Lipid-lowering therapy – fact, myth, and controversies
Lipid-lowering therapy, especially with the use of statins, is a very well-established treatment, leading to cardiovascular risk reduction. It has been with us for so long and has been tested in so many large placebo-controlled clinical trials, that within the medical field, there is generally no great controversy as to the efficacy of this treatment.
However, many patients are still unconvinced and believe that lipid-lowering treatment, and especially statins, are deleterious to one’s health and dangerous. They mostly cite sources from the web or social media, usually supported by isolated testimonies of various “experts”, but sometimes also people who are actual professionals.
Why is there so much conflicting and predominantly bad publicity for statins on the web and social media? Below are my private thoughts on the matter.
First, though, let’s quickly review what we know:
Evidence-based medicine (EBM) data on statins may be split into 2 categories: primary prevention (treating patients seemingly without evidence of cardiovascular disease to prevent events like a heart attack, stroke, or sudden cardiac death) and secondary prevention (treating patients with established cardiovascular disease, for example after a heart attack, to prevent anything more from happening). The efficacy of statins has been well established in large trials for both of these applications, but for the sake of simplicity and because it’s more relevant for an average patient, let us concentrate on primary prevention here (fewer trials, but efficacy more difficult to prove in seemingly healthy patients).
An article published in 2022 in JAMA addresses this for us very nicely [Chou et al. JAMA 2022; 328:754-771]. The authors look specifically at controlled and large cohort statin trials in primary prevention, pooling results related to efficacy or possible harm or side effects. They found 26 trials meeting pre-specified quality standards. Twenty-two of them (90624 patients) were high-quality evidence placebo-controlled trials. One trial compared different treatment intensities (5144 patients). Three large observational studies (those are not designed to test efficacy) on over 400000 patients were aimed at assessing potential risks of statin treatment.
Analyzing the above studies, the authors found that:
In patients with significant dyslipidemia and increased cardiovascular risk, but without established cardiovascular disease, lipid-lowering therapy with statins significantly reduces all-cause mortality, the incidence of stroke, heart attack, and several other composite endpoints. These are robust, but not huge risk reductions. Interestingly, these pooled studies do not show a significant reduction of isolated cardiovascular mortality (although that has repeatedly been shown in secondary prevention trials). The observed benefits, expectedly, were higher in higher cardiovascular risk patients.
The studies were also analyzed from a safety perspective.
Generally, patients on statins enrolled in the analyzed trials did not stop treatment due to adverse events more often than patients on placebo. There was no increased risk of any serious adverse events observed. The incidence of myalgia, myopathy, and rhabdomyolysis was also similar in statin and placebo groups. The incidence of elevated liver enzyme levels, malignancies, and newly diagnosed diabetes was the same. We know now (initially from the WOSCOPS trial, but also secondary prevention trials) that statin therapy, especially high intensity, does increase glucose levels. There was only one study in the analyzed pool testing high statin doses and in this one study, this correlation was indeed seen. Also, the potential benefits of statin therapy outweigh the risks related to mildly increased glucose levels.
In the discussion, the authors state that: “Similar to meta-analyses of primary and secondary prevention trials, statins were not associated with increased risk of muscle-related harms. Although observational studies of patients taking statins for various indications have found an increased risk of myopathy, as well as study withdrawal due to adverse events or muscle symptoms, these findings could be due to expectations regarding adverse effects and nocebo effects.” No significant harm related to kidney or cognitive function was identified in the discussed meta-analysis.
Regarding the nocebo effects (the patient knows that the medication may have some adverse effects, so he feels them) there is also another, very interesting study (Howard et al., JACC 2021) confirming that most of the adverse statin effects are nocebo. There is no point discussing it here in detail – everyone can look it up, but it is one of many studies showing that it is the fear of medication that is causing more harm than the medication itself.
All of the above data confirm that statins are effective not just in lowering cholesterol, but above all in lowering patients’ cardiovascular risk. There is a lot more data we have not touched upon, coming from secondary prevention studies (treating patients with known cardiovascular disease, e.g. after a heart attack). The evidence also shows that most statin-related side effects reported by patients may be a nocebo effect, as large trials show a similar frequency of side effects between statins and placebo.
Why then are so many people of the belief that statins are harmful?
There are, I believe several reasons, some of them historical, others more recent. Let’s begin with the historical ones. First statin was identified or isolated (as they originate from natural compounds synthetized by fungi) in 1976 by a Japanese biochemist Akira Endo (Endo et al. FEBS Lett. 1976). One of the names given to the compound was mevastatin and despite lowering cholesterol, it was found to be quite toxic and never entered clinical use, but did gain some negative publicity. And once something gets negative publicity, the damage is done.
