Confounding rather than causation may explain association between statin use and lower risk of colorectal cancer
Both statin use and increased cholesterol have been linked to lower risk of colorectal cancer. Some have questioned whether the apparent beneficial effects of statins are due to indication bias, which occurs when the indication (high cholesterol) for the medication under study (statin) is also related to the outcome of interest (colon cancer). A large case-control study published in this week's PLOS Medicine conducted by Ronac Mamtani, MD, MSCE, an assistant professor of Medicine at the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, USA, and colleagues provides evidence that indication bias may explain the link between statin use and reduced colorectal cancer risk.
The researchers identified 22,163 patients with colorectal cancer and 86,538 patients without known colorectal cancer from a computerized database of electronic records of >10 million UK patients in primary care practices (The Health Improvement Network [THIN]). They confirmed findings from previous studies that showed a decreased risk of colorectal cancer in statin users compared to non-users (OR, 0.95; 95% CI, 0.91-0.99), however, they found that the difference in the risk of colorectal cancer was not significantly different between those patients who continued statin therapy and those who discontinued (OR, 0.98; 95% CI, 0.79-1.22), suggesting that indication bias may explain the findings. Consistent with this observation, increased serum cholesterol was independently associated with decreased risk of colorectal cancer (OR, 0.89 per 1 mmol/L (~38.6 mg/dl) increase; 95% CI, 0.87-0.91).
Additionally, they observed that decreases in total serum cholesterol by >1 mmol/L at least a year before the cancer diagnosis were associated with 1.25-fold and 2.36-fold increased risk of colorectal cancer in users and nonusers of statins.
Although the researchers adjusted for numerous confounding factors in their analysis, given the observational nature of the study, the findings are limited by the potential for residual confounding by unmeasured factors.
The authors say: "Together, these data demonstrate a complex association between statins, cholesterol, and colorectal cancer, suggesting that unexplained cholesterol lowering in statin users or nonusers may be a marker of undiagnosed colorectal cancer."
They continue, "Clinical judgment should be used when considering causes of cholesterol reduction in patients, including those on statin therapy."
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Research Article
Funding:
This research was supported by the National Institutes of Health (grant number K23-CA187185 to RM, K08-DK095951-02 to FIS, K08-DK098272 to DSG, and K24-DK078228 to JDL). The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; or preparation, review, or approval of the manuscript.
Competing Interests:
I have read the journal's policy and the authors of this manuscript have the following competing interests: RM reports personal fees from Takeda, outside the submitted work; JDL reports personal fees from Pfizer, Merck, and AstraZeneca, and grants from Shire, Takeda, Bayer, and Nestle Health Science, outside the submitted work; FIS has received research support from Takeda, outside the submitted work; and TA reports personal fees from Roche, outside the submitted work. Pfizer, Merck, AstraZeneca, Takeda, and Bayer are manufacturers of statins. The remaining authors (DSG YXY BB JD) have declared that no competing interests exist.
Citation:
Mamtani R, Lewis JD, Scott FI, Ahmad T, Goldberg DS, Datta J, et al. (2016) Disentangling the Association between Statins, Cholesterol, and Colorectal Cancer: A Nested Case-Control Study. PLoS Med 13(4): e1002007. doi:10.1371/journal.pmed.1002007
Author Affiliations:
Division of Hematology/Oncology, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America Division of Gastroenterology, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America Section of Cardiovascular Medicine, Yale School of Medicine, New Haven, Connecticut, United States of America Department of Surgery, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America Tel-Aviv University, Tel-Aviv, Israel
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http://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1002007
Contact:
Ronac Mamtani
Perelman School of Medicine at the University of Pennsylvania
Division of Hematology-Oncology
Abramson Cancer Center
Philadelphia, Pennsylvania 19104
UNITED STATES
215-360-0699
ronac.mamtani@uphs.upenn.edu
Journal
PLoS Medicine