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.