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Randomized Controlled Trial
. 2016 May 1;37(17):1373-9.
doi: 10.1093/eurheartj/ehw046. Epub 2016 Feb 24.

Percent reduction in LDL cholesterol following high-intensity statin therapy: potential implications for guidelines and for the prescription of emerging lipid-lowering agents

Paul M Ridker  1 , Samia Mora  2 , Lynda Rose  2 ; JUPITER Trial Study Group
Affiliations
Randomized Controlled Trial

Percent reduction in LDL cholesterol following high-intensity statin therapy: potential implications for guidelines and for the prescription of emerging lipid-lowering agents

Paul M Ridker et al. Eur Heart J. .

Abstract

Aims: Current statin guidelines in Europe and Canada advocate achieving a fixed LDL target or the attainment of a ≥50% reduction in low-density lipoprotein cholesterol (LDLC), while current US guidelines advocate the use of statin therapies that reduce LDLC by <50% (moderate intensity) or ≥50% (high intensity). Data are limited, however, linking the achievement of these % reduction thresholds to subsequent cardiovascular outcomes particularly for contemporary high-intensity regimens.

Methods and results: In a randomized trial of 17 082 initially healthy men and women with median baseline LDLC of 108 mg/dL (interquartile range 94-119), we (i) used waterfall plots to assess the variability in LDLC response to rosuvastatin 20 mg daily and (ii) evaluated the impact of reaching ≥50% reductions in LDLC on risk of developing the first cardiovascular events. Among rosuvastatin allocated participants, 3640 individuals (46.3%) experienced an LDLC reduction ≥50%; 3365 individuals (42.8%) experienced an LDLC reduction >0 but <50%; and 851 individuals (10.8%) experienced no reduction or an increase in LDLC compared with baseline. These % LDLC reductions directly related to the risks of first cardiovascular events; at trial completion, incidence rates for the primary endpoint were 11.2, 9.2, 6.7, and 4.8 per 1000 person-years for those in the placebo, no LDLC reduction, LDLC reduction <50%, and LDLC reduction ≥50% groups, respectively. Compared with placebo, the multivariable adjusted hazard ratios for sequentially greater on-treatment per cent reductions in LDLC were 0.91 (95%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-HDLC or apolipoprotein B.

Conclusions: As documented for low- and moderate-intensity regimens, variability in % LDLC 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.

Keywords: Apolipoprotein B; Guidelines; LDLC; PCSK9; Prevention; Statin therapy.

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Figures

Figure 1
Figure 1
Waterfall plot for individual trial participants allocated to rosuvastatin 20 mg for the per cent change in low-density lipoprotein cholesterol (left) and concordant incident event rates (per 1000 person-years) for the Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin primary endpoint (right). Data are shown for the placebo group (white bars) and for those allocated to rosuvastatin who had no reduction or an increase in low-density lipoprotein cholesterol (pink), a >0 but <50% reduction in low-density lipoprotein cholesterol (light green), and a ≥50% reduction in low-density lipoprotein cholesterol (dark green).
Figure 2
Figure 2
Waterfall plot for individual trial participants allocated to rosuvastatin 20 mg for the per cent change in non-high-density lipoprotein cholesterol (left) and concordant incident event rates (per 1000 person years) for the Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin primary endpoint (right). Data are shown for the placebo group (white bars) and for those allocated to rosuvastatin who had no reduction or an increase in non-high-density lipoprotein cholesterol (pink), a ≥0 but <50% reduction in non-high-density lipoprotein cholesterol (light green), and a ≥50% reduction in non-high-density lipoprotein cholesterol (dark green).
Figure 3
Figure 3
Waterfall plot for individual trial participants allocated to rosuvastatin 20 mg for the per cent change in apolipoprotein B (left) and concordant incident event rates (per 1000 person-years) for the Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin primary endpoint (right). Data are shown for the placebo group (white bars) and for those allocated to rosuvastatin who had no reduction or an increase in apolipoprotein B (pink), a >0 but <50% reduction in apolipoprotein B (light green), and a ≥50% reduction in apolipoprotein B (dark green).
Figure 4
Figure 4
Variability in low-density lipoprotein cholesterol response following high-intensity statin therapy and its theoretical implications for the allocation of PCSK9 inhibitors.
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