“We must admit that our opponents in this argument have a marked advantage over us. They need only a few words to set forth a half-truth; whereas, in order to show that it is a half-truth, we have to resort to long and arid dissertations.”
― Frédéric Bastiat
The quote above encapsulates one of the great challenges in our work. We live in an age in which half-truths (and even outright falsehoods) regarding health and science are all too common—particularly on social media, where simplicity and novelty often trump nuance and accuracy. Thus, we tend to face an uphill battle in our efforts to share reliable information about human health and expose the holes in faulty or incomplete information about human health.
The subject of cardiovascular health is one hill where we are perennially fighting those battles. A growing (and alarming) contingent of health influencers are expressing profound skepticism of our conventional understanding of the processes that drive development of atherosclerotic cardiovascular disease (ASCVD). This understanding, which has been built upon volumes of highly consistent research, rests on the idea that circulating apolipoprotein B (apoB)-containing lipoproteins—mainly low-density lipoprotein, or LDL—drive atherogenesis. Thus, lowering plasma LDL (which is commonly approximated by measuring LDL cholesterol content, or LDL-C) through treatments such as statins or PCSK9 inhibitors can therefore reduce ASCVD risk. Indeed, this mechanism is supported by decades of research, including dozens of large-scale clinical trials (a fraction of which we covered in a past premium article) and Mendelian randomization studies, which have been remarkably consistent in their results.
But every so often, critics of this conventional wisdom will latch onto some new source of data—typically coming from a heavily flawed study—that might be viewed as inharmonious with the causal role of apoB in ASCVD. Rather than evaluating these data in the context of the larger body of literature and with a careful eye for alternative explanations, the skeptics often take the opposite approach: unjustifiably extrapolating the results to make flashy, provocative claims about statins being a pharma conspiracy and high cholesterol being beneficial for health.
In recent days, this pattern of misinformation has emerged yet again—this time with the viral spread of faulty interpretation of a study published over two years ago. And yet again, we and others in the medical and scientific communities are left to battle this dangerous messaging, pitting facts and reason against sensationalism and oversimplification.
Our research team spends hundreds of hours each month vetting studies and distilling dense literature to deliver evidence-informed insights on health and longevity. If you find value in our work, consider becoming a premium member and supporting our mission.
Bold claims based on a single metric
The focus of the recent excitement among apoB iconoclasts is research out of Sweden often referred to as the AMORIS (Apolipoprotein-related MOrtality RISk) study, the results of which were first published in 2023.1 This study was designed to assess various blood-based biomarkers and how they related to the probability of living to the age of 100 years. A total of 44,636 participants were tested for biomarkers including total cholesterol, blood glucose, creatinine, and others and subsequently followed until death. Biomarker data from the group that reached centenarian status (n=1,224; mean age at baseline: 79.6±7.5 years) were then compared to biomarker data from those who passed away before reaching age 100 (n=43,412; mean age at baseline: 76.7±6.2 years). (Of note, many citing this study on social media erroneously claim that it included over 800,000 centenarians. To reiterate, the total study population that met inclusion criteria was only 44,636, and only 1,224 of these individuals, or 2.7%, reached centenarian status.)
Though the investigators analyzed several biomarkers, for the purpose of our discussion, we will focus on the single test that prompted so much buzz among those who would tear down conventional wisdom on ASCVD: total cholesterol. Results showed that those who reached age 100 had, on average, higher total cholesterol than those who died before age 100. The investigators only tested total cholesterol and did not break this down further by testing LDL-C, apoB, or HDL-C (high-density lipoprotein cholesterol), so it’s entirely possible that higher total cholesterol in the centenarian group was due primarily to elevated HDL-C, which is non-atherogenic, rather than to elevated LDL-C. (Of note, in a subsequent correction to the original research article, the authors themselves clarify that even the total cholesterol result would more accurately be described as showing that low cholesterol was associated with an increased risk of not reaching age 100, but that “high cholesterol neither increases nor decreases the probability of living to 100 years of age.”)2
Still, many on social media have interpreted this result as evidence that we should all be aiming for a higher—rather than lower—LDL cholesterol to promote longevity. That’s like knowing only a person’s body weight and suggesting you know how much body fat they have. Or knowing only the population of a city and claiming you can impute the crime rate. Or knowing only the assets on a company’s balance sheet and claiming you know how much debt they carry. We could go on all day with equally stupid examples of how misguided this logic is.
What else might explain the AMORIS result?
Let’s put aside the absence of LDL-C data and assume that the higher total cholesterol levels among participants who went on to become centenarians did indeed correspond to higher levels of LDL particles. Even with this [huge] assumption, we still can’t conclude that these results upend all that we know from decades of research about the relationship between LDL and atherosclerosis. A much simpler explanation is far more likely—and supports, rather than refutes, conventional thinking.
To start, recall that observational studies such as AMORIS cannot be used to infer causality between variables due in part to the possible influence of other variables not under study. This is the intro course before you get to epidemiology 101. But in the case of studies on LDL, observational research can often be especially misleading because it frequently fails to account for one key variable in particular: lipid-lowering medication. With the AMORIS study, the seemingly lower cholesterol levels in the non-centenarian group might represent the natural, unmedicated physiology of these individuals, or it might represent an increased use of cholesterol-lowering drugs. Indeed, the latter explanation would seem to be the more likely possibility when we examine other baseline characteristics of the two groups, which show that those in the non-centenarian group were roughly five times more likely to have already experienced a heart attack by baseline than those in the centenarian group. Similarly large discrepancies also existed in other baseline health factors related to ASCVD, such as cerebrovascular disease and congestive heart failure. In other words, those who did not go on to reach age 100 likely had lower average total cholesterol because they were already much sicker than the group that reached centenarian status and therefore likely included a larger proportion of individuals on statins and other lipid-lowering medications.
The big picture
One of the dangers of social media is that information is usually presented in quick bites, often without context, depth, or consideration of alternative evidence. But the subject of ASCVD—the leading cause of death in the US and worldwide—is far too important for us to allow click-bait conspiracy theories to dominate the conversation. While there’s always room for revising long-held beliefs in science, such revision must come only when opposing evidence truly outweighs evidence for traditional thinking—not when it happens to have more shares and likes on social media.
With respect to the role of apoB-containing lipoproteins (e.g., LDL) in driving atherosclerosis, the scale isn’t even close to a tipping point. The body of evidence supporting this mechanism has reached a level of thoroughness and consistency that we rarely see with any topic in biomedical science, and opposing theories—whether the so-called “cholesterol paradox,” statin conspiracies, or the hypothesized “lean-mass hyperresponder” phenotype (to be discussed in depth later this year)—have been equally consistent in failing to be substantiated by rigorous investigation. Keeping in mind the words of Bastiat, we’ve tried to expose these failures without getting too long or arid, but it surely won’t be our last trip down ASCVD lane.
For a list of all previous weekly emails, click here.
References
- Murata S, Ebeling M, Meyer AC, Schmidt-Mende K, Hammar N, Modig K. Blood biomarker profiles and exceptional longevity: comparison of centenarians and non-centenarians in a 35-year follow-up of the Swedish AMORIS cohort. GeroScience. 2024;46(2):1693-1702. doi:10.1007/s11357-023-00936-w
- Murata S, Ebeling M, Meyer AC, Schmidt-Mende K, Hammar N, Modig K. Correction to: Blood biomarker profiles and exceptional longevity: comparison of centenarians and non‑centenarians in a 35‑year follow‑up of the Swedish AMORIS cohort. GeroScience. 2024;46(2):2793-2794. doi:10.1007/s11357-023-00996-y
