Percent Reduction in LDL-C After High-Intensity Statin Therapy

Study Questions:

What is the evidence that fixed low-density lipoprotein cholesterol (LDL-C) targets or percent reduction in LDL-C are appropriate targets to reduce subsequent cardiovascular events (CVEs), particularly for contemporary high-intensity regimens?

Methods:

The authors used a secondary analysis of the JUPITER (Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin), a randomized trial of 17,082 initially healthy men and women with median baseline LDL-C of 108 mg/dl (interquartile range, 94-119 mg/dl). Waterfall plots were used to assess the variability in LDL-C response to rosuvastatin 20 mg daily and evaluate the impact of reaching ≥50% reductions in LDL-C on risk of developing the first CVE.

Results:

Among rosuvastatin-allocated participants, 3,640 individuals (46.3%) experienced an LDL-C reduction ≥50%; 3,365 individuals (42.8%) experienced an LDL-C reduction >0 but <50%; and 851 individuals (10.8%) experienced no reduction or an increase in LDL-C compared with baseline. These % LDL-C reductions directly related to the risks of first CVE. At completion, incidence rates for the primary endpoint were 11.2, 9.2, 6.7, and 4.8 per 1,000 person-years for those in the placebo, no LDL-C reduction, LDL-C reduction <50%, and LDL-C reduction ≥50% groups, respectively. Compared with placebo, the multivariable adjusted hazard ratios for sequentially greater on-treatment percent reductions in LDL-C were 0.91 (95% confidence interval [CI], 0.54–1.53), 0.61 (95% CI, 0.44–0.83), and 0.43 (95% CI, 0.30–0.60) (p < 0.00001). Similar relationships between % reduction and clinical outcomes were observed in analyses focusing on non–high-density lipoprotein cholesterol or apolipoprotein B.

Conclusions:

As documented for low- and moderate-intensity regimens, variability in % LDL-C reduction following high-intensity statin therapy is wide yet the magnitude of this % reduction directly relates to efficacy. These data support guideline approaches that incorporate % reduction targets for statin therapy as well as absolute targets, and might provide a structure for the allocation of emerging adjunctive lipid-lowering therapies such as PCSK9 inhibitors, should these agents prove broadly effective for cardiovascular event reduction.

Perspective:

The ‘lower is better’ hypothesis has been difficult to prove based on the design of primary and secondary prevention trials. This secondary analysis of a primary prevention trial supports the findings in IMPROVE IT, a secondary prevention trial, in which the addition of ezetimibe to simvastatin further reduced CVEs when the mean LDL-C with simvastatin alone was <70 mg/dl. Observing the waterfall plots of range of response to treatment is very useful for guiding treatment paradigms. Considering the marked variability in response to rosuvastatin 20 mg in the JUPITER trial, simply prescribing intermediate- or high-intensity statins without follow-up lipids would be imprudent for both primary and secondary prevention.

Clinical Topics: Diabetes and Cardiometabolic Disease, Clinical Topic Collection: Dyslipidemia, Prevention, Lipid Metabolism, Nonstatins, Novel Agents, Statins

Keywords: Apolipoproteins B, Cholesterol, LDL, Dyslipidemias, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Lipids, Lipoproteins, HDL, Lipoproteins, LDL, Primary Prevention, Secondary Prevention, Simvastatin


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