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

Abstract

BackgroundIt 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 ResultsIn 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.ConclusionsPharmacological 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 RegistrationURL: https://www.clinicaltrials.gov. Unique identifier: NCT00239681.

Metabolomic signature of angiopoietin-like protein 3 deficiency in fasting and postprandial state

“…Experimental models and human genetics have indicated that triglyceride-rich lipoproteins (TRL) play a causal role in the pathogenesis of CVD 2 . Post-hoc analyses of statin trials have further shown that reductions of TRL is associated with lower cardiovascular event risk independently of the LDL cholesterol reduction achieved from statins 3,4 . These observations have accelerated the development of novel TRL-lowering therapeutics for CVD prevention, with drug targets informed by recent discoveries from genetic studies 5 .…”

Metabolomic consequences of genetic inhibition of PCSK9 compared with statin treatment

“…The causal consequences of these differences in mediumsized and large VLDL particles, that are rich in triglycerides, remains unclear and warrants further investigations; whereas IDL and the smallest VLDL particles can penetrate the arterial wall to cause atherosclerosis, it is commonly perceived not be to the case for larger VLDL particles (37,46). We also observed a difference in lowering of VLDL-cholesterol levels; the cholesterol concentrations of VLDL particles are strongly associated with risk of myocardial infarction (43) and some studies have suggested that VLDL-cholesterol could underpin the link between triglycerides and cardiovascular risk (37,40). If these VLDL particles do play a causal role in vascular disease, the discrepancy between statin therapy and PCSK9 inhibition could translate into slightly more potent cardiovascular risk reduction for the same LDL-C lowering for statins as compared with PCSK9 inhibition.…”

“…This could potentially contribute to subtle differences in potency for cardiovascular event lowering for the same LDL-C lowering (6), since recent evidence suggests that VLDL-cholesterol and other triglyceride-rich lipoprotein measures may causally contribute to the development of coronary heart disease independent of LDL-C (37-39). Moreover, trial data show that VLDL-cholesterol is a stronger predictor of cardiovascular event risk than is LDL-C among patients on statin therapy (40,41).…”

Dissimilar Effects of Anagliptin and Sitagliptin on Lipoprotein Subclass in Standard or Strong Statin-Treated Patients with Type-2 Diabetes Mellitus: A Subanalysis of the REASON (Randomized Evaluation of Anagliptin versus Sitagliptin on Low-Density LipoproteiN Cholesterol in Diabetes) Trial

“…In T2DM, possible candidates for residual risks include sdLDL [12], postprandial hypertriglyceridemia [25], and TG-rich lipoproteins [21,25,26]. Our findings may provide a unique approach to this important "beyond statin" issue [21][22][23][24]. Previous studies have reported the effects of anagliptin on the lipid profiles of patients with type-2 diabetes, but these were not controlled for statin treatment [14,19,27].…”

“…Although statins are beneficial in preventing ASCVD [3,4], residual risk after statin treatment should be considered in specific conditions [5,6,12,[21][22][23][24][25][26]. In T2DM, possible candidates for residual risks include sdLDL [12], postprandial hypertriglyceridemia [25], and TG-rich lipoproteins [21,25,26].…”