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This post has reached the “Post too long for email” bandwidth, so please continue reading the article on the Substack website or app if it is unavailable through email.

Also, note that several of the links were found through Petersen’s article in the LA Times. This helped to find some of the available information on ARIA which I appreciate.

Readers who have read my prior postings on Alzheimer’s immunotherapies should be privy to the acronym “ARIA”, short for Amyloid Related Imaging Abnormalities. ARIA is a possible side effect of these immunotherapies seeing rapid approval by the FDA and is broadly categorized into two groups based upon imaging findings related to brain swelling (ARIA-E for “edema”) and ones related to brain microbleeds (ARIA-H for “hemorrhage”).

Now, in my typical ignorant fashion I realized that the word “aria” sounded familiar but didn’t think much of it.

Of course, more cultured readers would be aware that aria refers to a piece in opera usually involving a single voice. It’s a word that usually signals a beautiful, expressive piece of art.

A collection of some ARIA I randomly found on YouTube as some examples:

So, it would be rather shocking to associate such a word with something as terrible as brain bleeds or brain swelling.

That is, unless one is trying to obscure side effects of a drug through conflation…

A few months ago, an article published in the Los Angeles Times caught my attention for raising this concern.

The author of this piece Melody Petersen (an ironic name tbh) notes an incident in which an elderly woman named Genevieve Lane died from a seizure days after her third dose of the immunotherapy Leqembi:

Infusions of the drug gave her headaches so severe they sent her to bed. A week after the third dose, she was at a restaurant with her best friend when her speech slurred and she had a seizure. Five days later she was dead.

Seemingly unknown to Lane and those around her was the risk of developing ARIA while taking Leqembi, and it’s likely this lack of knowledge that caused many of the signs of ARIA development to have been missed, leading to the unfortunate passing of Lane:

“Mom believed the drug would help slow progression of her memory problems or do nothing,” said Lane’s daughter, Yvonne Battaglia. “She didn’t know it might kill her.”

Those who have been keeping up with the Alzheimer’s immunotherapy debacle should recognize how much obfuscation is occurring with respect to these side effects. It’s not difficult to find comments that would simultaneously warn of serious complications on these medications that are also paired with the idea that these events of ARIA are “transient” or “resolve without issues”.

A brochure produced by the pharmaceutical company Eisai, the developers of Leqembi, even downplays these concerning side effects:

Things can be “usually asymptomatic” … until the one time that it isn’t… Unfortunately for Lane she seems to have been one of those instances in which her ARIA was not “asymptomatic” and did not “resolved over time”.

Remember that the FDA has sought fast-tracked approval of these medications under the guise that having some sort of treatment is better than having nothing- after all, you need to give people whose loved ones have Alzheimer’s some bit of hope (even if that hope comes with serious side effects…). This comes with the other fact that those on the FDA’s approval committee argued that the benefits of these medications greatly outweigh the risk.

In contrast to the latter point, remember that European drug regulators have recently rejected Leqembi’s approval in European markets arguing that the benefits of the immunotherapy did not in fact outweigh the risks associated with it.

Nonetheless, many people seem to continue to downplay these concerning side effects while touting the actual efficacy of these medications, which can be noted in an article from UC Irvine which rebuts Petersen’s concerns regarding ARIA [context included]:

What was largely missing from the [LA Times] article was a balanced review of lecanemab and other anti-amyloid monoclonal antibodies, which are the product of decades of research progress and are the first ever approved treatments that directly target the biology of Alzheimer’s disease. Around 13% of patients treated with lecanemab in a large phase 3 clinical trial experienced ARIA-E, though the risk was higher in patients of particular genotypes. Most cases of ARIA do not cause symptoms and therefore require routine imaging to be detected (and thus accounted for the naming of the of the phenomenon).

The rebuttal goes on to further note that most patients should not actually notice changes in their loved one’s memory loss as no change would be indicative of the drug working. After all, these medications are intended to slow down the progression of the disease rather than lead to improved memory and cognition:

The article downplayed the efficacy of these treatments, noting that patients and families wouldn’t notice the difference. In fact, the goal with these medications is to slow disease progression, which would be largely imperceptible to patients and families. This is a key point of education when we enroll patients and families in these clinical trials—not noticing a change could be the best sign that the drugs are working.

It's ironic to see such a comment that people shouldn’t see any difference. For anyone who read my post on the FDA’s committee meeting over Leqembi’s approval I noted that several testimonials were provided by loved ones of Leqembi patients in which they said the opposite- they commented that their loved ones were “returning back to their old selves” or at least made comments along those lines. Of course, no one who is for the drugs approval (certainly not Eisai) would dare to make such a comment that loved ones on Leqembi shouldn’t see any improvement- they should just see their loved ones not getting any worse.

(The following post is one that may not have garnered much attention, but it’s important in order to contextualize the actual “meaningfulness” of these products.)

It's further example of how there’s so much obscuring going on with these medications. The public has no idea what these drugs are even supposed to do or what side effects to look out for, and certainly no one invested in getting these drugs approved would contextualize people’s expectations of benefits and risk in a realistic manner.

Unfortunately, this seems to be intentional, and is possibly one of the reasons why the term “ARIA” was provided as alluded to by Pertesen’s writings:

In a recent article, a Stanford neurologist and his colleagues detailed their concerns about ARIA, which they called a “soothing acronym” for brain bleeding and swelling.

“It does certainly have the ring of something that a pharmaceutical company or public relations person would come up with,” Dr. Michael Greicius said in an interview.

Unfortunately, I can’t access the article provided and therefore can’t contextualize the “soothing acronym” phrase, or the exact evidence used to make such an association.

Nonetheless, this claim does make one wonder how exactly one comes to create such an acronym, and why one associate with an otherwise positive, melodious word?

The origins of ARIA appear to have been derived from a 2011 Alzheimer’s Association Research Roundtable Workgroup between FDA advisors, clinicians, pharmaceutical representatives, and members of the Alzheimer’s Association, which published the below article because of the workgroup:

Prior to the workgroup the FDA established strict criteria regarding the exclusion of participants in Alzheimer’s immunotherapy clinical trials. This included researchers excluding patients who had evidence of more than two brain microhemorrhages prior to treatment, increased monitoring of patients for evidence of ARIA, as well as exclusion of participants who develop signs of ARIA during trial participant.

However, these stringent criteria seemed to work against those in the pharmaceutical industry who saw such criteria as a roadblock in drug approval:

Some stakeholders found the original FDA guidance, which was shared with clinical trial sponsors just before AAIC 2010, excessively restrictive. They expressed that these restrictions had the potential to (a) stall progress in evaluating this class of investigational drugs, (b) create a barrier to participant access to clinical studies, and (c) limit the applicability of new therapies in real-world community treatment settings outside research centers.

In response to these remarks the 2011 workgroup was constructed1, eventually resulting in the nomenclature ARIA to describe these side effects.

This also resulted in far-less stringent exclusionary criteria for trial participants, with new guidelines:

Of note, participants are now allowed nearly double the amount of pre-existing microbleeds to be considered within clinical trials upping the number up to 4, and if ARIA is detected during a trial a participant is allowed to continue so long as the participant does now show worse symptoms.

Now, all of this would appear rather fishy for many readers. It’s almost as if guidelines for trial participants were modified to better fit the needs of pharmaceutical representatives- allow for greater leniency to help push drugs towards quicker approval.

Of course, if the FDA found it wise to allow for more lenient guidelines one would have to wonder what evidence was looked at to make such a claim.

What’s rather striking is that this new set of guidelines, along with the adoption of the acronym “ARIA” seem to be based on highly limited, circumstantial evidence.

The adoption of the term “ARIA” seems to be related to the fact that brain microbleeds have been associated with age as well as progression of AD itself, and therefore the direct link between these immunotherapies and side effects of microbleeds and edema are not one to one (emphasis mine):

The Workgroup was composed of academic and industry representatives identified on the basis of their expertise and interest in this area, and was tasked with the objective of providing expert advice regarding the FDA’s concerns related to MRI abnormalities, including signal changes thought to represent “vasogenic edema” (VE) and microhemorrhages (mH) and the relationship of these MR abnormalities to experimental treatment with amyloid-modifying therapies. As VE and mH are typically detected on different MRI sequences, and appear to represent a spectrum of image abnormalities which may share some common underlying pathophysiological mechanisms, both in the natural history of AD and in the setting of amyloid-modifying therapeutic approaches, the Workgroup suggests referring to this spectrum as Amyloid Related Imaging Abnormalities (ARIA).

If one were to dig a little into the workgroup to figure out what evidence was looked at, you’ll note that hardly any clinical evidence was available, with some of the only available clinical evidence coming from Phase I and Phase II clinical trials of the trial immunotherapy Bapineuzumab:

There are currently very limited publicly available data regarding the clinical course associated with ARIA-E occurring in the setting of clinical trials of amyloid modifying therapies. Thus the Workgroup reviewed the data from bapineuzumab trials, but it is unknown whether ARIA seen in other amyloid-modifying therapies will have similar clinical course.

And this emphasis on limited data is seen near the end of the article as well (emphasis mine):

The Workgroup concluded that there is very limited information thus far regarding ARIA in the natural setting or publicly available information from ongoing clinical trial programs to make conclusive recommendations for clinical trial policies. In particular, there is limited data regarding the relationship between ARIA-H and ARIA-E. Additional information regarding whether the presence of baseline ARIA-H as a potential risk factor for ARIA-E, and ARIA-E as a risk factor for incident ARIA-H is needed to provide guidance for the conduct of these studies. Most importantly, we need information about whether specific components of ARIA have an impact on clinical course and response to treatment.

In short, these new research guidelines seem to have been developed based upon very limited data from clinical trials for one immunotherapy drug, and unsurprisingly it’s a drug which several members of the workgroup have a tie to.

That is, Bapineuzumab was developed jointly between both Pfizer and J&J, with Irish pharmaceutical company Elan helping to fund the R&D as well.

If you look at the PubMed article, you’ll find that 4 of the 7 pharmaceutical representatives in the roundtable workgroup were from these companies (3 from Pfizer and 1 from J&J).

And aside from members of the Alzheimer’s Association all the clinicians included in the workgroup had conflicts of interest, with some serving as site investigators for clinical trials, receiving grant funding from pharmaceutical companies, having stock in some of these companies, as well as receiving awards.

Usually, such conflicts of interest are not worth mentioning since nearly any bit of research that gets conducted is likely to be funding by the government or pharma.

But in this case, it’s quite pertinent since the purpose of this roundtable was to consider greater leniency in clinical trial guidelines, which would work to the benefit of pharma and researchers who help to conduct clinical trials. Thus, it’s not without reason to assume that there was a perverse incentive to create such a workgroup and push for more drug trials and faster approval.

