CHICAGO – Lowering LDL cholesterol early in life would prevent three times more cardiovascular events per unit of LDL-reduction compared to the current practice of initiating LDL-lowering statin therapy decades later, based on the findings of a novel genomic analysis known as a mendelian randomized controlled trial.
"People who’ve already been exposed to a lifetime of (elevated levels of) LDL have developed a certain underlying atherosclerotic burden. Lowering LDL at that point – even intensively – can merely stabilize the plaque or cause it to regress only slightly. One is still left with an underlying atherosclerotic plaque that can disrupt and cause symptoms or acute events. The alternative would be to start much earlier in life, before the plaque develops. And that’s what we tested," Dr. Brian A. Ference explained at the annual meeting of the American College of Cardiology.
Dr. Ference emphasized that he wasn’t arguing in favor of routinely starting statin therapy in children with high LDL levels. "A reasonable policy may be to promote a greater awareness of LDL cholesterol levels and a new emphasis on diet and lifestyle to keep LDL low, and in those persons in their 20s who can’t maintain ideal levels of cholesterol – somewhere between 50 and 70 mg/dL – it may be reasonable at that time to begin contemplating adding medication to prevent the development of atherosclerotic plaque."
His mendelian randomized controlled trial was not a conventional prospective clinical trial. That would be utterly impractical because it would take half a century or more. Rather, the mendelian randomized controlled trial was essentially a series of nine natural randomized trials conducted using a database comprised of more than 326,000 people whose genetic status was known with regard to nine single nucleotide polymorphisms (SNPs) associated with low LDL levels throughout life.
"We based this study on the concept of in vivo randomization, which suggests that at the time of conception polymorphisms are allocated randomly and that inheriting an allele that is associated with a lower LDL is analogous to being randomized at the time of birth to a medicine that lowers LDL for the whole of one’s lifetime. In contrast, inheriting the other allele is analogous to being allocated to usual care. So if one compares the risk of coronary [heart] disease (CHD) between the two groups, it should be analogous to a long-term trial," according to Dr. Ference, director of the cardiovascular genomic research center at Wayne State University, Detroit.
He and his fellow researchers compared CHD rates in individuals with the low-LDL SNPs to those in the huge database without the SNPs. Next they compared CHD rates in subjects with each of the nine SNPs to rates in statin-treated patients included in a large meta-analysis of statin randomized controlled trials that was carried out by the Cholesterol Treatment Trialists’ Collaboration.
Each of the nine SNPs was consistently associated with a 55% reduction in CHD risk for each 39 mg/dL lower lifetime exposure to LDL. In contrast, to achieve the same 55% reduction in CHD risk by starting statin therapy at age 63 – the average age at enrollment in the statin trials – a 116 mg/dL decrease in LDL would be required.
Dr. Ference noted that the nine SNPs lowered LDL via different mechanisms, suggesting that the associated beneficial decrease in CHD was mediated through LDL lowering per se and that the manner in which the reductions are achieved wasn’t important. Thus, lowering LDL via diet and exercise beginning early in life should be as effective in terms of reducing CHD risk as any other means of doing so, including drug therapy.
Dr. Ference reported having no financial conflicts.