Boston—While statins should remain the first-line therapy for lowering low-density lipoprotein cholesterol (LDL-C) for a range of benefits, a new study suggests, nonstatin medications also appear to be effective.

The study, appearing recently in the Journal of the American Medical Association, evaluated the association between lowering LDL-C and relative cardiovascular risk reduction across different statin and nonstatin therapies.

Background information in the article notes that LDL-C is a well-established risk factor for cardiovascular disease, and the clinical benefit of lowering LDL-C with statins remains widely accepted. Study authors led by Brigham and Women’s Hospital and Harvard Medical School researchers add that the comparative clinical benefit of nonstatin therapies that reduce LDL-C has been uncertain, however.

For this study, a review and meta-analysis of 49 trials that met criteria for inclusion were conducted. Included were 312,175 participants using nine different interventions to lower LDL-C with 39,645 major vascular events.  

The study was divided into four groups based on intervention:
• Participants using statins;
• Participants using nonstatin therapies that work predominantly through upregulation of LDL receptor expression, such as diet, bile acid sequestrants, ileal bypass, and ezetimibe;
• Participants using interventions that do not reduce LDL-C levels primarily through upregulation of LDL receptor expression, such as fibrates, niacin, cholesteryl ester transfer protein [CETP] inhibitors; and
• Participants using PCSK9 inhibitors, which upregulate LDL-C clearance through the LDL receptor, but for which dedicated cardiovascular outcome trials have not yet been completed.

The last group, involving PCSK9 inhibitors as the intervention, was considered separately to evaluate how the data to date compare with established therapies that upregulate LDL receptor expression.

Results indicate a similar association between absolute reductions in LDL-C and lower relative risks for major vascular events—defined as cardiovascular death, acute heart attack or other acute coronary syndrome, coronary revascularization, or stroke—across therapies that lead to upregulation of LDL receptor expression.

The researchers report that each 1-mmol/L (39 mg/dL) reduction in LDL-C was associated with a 23% relative reduction in the risk of major vascular events. A significant linear association between achieved LDL-C and the rate of cardiovascular outcomes over the range of LDL-C studied also was detected.

“The implications of these results deserve careful consideration in light of the strength of the available trial evidence for different types of therapies,” study authors write.

“As per current guidelines, when tolerated, statins should be the first-line therapy given the large reductions observed for LDL-C, the excellent safety profile, the demonstrated clinical benefit, and low cost (now that most are generic). However, the data in the present meta-regression analysis raise the possibility that other interventions, especially those that ultimately act predominantly through upregulation of LDL receptor expression, may provide additional options and may potentially be associated with the same relative clinical benefit per each 1-mmol/L reduction in LDL-C.”


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