It’s important to note that Bapineuzumab went on to fail two Phase III clinical trials as it was seen as not faring any better compared to placebo, resulting in the halting of the drug and even comments criticizing the amyloid hypothesis as a whole:

The article from Forbes mentions that Elan, as well as Eli Lilly (with 1 member on the ARIA workgroup) had their own blow ups with their immunotherapies failing to show any clinical benefit in further clinical trials.

Again, not only is ARIA being defined by limited clinical data, it’s being derived from companies who failed to produce any drug with clear clinical efficacy.

The purpose of this article was to provide a quick glance at the LA Times article, mostly as it raised an interesting question regarding the influence pharmaceutical companies have on drug marketing. In this case, it would be rather insidious of companies to create acronyms to try and hide serious side effects.

In the case of ARIA it seems that this association may be circumstantial. There isn’t anything aside from speculation to suggest that the acronym ARIA was intended to hide harms by associating it with an otherwise innocuous music term.

However, that doesn’t make the situation seem like coincidence.

Also, this doesn’t mean that patients may not understand ARIA, especially if not provided any information from clinicians. If patients and loved ones are not properly briefed on medical terms then they may become confused when trying to search for ARIA online and come across operas and other music-related articles. ARIA related to Alzheimer’s is highly unlikely to be at the top of any search engine.

In that sense it’s not necessarily the fact that patients may underestimate their side effects, but rather that they may not be able to access any information regarding the side effects online unless they know where to look. In the case of Lane it’s possible that her scenario is a culmination of many factors, and I wouldn’t be surprised if lack of information on ARIA symptoms and lack of observation from clinicians is included in that list.

That being said, what I find more compelling may be the fact that ARIA is representative of the nefarious influence that pharmaceutical companies can have on drug regulation and approval.

Consider the fact that:

1. The roundtable workgroup was put together because stakeholder and pharmaceutical representatives believed that the FDA guidelines on clinical trials was too stringent.

2. Many of the people in the workgroup were from pharma or had ties to pharma, all of whom had an incentive for allowing more clinical trials and drug approvals.

3. Hardly any clinical evidence was examined to construct ARIA and create more lenient guidelines, and the one drug that was examined would go on to fail further clinical trials, with meta-analysis reporting clear evidence of increased risk of developing adverse events based on clinical trial data.2

4. The term ARIA gets adopted as “established nomenclature”, resulting in confusion among clinicians and patients regarding the actual safety and efficacy of these therapies, with the most egregious consequence being the loss of life as has happened to Lane and several others who participated in clinical trials.

So the coining of the “ARIA” acronym may not be as interesting as the circumstances surrounding its creation, in which we can recognize a long list of issues regarding the nature of Alzheimer’s research that have come to surface in recent years.

It highlights one of many failures in how drugs are brought to market, where regulatory bodies are captured by those in the pharmaceutical industry to direct guidelines and practices that work against the betterment of the public.

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A few weeks ago a concerning study was published alleging an increased risk of vision loss in those who take Semaglutide called Nonarteritic Anterior Ischemic Optic Neuropathy, or NAION1.

This would add to the growing body of evidence suggesting various adverse events related to these growingly popular medications.

However, at the time of this study’s publication I didn’t pay it much attention, mainly because the condition in question here seemed peculiar relative to how the GLP-1 RAs are alleged to work.

For instance, in previous writings I wrote that GLP-1 slows down digestion by reducing stomach and intestinal contractions, the consequence of which includes feelings of satiety. This is one of the mechanisms by which GLP-1 RAs induce weight loss by producing feelings of satiety for longer, and thus reducing eating.

However, in some individuals it appears (although has not been elucidated) that a possible hypersensitive/hyperresponsiveness to GLP-1 RAs may cause an overexaggerated slowing of the intestines and stomach, likely resulting in paralytic conditions such as gastroparesis (stomach paralysis) as well as ileus (intestinal paralysis).

In those cases we can see a clear association between a drug’s mechanism of action and the relationship with an adverse event.

Here, the association isn’t quite clear. Exactly what relationship would GLP-1 have with the eyes? And why would researchers consider such an association to begin with?

The last question is fairly relevant to this study. Usually, one would consider that a researcher provide some reasoning for their hypothesis formation.

Here, the author’s don’t provide any reason for why they chose to look into NAION aside from “anecdotal experience”:

Anecdotal experience raised the possibility that semaglutide, a glucagon-like peptide 1 receptor agonist (GLP-1 RA) with rapidly increasing use, is associated with nonarteritic anterior ischemic optic neuropathy (NAION).

Curious why such an ambiguous statement was used to catapult such a study, and given the amount of uncertainties related to these GLP-1 RA medications any additional context would help create better understanding for what these drugs are doing within our bodies.

Nonetheless, the study itself is rather uneventful. Researchers examined referrals to neuro-ophthalmology clinics between the time periods of December 2017-November 2023:

The number of unique patients who had been referred for any presumed neuro-ophthalmology indication and evaluated in our neuro-ophthalmology clinic from December 1, 2017, through November 30, 2023, was determined from the MGB centralized clinical data registry and composed our eligible cohort.

Patients were identified for confirmed cases of NAION, and were then categorized based upon Type II Diabetes and overweight/obesity status in order to create independent cohorts. Patients who were taking Semaglutide were matched with patients on non-GLP-1 RAs and assessed for events of NAION within the years following medication prescription.

An outline of the study design can be seen below for better context:

Interestingly, researchers noted a stark difference in NAION events between the two groups, such that those within the Semaglutide group had far higher events of NAION relative to non-GLP-1RA users.

Even more interesting is the fact that these events of NAION appeared to occur predominately within the first 12 months of a Semaglutide prescription.

This effect was present in both the Type II Diabetes as well as the overweight/obesity cohorts:

In essence, there appeared to a 4-fold risk of developing NAION in Semaglutide patients with diabetes relative to non-GLP-1 RA users, and an 8-fold risk of developing NAION in Semaglutide patients who are overweight/obese relative to non-GLP-1 RA users:

The relatively high HRs (4.28 and 7.64 for our T2D and overweight or obese cohorts, respectively) identified by our Cox regression analyses reveal a substantially increased risk of NAION among individuals prescribed semaglutide relative to those prescribed other medications to treat T2D and obesity or overweight. This risk appears not to be due to differences in baseline characteristics between the cohorts.

Now, there’s a few things to point out regarding this study:

• The authors don’t make a distinction between the source of Semaglutide among the patients. This is a concern given recent findings that people prescribed compounded Semaglutide may not be adequately informed on dosing instructions, thus leading to excessive Semaglutide administration. Granted, this concern could be buffeted by the timing of this study, as it’s likely that many of the doses reported in this study are from brand-named Semaglutide products. Nonetheless, better clarity on Semaglutide sourcing should be encouraged in studies.

• There also isn’t any information regarding the additional medications that these patients may be on. The information regarding non-GLP-1 RA is itself ambiguous, as there isn’t any indication regarding what type of non-GLP-1 RA theses patients are taking, and if combinations of medications may be administered. Remember that obesity and diabetes themselves increase the risk of developing comorbidities such as cardiovascular disease, hypertension, and other maladies. Again, lack of clarity in prescription background leaves a lot of unnecessary gaps in information.

• There’s no elaboration on the strange prevalence of NAION within the first 12 months of prescribing Semaglutide. This is a rather important finding that could suggest possible drug tolerance, or attenuation of some factor that may make one more prone to developing NAION. We’ll elaborate on the last point further below.

So, from what can be gathered from this study we have another side effect related to the use of these GLP-1 RAs, and as mentioned by the authors the more people who are prescribed these medications the more likely that NAION events are to be reported.

That being said, what still remains unanswered is what the exact link between Semaglutide use and NAION could be. It’s a shame the authors don’t provide any background regarding their exploration into this relationship, and for many people this association may not seem to important.

However, as someone interested in mechanism this lack of context is insufficient, and in fact isn’t quite helpful for those who would like to find answers for their NAION development. It certainly doesn’t help clinicians who may not know what to look out for in order to determine risk of NAION development for any patients who choose to go onto Semaglutide or other GLP-1 RAs.

Therefore, in this absence of information I found it fitting to at least see what the literature says and see what we can piece together to try to form our own hypothesis regarding this Semaglutide/NAION relationship.

What is NAION?

First, it’s important to explain what NAION is and the underlying pathophysiology.

NAION is one of the most common causes of optic nerve injury and vision loss for those over the age of 50. It’s generally painless and acute, and it falls under the umbrella of Ischemic Optic Neuropathy. ION is categorized based upon the region of the eye in which complications are occurring:

• anterior ION refers to issues around the optic disk region of the eye- an area in which blood vessels and neurons attach to the eye.

• posterior ION refers to issues deeper/along the optic nerve.

Remember that the focus for this article is on NAION.

The underlying pathogenesis of NAION is generally unknown in most cases. However, the leading hypothesis suggests that NAION may be a result of improper blood flow to the eye2:

While the exact pathogenesis of a NAION has not been elucidated, the prevailing theory is that it is caused by hypoperfusion of the short posterior ciliary arteries supplying the optic nerve, which then causes ischemia that induces swelling of the portion of the optic nerve traveling through the small opening in a scleral canal.[2] This, in turn, leads to the compartment syndrome involving neighboring axons that are now compressed in a space limited by the small opening in the scleral canal, leading to apoptosis and death of the ganglion cells whose axons comprise the optic nerve.

In essence, blood flow to the eye gets reduced (ischemia), leading to lack of oxygen (hypoxia) and nutrients within the area. Axons then respond by swelling, which creates a feedback known as compartment syndrome in which swelling of the axons further cuts off blood flow to the eye and therefore exacerbating the problem.

If prolonged, cells within the area begin to undergo apoptosis, with the end result being vision impairment.3 Usually loss of vision is unilateral, meaning only one eye may experience blurred vision. And although NAION is said to occur acutely, the event may progress over the course of several days.

Now, readers may be curious- if there is a NAION then is there AION (Anterior Ischemic Optic Neuropathy)? Indeed there is, with the difference involving inflammation of the arteries in the case of AION.

Symptoms are quite different for AION as compared to NAION. Both tend to result in vision loss or color discoloration. However, where NAION is generally painless AION is generally painful due to the arteritis involved, and can result in headaches or muscle pain from chewing.

Unfortunately, vision loss from NAION can remain permanent. Some patients appear to regain some vision over time, but in most cases vision remains perturbed following a NAION event. Furthermore, there doesn’t appear to be any viable treatments for NAION, and general suggestions for managing NAION involves managing the underlying conditions that can contribute to further NAION development, or to manage underlying conditions in order to prevent a NAION event from occurring in the first place.

