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

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.

Figure 1.. Effect of Low-Density Lipoprotein Cholesterol (LDL-C) Lowering on the Risk of Major Vascular Events

A, Risk ratios (RRs) were generated from fixed-effects models. Size of data markers is weighted based on the inverse variance. I² for heterogeneity 0%, P > .99. B, Levels of LDL-C in the control arm (square symbols) and experimental arm (arrowheads) in each of the nonstatin trials (trial arms connected by lines). The black line and dashed 95% CI are from a fixed-effects meta-regression. FOURIER indicates Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Patients With Elevated Risk; IMPROVE-IT, Improved Reduction of Outcomes: Vytorin Efficacy International Trial; REVEAL, Randomized Evaluation of the Effects of Anacetrapib through Lipid Modification. To convert LDL-C from millimoles per liter to milligrams per deciliter, multiply by 38.67.

Figure 2.. Individual Efficacy Outcomes in Nonstatin Trials

In this analysis of the individual components of the composite outcome, ischemic stroke was used where available; otherwise all stroke was used. In Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT), per the trial end point definitions, coronary revascularizations were those that occurred at least 30 days after randomization. Patients could have had more than 1 event. The size of the boxes is proportional to the number of events. The horizontal lines represent 95% confidence intervals. LDL-C indicates low-density lipoprotein cholesterol.

Figure 3.. Safety Outcomes in Nonstatin Trials

The size of the boxes is proportional to the weight in the analysis for each trial. The horizontal lines represent 95% confidence intervals. FOURIER indicates Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Patients With Elevated Risk; IMPROVE-IT, Improved Reduction of Outcomes: Vytorin Efficacy International Trial; REVEAL, Randomized Evaluation of the Effects of Anacetrapib through Lipid Modification.