Update in “The Sticky Cholesterol”: Lipoprotein(a) AKA Lp(a), Bob Harper, and Your Risk of Disease

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If lipoprotein(a) was a stock, it would be time to invest. The interest is growing and growing.

The cynic would say that this is because an agent is in trials and the money for pharmacological therapy of this “sticky cholesterol”, also known as L(a), pronounced LP little a, will be flowing soon. The kind hearted would say that it is just the normal evolution of medical knowledge. I have written before about the high-profile health issues of one of the Biggest Loser trainers, Bob Harper, and how he has raised awareness about this common lipid disorder driven more by genetics than lifestyle. I have also written about how Lp(a) can cause coronary artery disease (CAD) and calcific aortic valvular disease (CAVD), why it isimportant to measure Lp(a), how it can predict heart disease, and how it helped Bob Harper to recover from his heart attack. What have we learned about Lp(a) recently? I am including mainly articles that have access to the full publication for free so you can study them in detail.

1) How much do you need to lower Lp(a) to protect your health

A recent analysis using genetic predictive tools as published but is not available easily in its full form unless you register. Nonetheless, it is instructive.

A genome-wide association study (GWAS) and meta-analysis on Lp(a) published in 2017 of 5 different primarily population-based studies of European ancestry were used to estimate how much lp(a) might need to be lowered to reduce heart events. . The study included 13,781 individuals from the Lp(a)-GWAS-Consortium from 5 primarily population-based studies and 20 793 CHD cases and 27 540 controls from a subsample of the CHD Exome+ consortium. It was estimated that the required reduction in Lp(a) effect size would be 66 mg/dl to reach the same potential effect on clinical outcomes that can be reached by lowering LDL-C by 38.67 mg/dL. It was concluded that calculations of the required Lp(a)-lowering potential of a drug to be clinically effective might have been overestimated in the past.

2) The Predictive Role of Lp(a) with a normal LDL cholesterol

A hospital-based observational study including 558 patients with a heart attack (AMI) and 1959 controls was conducted. Lp(a) level was significantly higher in AMI patients with normal LDL-C levels than that in non-CAD group (134.5 mg/l vs 108 mg/l, P<0.001). According to Lp(a) quartiles, the incidence of AMI increased with the elevated Lp(a) quartiles. The present large-scale study revealed that elevated Lp(a) levels were associated with increased AMI risk in Chinese population with normal LDL-C levels.

3) Lp(a) lowering with PCSK9 Inhibitors

PCSK9 inhibitors are a relatively new class of injectable antibodies approved for the lowering of LDL cholesterol in patients intolerant or unresponsive to other therapies. They also lower Lp(a). Data were analyzed from 4 randomized, 12-week, multicenter, phase 3 trials with the PCSK9 inhibitor evolocumab. Patients with familial hypercholesterolemia, nonfamilial hypercholesterolemia, or statin intolerance participated in the trials. The study cohort comprised 895 patients. The baseline mean level of LDL -C was 133.6 mg/dL. A discordant response was observed in 165 (19.7%) patients meaning that both LDL-C and Lp(a) were not reduced simultaneously. The authors concluded that the data demonstrated a high prevalence of discordance in LDL -C and Lp(a) reduction in response to evolocumab. They felt that this indicated the possibility of alternative pathways beyond LDL receptor mediated clearance involved in Lp(a) reduction by evolocumab.

4) Does Zetia (Ezitimibe) Lower Lp(a)

Ezitimibe is a popular non-statin agent to lower LDL cholesterol that works but inhibiting absorption of cholesterol in the intestine. A study evaluated randomized placebo-controlled trials investigating the impact of ezetimibe treatment on cholesterol lowering that include lipoprotein(a) measurement. A random-effects model and generic inverse variance method were used. The meta-analysis of data from 10 randomized placebo-controlled clinical trials (15 treatment arms) involving a total of 5188 (3020 ezetimibe and 2168 control). The data showed that ezetimibe therapy had no effect on altering plasma Lp(a) concentrations. In the subgroup analysis, no significant alteration in plasma Lp(a) levels was observed either in trials assessing the impact of monotherapy with ezetimibe versus placebo or in trials evaluating the impact of adding ezetimibe to a statin versus statin therapy alone. The results of the meta-analysis suggest that ezetimibe treatment either alone or in combination with a statin does not affect plasma Lp(a) levels.

5) Phase 2 Trial of a Therapy to Lower Lp(a)

There is currently no agent approved in the US for the lowering of Lp(a). At the November meeting of the American Heart Association, a phase 2 trial of a new agent was presented. The phase 2 clinical study was a randomized, double-blind, placebo-controlled, dose-ranging study of 286 patients with CVD and high Lp(a) (mean baseline levels, 100 mg/dL), meant to test the safety and tolerability of AKCEA-APO(a)-LRX while informing dose and dose frequency selection for the phase 3 CV outcomes study, according to the release. Patients were treated for 6 months to 1 year.

The efficacy finding showed dose-dependent reductions of Lp(a) compared with placebo at all dose levels, including low monthly doses of AKCEA-APO(a)-LRX, with most patients in the active group achieving Lp(a) reductions below the threshold of risk for CVD events. The safety finding showed that adverse effects were similar between the active and placebo groups with the most common adverse event being an injection site reaction.

We have much to learn about Lp(a) and its impact on CAD and CVAD. The studies presented here, recently shared in preliminary or full publication, give hope that in the next few years, the sticky cholesterol will measured routinely and will be amenable to safe therapeutic agents. In my advanced preventive heart clinic, I see many patients with elevated Lp(a) and consider all the current options. I welcome the availability of new and proven therapeutics including whole food plant diets proven to lower Lp(a). Hopefully stories like that I wrote about Bob Harper and others will be a thing of the past soon.

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