How Lp(a) Levels Compare With LDL-C in FH: Some Surprises

Understanding how risks conferred by Lp(a) levels equate with familial hypercholesterolemia can help in patient conversations.

How Lp(a) Levels Compare With LDL-C in FH: Some Surprises

Just how high does lipoprotein(a) need to be before it confers the same type of risk observed in patients with elevated LDL-cholesterol levels?

The answer to that equivalency question was largely unknown until now, but a new study of patients with familial hypercholesterolemia (FH) suggests as low as 70 mg/dL may be problematic. Published November 10, 2022, in the Journal of the American College of Cardiology, the study is intended to put some perspective on the risk of MI and atherosclerotic cardiovascular disease (ASCVD) conferred by high levels of Lp(a), say investigators.

“Many people, including clinicians, have heard about familial hypercholesteremia,” senior researcher Børge Nordestgaard, MD, DMSc (University of Copenhagen, Denmark), told TCTMD.  The lifelong, elevated LDL-cholesterol levels seen in people with FH cause premature ASCVD, increase MI risk, and lower life expectancy.

Like FH, elevated Lp(a) is also genetically determined, he noted, but the degree of risk conferred, relative to elevated LDL-cholesterol levels, was unknown. “We wanted to simply see what is the equivalent risk with lipoprotein(a),” Nordestgaard explained. “If you have familial hypercholesterolemia, we can look at the risk of atherosclerotic cardiovascular disease, but we wanted to know: what level of lipoprotein(a) do you need to have in order to have a similar risk.”

Lp(a) is a hot new target for potentially preventing ASCVD, with several Lp(a)-lowering drugs in development based on a wealth of mendelian randomization and genetic epidemiology studies showing that high levels are associated with a higher risk of ASCVD. The 2019 guidelines from the European Society of Cardiology and European Atherosclerosis Society (ESC/EAS) recommend measuring Lp(a) at least once in an individual’s lifetime to identify those with very high levels, which is defined as more than 180 mg/dL (> 430 nmol/L). But knowing how risk levels compare for LDL and Lp(a) could aid clinical conversations, particularly since the prevalence of elevated of Lp(a) in the population is greater than that of FH, Nordestgaard noted.

In an accompanying editorial, Pamela Morris, MD (The University of South Carolina, Charleston), Jagat Narula, MD, PhD (Icahn School of Medicine at Mount Sinai, New York), and Sotirios Tsimikas, MD (University of California, San Diego), agree, noting that the analysis highlights the need to be aware of both lipid disorders. “For the first time,” they write, “the current study puts into clinical context Lp(a)-associated risk with that of clinically and genetically diagnosed FH.”

Risks Even at Lower Levels

Researchers led by Berit Storgaard Hedegaard, RN (Viborg Regional Hospital, Denmark), investigated the influence of elevated Lp(a) in three patient groups: those with clinical heterozygous FH—as defined by MEDPED, Simon Broome, or the Dutch Lipid Clinic Network (DLCN)—genetic FH, or a family history of premature MI risk on clinical outcomes. To do so, they turned to the Copenhagen General Population Study (CGPS), which included 69,744 participants with Lp(a) measurements and a clinical or genetic FH diagnosis. During a median follow-up of 42 years, 4,166 participants had an MI and 11,464 had an ASCVD event (MI, fatal coronary heart disease, or stroke).

For MI risk, a plasma Lp(a) of 67 mg/dL was equivalent to the risk conferred by FH when using the MEDPED criteria to make a diagnosis. A plasma Lp(a) concentration of 110 and 402 mg/dL for MI risk prediction was equivalent to a diagnosis of FH or probable/definite FH, respectively, when using the stricter Simon Broome and DLCN criteria. Lastly, if genetics were used to confirm FH, the MI risk would be equivalent to a plasma Lp(a) level of 180 mg/dL.

For predicting ASCVD, the plasma Lp(a) levels equivalent to a MEDPED-, Simon Broome-, or DLCN-based diagnosis of FH were 130, 150, and 391 mg/dL, respectively, while a Lp(a) level of 175 mg/dL corresponded to a genetic FH diagnosis when it came to risk of ASCVD.

