番茄社区

This article is a collaboration between 番茄社区 and:

Reduction in lipoprotein(a) may have to pass a specified threshold in order to yield the same clinical benefits of coronary heart disease risk reduction as seen with lower LDL cholesterol levels, according to a Mendelian randomization analysis.

The association of genetically-predicted Lp(a) with coronary heart disease (CHD) risk tracked linearly with the actual difference in Lp(a) concentration, with each 10-mg/dL lower genetically-predicted Lp(a) tied to a 5.8% lower actual CHD risk (OR 0.942, 95% CI 0.933-0.951).

A drop of about 100 mg/dL would likely yield the clinical benefit of cutting LDL by about 39 mg/dL, Brian Ference, MD, MPhil, of the University of Cambridge, England, and colleagues reported in JAMA Cardiology.

That level of LDL reduction "has consistently been demonstrated to reduce the risk of cardiovascular events by approximately 20% in randomized trials," Ference explained to 番茄社区.

The association of Lp(a) and CHD appeared "independent of changes in LDL-C level owing to genetic variants that mimic the relationship of statins, PCSK9 inhibitors, and ezetimibe [Zetia] with CHD risk," his group added in the paper.

However, Christopher O'Donnell MD, MPH, of the VA Boston Healthcare System, cautioned against overinterpreting Mendelian randomization studies.

"For one thing, the Mendelian randomization study does not give us any estimates of the risks of LDL or lipoprotein(a) lowering, so you may have a drug that has the same level of Lp(a) or LDL lowering but it may confer very significant risks, and so Mendelian randomization studies can't really help us with risk benefit assessments," he commented in an interview with 番茄社区.

Ference said he was "surprised at the magnitude of the absolute reduction in Lp(a) that is needed to have the same effect on CHD risk as a 1 mmol/L change in LDL-C." But he suggested this is "largely an artifact of how Lp(a) and LDL-C are measured. When measured per particle, Lp(a) and LDL appear to have very similar effects on the risk of CHD per particle. This is also consistent with the fact that Lp(a) and LDL particles appear to have a very similar cumulative effect over time."

As to the implications for clinicians, he noted, "Lp(a) is an important causal risk factor for CHD, but only people with markedly elevated Lp(a) levels are likely to benefit from a Lp(a) lowering therapy ... the benefit of lowering Lp(a) will be determined by the absolute achieved reduction in Lp(a)."

Of note, by up to 30%, dependent on dose.

The analysis of participant-level data from five population-based prospective cohort and case control studies and study-level data from 48 more was used for external validation. The participant-level studies had 20,500 participants with CHD and about 27,500 controls. Summarized data included over 60,000 patients with CHD and more than 125,000 controls. The average age was 57.5; all were white.

In an accompanying editorial, O'Donnell identified the need for inclusion of more diverse patient populations in trials related to Lp(a) distribution. "As new trials are designed for novel Lp(a)-lowering therapies, a precision medicine focus is warranted on at-risk patient subsets, such as those in the high range of Lp(a) concentration," he explains.

Going forward, O'Donnell says, other "studies should also examine the potential benefits of Lp(a) lowering on the many atherosclerotic outcomes beyond CHD."