Cancer-related mortality among patients in the Danish population receiving a diagnosis of cancer at age ≥ 40 years between 1995 and 2007 was significantly reduced in those who were receiving statin therapy at the time of diagnosis, according to an analysis reported by Nielsen and colleagues in The New England Journal of Medicine.1 All-cause mortality was also significantly reduced among regular statin users.
Regular statin use was defined as filling of statin prescriptions within 6 months and for 2 years prior to the date of cancer diagnosis. Follow-up continued through 2009, and median follow-up was 2.6 years (range, 0–15 years). Among patients aged ≥ 40 years, 18,721 used statins regularly until cancer diagnosis and 277,204 never used statins. Statin users had a median age of 70 years and 57% were male; statin nonusers had a median age of 69 years and 46% were male.
Over a total of 1,072,503 person-years of follow-up, 195,594 patients died—162,067 from cancer, 14,489 from cardiovascular causes, and 19,038 from other causes. Almost all patents (97%) were white persons of Danish descent.
Reduced Cancer-related and All-cause Mortality
The cumulative incidences of death from any cause and death from cancer-related causes as a function of follow-up time from the date of cancer diagnosis were significantly reduced in statin users (both P < .001). For death from any cause, the cumulative incidence curves for statin users and nonusers crossed at 5 years, likely reflecting increased cardiovascular mortality among statin users.
On multivariate analyses, statin use was associated with a 15% reduction in risk for cancer-related death (hazard ratio [HR] = 0.85, 95% confidence interval [CI] = 0.82–0.87) and a 15% reduction in all-cause mortality (HR = 0.85, 95% CI = 0.83–0.87). The NEJM article does not report whether statin use influenced incidence of cancer.
All Statin Doses Reduced Mortality
Statin use was analyzed as “defined daily dose” per day (assumed average maintenance dose per day for a particular drug); the measure was calculated as total milligrams dispensed in the next-to-last prescription before cancer diagnosis divided by defined daily dose of the particular statin, with this value divided by the interval between the date of the last statin prescription and the date of the next-to-last statin prescription before diagnosis. No statin dose response was observed for reducing risk of mortality.
Compared with patients not receiving statins, those with defined daily doses per day of 0.1 to 0.75, 0.76 to 1.5, and > 1.5 had hazard ratios for death from cancer of 0.83, 0.87, and 0.87, respectively (all P < .001). Table 1 shows hazard ratios for various causes of death in each dosage group.
Subgroup Analyses
In subgroup analyses, cancer-related mortality was significantly reduced with regular statin use in both women and men, patients aged 40 to 69 years or > 69 years at diagnosis, those who did not receive chemotherapy, those who did and did not receive radiotherapy, those with small and large tumors, those with and without metastasis, those with and without cardiovascular disease before diagnosis, those with and without diabetes before diagnosis, and those diagnosed between 1995 and 2002 or between 2003 and 2007. Cancer-related mortality was also significantly reduced in patients with any statin use (rather than regular statin use; HR = 0.87, P < .001).
In patients who received chemotherapy, regular statin use was not associated with a significant reduction in cancer-related mortality. The article does not discuss any potential explanations for this latter finding.
It is possible that statin use was a marker of increased health awareness, potentially biasing the results of the analyses. Statin users were more likely to be men and to have diagnosed cardiovascular disease or diabetes. However, a nested 1:3 matched study (matching for sex, age at diagnosis, year of diagnosis, and cancer type) including equal numbers of men and women and excluding patients with cardiovascular disease and diabetes yielded results similar to the above analyses.
Further, in an attempt to avoid a “healthy-user” bias, the nested 1:3 matched study was repeated using propensity-score matching (matching for the probability that patients received statins on the basis of patterns in medical history). Results of this analysis were also similar to results of the primary analyses.
Among 27 types of cancer included in the analysis, regular statin use was associated with significantly reduced cancer-related mortality for 13. Among these 13, multivariable adjusted hazard ratios ranged from 0.64 for cervical cancer to 0.89 for pancreatic cancer.
Potential Mechanisms
Recent large-scale studies of statins in patients without cancer have not shown a reduced incidence of cancer or related mortality. Their apparent effect in reducing cancer-related mortality in patients receiving statin therapy when cancer is diagnosed may thus have to do with effects on cancer cells. Statins inhibit endogenous cholesterol by inhibiting the mevalonate pathway. Endogenous cholesterol is essential for cell proliferation, and reductions in available cholesterol could lead to reduced proliferation and migration of cancer cells.
As noted by the authors, “[T]he mevalonate pathway is upregulated by mutated p53 (tumor suppressor protein), which is common in cancer. Accordingly, inhibition of this pathway with statins reverts the malignancy phenotype of p53-mutated cancer cells. The decrease in downstream products of the mevalonate pathway has been linked to apoptosis and to reduced matrix-metalloproteinase production and angiogenesis, as well as a reduction in the invasiveness of in situ cancers. Statins have been linked to the halting of cell-cycle progression in cancer cells with resulting antiproliferative effects, to inhibition of key cellular functions in cancer cells, and to increased radiosensitization.”
The authors concluded, “[A]mong patients with cancer, we observed an association between statin use at the time of diagnosis and a reduced risk of cancer-related mortality, with a reduction of up to 15%. Prospective evaluation of the hypothesis that statin use prolongs survival of patients with cancer is needed.” ■
Reference
1. Nielsen SF, Nordestgaard BG, Bojesen SE: Statin use and reduced cancer-related mortality. N Engl J Med 367:1792-1802, 2012.
