The Science of Statins: Well, This Is Awkward.

I’ve been ignoring the “statin controversy” for a while now, because 1) the accepted guidelines are actually pretty damned clear and well-established, and 2) the kind of people and websites that are excitedly discussing it seriously also seem to be the kind that set up all sorts of false dichotomies between The Goodness of Nature and The Evils of Drugs.

But I’ve noticed a few doctors who are taking this all very seriously – one cardiologist at our hospital is taking all of his female patients off statins – so… what the hell.  I went ahead and looked into it.  And now I feel reasonably confident I can give you a Cliff’s Notes version of what everyone’s fighting about.

Spoiler alert: … holy crap, I think the dissenters have a valid point.

Main Arguments of The Current Statin Controversy:

1.  There’s no proof that statins actually lower all-cause mortality.  Many of the most famous studies use very soft end-points (like “need for revascularization”) in addition to hard end-points like “myocardial infarctions” or “death due to adverse cardiovascular events” or just “death”.  In many cases (I’m looking at you, JUPITER Trial), the end-points wouldn’t be statistically significant if it weren’t for the inclusion of the soft end-points.

If you think about it, all-cause mortality is really the end-point that should matter – especially in light of the growing evidence that statins hugely increase your risk of diabetes (especially for women) and are correlated with an increased incidence of cancer.

2.  The absolute risk reduction may be statistically significant, but it’s TINY.  I have a lot of reservations about this point.  Their argument is that drug companies are only reporting the relative risk-reduction (which means that if, for example, the rate of heart attack went from 2% to 1% on a statin, the relative risk reduction would be 50% while the absolute risk reduction would be 1%), which is false and deliberately misleading advertising.

But then these same people (ahem, Dr. Barbara Roberts) will rather hypocritically go on to use absolute numbers when discussing the adverse effects (i.e. “Statins increase the risk of myositis 50%!” instead of “Statins increase the risk of myositis from 1% to 2%), which frankly makes me want to hit them across the head with a large biostatistics book.

Personally, I think a 1% absolute risk reduction in absolute mortality isn’t “paltry” or “only barely statistically significant” if it’s YOUR absolute mortality that we’re talking about – but that’s just me.

Still, there does seem to be an arguable point that many of the biggest studies (for example, the JUPITER trial – which, interestingly, was regarded as a huge success for statins overall), showed no decrease in absolute mortality at all.

3.  The adverse effects of statins are horrific.  True – but a lot of this is based on very specific stories about very specific patients who had bad experiences (Dr. Barbara Roberts is especially guilty of this – it’s actually kind of embarrassing to the medical profession, in my opinion, to put that much emphasis on “Well, I heard this one story about a lady who NEARLY DIED” as opposed to the actual percentage likelihood of that happening, but whatever).  It’s still worth knowing that there’s a statistically significant increase in risk of developing diabetes if you’re on a statin [3], though – especially in light of point #4, which is:

4.  There is ZERO evidence that statins reduce strokes or MIs in women.  This was shocking to me.  It’s true.  There’s a statistically significant effect when men and women are lumped together, but if you look at women’s end-points separately from men’s, you’ll find there’s no statistical merit whatsoever.

An exception that is often raised is the JUPITER trial, which was initially heralded as showing a statistically significant decrease in end-points for women.  The problem is, there was no reduction in risk of fatal OR nonfatal heart attacks, or fatal or nonfatal strokes.

… which is sort of the point, isn’t it?  Instead, it’s only because the study authors included “need for revasculization” in their studied endpoints that any statistically significant advantage was found to rosuvastatin at all.  There was no difference in mortality or adverse CV events.  (Also: no women below the age of 60 were included in this trial.  So, there’s that.)

(This isn’t true for secondary prevention, though.  If a hyperlipidemic woman has already had a thrombotic stroke or MI and is looking to prevent another one, that’s a different story – though it’s true that the risk reduction is still less than it would be for men.)

4.  You can accomplish the same thing with diet and exercise.  Yes, but easier said than done.  Unless you’re an incredibly gifted motivational guru of a doctor, it’s kind of a drastic oversimplification.

5.  Drug companies are paying for all these studies – they’re inherently biased.  Personally, I doubt this makes the studies more biased than any other kind of research – no matter where the funding comes from, everyone’s careers are staked on a positive result.  But okay; valid.

6.  The Cholesterol Hypothesis is faulty.  Most medical professionals shy away from this one, but it’s out there, and it’s… not entirely wrong.  We do have surprisingly little evidence that cholesterol levels directly correlate with risks of adverse cardiac events – but that’s exactly the sort of study that would be really difficult to pull-off.  Correlation vs. causation is never easy.

The bottom line is that there’s ZERO evidence for putting women on statins for primary prevention – no matter how many risk factors they have.

And that’s… kind of mind-blowing.

Sources:  1. K.K. Ray et al, “Statins and All-Cause Mortality in High Risk Primary Prevention: A Meta-Analysis of 11 Randomized Control Trials Involving 65,229 Participants,” Archives of Internal Medicine, 170, no. 12 (June 28, 2010): 1024-31

2. J. Downs, et al., “Primary Prevention of Acute Coronary Events with Lovastatin in Men and Women with Average Cholesterol Levels: Results of AFCAPS/TexCAPS,” Journal of the AMA 279, no. 20 (May 27, 1998): 1615-22.

3. S. Mora, et al., “Statins for the Primary Prevention of Cardiovascular Events in Women with Elevated High-Sensitivity C-Reactive Protein or Dyslipidemia: Results from the Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) and Meta-Analysis of Women from Primary Prevention Trials,” Circulation 121, no. 9 (March 9, 2010): 1069-77.

4. M. de Logeril, et al., “Cholesteral Lowering, Cardiovascular Diseases, and the Rosuvastatin JUPITER Controversy: A Critical Reappraisal,” Archives of Internal Medicine 170, no. 12 (June 28, 2010): 1032-36.

5. “Prevention of Cardiovascular Events and Death with Pravastatin in Patients with Coronary Heart Disease and a Broad Range of Initial Cholesterol Levels: The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group,” New England Journal of Medicine 339, no. 19 (November 5, 1998): 1349-57.

6. “MRC/BHF Heart Protection Study of Cholesterol Lowering with Simvastatin in 20,536 High-Risk Individuals: A Randomized Placebo-Controlled Trial,” Lancet 360, no. 9326 (July 6, 2002): 7-22.