Visit-to-visit lipid variability: Clinical significance, effects of lipid-lowering treatment, and (pharmaco) genetics

Abstract

In recent years, visit-to-visit variability of serum lipids has been linked to both clinical outcomes and surrogate markers for vascular disease. In this article, we present an overview of the current evidence connecting this intraindividual variability to these outcome measures, discuss its interplay with lipid-lowering treatment, and describe the literature regarding genetic factors of possible interest. In addition, we undertook an explorative genome-wide association analysis on visit-to-visit variability of low-density lipoprotein cholesterol and high-density lipoprotein cholesterol, examining additive effects in 2530 participants from the placebo arm of the PROspective Study of Pravastatin in the Elderly at Risk trial. While we identified suggestive associations (P < 1 × 10) at 3 different loci (KIAA0391, amiloride-sensitive cation channel 1 neuronal [ACCN1], and Dickkopf WNT signaling pathway inhibitor 3 [DKK3]), previously published data from the genome-wide association study literature did not suggest plausible mechanistic pathways. Given the large degree of both clinical and methodological heterogeneity in the literature, additional research is needed to harmonize visit-to-visit variability parameters across studies and to definitively assess the possible role of (pharmaco)genetic factors.

Association of High-Density Lipoprotein Cholesterol With Cognitive Function: Findings From the PROspective Study of Pravastatin in the Elderly at Risk

“…However, our associations were significant even in models adjusted for C-reactive protein. Furthermore, lipid-lowering medication, especially nonadherence, may result in increased lipid variability (Smit et al, 2018). Indeed, subjects in the highest tertile of HDL-c variability were more likely to be from the pravastatin treatment arm.…”

Genetic Determinants of Visit-to-Visit Lipid Variability: Genome-Wide Association Study in Statin-Naïve Korean Population

“…Among the four lipid traits, including TC, TG, HDL-C, and LDL-C, we evaluated HDL-C and LDL-C variability in this study. Visit-to-visit lipid variability was defined as variability in HDL-C and LDL-C as measured at least three times during the health examinations, and four measurements of variability were used (8,16,17): (1) standard deviation (SD), (2) average successive variability (ASV), (3) coefficient of variation (CV), and (4) variation independent of mean (VIM). The CV was calculated by SD/mean, and VIM was calculated as 100 × SD/mean β , where β is the regression coefficient based on natural logarithm of SD on natural logarithm of mean.…”

Effects of Cardiovascular Risk Factor Variability on Health Outcomes

“…It is unclear whether statin treatment or dosing affects lipid variability. In the PROSPER study, the pravastatin treatment group had higher LDL-C and HDL-C variability than the placebo group [58]. However, in the TNT trial, an atorvastatin dose of 80 mg/day was associated with significantly lower LDL-C variability than an atorvastatin dose of 10 mg/day dose [12].…”

“…Polymorphisms in apolipoprotein genes have also been suggested as possible contributors to intra-individual lipid variability [56,57]. In a genome-wide association study, most genetic variants were not associated with lipid variability, although two suggestive signals for LDL-C variability (KIAA0391 and amiloride-sensitive cation channel 1 neuronal) and one for HDL-C variability (Dickkopf WNT signaling pathway inhibitor 3) were detected [58].…”