Results are presented from the unsuccessful first clinical trial that aimed to reduce cardiovascular risk by lowering lipoprotein(a) levels

This is a well-conducted study. It involved over 8,000 patients who were followed for nearly five years, and the drug was compared against a placebo—which is exactly how such a study should be designed. The medication significantly reduces Lp(a) levels—by more than 70%. The issue, however, is that patients who received the drug experienced the same rates of heart attacks, strokes, and cardiovascular deaths as those who received the placebo: 12.3% versus 12.1%. There was no difference, even among those with the highest Lp(a) levels. The result is clear and negative. That said, for now, we only have the summary; the full article will need to be read.

Genetic studies had indicated that high Lp(a) levels increase the risk of heart attack, so these results have come as a surprise to us all. Yet, this is not the first time such a scenario has unfolded in medicine.

In my view, there is a fundamental difference between being born with high Lp(a) levels—and living with them throughout one’s life—versus lowering those levels with a drug at age 60, by which point atherosclerotic plaques have already formed and arterial damage has already occurred. Genetics is often more useful for identifying paths to avoid than for charting a clear course forward.

What, then, should we do? Measuring Lp(a) once in a lifetime remains useful, as it helps identify those at higher risk. For these individuals, the goal should be to lower their LDL cholesterol even further—an approach we know to be effective. As for targeted treatments, the outlook is less promising, at least for patients who have already experienced a heart attack or stroke. Other drugs are currently being studied, including trials involving healthy individuals who are not taking statins and have higher cholesterol levels; the outcomes there might differ. If they do, those treatments would need to be compared directly against statins.

The study has several limitations. The patients had already experienced a cardiovascular event and were receiving good treatment, so these findings cannot be applied to young or healthy individuals. Five years may be too short a period for something that has an effect over an entire lifetime. The events recorded include some that are less severe, such as urgent catheterizations. We also do not know how many patients stopped receiving the monthly injection. Furthermore, it is unclear whether the drug might be effective for aortic stenosis, another condition linked to Lp(a). On the positive side, the medication appears to be safe: there were actually slightly fewer serious adverse events than with the placebo.

This is a high-quality study that marks a milestone in the approach to treating lipoprotein(a), or Lp(a). The results are disappointing, but that is the nature of science.

The study meets the highest quality standards: it examines a biological alteration—elevated Lp(a)—plausibly linked to a specific outcome (the development of cardiovascular complications) and attempts to reverse it through a targeted mechanism: suppressing Lp(a) synthesis using an antisense oligonucleotide. The goal was to determine whether this intervention provides a protective effect. The study was designed based on a plausible estimate of the potential protective effect and the expected reduction in cardiovascular complications.

In short: an optimal study design with a surprisingly negative—or rather, null—result. Reducing this putative risk factor by 80% provides NO protective benefit.

While the study does not negate the epidemiological significance of Lp(a), it casts doubt on its causal role—or, at the very least, on our ability to improve patient outcomes by targeting it. Screening remains useful, but the question of how to treat it effectively remains unresolved.

This is how science progresses: plausible hypotheses are formulated and then subjected to experimental scrutiny. A well-developed, plausible hypothesis is not enough; it must be tested against reality. The answer is clear: in this specific population, this intervention offers no benefit—not even a hint of one.

This does not in any way invalidate the predictive value of elevated lipoprotein(a) for estimating vascular risk; it remains a useful indicator. However, it raises serious questions as to whether Lp(a) is a causal factor, or merely a marker—an epiphenomenon. Similarly, we know that CRP [C-reactive protein] is a risk marker, but not a causal agent (Mendelian randomization studies indicate that elevated CRP, in and of itself, does not cause atherosclerosis); however, this does not preclude its use as a marker. A similar point can be made regarding HDL cholesterol: in general, low HDL is a marker for vascular risk (HDL is included, either directly or indirectly, in vascular risk calculators), yet its genetic variants do not imply an etiological role, and it is not currently a therapeutic target (treatments aimed at increasing HDL cholesterol have failed).

