Statins and mortality: fat benefits or slim pickings?

If 50% of people die from CVD, the rest from cancer, and statins halve CVD mortality. What will be the impact on all-cause mortality? What will be the impact on life expectancy? Probably less than expected.

This goes back to a very real issue with statins and all other drugs but there may be some additional confusion among lay people because statins have a bad reputation in some circles. Not that I am an expert on statins or epidemiology, but I want to offer an interesting take on this problem.

It's true, all else being equal, we can expect that a drug which protects from CVD should lower all-cause mortality. We won't be able to see an effect on mortality in two cases, 1. statistical power is too low, because non-CVD mortality is a rare event, among other reasons, or 2. the benefits are offset by real harm. In the case of statins, as in most cases, it is really hard to distinguish between both of these explanations.

A popular health blog favours explanation 2:

Even though statins can reduce mortality from heart disease in certain populations, they consistently fail to reduce all-cause mortality in everyone but people with an established clinical history of heart disease. For primary prevention in people without prior history of heart disease, even those considered to be at the “highest risk” (high LDL and such), statins do not reduce all-cause mortality. Same goes for the elderly (who seem to suffer more depression and cognitive decline when taking statins). Nor do statins lower the total number of serious adverse events (PDF), which include death (from any cause), hospital admissions, hospital stays, permanent disability, and cancer.  That’s the story, time and time again. You might be less likely to die from a heart attack, but you’re more likely to die from something else. It’s a wash in the end – unless you have prior history of heart disease/attacks. 

The bolded text is actually interesting. Does it not remind us of Tauber's paradox? If a person who suffers from cancer is saved from a heart attack, we can't expect much of an effect on overall mortality. Since most people taking statins are 55-60 years old and in worse health than the average population, it is likely that many of them have underlying diseases which will kill them soon anyway. This is the essence of "competing causes of death" in epidemiology. This means that even a perfect drug that protects against CVD will have only a diminished effect on life expectancy and overall mortality. Due to an unmasking effect on co-morbidities it is also possible that we would see an artificially elevated cancer mortality. This is easy to understand, going back to our initial simplification (50% die from cancer, 50% from CVD). So if we eradicate CVD, then 100% of people will die from something else (cancer). This doubles the mortality rate from cancer, although cancer incidence might be less affected.

An interesting counterpoint is that: "There were also no clear differences in the association between statin use and outcomes in analyses stratified by age older or younger than 55, 60, 65, or 70 years, with very similar estimates from 7 trials" (US Preventive Services Task Force)

This argues that the effect of competing risks in the mid term (all-cause mortality as studied in drug trials) is perhaps small, but instead it must operate over longer spans (life expectancy). So now that we understand the potentially diminishing returns on health. What does the recent evidence on statins say? Do they really fail to reduce all-cause mortality?

One of the most recent and most rigorous meta-analyses to date by the US Preventive Services Task Force finds that there is no effect on cancer and most other diseases and altogether it's looking quite good for statins:

What are the benefits of statins in reducing the incidence of CVD-related morbidity or mortality or all-cause mortality in asymptomatic adults 40 years or older without prior CVD events?
Statins were associated with reduced risk vs placebo of all-cause mortality (15 trials; RR, 0.86 after 1-6 years [95% CI, 0.80 to 0.93]; I2 = 0%
... [on the other hand]An individual-patient data meta-analysis found that the association between use of statins for primary prevention and all-cause mortality did not reach statistical significance (RR, 0.91 [95% CI, 0.83 to 1.01]) but did not include the recently published, large HOPE-3 trial,14 which reported results consistent with the pooled estimates in this review.

A increased risk of cancer would be an important factor that can offset any benefits from statins. However, almost the opposite appears to be true. In fact there is some preliminary evidence on benefits to cancer patients, with no influence for those who are healthy (Zubing et al 2017):

A meta-analysis based on 22 randomized controlled trials showed that statin use was not associated with reduced cancer related mortality (hazard ratio [HR], 1.01; 95% confidence interval [CI], 0.93–1.09) compared with nonstatin use.[41] However, it is unclear whether statins affect prognostic outcomes for patients with established malignancy...This systematic review and meta-analysis of 95 studies involving over 18 cancer types with a total of 1,111,407 patients provides consistent evidence..Statin therapy has potential survival benefit for patients with malignancy. Further large-scale prospective studies emphasising survival outcomes of individual cancer type are strongly encouraged.

Statins in aging research

Two studies have been performed in mice. When giving simvastatin to UM-HET3 mice the ITP program found no benefit on lifespan. In contrast, Stephen Spindler did find a small benefit of a statin + ACE-inhibitor given to long-lived F1 male mice. I can't say that I am particularly excited by these studies, but it is reassuring that a statin given over 100% of the lifespan has no harmful effects in contrast to concerns often voiced by critics. In future studies, a more promising polypill intervention including aspirin could provide incremental benefits and should be tested.

References and Notes

CVD patients are highly co-morbid: "the prevalence of possible new underlying causes of death was relatively high among persons who died from cardiovascular diseases...The results of our analysis suggest that if one were to eliminate cardiovascular diseases as an underlying cause of death, those who were saved would have a relatively high prevalence of other diseases that could develop into new underlying causes of death. This implies that, relative to other underlying causes, the years to be gained by eradicating cardiovascular diseases are overestimated by cause-elimination life tables. In addition, the relative importance of cardiovascular diseases as a cause of life-years that are currently being lost is overestimated. Patients who die from cardiovascular diseases are more likely than those who die from other causes to also have one or more chronic diseases such as chronic obstructive lung disease, diabetes mellitus, Parkinson's disease, etc."
Mackenbach, JP1, et al. "Competing causes of death: an analysis using multiple-cause-of-death data from The Netherlands." American Journal of Epidemiology 141.5 (1995): 466-475.

Statins are associated with a mortality benefit in primary prevention. We can see the mean age of participants is 55 to 60.
Chou, Roger, et al. "Statins for prevention of cardiovascular disease in adults: evidence report and systematic review for the US Preventive Services Task Force." Jama 316.19 (2016): 2008-2024.

Mei, Zubing, et al. "Effects of statins on cancer mortality and progression: A systematic review and meta‐analysis of 95 cohorts including 1,111,407 individuals." International journal of cancer 140.5 (2017): 1068-1081.

Spindler, Stephen R., Patricia L. Mote, and James M. Flegal. "Combined statin and angiotensin-converting enzyme (ACE) inhibitor treatment increases the lifespan of long-lived F1 male mice." Age 38.5-6 (2016): 379.

Miller, Richard A., et al. "Rapamycin, but not resveratrol or simvastatin, extends life span of genetically heterogeneous mice." The Journals of Gerontology: Series A 66.2 (2011): 191-201.