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Indication bias, statins and reduced colorectal cancer risk

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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 conducted by Dr Ronac Mamtani, an assistant professor of medicine at the Perelman School of Medicine at the University of Pennsylvania, 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 >10m 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.”

Abstract
Background: Several prior studies have found an association between statin use and reduced risk of colorectal cancer. We hypothesized that these findings may be due to systematic bias and examined the independent association of colorectal cancer risk with statin use, serum cholesterol, and change in cholesterol concentration.
Methods and Findings: 22,163 colorectal cancer cases and 86,538 matched controls between 1995 and 2013 were identified within The Health Improvement Network (THIN) a population-representative database. Conditional logistic regression models estimated colorectal cancer risk with statin use, serum total cholesterol (mmol/L), and change in total cholesterol level. We confirmed a decreased risk of colorectal cancer with statin use (long-term: odds ratio [OR], 0.95; 95% confidence interval [CI], 0.91–0.99; short-term: OR, 0.92; 95% CI, 0.85–0.99). However, to assess whether the observed association may result from indication bias, a subgroup analysis was conducted among patients prescribed a statin. In this subgroup (n = 5,102 cases, n = 19,032 controls), 3.1% of case subjects and 3.1% of controls discontinued therapy. The risk of colorectal cancer was not significantly different among those who continued statin therapy and those who discontinued (OR, 0.98; 95% CI, 0.79–1.22). Increased serum cholesterol was independently associated with decreased risk of colorectal cancer (OR, 0.89 per mmol/L increase; 95% CI, 0.87–0.91); the association was only present if serum cholesterol was measured near the cancer diagnosis (24 mo: OR, 0.98; 95% CI, 0.93–1.03). Decreases in serum total cholesterol >1 mmol/L ≥1 year prior to cancer diagnosis were associated with subsequent colorectal cancer (statin users: OR, 1.25; 95 CI%, 1.03–1.53; nonusers: OR, 2.36; 95 CI%, 1.78–3.12). As an observational study, limitations included incomplete data and residual confounding.
Conclusions: Although the risk of colorectal cancer was lower in statin users versus nonusers, no difference was observed among those who continued versus discontinued statin therapy, suggesting the potential for indication bias. The association between decreased serum cholesterol and colorectal cancer risk suggests a cholesterol-lowering effect of undiagnosed malignancy. Clinical judgment should be used when considering causes of cholesterol reduction in patients, including those on statin therapy.

PLOS Medicine material
PLOS Medicine abstract


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