[Regarding potential limitations,] I believe that patients with only modestly elevated Lp(a) levels were permitted to enroll, which may have resulted in a modest effect. It is estimated that the benefit for cardiovascular prevention—achieved by reducing Lp(a) by 100 mg/dL (an impossible feat if the baseline Lp(a) is < 100 mg/dL)—would be equivalent to the benefit gained from a 40 mg/dL reduction in LDL cholesterol (which is much easier to achieve).

It is very easy to offer criticism in hindsight when a treatment has failed. One might question the suitability of the study population: the trial included patients with advanced disease—who are at higher risk, meaning events may occur sooner, but whose existing lesions are also harder to reverse—as well as patients with only moderately elevated Lp(a) levels (perhaps due to a desire to secure a broad clinical indication for such moderate elevations). Nevertheless, the fact that the hazard ratio (HR)—a measure of relative risk—is essentially 1.0 raises significant concerns. This is not merely a case of the study lacking sufficient statistical power; rather, a relative risk of nearly 1.0 effectively dooms the development of this drug for this specific indication. This result makes it even more necessary to conduct studies in other populations using siRNAs [a different type of drug] that achieve an Lp(a) reduction of > 95% in high-risk individuals who do not yet have established clinical cardiovascular disease.

Lipoprotein(a), or Lp(a), is a particle that circulates in the blood—similar to LDL cholesterol—with levels determined primarily by genetics. For years, it has been known that individuals with high concentrations face an increased risk of cardiovascular disease, such as myocardial infarction (heart attack) or stroke, even when their cholesterol levels are well-controlled. Consequently, there were high expectations surrounding new treatments capable of lowering it.

The Lp(a)HORIZON study is a high-quality clinical trial involving more than 8,300 patients, with a follow-up period of nearly five years. Its results, however, are somewhat disappointing. Although pelacarsen succeeded in reducing Lp(a) levels by approximately 73%, this reduction did not translate into a decrease in cardiovascular events. The cardiovascular complications studied occurred with virtually the same frequency in treated patients as in those who received a placebo. This finding is significant because it serves as a reminder that lowering a risk marker in a blood test does not necessarily equate to reducing the risk of developing a disease. It encourages us to consider a comprehensive approach that addresses all vascular risk factors.

Nevertheless—and this is an important point—the study does not call into question the evidence linking Lp(a) to cardiovascular risk, nor does it suggest that we should stop measuring it. Knowing a patient’s Lp(a) levels remains useful for identifying those at higher risk and for strengthening the management of other factors, particularly LDL cholesterol.

One limitation is that the trial was conducted on patients who already had cardiovascular disease; therefore, the results cannot be directly extrapolated to healthy individuals with elevated Lp(a). Furthermore, it is possible that other treatments, mechanisms, or earlier intervention strategies could yield different outcomes.

Ultimately, while this represents a significant setback for the expectations placed on pelacarsen, it does not necessarily mark the end of strategies targeting Lp(a). What is clear is that any new treatment must demonstrate that, in addition to reducing these levels, it truly improves the patients' prognosis.

This is an important study—the first large-scale trial designed to evaluate the effect of treatments aimed at reducing Lp(a), a lipoprotein for which elevated levels are linked to an increased risk of cardiovascular disease.

Unfortunately, despite a significant reduction in Lp(a) levels among patients who received pelacarsen, the incidence of cardiovascular events was similar between the treated and untreated groups after nearly five years of follow-up.

It is worth noting that this lack of benefit was observed in a population with a history of cardiovascular events—the very profile that would seem most likely to benefit from the drug.

The takeaway is that further research is needed, and we cannot recommend this treatment.

Lipoprotein(a) [Lp(a)] is known to be a significant risk factor for cardiovascular disease—comparable, in effect, to LDL cholesterol ("bad" cholesterol). There is no established "normal" value; the higher the blood levels, the greater the risk, although many laboratories set a desirable threshold at < 125 nmol/L (or 50 mg/dL).

