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Original Investigation
September 2018

Efficacy and Safety of Further Lowering of Low-Density Lipoprotein Cholesterol in Patients Starting With Very Low Levels: A Meta-analysis

Author Affiliations
  • 1TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
  • 2Deputy Editor, JAMA Cardiology
JAMA Cardiol. 2018;3(9):823-828. doi:10.1001/jamacardio.2018.2258
Key Points

Question  Is the clinical benefit of low-density lipoprotein cholesterol (LDL-C) lowering preserved in patient populations starting with LDL-C levels averaging 1.8 mmol/L (70 mg/dL) or less, and is LDL-C lowering safe in such patients?

Findings  In this meta-analysis, for statins and nonstatins, the risk of major vascular events was significantly reduced by 21% for each 1-mmol/L (38.7-mg/dL) reduction in LDL-C, which was virtually the same magnitude as seen in the overall Cholesterol Treatment Trialists Collaboration analysis in which the starting LDL-C was nearly twice as high. No adverse safety signal was detected for LDL-C lowering.

Meaning  Further lowering of LDL-C beyond the lowest current targets is associated with further reduced cardiovascular risk with no offsetting safety risks.

Abstract

Importance  In the Cholesterol Treatment Trialists Collaboration (CTTC), in patients starting with low-density lipoprotein cholesterol (LDL-C) levels of approximately 3.4 mmol/L (131.5 mg/dL), there was a 22% reduction in major vascular events per 1-mmol/L (38.7-mg/dL) lowering of LDL-C. The magnitude of clinical benefit of further LDL-C lowering in patients already with very low LDL-C levels remains debated.

Objective  To evaluate efficacy and safety of further lowering LDL-C levels in patient populations presenting with median LDL-C levels of 1.8 mmol/L (70 mg/dL) or less.

Data Sources and Study Selection  The CTTC was used for statin data. For nonstatin therapy, Medline database was searched (2015-April 2018). Key inclusion criteria were a randomized, double-blind, controlled cardiovascular outcome trial of LDL-C lowering with data in populations starting with LDL-C levels averaging 1.8 mmol/L (70 mg/dL) or less.

Data Extraction and Synthesis  Two authors independently extracted data into standardized data sheets, and data were analyzed using meta-analysis.

Main Outcomes and Measures  The risk ratio (RR) of major vascular events (a composite of coronary heart death, myocardial infarction, ischemic stroke, or coronary revascularization) per 1-mmol/L (38.7-mg/dL) reduction in LDL-C level.

Results  In the subgroup of patients from the CTTC meta-analysis of statins with a mean LDL-C in the control arm of 1.7 mmol/L (65.7 mg/dL), 1922 major vascular events occurred and the RR for major vascular events per 1-mmol/L (38.7-mg/dL) reduction in LDL-C was 0.78 (95% CI, 0.65-0.94). For 3 trials of nonstatin LDL-C–lowering therapies added to statins, there were 50 627 patients, the median LDL-C in the control arms ranged from 1.6 mmol/L to 1.8 mmol/L (63 mg/dL to 70 mg/dL), and 9570 major vascular events occurred. Nonstatin therapy lowered LDL-C 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-C was 0.79 (95% CI, 0.70-0.88). For statins and nonstatins combined, the RR was 0.79 (95% CI, 0.71-0.87; P < .001). Low-density lipoprotein cholesterol lowering was not associated with an increased risk of serious adverse events, myalgias and/or myositis, elevation in the level of aminotransferases, new-onset diabetes, hemorrhagic stroke, or cancer.

Conclusions and Relevance  There is 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. These data suggest further lowering of LDL-C beyond the lowest current targets would further reduce cardiovascular risk.

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