Lp(a) Levels, Still Mostly Genetic, Sometimes Vary Over a Lifetime

Lipoprotein(a) levels, which are largely determined by genetics, appear to fluctuate over time, particularly in individuals with moderately elevated concentrations, a UK Biobank analysis shows.

People with low and very high Lp(a) values—those with concentrations less than 75 and greater than 189 nmol/L—remained stable over time, but those who fell within these two extremes had fluctuations over a 4-year period.

The findings, say researchers, could have clinical implications, because the shifts in Lp(a) imparted changes in risk categorization.

“Specifically, almost one-third of those initially categorized within the intermediate-risk range had Lp(a) levels in the high-risk range at follow-up,” write Jonas Ghouse, MD (Rigshospitalet, Copenhagen University Hospital, Denmark), and colleagues in a paper published online recently in the European Heart Journal. “Conversely, nearly one in five initially classified as high risk at baseline transitioned to the intermediate-risk range upon subsequent assessment.”   

Elevated Lp(a) has emerged as an independent causal risk factor for atherosclerotic cardiovascular disease and aortic valve stenosis in multiple observational studies with different patient populations. Plasma Lp(a) levels are roughly 70% to 90% genetically determined, with the LPA gene mostly responsible for determining concentrations. As such, it had been suggested that individuals should have Lp(a) measured once during their lifetime.

Christie Ballantyne, MD (Baylor College of Medicine, Houston, TX), senior author of the 2024 National Lipid Association (NLA) statement on the use of Lp(a) in clinical practice, said that while it was initially thought there’d be little variability in Lp(a) levels over time, it’s now understood that they can change in some people. The ARIC study, for example, showed that people with borderline high Lp(a) levels in middle age had high Lp(a) concentrations later in life.

“If you have a low level, low levels stay low,” Ballantyne told TCTMD. “In the ARIC study, if you were in this intermediate-risk zone, about half of them drifted up into the high zone.” Unlike the UK Biobank analysis, the ARIC study documented the variability over an approximate follow-up period of 15 years.

For this reason, the NLA rephrased its recommendation to state that people should have Lp(a) measured “at least once” during the lifetime. “If you’re in this intermediate zone where it’s not desirable—it’s not super high, but it’s not normal—you may need to recheck it,” said Ballantyne.

If It’s Low, It Will Stay Low

In the UK Biobank analysis, the median Lp(a) level was 21.0 nmol/L at baseline among 12,202 study participants. After a median time between measurements of 4.4 years, the median follow-up Lp(a) was 22.4 nmol/L. Correlation between the two measurements was strong (Spearman r = 0.94, P < 0.0001) but varied by baseline Lp(a) levels.

For participants with Lp(a) levels < 75 nmol/L (< 30 mg/dL), which is considered normal, there was a strong correlation with follow-up Lp(a) levels (Spearman r = 0.90, P < 0.0001). For those with levels of 75 to 125 nmol/L and 125 to 189 nmol/L, the correlation was much weaker (Spearman r = 0.50, P < 0.0001 and r = 0.39, P < 0.0001, respectively).

Only 3.2% of participants with normal Lp(a) levels had changes of 25 nmol/L or greater during follow-up, with just 2.6% and 0.2% having changes large enough to shift them into the intermediate- and high-risk Lp(a) categories. On the other hand, 31% of people in both the intermediate- and high-risk categories had changes in Lp(a) over time. Overall, 29.5% of those in the intermediate-risk Lp(a) group moved to a higher-risk group during follow-up and 9.0% were reclassified as low risk. For those with high Lp(a) levels, 17.5% moved down to intermediate risk and 0.9% to low risk. 

“While a single measurement may suffice for those with Lp(a) < 75 nmol/L or > 189 nmol/L, individuals with values between these extremes may benefit from repeat assessments to avoid misclassification,” say researchers. “Furthermore, with the potential advent of novel Lp(a)-lowering therapies, accurate risk stratification and identification of treatment-eligible individuals become increasingly important.”

The message ends up being, at least to me as an enthusiast in this area, is everybody should get it checked at least once. Christie Ballantyne

To TCTMD, Ballantyne said the NLA defines high Lp(a) as greater than 125 nmol/L (> 50 mg/dL), which is different than the cutoffs used by the researchers. In general, he said, the upward drift of Lp(a) for those with moderately high or high Lp(a) may be related to aging and menopause, but they showed in ARIC that Black race, female sex, diabetes, hypertension, total cholesterol, and high albumin-to-creatinine ratio were all risk factors for an Lp(a) change of 20 mg/dL or greater over the 15-year follow-up.   

“The message ends up being, at least to me as an enthusiast in this area, is everybody should get it checked at least once,” said Ballantyne. “If you're in that zone that's low, particularly if it’s very low, then you don't have to worry about it. If you’re in the high zone, and we’re talking about 125 [nmol/L], which is quite far from 75 [nmol/L], the odds of you moving into a normal zone are quite low. If you’re in the intermediate-risk zone, then you may want to repeat [Lp(a) testing] at some point.”

There are a number of Lp(a)-lowering therapies in development, including therapies in large-scale, cardiovascular outcomes trials. Pelacarsen (Novartis/Ionis Pharmaceuticals), an antisense oligonucleotide, is currently being tested in Lp(a)HORIZON, a study that has completed enrollment, and results are expected in 2025. Lepodisiran (Eli Lilly), olpasiran (Amgen), and zerlasiran (Silence Therapeutics) are small-interfering RNA therapies that have been shown to dramatically cut Lp(a) concentrations. Muvalaplin, a selective, small molecule inhibitor of Lp(a), is an oral agent also in development.

Right now, Ballantyne said, if he’s taking care of a patient with intermediate Lp(a), then he would try to be a little more aggressive with risk factor control.

“We don’t have any treatment that will help Lp(a), but if someone's had a heart attack and they had an Lp(a) of 100 [nmol/L] and their LDL cholesterol was 70 [mg/dL] on a statin and ezetimibe, I might think about a PCSK9 inhibitor to get the LDL down to 30 [mg/dL]. It's another argument for being more aggressive in a high-risk patient.”