March 27, 2012

March 26, 2012 (Chicago, Illinois) — Lowering LDL early in life has the potential to reduce coronary heart disease to a far greater extent than starting treatment later in life--the current standard practice--a "Mendelian" randomized, controlled trial suggests.

Lead author Dr Brian Ference (Wayne State University School of Medicine, Detroit, MI) commented: "We are not suggesting that everyone take statins from childhood; rather, that lowering LDL through more attention to healthy diet and exercise from a young age could make a big difference to public health."

The study appeared to be well received. At the late-breaking session here today at the American College of Cardiology 2012 Scientific Sessions, designated discussant Dr Noel Bairey Merz (Cedars-Sinai Medical Center, Los Angeles, CA) said: "These are beautiful data." She later commented to heartwire : "The big public-health question is whether it is better to start early and lower LDL in everyone rather than to wait to find the high-risk subjects and just treat them later. And these data suggest it is better to go for the first option; you get three times more bang for your buck that way."

At the ACC press conference for the trial, moderator Dr Rick Nishimura (Mayo Clinic, Rochester, MN) said: "From my standpoint, this was a fancy genetic analysis in which low cholesterol from birth showed a marked reduction in cardiovascular events--more than if we start treatment at age 65 or so. This has incredible public-health implications."

A Natural Randomized Trial

In his presentation, Ference noted that by the time most people begin treatment to lower LDL, CHD has often been quietly developing for decades. "We wanted to test the hypothesis that lowering LDL early in life may produce greater reductions in the risk of CHD than waiting until later in life." To do this, Ference and his colleagues used genetic data from over one million patients, which he said simulated a "natural" randomized controlled trial.

To estimate the clinical benefit of lowering LDL early in life, they used nine single nucleotide polymorphisms (SNPs) from six genes associated with lower LDL as a proxy for a treatment that lowers LDL beginning at birth.

"Because each of these SNPs is allocated randomly at the time of conception, inheriting one of these SNPs is like being randomly allocated to a treatment that lowers LDL cholesterol beginning at birth," Ference explained.

Threefold Greater Clinical Benefit

Results showed that all nine SNPs were associated with a consistent 54% reduction in the risk of the primary end point (a composite of CV death, MI, and coronary revascularization) for each 1-mmol/L (38.7 mg/dL) lower lifetime exposure to LDL cholesterol.

In comparison, Ference reported that data from statin meta-analyses suggest that lowering LDL by 1 mmol/L with statins later in life gives a 24% reduction in the same end point. And to get a 54% reduction with statins in later life, LDL would have to be lowered by 3 mmol/L.

Therefore, Ference concluded that "prolonged exposure to lower LDL beginning early in life is associated with a threefold greater clinical benefit for each unit of LDL reduction than treatment with a statin started later in life."

The study showed no heterogeneity between SNPs with regard to the decrease in CHD risk per unit of LDL reduction, which Ference said suggests that "the effect of each of the included SNPs on risk of CHD is mediated largely or entirely through effect on circulating levels of LDL, rather than through some other pleiotropic effect."

"This can be interpreted as the increased clinical benefit associated with lowering LDL beginning early in life appears to be independent of the mechanism by which LDL is lowered. This means that diet and exercise are probably as effective as statins or other medications at reducing the risk of CHD when started early in life.”