Statins have been controversial and are used by alternative medicine (not medicine) lovers as an example of all kinds of malfeasance from Big Pharma. However, real studies show quite the opposite — they protect cardiovascular health and reduce the risk of death.
So let’s take a look at the best systematic reviews and try to put to rest the nonsensical dismissal of the claim that statins prevent cardiovascular events, including death.
First, what are statins?
Statins are officially known as HMG-CoA reductase inhibitors, which have an effect on lowering cholesterol levels. HMG-CoA reductase is an enzyme in the pathway for cholesterol synthesis in the liver. By blocking this enzyme, statins effectively reduce cholesterol production. This is important because most blood cholesterol comes from liver production rather than diet (see Note 1). With decreased production of cholesterol, blood levels of cholesterol will fall concomitantly.
Hepatic cholesterol synthesis is mostly at night, so generally, statins should be taken in the evening to maximize their effectiveness. However, there are some new long-acting statins that can be taken at any time, and block cholesterol production throughout the day.
Despite the Nirvana fallacy loved by the anti-medicine world, statins aren’t perfect — they have important side effects, such as muscle problems, increased risk of type 2 diabetes mellitus, and increased liver enzymes as a result of liver damage from the medication. Per 100,000 people treated with statins over five years, there could be 75 cases of diabetes, 7.5 cases of stroke, and 5 cases of muscle damage. I think a lot of those who are opposed to statins focus on these findings of side effects.
However, a recent systematic review (and on the hierarchy of scientific research, systematic reviews are at the top), published in the European Journal of Preventative Cardiology, reported that only a small fraction of side effects reported by patients using statins are actually attributable to the statin itself (see Note 2). They concluded:
Only a small minority of symptoms reported on statins are genuinely due to the statins: almost all would occur just as frequently on placebo. Only development of new-onset diabetes mellitus was significantly higher on statins than placebo; nevertheless only 1 in 5 of new cases were actually caused by statins. Higher statin doses produce a detectable effect, but even still the proportion attributable to statins is variable: for asymptomatic liver enzyme elevation, the majority are attributable to the higher dose; in contrast for muscle aches, the majority are not.
In other words, the adverse events after using statins may be vastly overstated, to the point where these side effects are tiny compared to the benefits of the drug. Frankly, the risk of death (which we’ll see) from a higher LDL level is so significant, that the relatively rare side effects pale in comparison.
Do statins prevent cardiovascular events?
Yes, there is robust evidence that actually shows that statins prevent cardiovascular events, including death. The benefits of the drugs far outweigh the risks. For example, a systematic review (considered the peak of the hierarchy of medical research), published by the Cochrane Database Systematic Reviews in 2013, concluded that:
Reductions in all-cause mortality, major vascular events and revascularisations were found with no excess of adverse events among people without evidence of cardiovascular disease (CVD) treated with statins.
This review included 18 randomized control trials, with 56,934 participants. In other words, that’s fairly solid evidence that, in fact, statins prevent cardiovascular events, including all-cause mortality. I’m not cherry-picking a positive systematic review – I was unable to find reviews that showed negative results, but maybe there is a robust one out there. There are nearly 4000 published studies on statins and cardiovascular health, adverse events, and other issues. And the bulk of them was strongly positive and, of course, leads to positive systematic reviews.
But yet, there is a controversy about statins, as there is a small but vocal group who dispute the link between cholesterol and heart disease, while also being anti-statins.
Dr. Steven Novella, in an article reviewing the newly published systematic review, calls these people “statin and cholesterol ‘skeptics’ (really deniers, at this point) who think the cholesterol theory of vascular disease is wrong.” I actually didn’t know there are people who think that cholesterol has nothing to do with cardiovascular disease. I want to say I’ve now heard it all, but I know better.
A meta-analysis
In a review, published in JAMA in April 2018, researchers performed a meta-analysis of 34 randomized clinical trials that included over 270 thousand participants. A meta-analysis has its strengths and weaknesses, but it gets much more powerful as you add more participants – with over 270,000 data points, this becomes a very solid review.
The researchers’ review found:
…more intensive LDL-C–lowering therapy was associated with a progressive reduction in total mortality with higher baseline LDL-C levels (rate ratio, 0.91 for each 40-mg/dL increase in baseline level); however, this relationship was not present with baseline LDL-C levels less than 100 mg/dL. There was a similar relationship for cardiovascular mortality.
