Four-Year Outcomes of Wegovy (Semaglutide 2.4mg) Cardiovascular Study - Part 1

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As you might imagine, I subscribe to a large number of medical publications and in the last couple of days I’ve been receiving updates from them falling all over themselves to breathlessly claim that weight loss was maintained for 4 years on Semaglutide 2.4mg (aka Wegovy) in the SELECT trial.

The ways in which these claims are misleading are egregious and anti-science are many. In part 1 I’ll look at the initial claims and the people making them, in part 2 I’ll do a deeper analysis of the study.

The study is “Long-term weight loss effects of semaglutide in ob*sity without diabetes in the SELECT trial” by Ryan et al, published in the Nature Medicine Journal.

Their abstract begins:

“In the SELECT cardiovascular outcomes trial, semaglutide showed a 20% reduction in major adverse cardiovascular events in 17,604 adults with preexisting cardiovascular disease, overw*ight or ob*sity, without diabetes.”

Already the veracity of the claims in this study is pulled into serious question. First of all, 17,604 is the TOTAL number of original participants of which 8,782 were in the placebo group, not the group that experienced a the semaglutide treatment effect. Next, 20% is the relative risk reduction (which gives information only about the relationship between the two trial groups) the absolute risk reduction, which gives information about applicability outside the trial group, was only 1.5% (8% of people in the non-treatment group vs 6.5% of people in the treatment group experienced one of the major adverse cardiac events the trial tracked.)

It seems to me that we are either to believe that these authors are unaware of an extremely basic statistics principle that is taught in high school statistics classes, or they are being purposefully misleading in their writing. If you (or, hey, these authors, want to learn more about relative vs absolute risk I have an explanation here.)

But it’s actually even more misleading than that. Their claim that this trial was of “adults” is patently ridiculous. The trial only accepted people who were 45 and older, and the mean age was  61.6 +/- 8.9 (where 8.9 is the standard deviation) which means we can infer that two-thirds of subjects were between 54 and 71. Table S1 tells us that 76.7% were older than 55.

But wait, there’s more. 72.3% of the subjects were cisgender men (there was no trans or nonbinary representation) and 83.9% in the semaglutide group and 84.1% in the placebo group were white.

But wait, there’s more. As Deb Burgard pointed out, “in SA Figure S5, the hazard ratios are not significant for women, Black people, Hispanic people, people over 75, and - big one - fatter people.”

So, let’s re-write their opening paragraph to be..what’s the word…oh, yeah:  Accurate.

In the SELECT cardiovascular outcomes trial, semaglutide showed a 1.5% reduction in major adverse cardiovascular events in white, cis men older than 45 with an average age of 61.6 at the lower end of the overw*eight/ob*se BMI scale who had preexisting cardiovascular disease without diabetes.

There. That’s better.  I have a full analysis of the SELECT cardiovascular trial here.

We’ll get to the rest of the claims, but for now, let’s look at who is making them. Before I get into author disclosures (the inadequacies of which I wrote about here,) I want to point out a couple of things.

First, I’m only including their direct affiliations with, and the payments they’ve taken from, Novo Nordisk. Many of these authors have relationships with, and take (in some cases enormous,) payments from companies that either re-sell these medications, and/or develop/sell similar medications, and/or are trying to create cottage industries around them which creates an even greater conflict of interest. For funsies I’ve copied their entire disclosure statement at the end of this piece.

Second, only US-based physicians are listed on the openpayments database which only contains information from 2015-2022 currently. Given the huge ramp-up of marketing of these drugs that Novo has been doing, it's very possible that significant additional payments were made between 2022 and now that are not yet included in the database. Further, authors who aren’t US-based physicians may have taken payments that would not appear in openpayments.

Finally, the authors whose names are in bold are also listed authors for the original SELECT Trial. I’ve included their original disclosure and the information I discovered on openpayments when I wrote about that trial, as well as their disclosure for this study. The authors not in bold were not listed authors in the original trial and so I have included their disclosure from this study as well as any openpayments data I found.

Let’s dig in:

Donna H. Ryan

Original Disclosure: Consultant to Novo Nordisk AS “since 2012,” advisor and speaker (non-cme) for Novo Nordisk, Inc since 2012.
Open payments: $703,672.48 in general payments, $34,568.25 in research payments

This study: D.H.R. declares having received consulting honoraria from Novo Nordisk

Ildiko Lingvay

Original Disclosure: Consultant, presents research and attends advisory board meetings around the world
Open Payments: $196,422.32 in General payments, $82,115.58 in research payments, $5,388,978.67 in associated research funding

This study: I.L. declares having received research funding (paid to institution) from Novo Nordisk. I.L. received advisory/consulting fees and/or other support from Novo Nordisk.

John Deanfield

Original Disclosure: Received CME honoraria and/or consulting fees from Novo Nordisk.

This study: J.D. declares having received consulting honoraria from Novo Nordisk.

