developing them when used for 3 years or more, according to new research.

However, the increased risk is in need of further study, and not cause for patients to stop taking statins for cardiovascular benefit, said lead researcher Monica Bertagnolli, MD, who presented study results here at the American Association for Cancer Research (AACR) 101st Annual Meeting.

I would hate to take away a life-saving drug for a theoretical risk.
"The clear message is that statins save lives in patients with cardiovascular disease. I would hate to take away a life-saving drug for a theoretical risk," said Dr. Bertagnolli, chief of the Division of Surgical Oncology at Brigham and Women's Hospital and professor of surgery at Harvard Medical School in Boston, Massachusetts. She spoke to Medscape Oncology in the press room at AACR.

The new results come from the Adenoma Prevention with Celecoxib (APC) trial, which was primarily designed to evaluate whether the arthritis drug celecoxib (Celebrex, Pfizer) could be used to prevent colon cancer (N Engl J Med. 2006;355:873-884).

However, about a third of the 2035 patients in the study also took cholesterol-lowering statins.

The new statin results are from a planned secondary analysis of the ACP trial and were published online April 19 in Cancer Prevention Research to coincide with the presentation at the meeting.

The randomized placebo-controlled APC trial was designed to assess the effect of concomitant medications on the development of adenomas and other study end points, Dr. Bertagnolli explained.

To make this assessment, the investigators separated out the 679 placebo users, 221 of whom used statins.

Like the rest of the participants in the trial, the patients on placebo were at high risk for adenomas, and underwent colonoscopic surveillance for 5 years after study enrollment.

After adjustment for covariates, including cardioprotective aspirin use, age, and sex, participants in the placebo group who used statins at any time had no benefit over 5 years, compared with participants who had never used statins (risk ratio, 1.24; 95% confidence interval [CI], 0.99 - 1.56; P = .065)

"Statins definitely did not prevent adenomas," said Dr. Bertagnolli.

However, an increased risk for adenomas over the 5-year study period was found in a subset analysis of patients taking statins for more than 3 years (risk ratio, 1.39; 95% CI, 1.04 - 1.86; P = .024).

"We found more adenomas in this group," said Dr. Bertagnolli about the subset analysis. However, the finding was "intriguing only" and was in need of follow-up study, she said.

"We ought to study what happens to patients who take statins for more than 3 years," she said.

Accumulating Evidence or Final Word?

The results add to a literature that has mostly found statins not to be protective against colorectal neoplasia, according to an editorial that accompanies the study.

"The negative data that Bertagnolli et al provide add to the accumulating evidence that, at least overall, statins probably do not prevent colorectal neoplasia," writes John Baron, MD, of the Departments of Medicine and Community and Family Medicine at Dartmouth Medical School in Hanover, New Hampshire.

It is conceivable that there are benefits.
However, Dr. Baron did not entirely close the door on a chemoprotective effect of statins. "It is conceivable that there are benefits with high cumulative doses or in genetically defined subgroups," he writes.

Dr. Baron's reference to genetically defined subgroups is related to another paper, also published online April 19 in Cancer Prevention Research.

In that study, an international group of researchers looked at 40 genes "important to cholesterol synthesis and metabolism." It was an effort to explain the mixed results found in different observational studies of colorectal cancer risk and statin use.

The researchers found that the colorectal cancer–statin association varied according to genotype of the HMG-CoA reductase (HMGCR) gene, with relative risks varying from 0.30 to 0.60.

"It is theoretically possible that the variants might differ from population to population, and so explain the varying observational findings," summarized Dr. Baron about the study.

However, at the AACR meeting, Dr. Bertagnolli spoke very differently about any possible connection between statin use and adenomas. "We feel very confident that stains don't prevent adenomas," she said.

Also, in a press statement, Dr. Bertagnolli closed the door on the possibility of any chemoprotective effect. "Given our results, we do not think that it is reasonable to further study statins for chemoprevention of colorectal cancer, as the chance that they have this activity is very small."

Dr. Bertagnolli reports receiving research funding from Pfizer and from the National Cancer Institute for this study. Dr. Baron reports being either a consultant to or on the advisory board of Merck and Bayer.

American Association for Cancer Research 101st Annual Meeting. Abstract 1136. Presented April 19, 2010.

Cancer Prev Res. Published online April 19, 2010.