Trial-level surrogacy of non-high-density and low-density lipoprotein cholesterol reduction on the clinical efficacy of statins

LDL cholesterol (LDL - c) and non-HDL cholesterol (non-HDL-c) are prognostic factors of cardiovascular risk. However, their validity as trial-level surrogates for cardiovascular outcomes is debated. This study aimed to determine whether LDL - c and non-HDL-c are reliable surrogates for cardiovascular events in statin trials, and to explore discrepancies in previous studies. We conducted an umbrella review of meta-analyses of randomized controlled trials (RCTs) assessing statin efficacy versus placebo or usual care on all-cause mortality and cardiovascular events. We search studies published between 1987 and August 2023 from PubMed, Embase, and the Cochrane Library. Baseline lipid levels, absolute risk differences (ARDs), and hazard ratios or risk ratios (RRs) for major cardiovascular events and all-cause or cardiovascular mortality were analysed. Weighted linear regressions between log RR or ARD, and absolute difference in non-HDL-c or LDL - c were performed. The coefficients of determination (R²_trial) were calculated, with their 95% CI computed through bootstrapping. The surrogate threshold effect (STE) was also estimated. Twenty RCTs and 194 686 participants were included, with a median follow-up of 4.85 years. Statin treatment showed significant efficacy in improving all clinical outcomes. However, the association between treatment effects on LDL - c or non-HDL-c reduction and clinical outcomes was weak. The R²_trial were ranging from 0 to 0.1 for LDL - c, and from 0 to 0.04 for non-HDL-c. The STE for major adverse cardiovascular event was 0.76 (0.36–1.69) mmol/L for LDL - c, and 0.87 (0.49–2.19) mmol/L for non-HDL-c. Neither LDL - c nor non-HDL-c demonstrated trial-level surrogacy for predicting treatment effects on mortality and cardiovascular events in statin trials. Although they are relevant biomarkers for the follow-up of patients treated with statins, their reduction does not reliably predict a similar reduction in cardiovascular risk. As such, they should not be used as pivotal evidence in drug trials.