Excess ApoB Linked to Increased MI, ASCVD Risk in Adults

Excess apolipoprotein B (apoB) levels—in amounts higher than expected based on LDL cholesterol levels alone—provide important clinical information about the risk of future cardiovascular disease not captured by LDL cholesterol, according to results of a new study.

Excess apoB was associated with a dose-dependent increased risk of MI and atherosclerotic cardiovascular disease (ASCVD) in men and women, and a higher risk of all-cause mortality in women alone, report investigators.

“Notably, our results showed that by assessing excess apoB, one in 10 individuals in the general population had excess apoB associated approximately with a 50% higher risk of MI, a 35% higher risk of ASCVD, and a 15% higher risk for all-cause mortality (the last in women only) compared with what would be expected on the basis of LDL cholesterol alone,” report Camila Johannesen, MD (Copenhagen University Hospital-Herlev Gentofte, Denmark), and colleagues online June 3, 2024, in the Journal of the American College of Cardiology.

The US and European clinical guidelines recommend treating LDL cholesterol for disease prevention, as well as using it as a marker of risk, given its causal role in cardiovascular disease, but several studies have shown there may be an advantage to measuring various other lipoproteins, including apoB.

Nicholas Marston, MD, MPH (Brigham and Women’s Hospital, Boston, MA), who has studied the role apoB plays in cardiovascular disease, said the new study adds to other evidence showing that it is a better predictor of risk than LDL cholesterol.

“While LDL is the predominant atherogenic particle in the majority of individuals, LDL cholesterol does not measure other atherogenic particles such as very-low-density lipoproteins, intermediate-density lipoproteins, or chylomicron remnants,” he told TCTMD. On the other hand, apoB measures the total amount of atherogenic particles.

Untangling the risk associated with apoB and LDL cholesterol isn’t easy, though, because they are highly correlated. However, as Marston explains, “individuals can have discordant values such that apoB can be higher than would be expected by their LDL cholesterol level, representing additional risk above and beyond what is captured by the LDL cholesterol measurement.”

In such patients, that information is “especially useful as it may identify who needs more intensive therapy,” said Marston.

Looking for Discordance

To tease out the risk attributable to LDL cholesterol and apoB in this new study, the researchers performed a discordance analysis, first flushing out the relationship between LDL cholesterol and apoB in patients with normal triglyceride levels (< 1 mmol/L or 89 mg/dL). The regression captured the minimum apoB that is present for any given value of LDL cholesterol. This then allowed them to identify “excess apoB,” which is the difference between the observed and predicted apoB based on the regression analysis.

The study included 95,108 men and women enrolled in the Copenhagen General Population Study not taking statins at baseline. During a median follow-up of 9.6 years, there were 2,048 first MI events, 4,282 first ASCVD events, and 8,873 deaths.

When compared with those with excess apoB less than 11 mg/dL, which served as the comparator group, women with excess apoB levels of 11 to 25, 26 to 45, 46 to 100, and greater than 100 mg/dL had an 8%, 55%, 52%, and 87% relative higher risk of MI (P for trend < 0.0001), respectively. Similarly, men had a 20%, 65%, 82%, and 85% relative higher risk of MI at the respective excess apoB levels (P for trend < 0.0001). With ASCVD, there was also a dose-dependent increase in risk with increasing apoB levels in men and women (P for trend < 0.0001). For women alone, excess apoB was associated with an increased risk of all-cause mortality in a dose-dependent manner.

The researchers also looked at absolute values of apoB across different LDL cholesterols. For a measured LDL of 77 mg/dL, for example, the expected apoB level is 111 mg/dL. At the higher end, a measured LDL of 193 mg/dL yields an expected apoB of 130 mg/dL. Across this spectrum of LDL levels, if the excess apoB was greater than the 90th percentile of what would be expected, there was a heightened risk of ASCVD.

The results were similar when those who started statin therapy during follow-up were excluded. Additionally, the findings were validated in 9,360 men and women enrolled in the Copenhagen City Heart Study.

In an accompanying editorial, Alan Remaley, MD (National Heart, Lung, and Blood Institute, Bethesda, MD), Justine Cole, MD, and Allan Sniderman, MD (both McGill University Health Centre, Montreal, Canada), say there is “compelling evidence that apoB is clinically, not just statistically, superior to LDL cholesterol and, critically, that this advantage applies to a substantial number of patients.”

ApoB, say the editorialists, is ready for “prime time” right now. 

“We believe that apoB should be widely available for clinical care because more accurate estimation of cardiovascular risk and more precise estimation of the adequacy of therapy will lower the number of myocardial infarcts and strokes and save lives,” they write.

Marston said the accumulating evidence for apoB doesn’t mean it needs to replace LDL cholesterol, but rather could be part of a routine lipid panel for a “more comprehensive evaluation.” He noted that the National Lipid Association (NLA) plans to publish a consensus statement on apoB shortly that will outline when to measure apoB, as well as information about clinically relevant thresholds.