What does this research mean for the field?

ApoA-1 and HDL-C have similar predictive precision for atherosclerotic cardiovascular disease risk, and the risk associated with HDL is primarily driven by apoA-1 rather than concurrent hypertriglyceridemia. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.CHALLENGES_CONSENSUS.

September 10, 2025Open Access

ApoA-1 versus HDL-C as Markers of Cardiovascular Risk

Structured PICO

Do HDL-C and apoA-1 have similar predictive precision for incident ASCVD risk in a primary prevention cohort?

Population

291,995 participants from the UK Biobank without baseline cardiovascular disease or lipid-lowering therapy, median age 56, 42.1% male. Key exclusions: missing records, triglycerides ≥ 400 mg/dL, apoB <20 mg/dL or >400 mg/dL, or LDL-C ≥ 250 mg/dL.

Outcome

Incident atherosclerotic cardiovascular disease (ASCVD) over a median follow-up of 11 yearshard clinical

HDL-C and apoA-I are equally potent predictors of ASCVD risk, but apoA-I accounts for the majority of the risk reduction associated with HDL, challenging the notion that concurrent hypertriglyceridemia is the primary driver.

Abstract

Abstract Background Conflicting results have been reported as to the relative importance of apoA-1 versus HDL-C as markers of ASCVD risk. Methods Residual discordance analysis with Cox proportional hazard models comparing apoA-1 and HDL-C as markers of ASCVD risk was applied to a sample of 291,995 UK Biobank, followed for a median of 11 years. Interaction test for the two markers and estimation of the effects of partitioning HDL-C into apoA-I, log-triglyceride and the remaining residual were also performed. Results ApoA-1 and HDL-C had similar associations with ASCVD risk (HRs of 0.85, p-value < 0.001 for both). The residual of HDL-C added significantly to the risk associated with apoA-1 as did the residual of apoA-1 to HDL-C. There was a statistically significant interaction between apoA-I and HDL-C ( HR = 1.05, 95% CI: (1.04, 1.06); p < 0.001 ). Decomposing HDL-C into the 3 components, apoA-I accounted for the largest portion of the effect with a HR of 0.85 95%CI: (0.83, 0.86) with smaller effects for lnTG: 1.04 (1.02, 1.06) and residual of HDL-C: 0.98 95%CI: (0.96, 0.995). Conclusions HDL-C and apoA-1 have associations of equivalent strength with ASCVD risk with significant interaction modifying the effect of one by the other. Upon decomposition, ApoA-I retained more of the effect of HDL-C as compared to log-triglycerides. While only observational, the results are consistent with the relation of HDL to risk not being determined by the concurrent level of triglyceride. Clinical Perspective The plasma levels of HDL-C and apoA-I are potent predictors of cardiovascular risk. However, there are few data comparing the relative precision of HDL-C and apoA-I for this purpose. Moreover, the risk of low HDL-C has been attributed to concurrent hypertriglyceridemia, consequently downgrading the potential importance of HDL in predicting or explaining risk. Novel Findings Based on residual discordance analysis, HDL-C and apoA-I have similar predictive precision for ASCVD risk. However, each adds significantly to the other and. Moreover, triglycerides account for only a small portion of the risk attributable to HDL with apoA-I accounting for the principal portion. Clinical Significance HDL, whether measured as HDL-C or apoA-I, is a potent predictor of ASCVD risk. It remains essential to search for the biological basis or bases for these relationships.

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