Simulated intervention and optimal timing for attenuating dyslipidaemia-related atherosclerotic progression in the young: a temporal inverse allocation analysis of the ALSPAC cohort
Authors: Agbaje A O , Lloyd-Jones D M , Magnussen C G , Tuomainen T P 
Published: October 2022

Abstract

Background
Carotid intima-media thickness (cIMT) progression strongly predicts cardiovascular events among adults. We recently reported that cumulative dyslipidaemia was longitudinally associated with cIMT progression among adolescents and young adults. It is of clinical and public health significance to identify the most sensitive or crucial timing for preventing cardiovascular diseases before mid-adulthood. One method for addressing these issues is to perform a temporal inverse allocation to simulate the effects of treatment for dyslipidaemia at specific life stages, in order to inform effective timing of treatment. The temporal inverse allocation is similar to the principle of isotemporal substitution, however, rather than eliminating variables of interest, participants' categories are reversed, i.e participants with dyslipidaemia at a specific time point are assigned normal lipid levels and vice versa, while variables at other time points are unchanged.

Purpose
To simulate a treatment intervention on the longitudinal associations of total cholesterol (TC), non–high-density lipoprotein cholesterol (non–HDL-C), high-density lipoprotein cholesterol (HDL-C), triglyceride, and low-density lipoprotein cholesterol (LDL-C) with cIMT progression.

Methods
We studied 1779 British 15-year-olds (50% females) followed up for 9 years. TC, triglyceride, and HDL-C were measured in line with standard protocols at ages 15, 17, and 24 years, respectively. non-HDL-C and LDL-C were estimated. Lipid phenotypes were categorized based on the 2011 National Heart, Lung, and Blood Institute classification into normal (reference) and elevated/dyslipidaemia. cIMT of the right and left common carotid arteries were measured at 17 and 24 years with ultrasound. We conducted linear mixed-effect model analyses with temporal inverse allocation and adjusted for age, sex, cardiometabolic, and lifestyle factors.

Results
Normalized lipid at age 24 years, with elevated lipid and dyslipidaemia at 15 and 17 years did not alter the longitudinal associations of elevated/dyslipidaemia TC: effect estimate 0.028 mm [95% CI 0.007 to 0.049; p=0.010], non–HDL-C: 0.027 mm [0.006 to 0.049; p=0.013], and low HDL-C: −0.030 mm [−0.048 to −0.013; p=0.001] from 15 through 24 years with the 7-year cIMT progression. However, normalized lipid level at age 17 years with elevated lipid and dyslipidaemia at 15 and 24 years significantly attenuated the longitudinal associations of elevated/dyslipidaemia TC: effect estimate 0.005 mm [−0.015 to 0.025; p=0.627], non–HDL-C: 0.013 mm [−0.008 to 0.034; p=0.235], and low HDL-C: −0.016 mm [−0.031 to −0.0001; p=0.049] from 15 through 24 years with cIMT progression. Triglyceride and LDL-C were not associated with cIMT progression.

Conclusion
This simulated intervention suggests that lowering lipids during late adolescence may be effective in preventing and reversing cIMT progression, a marker of preclinical atherosclerosis, in the young.

Funding Acknowledgement
Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Finnish Cultural Foundation