COMMENTARY

Harnessing Nature to Prevent CVD: Practice Takeaways, Part 2: Lp(a) and ApoA-1

Melissa Walton-Shirley, MD

Disclosures

March 21, 2017

 Lp(a) is one of those enigmatic entities in cardiology that we measure but don't know how to treat. Triglycerides have also been a bit of a mystery for me, too. I ask patients with high levels the standard question about alcohol intake, measure the thyroid-stimulating hormone (TSH) level, and do a glucose tolerance test (GTT) to assess for occult diabetes. In today's session, I learned a pearl or two about triglycerides and revisited an odd HDL mutation as well.

The Enigmatic Particle—New Frontiers in Lp(a)

Nothing much has lowered Lp(a) in the past two decades. Dr Boerge G Nordestgaard (Copenhagen University Hospital, Denmark) described possible mechanisms of disease from Lp(a), including thrombosis through fibrinolysis inhibition, atherosclerosis through LDL deposition, and MI as well as aortic-valve calcification leading to valvular stenosis and heart failure. He then explained that not all the effects of Lp(a) are detrimental since it also confers a protective effect from bleeding and can promote wound healing.

What About Evolocumab's Impact on Lp(a)?  A pooled analysis of 1300 patient in phase 2 trials treated for 12 weeks with evolocumab[1]showed a 29.5% and a 24.5% reduction in Lp(a) with the twice-monthly 140-mg dose and once-monthly 420-mg dose, respectively, with no plateau of effect. I did not hear it mentioned in the presentation for FOURIER, but there is a table in the  supplementary materials of the New England Journal of Medicine paper showing a median 26.9% reduction in Lp(a) in the evolocumab group.

The most salient point made in Dr Nordestgaard's presentation, however, was from a prospective cohort study illustrating the importance of genetic testing in patients with significant Lp(a) elevation.[2] The presence of familial hyperlipidemia (FH) markedly increased the risk of MI with age, especially if Lp(a) levels were greater than 50 mg/dL. Again, this study validates the need for genetic testing in these patients so that appropriate surveillance can be undertaken.

Genetic Insights Into Triglyceride Related Risk and Treatment

Dr Daniel Gaudet (University of Montreal, Quebec) gave a talk that included the most relevant point of the day on lipids and prevention: "The expression of several triglyceride genes is conditionally influenced by BMI." I tweeted that this is why doctors harp on weight so much. He also pointed out that the risk of high triglycerides is not linear across all plasma concentrations and is not limited to CHD (think pancreatitis when levels are above 1000 mg/dL).  He also stated that a postprandial triglyceride level is often more helpful than a fasting level.

HDL: Causal Confounding or Confusing?

Dr John Kastelein (University of Amsterdam, the Netherlands) discussed the Italian apolipoprotein A-1 (apoA-1) Milano carriers discovered in 1979 who are apparently long-living. They have a rare R173 mutation in apoA-1, resulting in an HDL/apoA-1 deficiency with mild hypertriglyceridemia and yet a paradoxical resistance to heart disease. He flashed a slide from a 2003 study[3] showing that infusions of apoA-1 Milano regressed atheroma (a 4.2% change from baseline volume) as measured by intravascular ultrasound. Statins could not compete with the effect of apoA-1 Milano.  More recent data were not so optimistic, and the Medicines Company discontinued development of MDCO-216, but there are wild-type apoA-1 products in development that differ in structure and function from apoA-1 Milano. I'll keep an open mind.

Having spent my morning listening to some of the greatest minds in lipidology, I am now tasked with taking some of their knowledge into my exam room. I hope you can carry some of it into yours.

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