Currently, no specific treatment aimed at lowering Lp(a) levels has demonstrated a clear clinical benefit—defined in clinical trials as a reduction in cardiovascular mortality, heart attack, or stroke.

The Lp(a) HORIZON study was designed to determine whether pelacarsen—a drug effective at lowering Lp(a) levels—could reduce the incidence of cardiovascular complications in patients already diagnosed with cardiovascular disease.

Contrary to expectations, the study yielded a neutral result; no significant difference was observed in cardiovascular mortality, heart attack, or stroke between patients who received the active drug and those who received a placebo.

The study is considered to be of the highest quality, designed by experts with extensive experience in conducting such clinical trials. It involved more than 8,000 patients, with a follow-up period of 4.7 years.

Because the study results did not meet expectations, the drug will not be approved for clinical use, due to a lack of proven efficacy. Nevertheless, the hypothesis that lowering Lp(a) levels could be beneficial remains. A well-designed study can yield negative results for various reasons, such as the criteria used for patient selection or the dosage of the drug. One potential shortcoming may have been the inclusion of patients with relatively low Lp(a) levels; such individuals naturally face a lower risk, making it more difficult to demonstrate a clinical benefit.

It is worth noting that, at present, the risk faced by individuals with cardiovascular disease has been progressively reduced thanks to modern treatment approaches. In the Lp(a)Horizon study, the annual incidence of the composite endpoint—cardiovascular mortality, heart attack, or stroke—was approximately 2.5% per year, a figure that is very difficult to improve upon with new treatments.

The positive contribution of this study lies in its meticulous data analysis, which helps identify the patients most likely to benefit—a finding that will need to be validated in a subsequent study.

High blood cholesterol is associated with an increased presence of atherosclerotic plaques in our arteries, particularly in the heart and brain. When these plaques rupture, a thrombus (blood clot) forms, blocking blood flow and triggering a heart attack. However, we know that total cholesterol consists of both "good," artery-protective particles—known as HDL—and "bad" particles—known as LDL—which not only promote the formation of plaques but also contribute to their rupture. Furthermore, numerous studies have shown that lowering LDL cholesterol levels—through lifestyle changes and medications such as statins—leads to a dramatic reduction in heart attacks.

Research has identified a lipoprotein known as lipoprotein(a), or Lp(a), which is structurally very similar to LDL particles. Individuals with higher levels of Lp(a) experience a greater number of heart attacks. Consequently, it has been recommended that everyone have their Lp(a) levels measured at least once in their lifetime. These levels are not influenced by diet or lifestyle; rather, they are genetically determined—we inherit them. It therefore seemed logical to assume that reducing Lp(a) levels would decrease cardiovascular complications, much as lowering "bad" LDL cholesterol has been shown to do.

However, this has not proven to be the case. The Lp(a)HORIZON study, which involved approximately 8,300 patients with established cardiovascular disease and elevated Lp(a) levels, yielded a negative result:

While the drug pelacarsen did successfully reduce Lp(a) levels, it failed to demonstrate a reduction in the incidence of heart attacks or strokes. A similar scenario occurred previously—though in the opposite direction—with "good" HDL cholesterol: while higher levels are generally considered beneficial, increasing them through medication did not improve patient outcomes.

Why, then, was a medication that effectively lowers Lp(a) not clinically efficacious in the studied population? At the moment, we do not know for sure, but one proposed explanation is that when Lp(a) levels are reduced later in life, the damage to the arteries has already occurred, which is why the expected benefits are not clearly observed. This aligns well with the concept that the prevention of atherosclerosis should begin much earlier—ideally, as early as childhood.

However, there remains the possibility that this lipoprotein is not as significant a driver of vascular damage as we have previously believed. Regardless, I do believe it is advisable to have one’s Lp(a) levels measured at least once in a lifetime. For individuals with elevated levels—much like those with a family history of cardiovascular disease or high cholesterol—such testing can help raise awareness that effective medications are now available, which can significantly improve both the length and quality of their lives. Ultimately, it is crucial to remember that the majority of our health depends on us and the lifestyle we choose to lead—and this is not something we can afford to put off until we are older.