Patients treated with the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor evolocumab (Repatha, Amgen) may experience a greater reduction in cardiovascular events if they have higher baseline levels of lipoprotein(a) [Lp(a)], US investigators have shown.
The results are from a preplanned analysis of the Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) trial, published in March 2017 in the New England Journal of Medicine.
As reported by theheart.org | Medscape Cardiology at that time, main FOURIER results showed that evolocumab was associated with a 15% reduced risk for a composite of myocardial infarction (MI), stroke, cardiovascular disease (CVD), coronary revascularization, and unstable angina hospitalization at 22 months compared with placebo (P < .001).
Moreover, treatment was associated with a 20% reduction in a composite of CVD, MI, and stroke vs placebo (P < .001), which occurred in tandem with large reductions in low-density lipoprotein (LDL) cholesterol levels.
The current analysis, presented here at the European Atherosclerosis Society (EAS) 2018 meeting, shows evolocumab also achieves significant reductions in Lp(a) levels of more than 25%.
The researchers found that the greatest effect of the drug compared with placebo on the risk for cardiovascular death, MI, and stroke was in patients with higher baseline Lp(a) levels, at 24% vs 15% in those with lower levels, at a twofold increase in the absolute risk reduction.
Study presenter Michelle L. O’Donoghue, MD, Brigham and Women’s Hospital, Boston, Massachusetts, told theheart.org | Medscape Cardiology that whether or not the benefits offered by Lp(a) reduction are “above and beyond” the LDL reduction is an area of ongoing study.
“But I think it’s worthwhile that we were able to see that baseline Lp(a) concentration appears to help identify individuals who derive greater benefit from treatment with evolocumab,” she added.
“So if those individuals have a larger magnitude of benefit and a smaller number needed to treat, then that’s perfect, as we’re trying to think about different high-risk features that might help to identify individuals who get the greatest benefit from the drug in a cost-effective manner.”
For O’Donoghue, one of the key aspects of their results is that they suggest that evolocumab affects both Lp(a) and LDL separately to lower the risk for cardiovascular outcomes. This was underlined by data showing that the greatest benefit was seen in individuals who achieved both their Lp(a) and LDL cholesterol target.
“With a drug like evolocumab, you’ve got multiple effects, and it becomes almost like a pleiotropic effect, because you’ve got LDL lowering, which is obviously very compelling, in addition to the effects on Lp(a),” she said.
“I think there’s a lot of work to be done to figure out whether or not the Lp(a) reduction on its own offers as much, or greater, or less benefit than LDL reduction on its own,” she added. “It’s interesting to see, though, that those who achieved the dual targets of lower levels of both are those who do best.”
Evolocumab and Lp(a)
The FOURIER trial involved 27,564 patients with stable atherosclerotic CVD and LDL cholesterol levels of 1.8 mmol/L (70 mg/dL) or higher who were receiving statin therapy and were randomly assigned to evolocumab, 140-mg injections every other week or 420-mg injections monthly, or to placebo.
After a mean follow-up of 2.2 years, evolocumab treatment was associated with a 59% relative reduction (P < .00001), or a 56-mg/dL absolute reduction, in LDL levels down to a median of 30 mg/dL, alongside the observed clinical benefits.
Previous Mendelian randomization data suggested that Lp(a) plays a causal role in the risk for coronary heart disease (CHD), and PCSK9 inhibitors have been shown to significantly reduce Lp(a) levels, so the team examined the impact of evolocumab on Lp(a) in FOURIER.
As part of the trial, Lp(a) levels were measured at baseline and weeks 12 and 58, with results available for 25,096 participants. The median Lp(a) level was 37 nmol/L (interquartile range [IQR], 13 – 165 nmol/L).
Individuals in the highest quartile of Lp(a) levels were, compared with those in the lower quartiles, significantly less likely to be male, to have ischemic stroke and diabetes mellitus, and to currently use tobacco (P < .001 for trend).
In contrast, individuals in the highest quartile were significantly more likely to have had a MI, to have peripheral artery disease, and to have higher baseline LDL cholesterol levels than those in the lower quartiles (P < .001 for trend).
As expected, higher baseline Lp(a) levels were associated in the placebo group with a significantly higher risk for CHD death or MI, cardiovascular death, MI or stroke, and MI and coronary death individually on multivariate analyses taking into account a range of potential confounding factors.
For example, the adjusted hazard ratio of CHD death or MI in participants with an Lp(a) in quartile 4 vs those in quartile 1 was 1.26 (95% CI, 1.02 – 1.56).
