Using an unconventional mathematical approach, a group of Japanese researchers say there may be no good reason to reduce LDL cholesterol more than 40 mg/dl. Their research letter has been published online in JAMA Internal Medicine.

According to the authors, members of the ALICE (All-Literature Investigation of Cardiovascular Evidence) Group, most meta-analyses use linear models that assume "a constantly increasing or decreasing risk as the exposure increases or decreases." Linear models, however, can be "misleading," they write, because they assume a specific dose-response relationship. By contrast, their new analysis utilizes "flexible" models that can more readily uncover "threshold effects."

Reanalyzing data from 25 large randomized controlled trials including 155,613 participants, the authors found "almost no additional benefit in the use of statins beyond a 40 mg/dL decrease in LDL-C level in preventing major vascular events." They point to a somewhat similar finding by the Cholesterol Treatment Trailists' Collaboration that increasing the dose of atorvastaitn from 40 to 80 mg would yield only marginal improvements in efficacy but would also increase adverse effects and noncompliance.

The authors write that "definitive evidence supporting maximal lowering of LDL-C level or maximal dose of statins is still lacking and that guidelines, if they are to be evidence based, should acknowledge this uncertainty." They conclude that "further analysis" is required to confirm their findings.

Asked for his response to the paper, Sanjay Kaul said that it "makes sense:  Biological phenomena, except for our thought process, are seldom linear!" He strongly agreed with the authors conclusion about the lack of definitive evidence for aggressive statin therapy.