Steven E. Kahn

Original Disclosure: Novo Nordisk “Scientific Advisory Board and Study Steering Committee”
Open Payments: $63,996.32 general payments, $11,500 in research payments, $155,219.46 Associated Research Funding

This study: S.E.K. declares having received consulting honoraria from Novo Nordisk

Eric Barros:

Novo Nordisk A/S employee

Bartolome Burguera:

B.B. declares having received honoraria related to participation on this trial and has no financial conflicts related to this publication.

Open Payments: $56,470.72 in general payments, $6685 in research payments, $3,190,749.34 in associated research payments

Helen M. Colhoun

Original Disclosure: Novo Nordisk advisory board and speaker’s bureau

This study: H.M.C. declares serving on an advisory board and speaker’s bureau for Novo Nordisk

Cintia Cercato

C.C. declares having received consulting honoraria from Novo Nordisk

Dror Dicker

D.D. declares having received consulting honoraria from Novo Nordisk and received research grants through his affiliation from Novo Nordisk

Deborah B. Horn

D.B.H. declares having received research grants through her academic affiliation from Novo Nordisk and advisory/consulting honoraria from Novo Nordisk

Open payments: $596,830.21 in direct payments, $27,350.38 in research payments

G. Kees Hovingh

Original Disclosure: is an employee of Novo Nordisk (“Senior Medical Officer,”) and owns stock in Novo Nordisk

This study: Novo Nordisk A/S employee

Ole Kleist Jeppesen:

Novo Nordisk A/S employee

Alexander Kokkinos:

A.K. declares having received research grants through his affiliation from Novo Nordisk and consulting honoraria from Novo Nordisk

A. Michael Lincoff           

Original Disclosure: Novo Nordisk “consultant”
Open Payments: $179,905.97 in general payments, $19,377.09 in research payments

This study: A.M.L. declares having received honoraria from Novo Nordisk for consulting activities

Sebastian M. Meyhöfer:

 S.M.M. declares having received consulting honoraria from Novo Nordisk; he declares he received research grants from Novo Nordisk.

Tugce Kalayci Oral

Original Disclosure: employee of Novo Nordisk (“ Associate Global Medical Director”) with stock options

This study: Novo Nordisk A/S employee

Jorge Plutzky

Original Disclosure: Novo Nordisk “consultant”
Open payments: $287,015.48 in general payments, $21,165.72 in research payments

This study: J.P. declares having received consulting honoraria from Novo Nordisk

André P. van Beek

A.P.v.B. is contracted via the University of Groningen (no personal payment) to undertake consultancy for Novo Nordisk

John P. H. Wilding

J.P.H.W. is contracted via the University of Liverpool (no personal payment) to undertake consultancy for Novo Nordisk. J.P.H.W. also declares personal honoraria/lecture fees from Novo Nordisk.

Robert F. Kushner

Original Disclosure: Novo Nordisk “consultant,” “Medical Advisory Board
Open Payments: $381,417.79 in general payments, $7,280 in research payments, $165,885.37 in associated research funding

This study: R.F.K. declares having received consulting honoraria from Novo Nordisk.

So every listed author has either taken money from, was contracted by, or is a direct employee of Novo Nordisk. Together, those who are listed in open payments have taken a group total of $11,576,646.15 (and again, that’s just from what the US-based physicians have taken directly from Novo Nordisk.)

They also thanked their peer reviewers so I took a look.

Christiana Kartsonaki appears to have co-authored a study that was partially supported by the Novo Nordisk Foundation

I found a Peter Rossing who has received consultancy and/or speaking fees (to institution) from Novo Nordisk, research grants from Novo Nordisk, and owns shares in Novo Nordisk and has his own page on the Novo Nordisk Foundation page

Vikas Sridhar as of 2021 was a Banting and Best Postdoctoral Fellow  I do not know if it was one of the Banting and Best postdoctoral fellowships funded by Novo Nordisk.

Now, it’s possible that these are different people with the same name, and even if all of these connections were confirmed, none of them would mean that these peer reviewers are necessarily biased (though, nature medicine does have information on competing interests here that would make it seem questionable.) In truth, this could also just be a testament to the sheer amount of money Novo is throwing around.

Still, given that the introductory sentence of the abstract of this peer-reviewed study sounds a lot like someone asked ChatGPT to do their statistics homework, I think these are questions worth asking.

Believe it or not, this actually gets worse, but we’ll get into that in part 2.