Ok, let me put it into plain English. A higher statin dose lowers LDL-C (or low-density lipoprotein cholesterol, or the “bad” cholesterol) and was associated with a reduction in total mortality and cardiovascular mortality for individuals with higher starting point LDL-C levels. Individuals with lower starting LDL-C levels didn’t see these benefits.
There are several conclusions one can make from this powerful study:
- This review establishes a dose-response relationship between statins and cardiovascular mortality – the more statins are given, the better the outcomes. Of course, this isn’t an infinite response, there are maximum doses beyond which the effects don’t increase, and potentially, side effects are worse.
- The benefits of statins are higher in patients with an LDL-C level greater than 100 mg/dl. There appears to be a benefit to those with <100 mg/dl of LDL-C, but it’s not statistically significant.
- The results support the lipid theory of cardiovascular disease, which states that higher cholesterol levels are linked to heart and vascular diseases. Moreover, high LDL levels are linked to stroke, heart disease, and mortality – and those are all reduced by statins.
If your blood LDL-C levels are above 100 mg/DL, there is good evidence that statins will save your life with little risk.
And another systematic review
A systematic review, published in September 2022 in the Journal of Clinical Medicine, examined 54 studies which included 21 in CVD, six in chronic kidney disease, six in chronic inflammatory diseases, three in cancer, and 18 in other diseases.
The researchers found that:
- The risk of all-cause mortality was significantly reduced in statin users, with a hazard ratio (HR) = 0.72 — that’s a 28% reduction in the risk of all-cause mortality.
- The reduction in mortality risk was similar in CVD studies HR =0.73 and non-CVD studies HR = 0.70. In other words, a 27% decrease in the risk of death in those with cardiovascular disease and a 30% decrease in the risk of death in non-cardiovascular disease group.
Yeah but Big Pharma
I probably could cut and paste many of the complaints about vaccines, change a couple of words, and apply them to statins. Yeah, statins are a huge moneymaker for Big Pharma with a worldwide market of over US$14.3 billion in 2021.
On the other hand, Big Pharma also pushes new statins that have, at best, minor, and possibly clinically irrelevant, differences that are found with generic statins like simvastatin, which is not expensive. This makes it seem like statins are an unethical big business – it is a big business, but the drug works, as shown by huge studies. And newer statins, with minor improvements in clinical effectiveness, may convince some medical professionals that a minor improvement could reduce the risk of mortality even more than generic statins.
However, I tire of these arguments about pharmaceuticals – if they work, as shown by clinical evidence, then that should be the key point, irrespective of their profitability to Big Pharma. Arguing about the prices is a political problem, not a scientific or medical one. The scientific consensus says statins prevent cardiovascular death. That’s it, end of the story. If you don’t like how much Big Pharma makes from selling a life-saving drug, then file a complaint with your government about prices. (No, I’m not naive, I know that particularly in the USA, this is not going to make any changes.)
And, by the way, that trope that Big Pharma never saves lives? Oh yeah, that’s false, just based on these studies.
A generic statin, costing about US$15.00 a month, could save a patient from spending US$25,000 on a heart bypass surgery, US$10,000 on an angioplasty and stent, or US$20,000 on treating a stroke (see Note 3). Even the economics of this whole story supports the use of statins.
As Dr. Novella states in his review of one of the systematic reviews:
However, just because a drug is profitable, that does not mean it is not a good idea. In this case independent scientific study has clearly established that statins are safe and effective. Anti-pharmaceutical conspiracy theories are just poisoning the debate at this point. Generally they are counterproductive, tainting legitimate watchdog criticism with pseudoscientific conspiracy mongering and scaring people away from effective treatments.
Muscle pain and weakness from statins
One of the mysterious side effects of statins has always been muscle pain in the extremities, upper arms and legs more specifically. This has shown up in about 5% of participants in clinical studies and up to 30% in some observational studies.
A smaller proportion of individuals who take these drugs, around 1%, develop muscle weakness or myopathy severe enough that they find it hard to do normal activities like walking up stairs or getting up from the toilet.
Recently, scientists stumbled on the reason why some people may be susceptible to muscle weakness and pain from statins. It has to do with the HMG-CoA reductase enzyme that is blocked by statins (as discussed above).