With that, several underlying conditions can contribute to increased risk of NAION, including obesity, diabetes, cardiovascular disease, hypertension, smoking, and obstructive sleep apnea. Medications may also contribute to increased risk of NAION. In general, factors related to blood circulation tend to be variables worth considering with respect to NAION, and in many cases it’s likely that NAION risk is exacerbated by a combination of factors.

What’s rather interesting is the fact that recognition of vision loss related to NAION tends to occur after waking up. This may seem rather surprising at first, but this can be explained due to the decrease in blood pressure that occurs at night (nocturnal hypotension), which may result in ischemia and hypoxia of the optic disc region.

This appears to have a led to some controversy regarding the administration of antihypertensives at night, as the reduced risk of nocturnal cardiovascular events may be counteracted by increased risk of NAION.4

Is there a relationship between Semaglutide and NAION?

Now, it’s time to return to the prevailing question- is there a relationship between Semaglutide use and risk of NAION development?

Such a question is difficult to answer, and we have to rely on the scant information available to try to come up with some direction to look.

So far we have outlined that NAION is predominately a condition related to reduced blood flow/pressure to the eye made evident through the association between NAION and other factors related to blood circulation. Even more evident is the fact that NAION tends to occur during wake up, which follows nocturnal dips in blood pressure. All of this at least serves as a starting point to examine with respect to Semaglutide.

As in, does Semaglutide reduce itself blood pressure?

To answer such a question we should obviously consider the possibility that Semaglutide as an obesity/diabetes medication may peripherally influence blood pressure by way of attenuating the former maladies. Therefore, it’s going to be rather difficult to parse out independent effects of Semaglutide on blood pressure, and readers should take that into consideration when looking at the available information.

That being said, several lines of evidence point to Semaglutide having a hypotensive effect, with the greatest lines of evidence being one meta-analysis which examined a reduction in systolic blood pressure of ~4.85mmHg in patients who were overweight but did not have diabetes.5 Another systematic review/meta-analysis looking at studies with Type II diabetics also noted a decrease in systolic blood pressure with Semaglutide use, albeit with a smaller effect of 2.31mmHg decrease.6

It’s important to remember that such meta-analyses likely included studies that utilized different Semaglutide doses, as well as patients with different clinical backgrounds including comorbidities or medicine use.

Nonetheless, this does provide some evidence that Semaglutide can reduce blood pressure.

Now, how this translates to NAION is a whole separate question. One possibility could lie in the nature of nocturnal hypotension in a subset of patients. Although people generally experience a reduction of blood pressure while sleeping some individuals may experience an over-exaggerated response, in which a much greater dipping of blood pressure may occur (sometimes termed as “dippers” or “exaggerated” responses). This is made evident by a prior study which noted a far lower dip in blood pressure among those with NAION relative to those without, although these findings seem to be contradicted by additional studies (summary below from Salvetat, et al):

Nocturnal systemic arterial hypotension: considering that the acute vision loss at NA-AION presentation is noticed upon awakening in more than 70% of cases [52], it is suggested that nocturnal hypotension could be a precipitating risk factor for NA-AION, especially in so-called “deeper” subjects, i.e., subjects in which the physiological nocturnal hypotension occurring during sleep, due to the attenuation of the sympathetic tone, is significantly higher than in normal subjects; or in patients assuming anti-hypertensive medications at night. The effective role of the nocturnal systemic hypotension remains unclear and controversial. Comparing the 24 h blood pressure data amongst NA-AION, POAG and NTG patients, Hayreh et al. suggested that nocturnal systemic hypotension may have a role in the development of NA-AION in susceptible subjects [55]. On the other hand, Landau et al. [56] compared the 24 h blood pressure in NA-AION and controls matched for age, associated disease, and medications, and found a similar nocturnal decrease in blood pressure in the two groups, but a slower morning rise in pressure in NA-AION patients, that could explain the typical presentation of NA-AION upon awakening;

To put this into perspective, the hypotensive effects of Semaglutide may be mild, but in some individuals the effect may be even more pronounced and the hypotensive effects greater. Because Semaglutide is administered weekly we can argue that Semaglutide will continuously circulate in an individuals body, only attenuating near the end of the week when one is near their next dose.

Some individuals may also experience wide variations between daytime and night-time blood pressure levels. Ironically, this is argued to be a reason for the paradox of people with hypertension being at risk of NAION, as hypertensive individuals may see larger dips in blood pressure relative to non-hypertensive individuals.

Altogether, the combination here may make for a perfect scenario in which the combination of nocturnal hypotension and the hypotensive effects of Semaglutide may be enough to pose a risk for developing NAION.

Of course, all of this is mere speculation, and unfortunately there was less information to work with than I had hoped when writing this post.

Regardless, it’s more than what was provided by the authors, and it at least tries to draw a relationship between Semaglutide and this strange, rare condition.

There’s still a lot that is unknown about these medications, but what’s concerning is that we are learning about concerning side effects while more and more people are being prescribed these medications.

There’s a ton that is still not known, and rather than argue that these medications are “safe and effective” for everyone we should hesitate until more information comes out.

This is one example of a place in which we see a possible side effect that seems tangential to the medication in use, which should raise some important questions trying to tie the relationship together.

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Edit 8.25.2024: A link to the late July FDA report on compounded Semaglutide overdosing was not included in the initial publication. The link is now included below.

A few days ago I came across an interesting op-ed published in The Hill:

There’s a few problems with the headline, but the premise here is something that has been commented on several times in the mainstream press.

That is, the limited supply of Ozempic/Wegovy has not been able to keep up with the demand which has resulted in people turning to compounded versions of these brand-name medications.

Now, if you are like me the phrase “compounded version/medication” would sound confusing. Personally, I would take compounded to refer to a medication that is altered through the addition of another medication, as in a compounded version of Semaglutide would just be Semaglutide plus some other additional medications.

It doesn’t help that most definitions of compounded drugs are as ambiguous as the name’s implications, as one can see from this USA Today article that defines compounded Semaglutide the following way:

When there is a shortage of FDA-approved, brand-name medication – like with GLP-1 drugs Ozempic and Wegovy – the FDA says it allows compounding pharmacies to make alternative medications that are "essentially a copy" of the brand-name drug with the same active ingredient. In this case, it's semaglutide, an appetite suppressant.

The FDA defines drug compounding the following way:

Compounding is generally a practice in which a licensed pharmacist, a licensed physician, or, in the case of an outsourcing facility, a person under the supervision of a licensed pharmacist, combines, mixes, or alters ingredients of a drug to create a medication tailored to the needs of an individual patient. Although compounded drugs can serve an important medical need for certain patients, they also present a riskExternal Link Disclaimer to patients.

If this still seems confusing we can break it down the following way:

When prescribed a brand-named medication such as Ozempic you are being provided an active ingredient. The active ingredient is the agent intended to induce a pharmacological effect. In this case, the active ingredient in Ozempic is Semaglutide. However, other agents are also included into the medication, including the solution, agents that inhibit Semaglutide metabolism, and other factors that may increase the bioavailability of the medication such as Novo Nordisk’s inclusion of the compound sodium N-[8-(2-hydroxybenzoyl) aminocaprylate], or SNAC in their GLP-1 RA medications. This is all wrapped up in a specific method of administration such as an injectable pen.

Thus, when we talk about Ozempic we are talking about everything that comprises Ozempic from the active ingredient to every other agent used and the method in which the drug is administered.

So when you hear of people talking about limited supplies of Ozempic or Wegovy it does not necessarily mean that the active agent Semaglutide is in limited supply. It refers to the fact that the brand-named product, with all of its other specific ingredients and method of administration, is in short supply. Semaglutide may be aplenty, but the product Ozempic is not available.

Thus, this shortage of brand-named products has led to many online companies, clinicians, and pharmacists to turn to other means of formulating a usable drug which includes Semaglutide, resulting in many compounded versions flooding the market.

This is where many concerns have been raised regarding these medications, as highlighted by Solomon:

Recently, the FDA issued warnings about compounded versions of semaglutide, the active ingredient in drugs such as Ozempic, Wegovy and Rybelsus, highlighting a big problem: People are using these powerful drugs without enough medical supervision, setting the stage for potential medical malpractice. 

The FDA’s warnings aren’t about the agency’s approved versions of semaglutide, which come in handy pre-filled injection pens or oral tablets. The trouble lies with the less expensive compounded versions that are flooding the market. These are not held to the same strict standards, making them significantly riskier.  

Essentially, the world of compounded Semaglutide is akin to the wild west where formulations of these drugs is up to the discretion of whichever party the medication is being sourced from. That is, one website may formulate their compounded Semaglutide in a different manner than another. It may contain different ingredients, and in fact can even be administered differently as some sources provide a syringe and vial of compounded Semaglutide in which to administer the drug.

Even more concerning is that dosing of compounded Semaglutide may differ between sources.

For instance, note that Novo Nordisk uses fix-dosed pens:

These pens are designed to contain a specific volume of the drug with a specific concentration of Semaglutide.

These pens are intended to administer consistent amounts of Semaglutide, so that when a patient uses these pens they can do so with the assumption that whichever amount of Semaglutide they are administering to themselves is done with a fixed volume of a fixed concentration.

A bit redundant, but it’s important to emphasize that there is (hopefully) a degree of consistency when using these brand-named medications. One would hope that one Ozempic pen won’t differ too much from another.

However, the same can’t be said when one obtains compounded Semaglutide. Because concentrations and method of administration may differ between sources more due diligence is needed by patients, doctors, and pharmacists to ensure proper dosing is happening.

Unfortunately, this due diligence doesn’t appear to be occurring. In late July the FDA released a report with respect to adverse events from compounded Semaglutide, allegedly from patients overdosing themselves due to lack of knowledge on how to administer their compounded Semaglutide:

FDA has received reports of adverse events, some requiring hospitalization, that may be related to overdoses due to dosing errors associated with compounded semaglutide injectable products. Dosing errors have resulted from patients measuring and self-administering incorrect doses of the drug and health care providers miscalculating doses of the drug.

FDA encourages patients to talk with their health care provider or compounder about how to measure and administer the intended dose of compounded semaglutide.

Many of the patients who received vials of compounded semaglutide lacked experience with self-injections, according to the adverse event reports. Unfamiliarity with withdrawing medication from a vial into a syringe and coupled with confusion between different units of measurement (e.g., milliliters, milligrams and “units”) may have contributed to dosing errors.

Even worse, some of these instructions for dosing were ambiguous, with the FDA noting that some individuals were told to administer “5 units” of their compounded Semaglutide via a syringe. Most patients could not determine what the “5 units” was in reference to, resulting in patient dosing that was 5-20 times above the intended dose:

The majority of the reports described patients mistakenly drawing up more than the prescribed dose from a multiple-dose vial during self-administration. In these instances, patients administered five to 20 times more than the intended dose of semaglutide. Most of the reports indicated that patients were unfamiliar with how to measure the intended dose using a syringe.