Despite this, other compounds were developed which were found to be safe and effective. The first of those was lovastatin, used for many years until it was replaced by more efficacious compounds. Lovastatin gained FDA approval in 1987 after almost 10 years of clinical research proved its safety and efficacy. Other compounds followed, such as simvastatin, pravastatin, atorvastatin, rosuvastatin, and others.
Along the way, statins were dealt another major blow by cerivastatin, which was removed from the market by Bayer in 2001 due to reports of higher incidence of potentially the most serious side effect of statins – rhabdomyolysis. This is a complicated story that may warrant further discussion, as the side effects at least in part were related to the fact that the drug was often used not paying attention to certain contraindications, but as it is no longer in use, there is no point discussing it.
Now we come to the era of the internet and social media, which are the source of a lot of negative publicity regarding statins. On social media one can essentially post any information, be it true or false. That is great as it means freedom. But it also means that the information we get from the web or social media needs filtering and source verification. The main reason for posting things by people who have a huge following is a financial one. Nothing earns a better following in the media (not just social) than sensation.
There are, in my observations 2 types of people presenting negative comments about statins: “experts” and experts. The first type hardly needs comment. They use the negative publicity to make money and sometimes also sell some questionable supplements or “wonder strategies” to lower your cholesterol (incidentally, the widely advertised red rice yeast is just lovastatin in an unknown dose). Some “experts” also advocate that high cholesterol is good for you, for example, because it is used in brain cell synthesis. All this is based on half-truths, the selection of information out of context, and the mixing of true and false information to support one’s belief. In general, when a person like this says that “research shows” – there is either no reference to research or if you look at the research you can see that it is taken out of context.
The experts who are negative in their comments about statins may have various motivations, but they generally do not downplay statins as outright harmful. They usually underscore that instead of concentrating on non-pharmacological measures and lifestyle modification, physicians (and patients) just find it easier to “take a pill”, which addresses only a small part of the problem. They are of course right. Humans are lazy. Physicians and patients likewise. Especially in primary prevention lifestyle modification can work wonders and many patients might not need statins or other medications if they succeed in normalizing body weight, switching to vegan, vegetarian, DASH, Mediterranean, or pescatarian diet, and start exercising regularly and rationally. It’s just that most of us fail lifestyle modification.
Having said all of the above, I do not want anyone to understand that side effects of statins do not exist. They do and in rare cases may be very serious. The fact that most clinical trials show the incidence of side effects to be comparable to the placebo group only tells us that they are quite rare.
There are copious amounts of literature on statin side effects accumulated since the 1980s. For reference, I would recommend some review articles on the subject (eg. Thompson et al. JAAC 2016; Vinci et al. Int J Mol Sci. 2021; Newman et al. Arterioscler Thromb Vasc Biol. 2019). Based on what we know, the only possible fatal complication related to statin treatment is rhabdomyolysis. The reported incidence varies, with overall muscle toxicity below 0.1% and life-threatening cases in the range of no more than several cases per million patients treated. Statins may cause minor liver injury in some patients, usually with no clinical consequences. The risk of serious liver injury is around 0.001%.
Statins increase glucose levels slightly, with the incidence of newly diagnosed diabetes attributable to statins 0.2% per year of treatment. This is dependent on the risk of diabetes in a given population and somewhat related to statin dose. The cardiovascular risk reduction due to statins, however, by far compensates for the risk increase related to new-onset diabetes.
In patients with cerebrovascular disease, statins may slightly increase the risk of hemorrhagic stroke. However, they produce a greater reduction in the risk of ischemic stroke and total stroke risk. There have been isolated reports that cannot be completely dismissed, but there is no convincing evidence for a causal relationship between statins and cancer, cataracts, cognitive dysfunction, peripheral neuropathy, erectile dysfunction, or tendonitis. Even if we assume that these side effects could be attributed to statins, they are rare and may have other causes.
We must also remember that statins may interact with other drugs as many are metabolized by similar pathways. Many cases of rhabdomyolysis are caused by these interactions rather than statins as such.
In summary, statins are strong and effective medications that, by reducing our cardiovascular risk, may potentially prolong our lives. They are safe, but as all medications that work, may also have side effects. They should not be used without indications and especially they should complement lifestyle optimization rather than be used instead of it. Many patients in whom we may consider statins for primary prevention of cardiovascular events, may achieve enough improvement with lifestyle intervention only and may not always require statins.
To book an appointment with Dr. Krzysztof Kukula, please call +1 345 325 9000.
