Lowering LDL-C in Patients Starting With Very Low Levels

Study Questions:

What is the efficacy and safety of further lowering low-density lipoprotein cholesterol (LDL-C) levels in patient populations presenting with median LDL-C levels of 70 mg/dl (1.8 mmol/L) or less?

Methods:

The CTTC (Cholesterol Treatment Trialists Collaboration) was used for statin data. For addition of nonstatin therapy, the Medline database was searched (2015-April 2018). Nonstatin + statin interventions included ezetimibe in the IMPROVE IT trial, evolocumab, the PCSK9 antibody in the FOURIER trial, and anacetrapib, the CETP inhibitor in the REVEAL trial. Studies were limited to those with LDL-C measured by β quantification to avoid underestimation of LDL-C using the Friedewald equation and direct LDL-C assays. 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 70 mg/dl or less. The primary outcome was 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), 1,922 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% confidence interval [CI], 0.65-0.94). For three 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 9,570 major vascular events occurred. Nonstatin therapy lowered LDL-C further 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 < 0.001). LDL-C 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:

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 that further lowering of LDL-C beyond the lowest current targets would further reduce cardiovascular risk.

Perspective:

The "rule of thumb" has been that for every 40 mg/dl (about 1 mmol/L) reduction in LDL-C regardless of baseline LDL-C, the relative risk reduction for atherosclerotic cardiovascular events would be about 20%. Of course since event rates are related to LDL-C levels, the absolute reduction in atherosclerotic cardiovascular disease events would be greater at a baseline LDL-C of 100 mg/dl than of 70 mg/dl. New guidelines are in progress that will include the studies in this excellent meta-analysis. Most important is the demonstration of the safety in lowering the LDL-C to very low levels without an increase in muscle- or liver-related complications. The cost/benefit of incremental LDL-C lowering will need to be addressed.

Clinical Topics: Cardiac Surgery, Diabetes and Cardiometabolic Disease, Dyslipidemia, Invasive Cardiovascular Angiography and Intervention, Prevention, Cardiac Surgery and Arrhythmias, Lipid Metabolism, Nonstatins, Novel Agents, Statins

Keywords: Antibodies, Monoclonal, Atherosclerosis, Brain Ischemia, Cholesterol, Cholesterol, LDL, Cost-Benefit Analysis, Diabetes Mellitus, Dyslipidemias, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Myalgia, Myocardial Infarction, Myocardial Revascularization, Myositis, Primary Prevention, Risk Factors, Stroke, Vascular Diseases


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