In several reports, patients were instructed to use a U-100 (1 milliliter) insulin syringe to draw small doses, such as a 5-unit (0.05 milliliter) dose, from a multiple-dose vial.

As depicted in the figure below, these patients were directed to administer 5 units from a vial. However, these patients mistakenly administered 50 units instead.

The FDA goes on to note an instance in which an individual could not find information regarding dosing from his/her telehealth provider, leading him/her to search online for advice on dosing which resulted in administration of compounded Semaglutide 5 times above the intended dose.

The latter case is a very dangerous scenario given the fact that different sources are likely using different concentrations of Semaglutide, so patients can’t reliably conduct their own research online and get proper dosing instructions. It’s also concerning that some of the companies providing compounded Semaglutide don’t seem aware that dosing instructions should be made explicit to patients and doctors.

Even scarier, doctors don’t seem to be spared from dosing miscalculations. The FDA goes on to report instances in which healthcare providers gave patients wrong dosing instructions leading to adverse events:

Essentially, this is a problem from all sides. Whether telehealth companies, doctors, or patients, many people seem to be incorrectly prescribing, informing, or administering these compounded Semaglutide medications.

Even worse, there’s a large financial incentive structure now in place to administer even more of these medications. As more people turn to these weight-loss medications there should be a growing concern that accidental overdosing may become far more pervasive.

Doctors and telehealth providers may also encourage patients take these medications due to the growing financial incentive to do so, even if it means causing undue harm to patients through ignorance and lack of due diligence.

In response, Solomon believes that we are likely to see medical malpractice lawsuits coming in the near future:

What we’re going to see — and I’ve been predicting this since Ozempic use became prevalent for weight loss — is for Ozempic and medical malpractice to soon intersect far, far more.  

Here, we enter the world of medical malpractice, in which a healthcare provider deviates from the standard of care, harming the patient. In the case of compounded semaglutide, several factors come into play in a potential medical malpractice claim, including unclear instructions from healthcare providers, lack of supervision and miscalculations by providers. 

Healthcare providers always need to ensure patients understand how to use their medications correctly. When patients feel a need to turn to the internet for dosing instructions, it indicates that providers failed to give clear guidance.  

It’s no secret that letting patients self-administer potent drugs without supervision is risky. The many dosage errors show the dangers of this practice. Providers should either give pre-measured doses or ensure that patients know how to measure doses accurately. Instances of providers miscalculating doses shows a lack of diligence and care.

As of now several lawsuits have been filed against Novo Nordisk with respect to adverse events, so it wouldn’t come as a surprise if compounded Semaglutide manufacturers and prescribes face some lawsuits themselves, especially given the lack of due diligence and instruction for patients.

This also raises some serious questions regarding some of the adverse events reported to the FDA, as well as studies which are looking into these adverse events. In some cases it’s possible that researchers may be conflating brand-named GLP-1 RA products which contain fixed-doses of Semaglutide with compounded Semaglutide of which doses is unknown. Who’s to say that many of the adverse events being described are of compounded Semaglutide? If so, then that may suggest that some of these adverse events may just be a consequence of extreme overdosing rather than an issue related to Semaglutide’s pharmacological profile.

Now, Solomon’s response to these current issues is to encourage greater government oversight and regulation on these compounds:

The FDA’s warnings about compounded semaglutide are a step in the right direction, but only if they lead to far more robust regulatory measures. This could include stricter controls on the availability of compounded semaglutide products and more stringent guidelines for telemedicine providers who prescribe these drugs.  

It doesn’t help that Solomon’s headline seems to target Ozempic when the real problem seems to be directed towards compounded Semaglutide. After all, there’s an argument to be made that FDA-approved medications are likely to be more regulated than other products on the market, although the past few years have shown that regulatory oversight may not mean much, and may be a way to create the illusion of a drug’s safety and efficacy.

I personally don’t have an answer to this situation, but what I can say is that this is a clear example of the ignorance that pervades healthcare and medicine, and a pervasive epidemic of relying on trust in authority instead of doing your own research.

As more people continue to seek out these medications there’s a greater need for people to ask for transparency and explicit instructions. Ask your healthcare provider for clear instructions on how to take these medications, clear instructions on concentration and dosing, and clear instructions on what adverse events to look out for.

Doctors need to do their own due diligence and ensure the safety of patients, making sure that if they are prescribing these compounded Semaglutide products that they are well-informed regarding the source and the formulation of these products.

Patients must also be wary of doctors and telehealth medicine providers who are entering into this realm of business in order to make a quick buck. It seems that every day a new company or business comes out offering compounded Semaglutide on the cheap. There’s a question if some of these companies are even offering Semaglutide in their products, and unless patients stay vigilant they can be easily harmed by people who put profit over safety.

Be aware of what you put into your body, where that medication is sourced, and whether you are being provided accurate information regarding how to take your medicine and what adverse events to look out for. I think this speaks to a greater issue where many patients seem ignorant as a whole of their very own health.

In a world of uncertainty we need more people to be arbiters of their own health and become their own informed patient advocates.

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In another case of European regulators going against America’s otherwise reckless drug approval process The European Medicines Agency has recommended a refusal to approve the Alzheimer’s immunotherapy Leqembi in Europe.

The recommendation came a few days ago and served as a hit to the already struggling Japanese company Eisai who partnered with Biogen in the development of the drug, as the uptake of this therapy has lagged behind expectations in recent months.

In citing the recommendation to refuse approval the EMA argued that the benefits of reducing Alzheimer’s progression appeared small, with benefits not outweighing the risk of developing adverse events such as brain bleeding and brain swelling known as ARIA (emphasis mine):

Although patients given Leqembi had lower CDR-SB scores than those given placebo, the difference between the two groups was small. EMA’s human medicines committee, the CHMP, considered that the observed effect of Leqembi on delaying cognitive decline does not counterbalance the risk of serious adverse events associated with the medicine.

The most important safety concern with Leqembi is the frequent occurrence of amyloid-related imaging abnormalities (ARIA), a side effect, seen in brain imaging, that involves swelling and potential bleedings in the brain. Although most cases of ARIA in the main study were not serious and did not involve symptoms, some patients had serious events, including large bleeds in the brain which required hospitalisation. The seriousness of this side effect should be considered in the context of the small effect seen with the medicine.

[…]

Overall, the CHMP considered that the benefits of treatment are not large enough to outweigh the risks associated with Leqembi. Therefore, it recommended refusing marketing authorisation in the EU.

As I have previously covered the world of Alzheimer’s immunotherapy has been hit with constant controversies, including the fact that many of these immunotherapies appear to have been approved with questionable clinical data and concerning adverse events.

It also doesn’t help that the most cited paper in Alzheimer’s pathology has been retracted due to allegations of fraud, putting the entire field under scrutiny regarding the actual role of amyloid in disease progression and raising concerns regarding the billions of dollars in research put towards pursuing the amyloid hypothesis.

In some ways this refusal to approve could help to slow down the rush to approve drugs with questionable efficacy, and possibly bring more attention regarding the actual utility of these drugs.

That being said, this refusal to approve does not mean that Leqembi will not see approval at some point in the future as Eisai can seek out re-examination within 15 days of the ESA’s decision.

Regardless, it’s important to point out the juxtaposition between two regulator’s approval processes. That is, why did Leqembi see fast-tracked approval here in the US under the guise that any treatment is better than no treatment, with many people downplaying the side effects as narratives to remove providing people hope while Euorpean regulators see small benefits with Leqembi that don’t outweigh the adverse events?

Why are cases of ARIA seen as acceptable in here yet unacceptable abroad? Why is there inconsistency in how the clinical trials are being perceived even though people are looking at the same trials and results?

In the end, there are many reasons why medications see approval, and rarely is it about the actual clinical benefit…

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The header comes from a recent article published in The Atlantic, and it’s a sentiment that I have brought up multiple times when covering the Ozempic craze. So it’s a bit interesting to see mainstream press covering this topic:

Sadly, the article doesn’t actually engage with the idea that people should be able to get off of these GLP-1 RA medications and instead focuses on the cost of these medications as being difficult for patients to maintain:

To pharmaceutical companies selling the blockbuster drugs—known collectively as GLP-1 drugs, after the natural hormone they mimic—that might be a pretty good proposition. To patients paying more than $1,000 a month out of pocket, not so much. Most Americans simply cannot afford the cost month after month after month.

And strangely ends with this comment near the end of the article:

But tapering off obesity medications entirely, GLP-1 or otherwise, will probably not be possible for most patients. Weight loss tends to trigger a powerful set of compensatory mechanisms in the body, which evolved long ago to protect us from starvation. The more weight we lose, the more the body fights back. The fight never quite goes away, and most patients will likely require some kind of continued intervention just to stay at a lower weight.

Not much of a discussion in providing patients with an off-ramp when it emphasizes that most people may not be able to get off of these medications…

That’s a bit of a shame, because there hardly seems to be any discourse around the idea that these medications should be temporary, so seeing this be mentioned in mainstream outlets could help to persuade readers to consider foregoing these medications when possible. Patients who are using this to lose weight should be allowed other means of maintaining the weight-loss that shouldn’t require pharmaceutical interventions.

This is compounded by the fact that the discussion around these medications seem to forego the fact that we should be producing GLP-1 ourselves, and therefore shouldn’t the focus be on finding out what is going on with GLP-1 within people’s bodies and fixing that problem rather than managing GLP-1 dysfunction with medications?

Why is it that no one seems to be discussing the underlying biological mechanisms when discussing these medications?

Surprisingly, a bit of information has come out from the very same conference that is funded by Novo Nordisk.

One abstract listed1 at The 31st Congress on Obesity included a study in which some participants were tapered off of Semaglutide over the course of weeks and were provided a digital weight management program in tandem. Over half of the participants who agreed to tapering off of Semaglutide were able to stop taking the medication, and by the last available endpoint were able to keep the weight off.

The abstract can be seen below:

This study hasn’t been formally published, and we have to be careful from extrapolating too much from this data. I’ll refrain from entertaining the results until the full study is published. Note that the abstract never mentions the initial doses pre-cessation for the individuals, so it’s possible that some of these individuals who were able to stop taking Semaglutide may have been people taking lower doses to begin with. So be mindful that this study may have more pitfalls than we can discern from this abstract alone.

However, what’s worth noting here is the methodology that took place in this study.

Note that patients were tapered off of Semaglutide- something that doesn’t appear to be common in practice unless a patient is experiencing adverse events as a consequence of losing weight and being more sensitive to Semaglutide’s effects.

But along with the tapering was the online program that was intended to help maintain the weight lost. Now, this study doesn’t mention what the program entails (another reason for some reservation) but once again this is something that seems to be lacking within the discourse.

