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

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.