Among 11,864 participants given evolocumab, treatment was associated with a mean absolute change in Lp(a) levels at week 48 of –11 nmol/L (IQR, –31 nmol/L to –1 nmol/L), or a median percentage change of –26.9% (IQR, –46.7% to –6.2%).
The correlation between percentage change in Lp(a) and change in LDL cholesterol at 48 weeks in treated patients was r = 0.37 (P < .001), while that for absolute change was r = 0.21.
When the team divided the patients into those whose baseline Lp(a) level was above the median and those whose level was at or below the median, they found a difference in the impact of evolocumab on cardiovascular outcomes vs placebo.
Specifically, patients with a baseline Lp(a) level above the median had a hazard ratio of cardiovascular death, MI, or stroke with evolocumab vs placebo of 0.76 (95% CI, 0.66 – 0.86), or an absolute risk reduction of 2.8% and a number needed to treat of 36.
This compares with a hazard ratio for evolocumab vs placebo among patients with a baseline Lp(a) level at or below the median of 0.85 (95% CI, 0.73 – 0.97), or an absolute risk reduction of 1.28% and a number needed to treat of 79.
Next, the team looked at Lp(a) and LDL cholesterol together in terms of the impact of evolocumab treatment on the risk for combined cardiovascular events after week 12.
The risk was lower in patients who achieved a reduction of Lp(a) and LDL cholesterol to at or below the median at baseline (6.57%) than in those who achieved that milestone only with Lp(a) (7.88%), those who got there only with LDL cholesterol (8.45%), and those who achieved that for neither measure (9.43%) (P < .001 overall).
Concluding her presentation, O’Donoghue said their findings show that evolocumab significantly reduces Lp(a) levels and that “patients starting with higher Lp(a) levels appear to derive greater absolute benefit.”
Moreover, individuals “who achieve lower levels of both LDL cholesterol and Lp(a) have the lowest subsequent risk of CV events.”
Speaking after the session in an interview, she said that this latter finding is particularly interesting when one thinks of the individuals who have a reduction in Lp(a) levels “but a rise in LDL cholesterol levels at the same time.”
“What are those genetic predictors that help to identify those individuals? It’s not completely clear,” she said.
Completely Different Story
Commenting on the findings, Alberico L. Catapano, MD, PhD, professor of pharmacology at the University of Milan, Italy, and past president of the EAS, told theheart.org | Medscape Cardiology that “it’s a completely different story” between Lp(a) and LDL cholesterol.
He explained that with LDL cholesterol, the greater the reduction in plasma levels, the greater the benefit, while with Lp(a), “there’s always been a struggle” to demonstrate a similar relationship.
“Lp(a) is related to cardiovascular disease, but the strongest relationship is with calcification of the aortic wall, or aortic stenosis,” he said.
However, Catapano noted that the “exact mechanism is still not completely clear,” unlike the situation with LDL.
“Of course, we’ll never know everything for sure but we have robust evidence with LDL,” he said. “With Lp(a), it’s not clear whether it’s coagulation, whether it’s atherosclerosis and the buildup of cholesterol, or both together.”
“Having said that,” he added, “there is clearly a relationship that is not linear but sort-of hyperbolic, so that above a certain level, the correlation gets stronger and the risk becomes higher.”
Catapano pointed out, however, that the median Lp(a) levels seen in the FOURIER trial were lower than those seen in the general population and lower than the 50 mg/dL that has been linked to a substantially increased cardiovascular risk, “so you would not expect a huge benefit” with Lp(a) reduction in this population.
“The second point is they saw a benefit that was larger in absolute terms according to the levels of Lp(a), [which] is entirely in line with what we know,” he said. “We know that Lp(a) contributes to the risk and we know that we have a higher risk if we have higher Lp(a), and that reducing LDL cholesterol for sure reduces the risk.”
“Whether the contribution of Lp(a) to that reduction of risk is important, we do not know; it would be almost impossible to disentangle from the data,” he said. “That’s my personal view.”
However, Catapano believes, these answers may be provided with the results of ongoing studies into antisense nucleotides, which target Lp(a) specifically.
FOURIER was funded by Amgen. O’ Donoghue reports receiving research grant support from GlaxoSmithKline, Eisai, Merck & Co, Janssen, Amgen, The Medicines Company, and AstraZeneca. Catapano reports being a consultant for and receiving honoraria from Pfizer, Sanofi, Genzyme, Merck, Akcea, and Amgen; receiving honoraria from Kowa, Mediolanum, Farmaceuti, Menarini, Bayer, Eli Lilly, Recordati, and Genzyme; and receiving research grants from Pfizer, Merck, Sanofi, Menarini, Regeneron, Mediolanum, and Farmaceutici.
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