That is, people may lose weight on these medications but they may not be simultaneously taught how to eat right, exercise, or really engage in any lifestyle choices that would better help to provide a holistic approach to weight-loss and maintenance. Instead, the focus seems to be on the medications, and any dietary changes are a consequence of the medications due to not feeling the need to eat these bad foods.

Obviously, if someone is not made aware of the problem with their initial diet then it would be easy for them to just fall into those very same habits when they come off these medications. If you stopped liking chips while on Ozempic but stop taking these medications you can easily fall into the habit of consuming chips en masse rather than realizing that the chips may have been the problem to begin with. Introspection and understanding what made you obese to begin with is more important than the superficial image of losing weight, but again this doesn’t seem to be the message that is getting across to patients.

It doesn’t help that the idea of “forever-Ozempic” is made worse by comments regarding “Ozempic rebound”- as soon as you stop taking these medications you will gain the weight back.

Most of these comments are based on results from a study2 funded by Novo Nordisk and was part of their clinical trial process.

This study looked at patients who were on the highest-dose Semaglutide available (Wegovy/2.4 mg Semaglutide weekly) for 68 weeks and compared their weight gain relative to those given placebo after coming off the medication.

After coming off of the medications there was clear weight gained back within the Semaglutide group although they didn’t appear to return to their original weight (at least by the end of the 52-week off-treatment period):

However, note that in this case patients didn’t appear to be tapered off of Semaglutide and instead came off cold-turkey.

Not only that, but patients were not coached on how to alter their lifestyle to help maintain the lost weight.

The study mentions “lifestyle interventions” in conjunction to coming off of Semaglutide, but this is what these so-called “lifestyle interventions” entailed:

The lifestyle intervention consisted of counselling every 4 weeks on diet (500 kcal deficit per day relative to total estimated energy expenditure at randomization) and physical activity (150 minutes per week).

This is hardly much intervention, and is a 500 calorie deficit relative to time of randomization sufficient for all participants? How many calories were participants consuming at the time of the cessation? If their calorie consumption decreased substantially then clearly a 500 calorie deficit may still be more calories than these participants should be consuming in order to maintain their weight.

This is made even worse given the fact that the researchers didn’t appear to keep track of participants’ maintaining these lifestyle interventions (emphasis mine):

No treatments were actively administered or prohibited during the extension. Concomitant treatments or events that might impact weight (obesity pharmacotherapy or bariatric surgery; medications for hypertension, diabetes or reducing lipids; pregnancy) were recorded during the extension phase. Participation in lifestyle interventions that might impact weight were not recorded.

So not only were participants given very limited interventions, but it would seem that researchers didn’t even look to see if people were committed to these lifestyle interventions.

It seems that this study was just doomed to fail from the start, and would we expect anything less from a study funded by the drug manufacturer and comprised of researchers with many conflicts of interest associated with Novo Nordisk?

As these medications continue to become more popular patients need to be provided a meaningful off-ramp. They need to be able to understand that they don’t need to be on these medications forever, but that takes patients knowing why they ended up in that position to begin with. People need to better understand the eating habits and lifestyle choices that made them obese and make sure to avoid those pitfalls in the future. They also need to be aware that these drugs may alter brain chemistry in order to dissuade them from bad foods, and that these feelings may come back after coming off of these drugs. Being prepared and fully knowledgeable on the challenges of coming off these drugs should make people more resilient from gaining the weight back.

Better education requires that people be aware that there is an out, and that they don’t need to become subservient to these medications.

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Earlier this week various researchers and scientists met for the 31^st European Congress on Obesity (ECO2024) which took place in Venice, Italy. It serves as a routine meeting in which people within the medical community discuss current breakthroughs and ongoing research in obesity and weight management.

Sounds like a pretty good deal to be able to spend some time in Venice! It also serves a pretty big example of a conflict of interest as both Lilly (maker of Tirzepatide) and Novo Nordisk (Ozempic/Wegovy) were two of the major sponsors for ECO2024.

Therefore, it wouldn’t be too hard to assume that such a meeting would prop up these GLP-1 RAs as the breakthrough miracle drugs that they are made out to be.

And coincidentally a study was published in Nature1 on Monday which further reinforced benefits of these medications, with this study being part of the overall SELECT study and suggests that those who take the highest dose of Semaglutide available (i.e. Wegovy) were able to maintain long-term weight loss.

Ongoing debate has questioned how long people should stay on these medications, with consensus being that patients may have to be on them possibly for the rest of their life. Of course, this assumption was based on scant data suggesting that people who stop these medications gain their weight back, leading to this strange assumption that people should just take these medications for years to come. At the same time growing concerns about possible safety issues have been brought up which have cast doubt on the actual long-term use of these medications.

Given that this is a new frontier there is not much data regarding these possible safety issues as well. Therefore, a study such as this one would serve to encourage not only further use of GLP-1 RAs but their use for the rest of people’s lives.

Now, I have covered a portion of the SELECT trial previously, and so there shouldn’t be a surprise that this study has some of its own problems.

Study Overview

Note that the participants in this study are the same as the prior one focused on cardiovascular events (referred to as the “MACE-related study”). However, strangely this new study is the only place where deeper demographic breakdown is provided.

For instance, there was a higher proportion of Asian participants who were within the lower BMI categories relative to the higher categories. Also, note that the higher BMI categories began to skew more towards female even though males made up a large portion of the participants in the study:

Of note, in the lower BMI categories (<30 kg m−2 (overweight) and 30 to <35 kg m−2 (class I obesity)), the proportion of Asian individuals was higher (14.5% and 7.4%, respectively) compared with the proportion of Asian individuals in the higher BMI categories (BMI 35 to <40 kg m−2 (class II obesity; 3.8%) and ≥40 kg m−2 (class III obesity; 2.2%), respectively). As the BMI categories increased, the proportion of women was higher: in the class III BMI category, 45.5% were female, compared with 20.8%, 25.7% and 33.0% in the overweight, class I and class II categories, respectively.

It’s strange that only select demographic data is provided across the two studies, and this is reflected several times in how the data is presented making it rather difficult to get a complete picture of this study.

When the Wegovy group was compared to the placebo group there was a noticeable decrease in body weight relative to baseline up to the 65-week mark. Afterwards, it appears that those on Wegovy reached a weight-loss plateau. In contrast, minimal weight-loss occurred within the placebo group.

There are a few things here that are worth pointing out. Note that, for some reason, most participants appeared to stop losing weight around the 65-week mark. This effect, also known as “Ozempic Plateau” has been reported in the media in which people just seem to stop losing weight on Ozempic after some time.

The reason for this plateau is unknown, and for the most part many of the explanations don’t seem rather compelling as they refer to things that are not pharmacological in nature. Because most participants are supposed to be on the same dosage of Semaglutide there shouldn’t be a dose-dependent reason for the plateau, although the authors note that only around 77% of participants reached the full 2.4 mg dosage of Semaglutide. There’s no separation of partial-dosage patients and their weight loss so this data isn’t available.

Strange that no mention is put forth regarding why this plateau is occurring in some patients. Instead of referring to this as a plateau the researchers describe this phenomenon as a “sustaining” of weight loss. A strange choice of words, and it shows how researchers can engage with semantic wordplay to change how data is interpreted:

For those in the semaglutide group, the weight-loss trajectory continued to week 65 and then was sustained for the study period through week 208 (−10.2% for the semaglutide group, −1.5% for the placebo group; treatment difference −8.7%; 95% CI −9.42 to −7.88; P < 0.0001).

So what some may consider a plateau worth investigating some may see it as sustained loss of weight…

But there’s more strangeness with this dataset. For some reason the number of patients is sporadic between both the Semaglutide and the placebo group, and not in a way that trends towards lower participant numbers.

If you didn’t notice look at the bottom of the graphs from Figure 1 which notes the number of participants whose data was used for that specific time plot. Note that, at specific timepoints, there are sporadic jumps in participant numbers:

For the most part we should expect that participant numbers would decline over time as participants get lost from repeat visits. This raises some questions as to why these sudden jumps in participants are occurring. More importantly, note that these sporadic jumps are occurring at what the researchers refer to as “landmark visits”, likely because they are occurring at critical endpoints that are used for calculations.

So what exactly is happening to lead to these sudden bumps in participant numbers, especially at the year 2/104 week mark which is far higher than at the 52 week and 78 week mark?

The authors note this remark within their Methods section which raises some red alarms:

Missing data at the landmark visit, for example, week 104, were imputed using a multiple imputation model and done separately for each treatment arm and included baseline value as a covariate and fit to patients having an observed data point (irrespective of adherence to randomized treatment) at week 104. The fit model is used to impute values for all patients with missing data at week 104 to create 500 complete data sets.

Now, I’m not very good with statistical analyses so take my interpretation with a grain of salt. My (amateur) interpretation of this comment is that the authors “filled in” missing participant data at these landmark visit points.

That is, the endpoints for hundreds of patients appear to have been artificially constructed.

Even if we assume that the weight-loss plateau would persist past the 65- week mark and therefore would still lead to the same results as reported above the inclusion of constructed data should raise some concerns, especially if these timepoints are endpoints which the researchers are using to present their results. It’s obviously the endpoints that those in the media use, and so it seems fitting that this artificially constructed data should be criticized even if commonplace in clinical research.

In essence, this should bring into question the validity of these 104-week and 208-week endpoint values since it’s clear that some of this data was not collected from actual participants.

In a callback to findings from the other SELECT trial (MACE-related) note that I commented on the subgroup analysis showing the lines of both the placebo and the Semaglutide group converging. In such a study we should expect that both lines should diverge if we assume that a treatment group should experience fewer MACE relative to the placebo group.

It’s curious that this period also coincided with the jump in numbers boxed in red above, so were some of these values artificially constructed as well?

The serious issue here is that it almost feels as if we are looking at the exact same dataset but from different lenses and different interpretations. The MACE-related SELECT study doesn’t show the same degree of sporadic participant numbers, and this may be because reporting of MACE relies on some degree of documentation rather than just lab visit alone.

But even then, why is it that the same dataset just seems to sporadically collect different data? Why does it seem as if the same dataset comes with various inconsistencies in how it is being analyzed and interpreted.

And to that point let’s go back to a prior comment I made in how muddy of a picture this study presents.

Remember that the MACE-related SELECT study noted that around double the number of participants within the Semaglutide group dropped out due to adverse events relative to the placebo group, and this comment is also made in the current MACE study:

We reported in the primary outcome of the SELECT trial that adverse events (AEs) leading to permanent discontinuation of the trial product occurred in 1,461 patients (16.6%) in the semaglutide group and 718 patients (8.2%) in the placebo group (P < 0.001)21.

Strangely this comment seems to leave out the breakdown of the adverse events- again, remember that the MACE-related study made mention that 880 patients within the Semaglutide group experienced gastrointestinal problems.

