Elevated Risks From Lp(a) Can Be Offset by Lower Lifetime LDL Cholesterol

MILAN, Italy—Patients can overcome the added risk of coronary heart disease events associated with elevated lipoprotein(a) levels if they maintain lower LDL-cholesterol levels over their lifespan, according to a new analysis from UK Biobank.

For people with high levels of Lp(a)—defined as approximately 120 nmol/L—this requires lifetime LDL-cholesterol levels that are approximately 20 mg/dL lower than those of individuals without elevated Lp(a) to offset the associated risks of atherogenic lipoprotein.

Brian Ference, MD (University of Cambridge, England), who presented the study results during the late-breaking trial session at the European Atherosclerosis Society (EAS) Congress 2022, said physicians are often placed in a bind with patients who have elevated Lp(a). Higher Lp(a) levels are associated with an increased risk of atherosclerotic cardiovascular disease (ASCVD), and the current European guidelines recommend intensifying treatment in those with high levels.

But as of yet, there’s no treatment for elevated Lp(a).

“Unfortunately, unlike other lipoproteins, diet and exercise don’t reduce Lp(a) and there are no effective therapies to lower Lp(a) at the moment,” said Ference. “For that reason, guidelines simply recommend that we intensify risk-factor modification in persons with elevated risk due to Lp(a) in an attempt to ameliorate that risk. However, this guidance isn’t specific enough to be useful, and that’s created a great deal of inertia among clinicians who’ve concluded they don’t need to measure Lp(a) because there’s nothing they can do about it.”  

High Lp(a) Means Lower LDL Cholesterol is Necessary

The purpose of the present study, said Ference, was to quantify the amount of LDL-lowering that would be needed to overcome the increased risk caused by Lp(a). To do this, they studied 445,765 patients enrolled in the UK Biobank without a history of ASCVD, diabetes, or cancer before age 30 years. For the natural randomization study, patients were randomly allocated based on genetic variants to either the average Lp(a) values, to “higher” levels (20 nmol/L vs 123 nmol/L, respectively), or to both higher Lp(a) levels and low LDL cholesterol levels. 

Based on the calculations, the lifelong exposure to higher Lp(a) levels was associated with a projected 37% higher risk of major coronary events. However, for patients randomized to higher Lp(a) values and lower LDL-cholesterol levels, the risk of coronary events was completely attenuated. To overcome the 30% to 40% higher risk of major coronary events associated with higher Lp(a) concentrations, LDL-cholesterol levels must be 0.5 mmol/L (19 mg/dL) lower at every single age. The finding was similar in men and women.

Ference pointed out that the benefits of lowering LDL cholesterol deteriorate the later treatment is started in life. With that in mind, the researchers modeled the magnitude of LDL-lowering as a strategy to overcome the risk caused by Lp(a) if treatment was started at different stages in life.

The later we start, we require a progressively larger absolute magnitude of LDL-lowering to overcome that increased risk. Brian Ference

In a patient with Lp(a) 150 nmol/L higher than the median, a 0.6-mmol/L reduction in LDL cholesterol is needed to offset the lifetime risk of Lp(a) if treatment is started at age 30. If LDL-lowering is started at 40, 50, or 60 years, however, lifetime reductions in LDL cholesterol of 0.7, 0.9, and 1.1 mmol/L (27, 35, and 42.5 mg/dL) are needed, respectively. For the people with substantially elevated Lp(a), say 250 nmol/L above the median, starting LDL cholesterol-lowering at age 50 or 60 years would require LDL reductions of 1.5 and 1.9 mmol/L (58 and 73.5 mg/dL) to overcome the increased risk associated with Lp(a).   

“The later we start, we require a progressively larger absolute magnitude of LDL-lowering to overcome that increased risk,” Ference said.

Speaking about the modeling study, Ference said it has clinical implications because it “refines individual estimates of absolute lifetime risk of ASCVD and directly informs treatment decisions about the intensity of LDL-lowering.” For clinicians, these data should motivate them to measure Lp(a) at least once in all of their patients, and measure it early in life, to identify those at high risk of ASCVD so it can be addressed with relatively modest reductions in LDL cholesterol, said Ference.

Ulrich Laufs, MD (Leipzig University, Germany), who chaired the EAS session, agreed with Ference’s conclusions, telling TCTMD that physicians are encountering patients in clinic with high Lp(a) concentrations but aren’t sure what to do with the information. “The question is, what can you do?” he said. “Well, [this study shows] you can reduce their risk by lowering LDL cholesterol.”

Right now, there are several investigational therapies shown to lower Lp(a). Amgen and Silence Therapeutics are both working on small interfering RNA (siRNA) technologies, and their respective compounds have been shown to lower Lp(a). Novartis Pharmaceuticals has already begun the Lp(a)HORIZONS study, a phase III cardiovascular outcomes trial evaluating the antisense oligonucleotide pelacarsen in more than 8,000 patients with established ASCVD. Results from that trial, though, are not expected until 2025.