The contradiction in the 2018 update of the Merck Manual

The 2011 article spearheaded by Dr. Anne C. Goldberg was a pivotal moment.  Dr. Goldberg was the lead author in the declaration that the APOB and the PCSK9 mutations would thenceforward be included in the definition of “FH,” and by implication, would no longer be associated with the names “FDB” or “FH3.” Mention of the blending of names was dropped thereafter in pharma-funded publications. Today it almost appears as if this linguistic event never happened. Whatever reason there may have been for the conflation is refuted by Dr. Goldberg’s contributions to the 2018 Merck Manual update. FH prevalence is now 1:200 …. but FH is defined by the presence of the LDLR mutation alone. APOB and PCSK9 mutations are excluded from the definition. APOB and PCSK9 are listed immediately below … on separate rows, designating separate diseases. In short, the Merck Manual keeps the inflated math, while teasing the three names back out, linguistically, and listing the diseases and their causes separately again. Why do this?

How is this possible? This is the Merck Manual, not an “FH manual.” Not everyone visits this page to read about FH. Readers need to see all of the lipid diseases… separately. This presents a problem: either the prevalence of the LDLR must return to 1:500 or the APOB and PCSK9 mutations must be double counted. The lead author of the 2011 series and the expert who updated the 2018 Merck Manual are one and the same, Dr. Goldberg. We arrived at 1:200 largely by adding LDLR + APOB + PCSK9, but now LDLR alone is 1:200. It’s impossible; in an equation, LDLR = LDLR + APOB + PCSK9.

prevalence, Merck Manual, Familial hypercholesterolemia, LDLR, APOB, PCSK9

This conflation is also present from the 1st Danish report to the 2016 Regeneron report. We can use any of them for comparison. Let’s put Regeneron’s report next to the Merck Manual, 2018.

Regeneron, Merck Manual, Familial hypercholesterolemia, LDLR, APOB and PCSK, p.Arg3558Cys, FH prevalence
  • If there was any doubt as to whether the 2011 linguistic conflation took place in good faith, it is here refuted: in unpacking Dr. Goldberg’s earlier linguistic blending of terms, the underlying math should also have been unpacked.

A doctor must trust the experts … who are they? What’s the source for FH prevalence here? For diagnostic procedures? For treatments? The 1/200 number in the 2018 Merck Manual is most likely from the 2012 or 2016 Danish reports, led by Dr. Marianne Benn. The Merck Manual replied to my request for source material for the FH prevalence number in Dr Goldberg’s June 2018 Merck Manual article.

Merck Manual, FH prevalence, source material

Dr. Goldberg was the lead author in the 2011 Aegerion-sponsored publication that helped push the linguistic conflation into motion. Dr. Goldberg is even an author of a piece in the American Heart Association’s “Circulation” titled, “Knowing the Prevalence of Familial Hypercholesterolemia Matters.”[1] However, there are so many financial interests at work around FH issues and associated specifically with the original 2011 paper that it is difficult to tease out a clear line of influence. But Merck’s footprint is here along with the others. Merck Manual’s “Editorial Independence” is questionable.

Merck Manual, editorial independence

Although they eventually abandoned it, Merck had high hopes for anacetrapib as a treatment for FH, including the years 2011 through late 2017.

Anacetrapib

From the time of Goldberg’s 2011 article and through the years to the present, Merck and Merck’s investors have a financial interest in the prevalence of Familial Hypercholesterolemia. Products marketed in this space include Zetia, Zocor, and Vytorin.

Zetia, Zocor, Vytorin

[1] DOI: 10.1161/CIRCULATIONAHA.116.021673