Nielsen SF, Nordestgaard BG, Bojesen SE. Statin use and reduced cancer-related mortality. N Engl J Med. 2012 Nov 8;367(19):1792-1802.
Danish researchers examined whether statin use begun before a cancer diagnosis is associated with reduced cancer-related mortality. They assessed mortality among patients from the entire Danish population who had received a diagnosis of cancer between 1995 and 2007, with follow-up until December 31, 2009. Of patients 40 years of age or older, 18,721 had used statins regularly before the cancer diagnosis and 277,204 had never used statins.
Statin users had a 15% lower risk of dying from any cause or from cancer. The reduced cancer-related mortality among statin users was observed for each of 13 cancer types.
This study along with several other recent papers deserves our attention. If these results are real, then we should consider prescribing statins to many more of our patients rather than discouraging use.
In particular we should consider prescribing statins to patients who have had breast cancer. In April 2013, Dr. Teemu Murtola reported at the annual meeting of the American Association for Cancer Research that statin use was associated with up to a 66% reduction in the risk of dying from breast cancer.
Murtola et al conducted their retrospective study looking at statin use and breast cancer mortality among 31,114 women with breast cancer who were diagnosed in Finland between 1995-2003. During follow up 6,011 of the women died; 3,169 due to breast cancer. The death rate among statin users was 7.5% while among non-statin users it was 21%.
In other words, women with localized disease taking statins were 67% less likely to die than nonusers (hazard ratio, 0.33). Among those with metastatic disease, statins conferred a 48% decreased risk of death (HR, 0.52). Finland’s national health database allowed detailed analysis so that decreased risk of death could be calculated by the type of statin taken: including simvastatin (HR, 0.47), atorvastatin (HR, 0.27), fluvastatin (HR, 0.35), and pravastatin (HR, 0.50). Median follow-up was about 3 years, but ranged from less than 1 year to 9 years.1
Statins have an image in alternative medicine circles that is hard to shake. They are often considered the best example of all that is wrong with Big Pharma. They are seen as overpriced drugs that are over marketed and over prescribed while risks associated with use are underplayed. Thus we are obligated to seek other explanations for these results.
Nielsen argues that their findings “ …. are plausible because statins inhibit cholesterol synthesis within cells through the inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase, the rate-limiting enzyme in the mevalonate and cholesterol-synthesis pathway. Many of these downstream products are used in cell proliferation because they are required for critical cellular functions such as maintenance of membrane integrity, signaling, protein synthesis, and cell-cycle progression. Disruptions of these processes in malignant cells result in the inhibition of cancer growth and metastasis.”
Plausible yes but they are still not easy for us to accept. Statins have an image in alternative medicine circles that is hard to shake. They are often considered the best example of all that is wrong with Big Pharma. They are seen as overpriced drugs that are over marketed and over prescribed while risks associated with use are underplayed. Thus we are obligated to seek other explanations for these results.
Siddarth Singh of the Mayo Clinic writing in the May issue of the World Journal of Clinical Oncology provides several alternative explanations for Nielsen’s findings suggesting several confounding factors not accounted for. For one, data on smoking were not considered. Patients may have stopped smoking when they started taking statins, perhaps after suffering a recent myocardial infarction. Smoking reduction or cessation by statin-takers could account for a lower mortality risk.
Another possible explanation is what is called the ‘healthy user effect’ and also the ‘healthy adherer effect.’ Doctors may unconsciously but selectively under-prescribe statins to obese patients or smokers because of their unhealthy lifestyles. Again this could be what changes mortality.
The third possibility is the concomitant use of other drugs that possess anti-cancer activity.
In Nielsen’s study women taking statins were more likely to have cardiovascular disease (70% vs. 21%) and diabetes (18% vs. 3%) than non-statin users. This could have led to a disproportionately higher use of aspirin and metformin in the statin users. Both of these are associated with reduced cancer-related mortality. Nielsen did relook at the data with this possible aspirin use in mind, and eliminated all participants with cardiovascular disease (the only indication in Denmark for routine aspirin use) and analysis yielded the same results.2
Still it is hard to forget that the 2012 meta-analysis of 51 random controlled trials by Rothwell et al, which reported that aspirin users were 15% less likely to die from cancer (OR = 0.85; 95%CI: 0.76-0.96).
There are other studies that provide data that counter both the Nielsen and Murtola studies.
A 2012 meta-analysis on statin use and the risk of getting breast cancer found no significant benefit. “A total of 24 (13 cohort and 11 case-control) studies involving more than 2.4 million participants, including 76,759 breast cancer cases contributed to this analysis….. Statin use and long-term statin use did not significantly affect breast cancer risk (RR = 0.99, 95 % CI = 0.94, 1.04 and RR = 1.03, 95 % CI = 0.96, 1.11, respectively).”4 Obviously these results address the risk of getting breast cancer and not the risk of dying from it.
An argument might be made that statins really have their benefit post-breast cancer diagnosis.
Swedish data published in April 2013 suggest that there may be a way to predict which cancers will respond to statin treatment. Bjarnadottir et al treated 50 women diagnosed with invasive breast cancer with high dose atorvastatin (i.e., 80 mg/day) for two weeks before cancer surgery. Tissue samples pre and post statin therapy were compared. On average looking at all the paired samples Ki67 expression decreased non-significantly by only 7.6% after statin treatment (P=0.39) but in tumors expressing HMG-CoA reductase (HMGCR), the rate-limiting enzyme of the mevalonate pathway, Ki67 dropped significantly by 24% (P=0.02). Statins have the most anti-proliferative effect in HMGCR positive tumors. Thus testing for HMGCR could provide a way to selectively treat cancer patients who will respond positively to statins and benefit from treatment.5
Nielsen and Murtola’s studies are exciting. In the long run, their results may or may not hold up. The question now is whether or not we encourage patients, in particularly breast cancer patients, to take statin drugs, or hold off for a few years in the hope that large definitive prospective randomized controlled trials provide definitive answers.
Murtola’s data in particular is compelling. If true, statins can reduce risk of dying of breast cancer more than other adjuvant therapies in use. Statins do come with risks, but they seem to be of smaller magnitude than the cancer therapies currently considered routine. If we weigh risk versus benefit, the scale is starting to tip toward statins.
For more research involving integrative oncology, click here.
1. Murtola TJ, Visvanathan K, Artama M, Vainio H, Pukkala E. Statins and Breast Cancer mortality. Annual Meeting April 7, 2013. American Association for Cancer Research.
2. Singh S, Singh PP. Statin a day keeps cancer at bay. World J Clin Oncol. 2013;4(2):43-46.
3. Rothwell PM, Price JF, Fowkes FG, et al. Short-term effects of daily aspirin on cancer incidence, mortality, and non-vascular death: analysis of the time course of risks and benefits in 51 randomised controlled trials. Lancet. 2012;379(9826):1602-1612.
4. Undela K, Srikanth V, Bansal D. Statin use and risk of breast cancer: a meta-analysis of observational studies. Breast Cancer Res Treat. 2012;135(1):261-269.
5. Bjarnadottir O, Romero Q, Bendahl PO, et al. Targeting HMG-CoA reductase with statins in a window-of-opportunity breast cancer trial. Breast Cancer Res Treat. 2013;138(2):499-508.