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For people with already low LDL, going even further below 70 mg/dL is better for outcomes, a meta-analysis showed.

Among the subset of patients in the Cholesterol Treatment Trialists Collaboration's pool of 26 statin trials who had LDL averaging 65.7 mg/dL at baseline, risk of major vascular events fell 22% for every 38.7-mg/dL (1-mmol/L) reduction in LDL cholesterol (RR 0.78, 95% CI 0.65-0.94).

The findings were the same when pooling non-statin LDL-lowering trial findings separately, Marc Sabatine, MD, MPH, of Brigham and Women's Hospital in Boston, and colleagues reported online in .

The more than 50,000 patients who achieved sub-70 mg/dL LDL cholesterol in the IMPROVE-IT trial with ezetimibe (Zetia), FOURIER with PCSK9 inhibition, and REVEAL with CETP inhibition had the same event risk reduction on the non-statin therapy alone (RR 0.79, 95% CI 0.70-0.88) or with statins on top (RR 0.79, 95% CI 0.71-0.87).

Moreover, the clinical benefit associated with every 38.7-mg/dL (1-mmol/L) reduction in LDL cholesterol was "virtually identical" for statins, ezetimibe, PCSK9 inhibition, and CETP inhibition, reinforcing the notion that the reduction itself is the primary driver of clinical benefit, the investigators argued.

"There is a consistent relative risk reduction in major vascular events per change in LDL cholesterol in patient populations starting as low as a median of 1.6 mmol/L (63 mg/dL) and achieving levels as low as a median of 0.5 mmol/L (21 mg/dL), with no observed offsetting adverse effects. These data suggest further lowering of LDL cholesterol beyond the lowest current targets would further reduce cardiovascular risk," they concluded, noting that current guidelines suggest targets or thresholds of 70 to 100 mg/dL for additional non-statin therapies in high-risk patients.

There is a "strong case," then, for an update to the American Heart Association/American College of Cardiology 2013 guidelines to reflect this trend, according to an by Antonio Gotto, Jr., MD, DPhil, of Weill Cornell Medicine in New York City. "A revision is currently underway, and new guidelines are anticipated in the near future."

"Whether one calls it a target or a threshold, practicing physicians need some guidance as they venture into achieved levels of LDL cholesterol levels that are as foreign as travel to outer space," the editorialist said.

However, he acknowledged that just because there were no safety signals detected so far with very low LDL cholesterol doesn't mean they don't exist.

"The association of diabetes with statin use was not fully described until 23 years after lovastatin approval and millions of patients had received statins," Gotto recalled. "While it is possible to calculate how low LDL cholesterol levels can be reduced while still detecting a cardiovascular benefit, one reaches a point of diminishing returns, and it is not clear how low it is safe to go."