Boston—While past research has demonstrated a benefit of lowering LDL cholesterol in patients with high levels, a new study looks at the risks and benefits of treating those with LDL cholesterol levels averaging 1.8 mmol/L (70 mg/dL) or less.

A meta-analysis in JAMA Cardiology determined that therapy—either statin or nonstatin—significantly reduced the risk of major vascular events by 21% for each 1-mmol/L (38.7-mg/dL) reduction in LDL cholesterol.

Study authors led by Brigham and Women’s Hospital and Harvard Medical School researchers point out that the effect was about the same as that seen in the overall Cholesterol Treatment Trialists Collaboration (CTTC) analysis in which the starting LDL cholesterol level was nearly twice as high, about 3.4 mmol/L (131.5 mg/dL). Those patients experienced a 22% reduction in major vascular events per 1-mmol/L (38.7-mg/dL) lowering of LDL cholesterol.

“Further lowering of LDL-C beyond the lowest current targets is associated with further reduced cardiovascular risk with no offsetting safety risks,” the researchers write.

The current study used the CTTC for statin data and searched the Medline database from 2015 to April 2018 for information on nonstatin therapy. Studies included in the meta-analysis were randomized, double-blind, controlled cardiovascular-outcome trials of LDL cholesterol lowering with data in populations starting with LDL cholesterol levels averaging 1.8 mmol/L (70 mg/dL) or less.

Data for the study were extracted by two authors who independently entered data into standardized data sheets. The review focused on the risk ratio (RR) of major vascular events, defined as a composite of coronary heart death, myocardial infarction, ischemic stroke, or coronary revascularization per 1-mmol/L (38.7-mg/dL) reduction in LDL cholesterol level.

Results indicate that, in the subgroup of patients from the CTTC meta-analysis of statins with mean LDL cholesterol in the control arm of 1.7 mmol/L (65.7 mg/dL), 1,922 major vascular events occurred and the RR for major vascular events per 1-mmol/L (38.7-mg/dL) reduction in LDL cholesterol was 0.78 (95% CI, 0.65-0.94).

For three trials of nonstatin LDL cholesterol–lowering therapies added to statins—involving 50,627 patients—the median LDL cholesterol in the control arms ranged from 1.6 mmol/L to 1.8 mmol/L (63 mg/dL to 70 mg/dL), and 9,570 major vascular events occurred.

Researchers note that nonstatin therapy lowered LDL cholesterol by 0.3 to 1.2 mmol/L (11 mg/dL to 45 mg/dL), and the RR for major vascular events per 1-mmol/L (38.7-mg/dL) reduction in LDL cholesterol was 0.79 (95% CI, 0.70-0.88).

Overall, for statins and nonstatins combined, the study reports that the RR was 0.79 (95% CI, 0.71-0.87; P <.001).

The study team found no association with LDL cholesterol lowering and increased risk of serious adverse events, including myalgias and/or myositis, elevation in the level of aminotransferases, new-onset diabetes, hemorrhagic stroke, or cancer.

At the same time, they point out “a consistent relative risk reduction in major vascular events per change in LDL-C 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.”

“We are now in a new era with non-statin drugs that further lower LDL-C levels and further reduce cardiovascular risk when added to statins,” the study authors conclude. “Clinical trials with these drugs afford the opportunity to quantify the clinical benefit of LDL-C lowering and to examine whether it remains consistent even in individuals starting with and achieving lower levels than were examined in the CTTC meta-analysis and lower than current guideline targets. Likewise, they offer the opportunity to explore any signals of harm in patients with LDL-C lowering to such levels.”
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