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BONUS:

Here is the full list of competing interests:

D.H.R. declares having received consulting honoraria from Altimmune, Amgen, Biohaven, Boehringer Ingelheim, Calibrate, Carmot Therapeutics, CinRx, Eli Lilly, Epitomee, Gila Therapeutics, IFA Celtics, Novo Nordisk, Pfizer, Rhythm, Scientific Intake, Wondr Health and Zealand Pharma; she declares she received stock options from Calibrate, Epitomee, Scientific Intake and Xeno Bioscience. I.L. declares having received research funding (paid to institution) from Novo Nordisk, Sanofi, Mylan and Boehringer Ingelheim. I.L. received advisory/consulting fees and/or other support from Altimmune, AstraZeneca, Bayer, Biomea, Boehringer Ingelheim, Carmot Therapeutics, Cytoki Pharma, Eli Lilly, Intercept, Janssen/Johnson & Johnson, Mannkind, Mediflix, Merck, Metsera, Novo Nordisk, Pharmaventures, Pfizer, Regeneron, Sanofi, Shionogi, Structure Therapeutics, Target RWE, Terns Pharmaceuticals, The Comm Group, Valeritas, WebMD and Zealand Pharma. J.D. declares having received consulting honoraria from Amgen, Boehringer Ingelheim, Merck, Pfizer, Aegerion, Novartis, Sanofi, Takeda, Novo Nordisk and Bayer, and research grants from British Heart Foundation, MRC (UK), NIHR, PHE, MSD, Pfizer, Aegerion, Colgate and Roche. S.E.K. declares having received consulting honoraria from ANI Pharmaceuticals, Boehringer Ingelheim, Eli Lilly, Merck, Novo Nordisk and Oramed, and stock options from AltPep. B.B. declares having received honoraria related to participation on this trial and has no financial conflicts related to this publication. H.M.C. declares being a stockholder and serving on an advisory panel for Bayer; receiving research grants from Chief Scientist Office, Diabetes UK, European Commission, IQVIA, Juvenile Diabetes Research Foundation and Medical Research Council; serving on an advisory board and speaker’s bureau for Novo Nordisk; and holding stock in Roche Pharmaceuticals. C.C. declares having received consulting honoraria from Novo Nordisk, Eli Lilly, Merck, Brace Pharma and Eurofarma. D.D. declares having received consulting honoraria from Novo Nordisk, Eli Lilly, Boehringer Ingelheim and AstraZeneca, and received research grants through his affiliation from Novo Nordisk, Eli Lilly, Boehringer Ingelheim and Rhythm. D.B.H. declares having received research grants through her academic affiliation from Novo Nordisk and Eli Lilly, and advisory/consulting honoraria from Novo Nordisk, Eli Lilly and Gelesis. A.K. declares having received research grants through his affiliation from Novo Nordisk and Pharmaserve Lilly, and consulting honoraria from Pharmaserve Lilly, Sanofi-Aventis, Novo Nordisk, MSD, AstraZeneca, ELPEN Pharma, Boehringer Ingelheim, Galenica Pharma, Epsilon Health and WinMedica. A.M.L. declares having received honoraria from Novo Nordisk, Eli Lilly, Akebia Therapeutics, Ardelyx, Becton Dickinson, Endologix, FibroGen, GSK, Medtronic, Neovasc, Provention Bio, ReCor, BrainStorm Cell Therapeutics, Alnylam and Intarcia for consulting activities, and research funding to his institution from AbbVie, Esperion, AstraZeneca, CSL Behring, Novartis and Eli Lilly. S.M.M. declares having received consulting honoraria from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Daichii-Sankyo, esanum, Gilead, Ipsen, Eli Lilly, Novartis, Novo Nordisk, Sandoz and Sanofi; he declares he received research grants from AstraZeneca, Eli Lilly and Novo Nordisk. J.P. declares having received consulting honoraria from Altimmune, Amgen, Esperion, Merck, MJH Life Sciences, Novartis and Novo Nordisk; he has received a grant, paid to his institution, from Boehringer Ingelheim and holds the position of Director, Preventive Cardiology, at Brigham and Women’s Hospital. A.P.v.B. is contracted via the University of Groningen (no personal payment) to undertake consultancy for Novo Nordisk, Eli Lilly and Boehringer Ingelheim. J.P.H.W. is contracted via the University of Liverpool (no personal payment) to undertake consultancy for Altimmune, AstraZeneca, Boehringer Ingelheim, Cytoki, Eli Lilly, Napp, Novo Nordisk, Menarini, Pfizer, Rhythm Pharmaceuticals, Sanofi, Saniona, Tern Pharmaceuticals, Shionogi and Ysopia. J.P.H.W. also declares personal honoraria/lecture fees from AstraZeneca, Boehringer Ingelheim, Medscape, Napp, Menarini, Novo Nordisk and Rhythm. R.F.K. declares having received consulting honoraria from Novo Nordisk, Weight Watchers, Eli Lilly, Boehringer Ingelheim, Pfizer, Structure and Altimmune. E.B., G.K.H., O.K.J. and T.K.O. are employees of Novo Nordisk A/S.

*Note on language: I use “fat” as a neutral descriptor as used by the fat activist community, I use “ob*se” and “overw*ight” to acknowledge that these are terms that were created to medicalize and pathologize fat bodies, with roots in racism and specifically anti-Blackness. Please read Sabrina Strings’ Fearing the Black Body – the Racial Origins of Fat Phobia and Da’Shaun Harrison’s Belly of the Beast: The Politics of Anti-Fatness as Anti-Blackness for more on this.