In some individuals, there is a dysfunction in the enzyme caused by a mutation in the gene that codes for HMG-CoA reductase. How scientists discovered this link was based on plain good luck.
For most people, the less severe cases of myopathy disappear after they change their medication to a different statin or they use a lower dose. However, for that 1% who get the more severe cases of myopathy, changing medications or reducing the dose (or even eliminating statins altogether) may not reverse the condition.
In that case, there is a medication that seems to reverse the more severe cases, but unfortunately, it raises the level of cholesterol.
Nevertheless, the benefit-to-risk ratio of statins is still overwhelmingly on the side of statins.
Summary
I know some of you will yell out “Just exercise and become a vegan, and all your problems go away.” Yes, maintaining a healthy BMI will probably reduce your risk of cardiovascular death. However, as we discussed above, your liver produces LDL-cholesterol, and if your blood level is greater than 100 mg/dl, no matter how healthy your lifestyle is, you’re still at risk of dying. Of course, for many people, getting exercise or eating healthier can be difficult.
We have overwhelming evidence that supports the theory that statins prevent cardiovascular and all-cause deaths. The studies reviewed in this article are powerful and they just add to our body of evidence about statins.
I already know that cholesterol deniers (yeah, I’m owning that now) will claim that cholesterol is not related to anything, so it’s a waste of money to use statins. There are others that are going to claim that Big Pharma has bought off every physician on the planet to sell statins. And there will be others that claim that the blueberry-kale smoothie will treat all that ails us.
But the evidence is pretty solid – statins prevent cardiovascular deaths. And the benefits far outweigh the costs, whether it’s the economic risk or the minor side-effect risks.
Notes
- Please don’t conclude that because statins block the production of most of the blood cholesterol, you can eat all the pizza you want. A high fat/cholesterol diet can still have a significant negative impact on your overall health
- This study was co-authored by Dr. Ben Goldacre, who is extremely critical of Big Pharma and its clinical trials. Many of his writings have been deeply influential on my own thinking about clinical trials, especially the importance of systematic reviews (which is the point of this article). That he is involved with a systematic review of the side effect of statins should increase its value to the lay reader. Also, despite his criticism of Big Pharma, he specifically makes an exception for that wonderful class of drugs – vaccines.
- Yes, I know, these medical treatments are less expensive in other countries. First, few people actually pay that amount – if I had those procedures, the cost to me would be nearly free, and most Americans have insurance to pay those costs. Second, though those procedures are less expensive in other countries, they are still substantially more expensive than generic statins, which, of course, are somewhat less expensive in Europe and other countries.
Citations
- Finegold JA, Manisty CH, Goldacre B, Barron AJ, Francis DP. What proportion of symptomatic side effects in patients taking statins are genuinely caused by the drug? Systematic review of randomized placebo-controlled trials to aid individual patient choice. Eur J Prev Cardiol. 2014 Apr;21(4):464-74. doi: 10.1177/2047487314525531. Epub 2014 Mar 12. Review. PubMed PMID: 24623264.
- Finckh A, Tramèr MR. Primer: strengths and weaknesses of meta-analysis. Nat Clin Pract Rheumatol. 2008 Mar;4(3):146-52. doi: 10.1038/ncprheum0732. Review. PubMed PMID: 18227829.
- Navarese EP, Robinson JG, Kowalewski M, Kolodziejczak M, Andreotti F, Bliden K, Tantry U, Kubica J, Raggi P, Gurbel PA. Association between baseline LDL-C level and total and cardiovascular mortality after LDL-C lowering – a systematic review and meta analysis. JAMA2018; 319(15):1566-1579. doi:10.1001/jama.2018.2525.
- Nowak MM, Niemczyk M, Florczyk M, Kurzyna M, Pączek L. Effect of Statins on All-Cause Mortality in Adults: A Systematic Review and Meta-Analysis of Propensity Score-Matched Studies. J Clin Med. 2022 Sep 25;11(19):5643. doi: 10.3390/jcm11195643. PMID: 36233511; PMCID: PMC9572734.
- Taylor F, Huffman MD, Macedo AF, Moore TH, Burke M, Davey Smith G, Ward K, Ebrahim S. Statins for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2013 Jan 31;(1):CD004816. doi: 10.1002/14651858.CD004816.pub5. Review. PubMed PMID: 23440795.
