Residual Risk of Atherosclerotic Cardiovascular Events in Relation to Reductions in Very-Low-Density Lipoproteins

Abstract

Background: It is uncertain whether pharmacological reductions in very-low-density lipoproteins (VLDLs), and their component triglyceride and cholesterol could reduce residual risk of atherosclerotic cardiovascular disease (ASCVD) events among individuals in whom low-density lipoprotein cholesterol (LDL-C) has been adequately lowered. We examined whether individuals with greater on-statin reductions in VLDL-related measures-beyond reductions in LDL-C-were at further reduced risk of ASCVD.

Methods and results: In 9423 participants in the JUPITER (Justification for the Use of Statins in Prevention) trial (NCT00239681), at baseline and on statin we measured standard lipids, 400-MHz proton nuclear magnetic resonance spectroscopy-measured VLDL particle subclasses (small, medium, and large VLDL lipoprotein particle concentration), and total VLDL cholesterol mass. Compared with individuals allocated to placebo, we examined risk of incident ASCVD (N=211) among statin-allocated participants who achieved minimal (<median) or greater (≥median) marker reductions using adjusted Cox models. On-statin changes in VLDL-related markers were only modestly correlated (Spearman r≤0.29) with change in LDL-C. On-statin median LDL-C was 54 mg/dL and triglyceride was 101 mg/dL. Dose-response reductions in ASCVD risk were observed for greater reductions in LDL-C, VLDL cholesterol mass, and small VLDL lipoprotein particle concentration; the latter 2 remained significant after incremental adjustment for change in LDL-C (P≤0.006). Conversely, there was no further risk reduction with greater reductions in triglycerides or large/medium VLDL lipoprotein particle concentration.

Conclusions: Pharmacological reduction in small, cholesterol-enriched, triglyceride-depleted VLDL was associated with reduction in ASCVD risk. Chemically measured triglycerides may not sufficiently capture risk related to VLDL pathways. These findings also support broader profiling of lipid and lipoprotein changes in response to statins as prognostic markers of individual benefit, supporting more precision-medicine, individualized approaches to cardiovascular risk reduction.

Clinical trial registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00239681.

Keywords: arteriosclerosis; lipids; lipoproteins; metabolomics; personalized medicine; primary prevention; statin.

Figure 1

Illustrative schematic overview of study hypothesis, approach, and interpretation (hypothetical result shown). CVD indicates cardiovascular disease; HR, hazard ratio; JUPITER, Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin trial; LDL‐C, low‐density lipoprotein cholesterol; max., maximum; med., median; mo., months; VLDL, very‐low‐density lipoprotein; VLDL‐C, VLDL cholesterol; VLDL‐p, VLDL lipoprotein particle concentration.

Figure 2

Waterfall plot23 demonstrating the range of individuals’ changes in LDL‐C with rosuvastatin 20 mg daily. Subjects were divided into Minimal Response (red) and Larger Response (blue) groups based on whether they had greater than or less than the median change (a reduction) in LDL‐C. Cox models are adjusted for age, sex, race, smoking, body mass index, systolic blood pressure, fasting glucose, baseline HDL‐C, baseline hsCRP, and baseline LDL‐C and used placebo‐allocated individuals as a reference. *Between‐response group comparison among participants in this substudy (N=9423) P=0.17 and among all JUPITER participants with LDL‐C measure (N=15 546) P=0.01.

Figure 3

Waterfall plot demonstrating the range of individuals’ absolute changes in VLDL‐C, small and large VLDL‐p, and triglycerides with rosuvastatin 20 mg daily. Subjects were divided into Minimal Response (red) and Larger Response (blue) groups based on whether they had greater than or less than the median reduction in the given marker. Cox models (comparing risk with those in the current substudy allocated to placebo as the reference population) are adjusted for age, sex, race, smoking, body mass index, systolic blood pressure, fasting glucose, baseline HDL‐C, baseline hsCRP, baseline VLDL‐related marker level, and change in LDL‐C. Among those on rosuvastatin, the median (IQR) on‐treatment LDL‐C levels in the Minimal Response and Larger Response groups were 57 (45, 78) and 52 (42.0, 66.0) mg/dL, respectively, in the small VLDL‐p change group and 58 (45, 82) and 51 (45, 65) mg/dL, respectively, in the VLDL‐C change group. *Between‐response group comparison among participants in this stubstudy (N=9423) P=0.24 and among all JUPITER participants with triglyceride measure (N=15 546) P=0.28.