Cholesterol Skeptics Launch Another Attack

–But most experts say their study is highly flawed

Once again, a group of cholesterol skeptics has published an inflammatory attack on the cholesterol hypothesis. But critics say that the paper is deeply flawed and should not be used to influence treatment or policy decisions.

In a paper published in BMJ Open, Uffe Ravnskov, MD, PhD, and colleagues present a “systematic review” suggesting that elderly people with high LDL cholesterol live longer. Their finding, they wrote, “provides reason to question the validity of the cholesterol hypothesis… [and] provides the rationale for a re-evaluation of guidelines recommending pharmacological reduction of LDL cholesterol in the elderly as a component of cardiovascular disease prevention strategies.”

The authors analyzed data from 19 cohort studies that included more than 68,000 elderly people. They found an inverse association — high LDL cholesterol was associated with a lower mortality— in 92% of the study participants. In the remaining population, there was no association between LDL cholesterol and mortality.

Most of the authors of the paper are members of THINCS (The International Network of Cholesterol Skeptics), a group that has consistently attacked the mainstream notions that LDL cholesterol is an established risk factor for cardiovascular disease and that statins and other LDL-lowering drugs are safe and effective.

Serious Flaws

Two groups on either side of the Atlantic Ocean say the study is entirely unreliable and riddled with serious flaws.

The Oxford-based Centre for Evidence-Based Medicine posted a detailed critique of the paper. Some of their major points were:

  • There was no protocol or prospective registration of the review, or any rigorous explanation of the search strategy used to identify trials.
  • Inclusion and exclusion criteria were not applied uniformly. Notably, although the authors stated that they excluded studies without multivariate correction, one study (Bathum et al) did not report performing such a correction. This study accounted for about two-thirds of the patient population in the paper. In another case, the authors used an earlier analysis of a cohort that favored their position but did not use a later re-analysis that was much less favorable.
  • The authors did not calculate the effect of statins. People with high LDL levels were almost certainly more likely to receive statins. Thus, the protective effect of high LDL might actually be a reflection of the protective effect of statins. (Of course, because the authors also don’t believe in the benefits of statins, they wrote that the drugs’ effect “would have been minimal because most statin trials have had little effect… on mortality.”
  • Only three of the studies included in the analysis controlled for HDL levels. Because HDL has an inverse correlation with mortality, “it is highly possible that the observed inverse association for LDL cholesterol and mortality is entirely mediated by a high HDL cholesterol in the included cohorts,” wrote the Oxford group.

Unwarranted Conclusions

On this side of the Atlantic, Roger Blumenthal, MD, of Johns Hopkins, said that the authors “confuse LDL-cholesterol as a biologically-prime mediator of atherosclerosis (the data behind this involves genetic, epidemiological, and high-quality randomized controlled clinical trials ) with the fact that LDL cholesterol is a fairly modest biomarker of absolute cardiovascular disease risk.”

LDL should not be looked at in isolation, because its importance is tied to the presence of atherosclerosis or other risk factors for atherosclerosis. Risk assessment is based not on LDL in isolation but in combination with age, blood pressure and blood pressure medications, smoking, diabetes, and family history, he said.

Michael Blaha, MD, MPH, also of Johns Hopkins, said that he agrees with the authors that LDL by itself is a poor marker of risk in the elderly but thinks that the conclusions the authors drew from this observation are completely unwarranted.

According to Blaha, the fact that the role of LDL diminishes with age “has been known for a long time — and in fact is baked into equations like the Framingham Risk Score and the Pooled Cohort Equations.” One reason is that “cumulative exposure to high cholesterol is likely what matters most, thus very high LDL matters more in younger patients, while late-life elevation matters very little.”

In addition, Blaha said, “one must also account for survival bias in these studies,” as the older patients with high LDL are a selected group.

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  1. Just because the majority disagrees doesn’t make it wrong; the majority disagreed with Semmelweis when he postulated that puerpural fever was spread by obstetricians with poor hygiene.

    There are sufficient irreconcilable facts to make the LDL/heart disease construct highly improbable.

    • Larry Husten says

      No, the idea is that because they had high LDL they were then much more likely to be placed in statin therapy AFTER their high LDL had been recorded.

      • Ivan Velasquez, MD, FESC. says

        Well, then, why keep the initial High LDL patients in that group once their levels dropped after initiating a “probable” treatment with statins? Unless, of course, their LDL levels didn’t drop. The study by the contrarians follows High LDL patients in those trials, not formerly-High LDL patients.

      • Larry Husten says

        Because they were looking at observational cohort studies and they had no way to know who went on to get statins.

      • Ivan Velasquez, MD, FESC. says

        Exactly: “… they had no way to know who went on to get statins.” And that’s even an assumption that enough of them did, so as to explain the lower mortality, because if that’s the reasoning, it had to be more than half of them to give it enough power and significance.

  2. Ivan Velasquez, MD, FESC. says

    One of the criticisms is that the High LDL patients might have been taking statins, thence their lower mortality rate and wellness. Seriously? Such statement implies that statins can’t lower LDL in a substantial group of patients (contrary to our clinical experience), enough to warrant their inclusion as High LDL patients in trials. If we can’t lower LDL in such patients, then we come up with the anti-inflammatory and pleiotropic “reasons.” I make exception for the very few patients with familial hypercholesterolemia.

  3. John Cook says

    The confounding is simple. Those at very high risk of fatal events are those who have already had them. Invariably these patients are placed on statins regardless of LDL and as a result have very low LDL levels. Thus those with very low LDL levels are at very high risk of dying but would be at even higher risk if they didn’t take statins.

    The hypothesis that those with higher LDL levels were placed on statins after measurement was proposed by the study authors in the paper not by those supporting statins and is dubious.

    A classic case of reverse causality. Retropective analyses are always subject to confounding factors and in this one the main one is obvious and not even addressed by the study authors.

    Garbage in = garbage out.

  4. I can understand that it is difficult for researchers who have hailed a hypothesis for many years to admit that they have been wrong. But hitherto we have not seen any argument that contradict our findings. Let me answer the most important ones.

    A common objection is that those with high LDL-C have been treated with statins and therefore they live longer. Obviously our opponents haven´t read our paper in detail, because as we wrote: “In the largest study that included about two-thirds of the total number of participants in our study (Bathum et al.), the risk was lower among those with the highest LDL-C than among those on statin treatment.”

    Another objection is that in the study by Batum et al. there were no details of the factors corrected for. This is not true either. In their paper you can read the following: “Survival was estimated by the Kaplan – Meier method and analyzed using the Cox proportional hazards model, which included separate analyses of the lipoprotein for males and females, education levels and age.”

    Another objection is that we have ignored the survivor factor, because many of those with high LDL have not survived into their later years. This is nonsense, because more than 95% of those who die from heart disease have passed the age of 60.

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