Now, I’ll take the conservative position that the “880 patients” who dropped out are not because of gastrointestinal problems (i.e. not strictly related to one AE in particular) but rather that of the people who dropped out because of AEs 880 reported gastrointestinal problems. Note- 880 people, not 880 individual reports of GI-related adverse events.

Since we are looking at the same dataset wouldn’t it therefore make sense that this number should also appear when analyzing adverse events for this current study. That is, shouldn’t we expect that at least 880 different participants reported GI-related AEs?

This data is reported in the Supplemental material as serious adverse events stratified by BMI category, but surprisingly the numbers here are different:

When looking at the Semaglutide group, and if we add up the number of participants who reported GI-related AE (in the N column) do we get 880?

No, in fact we get around 342 participants- less than half of what was reported in the MACE-related SELECT study.

Remember that the 880-value reported is a conservative estimate of people who dropped out specifically due to AEs, while the data presented in the Supplemental for this current SELECT study doesn’t differentiate between those who experienced an AE and discontinued the study from those who experienced an AE and still participated.

For all intents and purposes, the data from this Supplement should be more generous, and should give a number higher than the 880 participants reported in the MACE-related study.

AGAIN, we are looking at the same dataset, yet the reporting of even AEs is different between the two studies. This study doesn’t even contain a category for gallbladder-related disorders even though this was mentioned in the MACE-related study! It does have a category for hepatobiliary disorders, but that would make the inconsistencies even worse given that such a category would include liver, pancreatic, and gallbladder-related complications- not just gallbladder issues alone.

So why so much inconsistency between the two studies- how are participants being categorized, and what data is being collected/excluded between the two studies that may present an appearance of good results?

And quite frankly how many of the people who are propping up this study even took much time to assess egregious issues? This is why we are seeing such failures in both science and journalism when outlets don’t do their due diligence to assess the data that they are being presented with.

In Addition

I could go on about other issues with this study, but I’ll try to summarize some more points below.

Note that subgroup analysis suggested a remarkably high decrease in weight loss among females:

That’d be a pretty good way of marketing these medications to women.

But if you were paying attention to my comment above note that the breakdown of women across the BMI categories is different. That is, even though females made up around ¼ of the study population they were nearly ½ of the participants who were within the highest BMI category (Class III Obesity). They also made up around 1/3 of those within the Class II Obesity category as well.

Essentially, women were overrepresented within the higher BMI categories, and therefore were likely the ones to benefit the most from taking Semaglutide. And so, it’s not that females as a subgroup are likely to see a huge benefit from this drug, but more so that many of the women in this study were within the highest BMI categories that may provide a better explanation.

It’s funny that the authors don’t mention this in their interpretation, and yet they include a comment that the lower weight-loss from Semaglutide among Asians within this study may be because Asians were overrepresented within the lower BMI category:

Asian patients were more likely to be in the lowest BMI category (<30 kg m−2), which is known to be associated with less weight loss, as discussed below.

It’s not that Asians may respond less to Semaglutide, but that Asians had lower BMIs within this study and therefore likely would have seen far less weight-loss overall.

This is one of the reasons why I have grown more critical of aggregate analyses of clinical data. Individual variances will regress to some norm when coalesced with other individuals of a subgroup. Coalesced subgroups will lose even further nuance and variance with even additional regression, and eventually you reach the point of “drug vs no drug” and examine whether a drug had an effect on a population level that misses the different trees for the overall forest.

Sure, maybe this is easier for clinical analysis and statistical measures, but by missing even slight variances in subgroups it becomes easy to report something that may not actually be present, or to extrapolate meaning that may otherwise be explained by other reasons.

I’ll end my post with one final comment- exactly how long is “long-term”?

We’ve grown quite critical of the term “long-term” and how nebulous of a phrase it has become. Anything more than a few days or months can be made out to be “long-term”, even though this term is being used to refer to medications or procedures that are intended to last for years and even a lifetime. After all, most clinicians and journalists have suggested that you would need to be on these GLP-1 RAs for the rest of your life to prevent gaining the weight back.

So, on the grand scale of many years how meaningful is a study that only encapsulates 4 years of data?

Really only 2/3 years of data since patient drop off accelerated after the 2-year mark. I’d be hard pressed to argue that there is sufficient participant data at the 208-week mark when nearly 1/10 of participants from both groups were lost by that time (this isn’t even including whether this number may be inflated as well!).

It also shows how inconsistent the data presentation is when most of the endpoint measures presented are for the 104-week mark and not the 208-week mark.

This makes me even more skeptical towards the presentation of this study as a “4-year” study, but this hasn’t stopped those in the media from running with this number without providing even a hint of scrutiny:

It’s just another good reason why people should be careful in trusting the media’s reporting on studies. Not many do it well, and quite frankly not many are reading the studies that they are covering anyways.

Hopefully I’ve made it clear that there’s quite more going on than what is being reported. There should be serious questions raised regarding why two separate studies relying on the same dataset seem to present different bits of information and appear to have some inconsistencies.

It’s why we need more due diligence in assessing information rather than rushing to report on studies that can have serious social/medical ramifications. As of now people are making a huge deal from the findings of the studies even though we’re nowhere near having enough long-term data despite what people are reporting.

As I have mentioned remember that we produce our own GLP-1, and before we go all in on the pharmaceutical route it’s important to consider what is going on with the GLP-1 we should be producing. We should understand why GLP-1 dysfunction may be happening within ourselves if we are to solve the problem that is being managed by exogenous use of a simulacrum.

That’s the real long-term study that needs to be conducted.

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The following is a quick update regarding investigations into GLP-1 RAs such as Ozempic Wegovy and some reports associating these medications with increased risk of suicidal ideation. In short, a review body in charge of the EU’s regulation of medications has recently argued that there isn’t sufficient evidence at this moment to update GLP-1 RA labels to reflect a possible increased risk of suicidal ideation.

With more people using GLP-1 RAs such as Ozempic there have been several concerning adverse events being reported. I have covered several of them previously so please wander around my Substack for some information regarding those adverse events.

A more recent and concerning question came about a few months ago, in which many regulatory agencies across the globe including the FDA as well as the EU’s European Medicines Agency (EMA) began investigating if the use of these now weight-loss drugs may be tied with suicidal ideation in some way:

However, last week the EMA has come back with their findings in which they argue that there doesn’t appear to be significant evidence tying suicidal thoughts to use of these medications, as suggested in their April 12 pharmacovigilance report:

With the first sentence of the article stating the following:

The PRAC has concluded that the available evidence does not support a causal association between the Glucagon-Like Peptide-1 receptor agonists (GLP-1) – dulaglutide, exenatide, liraglutide, lixisenatide and semaglutide – and suicidal and self-injurious thoughts and actions.

Bear in mind that this report doesn’t suggest that there may be no link between GLP-1 RAs and suicidal ideation, but that there isn’t enough evidence to warrant an update to these products’ warning labels to reflect these possible signals.

The decision appears to be based on available information, but it also appears that two studies in particular helped to sway the review committee:

Additionally, the committee analysed the results of a recent study¹, based on a large database of electronic health records, which investigated the incidence of suicidal thoughts in patients with overweight and type 2 diabetes mellitus treated with semaglutide or other non-GLP-1 receptor agonist medicines for diabetes or overweight. The study found no causal association between the use of semaglutide and suicidal thoughts.

Another study was conducted by EMA², based on electronic health records, which examined the risk of suicide-related and self-injury-related events in people with type 2 diabetes mellitus. The results did not support a causal association between the use of GLP-1 receptor agonists and this risk.

I haven’t been able to look at the data presented in its entirety so I can’t make any comment regarding the robustness of these studies.

That being said, note that the latter study cited refers to a study which looked at people on GLP-1 RAs for their Type II diabetes. These patients also likely had obesity, but when comparing studies to real-world populations it's important that referenced studies properly capture the intended group.

That is, because the second study looked at people with Type II diabetes in particular it doesn’t tell us much about these findings when GLP-1 RAs are used in a broader context as they are being used right now, and is even stated as a possible limitation of this study:

It is worth noting that the limited sample size of new users of GLP-1 receptor agonist patients with a history of obesity but not history of T2DM precludes the conduct of a study with a focus on this population.

Also, note that these studies generally don’t compare GLP-1 RA users to those not on medications but rather people who may be on other anti-obesity/anti-diabetes medications as well and therefore won’t take into account whether these medications as a whole may be associated with increased risk of suicidal ideation.

All this to say that the data referenced may not be a good representation of users of GLP-1 RAs. It also doesn’t suggest that these drugs may still be safe. Precaution should be taken as more users of GLP-1 RAs may come with other signals of possible adverse events.

It will be interesting to see if these findings are reflected in other regulatory bodies, and to see what evidence is used to make such arguments.

Other GLP-1 RA Adverse Events (for those interested)

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This is a dive into a rather newly discovered class of compounds, in particular one called Lac-Phe, which have been found as a byproduct of intense exercise. Evidence has eventually found that Lac-Phe may have an influence on hunger and leading researchers to look deeper into what these molecules can do. Interestingly, a recent study has suggested that Lac-Phe may also be produced by the anti-diabetic drug Metformin. Given the popularity of weight-loss I wanted to look at what was going on with Lac-Phe and Metformin. I may examine Metformin to a bigger degree some time in the future given how popular of a drug it is. Consider this a dive into a new field of research.

An Exercise Molecule that Suppresses Appetite?

Given the discourse around GLP-1 RAs I have become a bit interested in other alleged weight-loss medications. I’ve been meaning to investigate Metformin because of it being an FDA-approved medication derived from nature, juxtaposing the talk around Berberine. Unfortunately, I never really had the time to do as deep of an investigation as I would like.

So, it could be considered good timing that an article was published recently in Nature Metabolism1 suggesting one way in which Metformin appears to aid in weight-loss and appears to be related to a recently discovered molecule related to exercise called Lactoylphenylalanine, or Lac-Phe for short.2

And short is a rather appropriate term here. Lac-Phe is a pseudo-dipeptide meaning that it is comprised of what would appear to be two constituents- lactic acid and phenylalanine. Phenylalanine itself is an amino acid, but lactic acid serves as a byproduct of alternative metabolic pathways such as lactic acid fermentation.

It’s here where Lac-Phe finds its association to exercise. During strenuous exercise several factors are at play- the body may not be able to transport oxygen quick enough to muscles so energy is made by way of anaerobic respiration, the metabolism of glycolysis may lead to excess buildup of pyruvate, and cofactors such as NADH may have to be recycled to be reused for glycolysis.

In any case, strenuous exercise leads to the formation of lactate by way of an alternative metabolic pathway, and it’s the lactate that forms which is related to the soreness you experience while working out.

