The Semaglutide (Wegovy) Cardiovascular Outcome Trial - Part 1

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Wegovy is the weight-loss application for the drug Samglutide (Ozempic is the Type 2 Diabetes application of the same drug) which is owned by Novo Nordisk.

You may remember when Novo Nordisk put out a “company announcement” about this study (before the study was peer-reviewed or published). That company announcement contained staggeringly misleading claims which were (and still are) repeated by the press. One number that wasn’t overstated was that this stunt boosted Novo’s stock prices 17% in a single day. I wrote about that here.

Today, as promised, I’m writing about the actual trial.

Let’s start where we always do, with who was behind this trial and the ways in which they are involved with Novo Nordisk. Given the combination of misleading conclusions and frank misinformation that Novo is comfortable putting out into the world, I think it’s important to contextualize the study methods and conclusions with information about who designed and created them. It may also be helpful to know that they are using these additional outcomes as part of their full-court press for insurance coverage.

Per the study appendix, the trial was designed by Novo Nordisk (again, the manufacturer of the drug) and an “academic steering committee” (who are also the listed authors.) Novo Nordisk “maintained the clinical database and performed the statistical analyses.” In the supplement they point out that “The sponsor reviewed the manuscript and provided suggested revisions, but the final decision on content was reserved for the academic authors with no restrictions on the right to publish. All authors approved the final submission. The first and last authors vouch for the completeness and accuracy of the data and all analyses and the fidelity to the trial protocol and statistical analysis plan”

Let’s look at the academic steering committee/authors. I’m going to include the author disclosures from the study as well as the amount of money they’ve taken from Novo Nordisk from 2015-2022 per openpaymentsdata.cms.gov.

A couple of things to note:

First, I’ve only listed their direct affiliations with, and the payments they’ve taken from, Novo Nordisk. It’s worth mentioning that many of these authors have relationships with, and take sometimes massive payments from, companies that re-sell these medications, companies that are developing similar medications, and companies that are trying to create cottage industries around them (like smoothies for those who take this class of drug.) This, of course, creates an even greater conflict of interest.

Second, only physicians are listed on the openpayments database, and the database currently contains information from 2015-2022. Given the massive ramp-up of marketing these drugs that Novo has been doing, there may well be significant additional payments made between 2022 and now that are not yet included on openpayments and those who aren’t physicians may have taken payments, even though they don’t appear in the openpayments database.

You can find the full disclosures here: https://www.nejm.org/doi/suppl/10.1056/NEJMoa2307563/suppl_file/nejmoa2307563_disclosures.pdf

A. Michael Lincoff  (lead author)
Disclosure: Novo Nordisk “consultant”
Open Payments: $179,905.97 in general payments, $19,377.09 in research payments

Kirstine Brown-Frandsen

Disclosure: employee of Novo Nordisk (“Corporate Vice President,”) owns stock in Novo Nordisk

Helen Colhoun

Disclosure: Novo Nordisk advisory board and speaker’s bureau

John Deanfield

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

Scott Emerson

Disclosure: Novo Nordisk Consultant

Sille Esbjerg

Disclosure: employee of Novo Nordisk (“Principal statistician,”) owns stock in Novo Nordisk

Søren Hardt-Lindberg

Disclosure: employee of Novo Nordisk (“Project Vice President,”) owns stock in Novo Nordisk

G. Kees Hovingh

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

Steven Kahn

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

Robert Kushner

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

Ildiko Lingvay

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

Tugce Kalayci Oral

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

Marie Michelsen

Disclosure: Employee of Novo Nordisk “Senior Director”, owns stock n Novo Nordisk

Jorge Plutzky

Disclosure: Novo Nordisk “consultant”

Open payments: $287,015.48 in general payments, $21,165.72 in research payments,

Christoffer Tornøe

Disclosure: Novo Nordisk Employee “Corporate Project Vice President” owns shares, holds stock options

Donna Ryan

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

So the trial was designed by Novo Nordisk and an “academic steering committee” who took a collective total of, at minimum, $7,543,300.96 from Novo Nordisk (and those are the just those who are physicians and who aren’t directly employed by Novo Nordisk.)

Every single one of the listed authors has significant conflicts of interest (which is to say that favorable findings in this trial can benefit them financially.) The supplement points out that “The first and last authors vouch for the completeness and accuracy of the data and all analyses and the fidelity to the trial protocol and statistical analysis plan.” The first and last author are also deeply financially intertwined with the trial sponsor.

As always, this isn’t to say that these people are necessarily putting out bad research for money, it could also be about paradigm entrenchment.

Now, let’stake a look at the trial basics:

The trial was undertaken to see if taking Semaglutide reduced death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke (taken as a composite these are known as the primary cardiovascular end point.)

A total of 17,604 patients were enrolled with 8803 given the drug, and 8801 given a placebo. The average time on the drug or placebo was 34.2±13.7 months (though the first 16 weeks represent the minimum ramp-up time to the 2.4mg dose,) and the average follow-up was 39.8±9.4 months.

Per the study, 6.5% of patients who took semaglutide experienced death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke while 8% of the group taking the placebo did. This is where we start to see why they put out the “company announcement” before they put out the study. It’s much more difficult to claim a “20% reduction” when the actual numbers (6.5% vs 8%) are staring you in the face. (If you want a statistics refresher to see how they pulled 20% out of a 1.5% hat, check out the section on relative vs. absolute risk here.)

Also of note, a little more than twice as many participants in the semaglutide group (16.6%) dropped out due to adverse events than in the placebo group (8.2%) and, per the supplemental information, “Treatment discontinuations that occurred less than 30 days before the end-of-treatment visit were not counted.”

Those are the basics, in part 2 we’ll dig deeper into the study participants, outcomes, and what isn’t there.

If you want to learn more about the GLP-1 Agonist drugs, I have an online workshop coming on April 17th (with a recording if you can’t make it live) called: Beyond the Hype: Understanding the Research On The New GLP-1 Agonist Weight Loss Drugs. There is a pay-what-you-can-afford option and an unlimited Q&A. You can find the details and registration here!

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More research and resources:
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*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.