“When you’re with a patient with a certain lipoprotein(a) level, you can say this is like, for you and your family, having familial hypercholesterolemia,” said Nordestgaard.

Individuals with the highest Lp(a), those with concentrations in the top 5% of the CGPS (93 to 425 mg/dL), had a more than twofold higher risk of MI and a 52% higher risk of ASCVD when compared with those with Lp(a) levels 10 mg/dL or lower. A diagnosis of FH also conferred an elevated risk of MI and ASCVD, with the highest risks seen with the DLCN-based criteria.

When you’re with a patient with a certain lipoprotein(a), you can say this is like, for you and your family, having familial hypercholesterolemia. Børge Nordestgaard

Researchers also looked at the combined impact of both genetic disorders. Overall, people with elevated levels of Lp(a) and FH had a higher risk of MI and ASCVD than individuals with either high Lp(a) or high LDL-cholesterol levels alone, although the magnitude of that difference varied according to which criteria were used to diagnose FH.

High Levels of Lp(a) Prevalent in Population

To TCTMD, Nordestgaard said that patients with premature ASCVD are often aware of FH and the risks associated with high levels of LDL cholesterol, but less are familiar with Lp(a). “In fact, Lp(a) is even more genetically determined than familial hypercholesterolemia, but [patients don’t] know much about it,” he said. With FH, there is a lifestyle component that can modify LDL-cholesterol levels, but Lp(a) levels are largely (80% to 90%) determined by our genes, said Nordestgaard.

While the ESC/EAS guidelines state that 180 mg/dL or higher identifies patients with elevated Lp(a) corresponding to FH, this analysis shows that even much lower levels are equivalent to a clinical FH diagnosis and associated with higher risks of MI and ASCVD. At 70 mg/dL, Nordestgaard suspects there are a lot of people with these levels, likely more than 20% of the population, which far exceeds the number of people with FH.

In their editorial, Morris, Narula, and Tsimikas make a similar point, noting that even at Lp(a) > 255 mg/dL, the dyslipidemia is still more prevalent than FH.

“Thus, the population-attributable risk of Lp(a) is likely substantially higher than FH, and it is it imperative that clinicians do not miss the opportunity to diagnose Lp(a)-mediated risk properly in their patients,” they write. “Because Lp(a) is transmitted in an autosomal codominant fashion, there is significant yield of ~50% in making a diagnosis in potentially affected first-degree relatives through cascade screening.”

There are several drugs in development targeting Lp(a), including pelacarsen (Ionis Pharmaceuticals/Novartis), which is currently moving along in the Lp(a)HORIZON cardiovascular outcomes trial. But for now, Nordestgaard said he believes that patients with elevated Lp(a) should be managed with lifestyle modification and good medical therapy, which includes lowering LDL-cholesterol levels as much as possible with high-dose statins, as well as treating other risk factors, like blood pressure and diabetes.

Michael O’Riordan is the Associate Managing Editor for TCTMD and a Senior Journalist. He completed his undergraduate degrees at Queen’s…

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  • Hedegaard report speaking fees from Sanofi, Amgen, and Novartis.
  • Nordestgaard reports consulting/speaking fees from AstraZeneca, Sanofi, Regeneron, Akcea, Amgen, Kowa, Denka, Amarin, Novartis, Novo Nordisk, Silence Therapeutics, Abbott, and Esperion.
  • Morris reports serving as local principal investigator for the CLEAR Outcomes trial (Esperion).
  • Tsimikas reports grant support from the National Heart, Lung, and Blood Institute and Leducq Foundation. He reports being a co-inventor and receiving royalties from patents owned by the University of California-San Diego (UCSD). He is a co-founder and has acquired equity interest in Oxitope and its affiliates Kleanthi Diagnostics, and Covicept Therapeutics. He has dual appointments at UCSD and Ionis Pharmaceuticals.