Supposedly, as llactate begins to buildup it may encounter an enzyme called Cytosolic non-specific dipeptidase (aka carnosine dipeptidase 2/ CNDP2). Normally CNDP2 serves as a manganese-dependent metallopeptidase that breaks down dipeptides into amino acid constituents. However, it has been found that CNDP2 is also responsible for generating N-lactoyl amino acids in a process known as reverse proteolysis.

The discovery of this process process itself is also rather recent, as the pivotal study which discovered these N-lactoyl amino acids was published in 2015.3 This appears to be due to the fact that most studies that have discovered these N-lactoyl amino acids miscategorized these molecules as being derived from 1-carboxyethyl-amino acids rather than being derived from lactate.

Although researchers discovered Lac-Phe they were still unsure of what biochemical mechanisms this molecule serves. It wasn’t until a very recently published study in 2022 did researchers tie Lac-Phe to weight-loss.4

This pivotal study was comprised of some of the same members from the recent Metformin study. The investigation into Lac-Phe was based on various bits of evidence, such as the fact that there appears to be a correlation between BMI and two missense polymorphisms in CNDP2, suggesting that CNDP2 may play a role in energy homeostasis which may be perturbed in those carrying these mutations, thus tying CNDP2 with one of its metabolites Lac-Phe as possibly being related to obesity in some manner.

The study is rather long, but in short researchers examined whether exercise in monkeys, horses and humans would induce Lac-Phe production.

For humans two cohorts were used- one in which people were tasked with running on a treadmill and another in which people were tasked with endurance, sprint, and resistance exercises. Both cohorts compared Lac-Phe levels to those who did not exercise and noted an elevated level of Lac-Phe up to an hour post-strenuous exercise. Of note, the effects here appear to be related predominately to intense cardio exercises as resistance and endurance training did not appear to produce as much Lac-Phe. This is a rather interesting finding given that strength training is known to accumulate a large degree of lactate (again, the muscle soreness that comes from fatigue while performing a set of some sort of workout), so it's curious if not all lactate production are equal, but this may be related to the intensity of the exercise.

This at least confirms that exercise is related to the production of Lac-Phe. However, it’s worth noting that serum concentrations of both Lactate (the precursor) and Lac-Phe are not directly one-to-one. That is, Lac-Phe levels appeared higher than Lactate levels by the 15-minute post-exercise timepoint for the treadmill runners and continues to remain elevated while lactate levels decline. This may be due to removal of lactate and a possible long half-life of Lac-Phe. It could also be related to intracellelular/extracellular levels of Lactate vs Lac-Phe.

The authors further noted that several cell types including macrophages, epithelial cells, and CNDP2+ cells may be involved in biosynthesis of Lac-Phe. It’s possible that Lactate released from muscles can then be taken up by these cell types and converted into Lac-Phe.

Now, what’s interesting is that when Lac-Phe was administered to obese mice researchers noticed a decline in food consumption, and this decline continued through continual administration of Lac-Phe. Interestingly, this effect didn’t appear to occur in lean, chow-fed mice. Water consumption also did not appear to decline in the obese mice, suggesting that nausea may not have been a reason for the lack of eating.

Although rather impressive, the dosage of Lac-Phe used in the study equated to inducing circulating Lac-Phe levels of 50 mg/kg body weight- far above what would be achieved from exercise alone. Thus, if a dose-dependent response is needed to induce appetite suppression there’s a question whether this appetite-suppressing effect of Lac-Phe is achievable with exercise alone. However, the relatively low levels of Lac-Phe may be balanced by the fact that several N-lactoyl-peptides have been discovered, all of which may contribute to the overall appetite suppressing effect if they so happen to operate in a similar manner as Lac-Phe. It’s only Lac-Phe that appears to be the focus of much of the research that is going on.

There’s also the question of where Lac-Phe may be acting. A commentary article from Lund, et al.5 posits that these N-lactoyl peptides may bind to G protein-coupled receptors on neurons and therefore may be involved with sensory regulation of appetite:

How does Lac-Phe affect appetite? Where is it produced during exercise? And what is its primary target cell and receptor? CNDP2 is expressed in many different tissues of the body (Jansen et al., 2015), but Li et al., 2022 identify immune and epithelial cells as the potential main sites of Lac-Phe biosynthesis through single-cell transcriptomic database analysis. Regarding the molecular mechanism, a likely target for Lac-Phe is a G protein-coupled receptor (GPCR) sensor expressed on CNS neurons involved in appetite regulation (Figure 1B). Several GPCRs that recognize carboxylated metabolites or oligopeptides could, in principle, function as sensors for Lac-Phe and potentially other L-lactate-derived pseudo-dipeptides (Husted et al., 2017), but that remains to be experimentally addressed. Identification of a receptor or other molecular targets for Lac-Phe would allow for more specific genetic and pharmacological evaluation of both physiological and pharmacological effects of Lac-Phe.

The commentary provides more regarding what role Lac-Phe may play so check it out for further details.

This pathway is rather interesting since it overlaps in some ways to what is assumed to happen regarding GLP-1. It at least suggests that multiple agents may operate to stimulate neurons and produce an appetite-suppressing effect, although this process is still rather complex and not fully elucidated.

Overall, this study at least suggests a framework in which a byproduct of exercise can lead to hunger suppression and may help manage weight.

Of course, one may ask why such a mechanism may exist?

As in, why would there be a metabolite from exercise that would make someone feel less hungry? Shouldn’t the energy expenditure lead to an increase in appetite?

There’s plenty regarding these N-lactoyl peptides that are yet to be elucidated, but on the surface I’m curious if the response is likely associated with sympathetic nerve activation. That is, from an evolutionary standpoint it’s likely that strenuous exercise and sprinting may occur to escape predators or chase after prey, and in that regard directing energy towards the stomach and away from muscles may not be beneficial. Essentially, Lac-Phe may be a byproduct of the fight or flight response that may have

Metformin and Lac-Phe

This brings us to the currently released study. Again, we will be referring to the preprint in the meantime.6

The study relied on blood samples taken from previous cohorts in which participants were provided Metformin, had blood drawn, and stored for use for other means. One cohort, the Stanford Cohort, examined participants from 1998-2004 who had blood samples taken prior to taking metformin and 12 weeks post-metformin treatment. This was a small cohort in which the participants were described as Type-II diabetics, with the mean age being around 58 with a rather surprisingly low mean BMI of 29.4.

Metformin was administered twice a day at a dose of 500 mg and was increased to 2g/day.

As would be expected, administration of Metformin led to an increase of circulating Metformin among the Stanford Cohort. Coinciding with this increase in circulating Metformin participants also had increased levels of Lac-Phe at the 12-week post-metformin administration mark, although the results here are sporadic.

Note that some participants showed a low increase in Lac-Phe, some people showed a high spike, and one participant showed relatively elevated Lac-Phe both pre/post metformin administration, being the highest peak relative to the other participants. Note that some participants, strangely, showed reduced levels of Lac-Phe at the 12-week mark which would contradict the initial hypothesis. Bear this in mind when considering the mean value of 0.32 ± 0.11 μM of Lac-Phen, which may be biased by some of the more extreme values.

It's important to note that the blood samples examined were also nearly 20 years old. This may not affect the results too much, but it’s curious why newer samples were not considered (in this case it may have been easier to find a cohort that already followed a pre/post-Metformin study method).

Another cohort was also examined including several thousand participants enrolled in a cohort study titled Multi-Ethnic Study of Atherosclerosis (MESA) which is looking at people from different ethnic backgrounds for subclinical characteristics of cardiovascular disease and examining risk factors that may lead to clinical evidence of heart disease.

Out of the nearly 6,000 participants enrolled into MESA around 179 were on Metformin. This at least tells us that this cohort may be on various medications other than Metformin. Nonetheless, when blood samples from those on Metformin were examined, there were higher levels of Lac-Phen relative to those who were not on Metformin. This also appears to be correlated with circulating Metformin levels as well- when Metformin participants were separated into quartiles based on circulating Metformin levels there appeared to be an increase in Lac-Phen levels.

Strangely, no demographic data is provided for the MESA Cohort including BMI, age, and even Metformin dose and duration of use. The units used also don’t appear to be in uM but appear to be based on regression models, so they aren’t directly comparable to the Stanford Cohort- we can only tell that Lac-Phen levels were higher among Metformin users relative to those who weren’t prescribed Metformin.

This is a problem in some regard because the researchers are looking at two separate cohorts but aren’t using the same measurements. They both intend to suggest that Lac-Phen levels are higher post Metformin come to such a conclusion using different methods.

Lastly, researchers note that Metformin did not influence circulating lactate levels. This is shown in Figure 1F which appears to be improperly labeled. It’s worth considering that the half-life of lactate may be far lower than Lac-Phe, and collection of blood must be considered with respect to Metformin use.

So as not to get bogged down in the rest of the study one key experiment investigated how Metformin induces lactate production. In this case, the authors point to Metformin’s alleged mechanism of action as being a mitochondrial complex I inhibitor.

Complex I is the first complex that makes up the electron transport chain of the mitochondria. It’s here where NADH from the Krebs cycle gets stripped of electrons and used to eventually reduce oxygen into water.

The connection between this complex and lactate production is still unclear- one may suggest that inhibition of Complex I may influence lactate production to free up NADH, or it may be a way of producing energy in lieu of Complex I inhibition. Nonetheless, the authors suspected that metformin’s inhibition of Complex I would lead to glycolytic flux in which cells would be directed away from cellular respiration and towards lactate production.

When Caco-2 and primary macrophages were provided Metformin in vitro there appeared to be shift away from cellular respiration at higher doses, which appeared to correlate with increased Lac-Phe levels.

The following graph is a bit confusing, but I’ll break it down a bit. Note that OCR refers to oxygen consumption rate and is a measure of how much oxygen is being used up during a set time. Hypothetically speaking, if Complex I is inhibited then glycolytic flux would lead to less consumption of oxygen as movement of electrons along the ETC would be hindered (note that oxygen Is needed in Complex IV).

When we look at Figure 3A note that at higher doses of Metformin OCR is reduced which would coincide with Complex I inhibition, with 1 mM- 10 mM Metformin levels showing comparable but heavily reduced OCR.

Note that researchers also utilized 3 different compounds which also affect the ETC. Oligomycin acts on ATP Synthase- the final step of the ETC in which protons that have been pushed into the intermembrane space of mitochondrial are pushed across a proton gradient to produce ATP for energy. Use of Oligomycin also pushes towards lactate production, and therefore likely acts synergistically with Metformin which explains why OCR was reduced with the use of Oligomycin. Rotenone is also a Complex I inhibitor and thus makes sense that administration of Rotenone too would lead to reduced OCR.

The interesting drug here is DNP, or 2,4-dinitrophenol. DNP became rather popular during the early 20^th century when it was found that people working in DNP factories lost weight, leading to the use of DNP as a popular weight-loss drug. However, serious adverse effects were found with the drug and eventually they were banned in 1938. Today DNP may be obtained illicitly and is used by bodybuilders to help lose weight.

DNP’s mechanism of action is rather interesting: it serves as a mitochondrial uncoupler by shuttling protons across the mitochondria’s bilayer and thus bypassing ATP Synthase. This appears to be because DNP can pick up protons from the intermembrane space, move across the lipid bilayer, and remove the proton.7 This process is repeatable, and thus over time the proton gradient produced by the ETC is eventually lost.8

This uncoupling means that ATP cannot be produced and therefore signals a loss of possible energy for cells. Interestingly, it appears that this loss in energy causes the mitochondria to ramp up metabolism to compensate for the energy loss and thus explains some of the effects seen with DNP, including the production of excess heat by DNP users. Hyperthermia appears to be a rather common side effect of excess DNP use.

Essentially, the use of DNP in this experiment should ramp up metabolism and thus increase OCR. The pairing of Metformin with DNP emphasizes that oxygen consumption can be overcome, but at relatively high doses of Metformin even the use of DNP may not attenuate the glycolytic flux.

All this isn’t necessary for the study- it serves more to help get a better understanding for the study methodology. The main takeaway here is to confirm that Metformin inhibits Complex I, and it also appears that other inhibitors of the ETC may also contribute to Lac-Phe production as well, suggesting that Lac-Phe production may occur with other medications as well.

In addition, researchers noted an increase in Lac-Phe which appears to coincide with basal respiration inhibition as suggested in Figure 3B & C.

Refer to the preprint for more information regarding this part of the study, but what’s interesting is that researchers noted that, unlike exercise, Metformin appears to lead to intracellular production of Lac-Phe.

This contrasts exercise in which it is assumed that Lactate produced by myocytes gets released extracellular, picked up by cells such as macrophages, and then converted into Lac-Phe and released extracellularly and allowed to elicit its anti-hunger effects.

Further experimenting noted that knockout mice for CNDP2 were not affected by Metformin as food intake and body weight remained relatively consistent relative to wildtype mice which showed reduced food intake and loss of weight.

Overall, this study appears to suggest that weight-loss associated with Metformin may be related to production of Lac-Phe.

Precaution on Lac-Phe and Metformin

Over the past year or so Metformin has been made out to be a sort of wonder drug, and current research has investigated whether Metformin can help with cancer and even increase longevity. With comments suggesting that Metformin may help people lose weight there’s no doubt that Metformin may see even more interest, especially as drugs such as GLP-1 RAs have opened the door to miracle weight-loss drugs. Even though weight-loss with metformin appears modest relative to GLP-1 RAs the cost and relatively safe profile may make Metformin another popular drug for weight-loss, and maybe even more than Ozempic.

That being said, what’s concerning is that enthusiasm regarding this anti-hunger effect from Metformin comes without an understanding of why the body would produce Lac-Phe, and what reason would there need to be in order to produce this anti-hunger effect.

Again, why exactly would a molecule produced during strenuous exercise inhibit hunger? It seems paradoxical, and hence why I question whether this mechanism may be an evolutionary artifact of the fight or flight response. Thus, if Lac-Phe is tied to sympathetic activation then there may be a question regarding whether constant Lac-Phe release may pose some issue.

There’s much to consider given that Lac-Phe is a recently discovered molecule. Further research may help to better find answers for Lac-Phe’s mechanisms and whether these effects can extend to those that are not diabetic, and at that time we may better examine possible consequences of Lac-Phe. It’s important to consider the why and not just the what.

But as of now some hesitation should be considered regarding the reason for this anti-hunger mechanism existing. Precaution should be warranted before assuming that one should take metformin for weight loss before more evidence comes out regarding its MOA.

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It’s well known that drugs such as Ozempic and other GLP-1 RAs have been criticized for their exorbitant prices, with some doses costing upwards of nearly $1,000 dollars in some cases.

However, a study published on Wednesday in JAMA1 has now stirred up even greater scrutiny of possibly price gouging by these manufacturers as it appears to allege that some of these GLP-1 RAs, as well as diabetes medications may only cost several dollars to produce which juxtaposes their upwards cost of hundreds of dollars.

This has raised serious alarms regarding the actual price of these medications, and has even led to calls to reduce the price of these drugs as Senator Bernie Sanders has done in lieu of this study.

Bernie Sanders seems to be arguing that the price of the drug should be no more than what Canadians pay out of pocket, which is almost around 1/3 the cost that Americans are being charged.

All this raises serious questions regarding how much these drugs cost to produce and how much people should be charged.

As of now the market on GLP-1 RAs has been monopolized by only a handful of companies- and by companies that have also monopolized the diabetes medication industry, meaning that not many options are available for patients, and unfortunately have allowed companies to pressure people into forking out much of their hard-earned money.

“The True Cost of Ozempic”

Following the release of this study the head researcher Melissa Barber was interviewed by CNBC:

It’s a good starting point for people who haven’t read the study yet, but what drew my attention was the title on the chyron: “THE TRUE COST OF OZEMPIC”.

This is because the study itself doesn’t provide a truly accurate depiction for what the cost of these medications are to produce, but are instead estimates.

The study considers many variables when estimating the cost of a product, all they way down to the storage unit used, additives needed to create the product, and even the cost to fill:

API is an acronym for active pharmaceutical ingredient and refers to the compound that is intended to produce some effect within the body. For example, the API in Ozempic would be Semaglutide. This is where most of the cost of these products are coming from.

However, note that each variable listed above comes with its own estimate, meaning that assumptions have to be made for the actual cost of many of these items. Given that API is where the bulk of costs are to be derived from the cost per unit of other variables may be minimal, but it’s nonetheless important to note one of the limitations of this study.

That is, multiple assumptions need to be made regarding the cost to source some of these units and so readers should be aware that this may mean the values used may not be accurate.

As to API, Barber, et al. used data collected from export/import information regarding these drugs, as well as information from manufacturers whenever it can be sourced:

We extracted customs data from a commercial trade database (Panjiva) that systematically archives shipment-level import/export records for numerous countries (eTable 4). For medicines where no export/import data were available, we estimated API prices through direct solicitation of price quotes from 11 API manufacturers, and inference based on review of methods of synthesis and other information available in academic and trade literature. API manufacturers were identified through internet search, online purchasing platforms (Pharmacompass and Pharmaoffer), supplier listings in cross-country price data collected, and inclusion in an IQVIA report on biosimilar global suppliers.1

Barber, et al. notes that this methodology is used extensively to assume costs of various products.

However, one trouble I have is interpreting whether listed export/import prices are relative to the actual cost to manufacture the API, or whether other variables should be considered such as lower export prices for larger shipments, or whether the export/import prices are related to the price for shipping alone.

This may, in part, explain why Semaglutide costs are relative low as compared to other GLP-1 RAs. The popularity of these drugs may allow for larger shipments and thus lower export/import costs:

And is somewhat noticed in a graph which maps shipping sizes of Semaglutide along with API costs from the past few years, although the data on this graph only shows one data point for a 1kg shipment so it’s hard to make out the significance of this graph. That being said, note that this graph at least suggests that some of the export/import data collected may be for shipments far smaller than 1kg, which again raises a question if smaller shipments may be hit with larger fees/tariffs:

There’s also a question regarding how well export/import data correlates to actual quotes from manufacturers.

Be mindful that these comments are made from my own naïve perspective, and given that this sort of methodology is used extensively it may be considered an appropriate way to estimate costs.

There are additional things to point out- note that when provided both manufacturer quotes as well as export/import data the researchers went with the smaller number in their calculations:

Where both price quotes received from manufacturers and exim data were available, we assumed the lower price for the purposes of calculating a sustainable cost-based price.

This actually doesn’t mean much within the context of GLP-1 RA calculations as it would mean that Liraglutide would be the only calculation that would be biased by the lower number (i.e. the researchers likely went with the 500k figure rather than the 573k figure in their calculations). However, this may also suggest that there are likely discrepancies between manufacturer quotes and export/import data.

The point of highlighting this information is to point out that the JAMA study doesn’t quite provide an accurate detail for what the production costs of these medications are, but rather are estimates built upon estimates.

This may seem like a semantic argument, but it’s important to point this out, especially when mainstream outlets display inaccurate words such as “true cost”, which may mislead viewers into thinking that Semaglutide should only cost around $5 for consumers. Bernie Sanders seems to have run with this figure even given the limitations in the estimates, and is an example of why politicians should due their due diligence in understanding the context of this number before disseminating misinformation.

So although it’s certainly true that a huge degree of price gouging is at play, it doesn’t mean that studies such as this one are true measures for the cost of manufacturing- only the manufacturers have those numbers and we know they certainly won’t release that information!

Also, note that the “price to produce/manufacture” is not indicative of “costs to consumers”. As Barber notes in her interview the model isn’t intended to take into account factors such as financial recouping for R&D, which likely would increase the price of the drugs.

There are additional factors that go into considering how much a drug should cost.

But what should be pointed out, and something that readers should be made aware of, is the fact that there is an obvious tiered system at play that dictates the prices of these drugs.

Note that the US carries the largest ticket price for many diabetes medications including insulin and GLP-1 RAs:

And part of this appears to stem from the fact that relatively wealthier countries are likely paying a premium for the same API that less-wealthy nations are receiving, as noted in this note regarding Exenatide’s pricing:

For exenatide, all observed API was shipped by the same company, with prices ranging 542,500 US$/kg to 1,007,140 US$/kg, with more costly API destined for high income countries in Western Europe and lower-priced API observed sold to less wealthy countries. The most recent shipment was twice as expensive as shipments observed to less wealthy destinations, resulting in the linear prediction model showing a sharp increase in price. Given that the product description and company are identical, we assume that this is a tiered price model, and use the lower level (542,500 US$/kg) as the API price.

Not only does this suggest that the estimated cost for Exenatide would be higher for Americans, but it also suggests that prices are likely higher for Americans across the board due to being a wealthier nation.

This isn’t all too surprising as many people are aware of this huge price discrepancy for the US relative to other countries- it’s just more evidence that Americans are for reason being forced to pay a premium on medications.

It’s somewhere in the middle

Here we are faced with two inherent truths:

• People, and Americans in particular, are being price gouged for their medications.

• This JAMA piece may not be an accurate representation of what consumers should expect to pay for GLP-1 RAs. To be fair, the study isn’t intended to show that, but it hasn’t stopped people from running away with that sentiment. Factors such as cost for R&D and the shipping of finished products vs API were not factored into the calculations.

As Barber puts it in her interview the true cost for consumers likely falls somewhere in the middle of what Barber and her colleagues have estimated and what people are actually paying.

And irrespective of what that number is it will certainly be far lower than the current price for these medications.

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This month a hearing is underway regarding lawsuits tied to GLP-1 RA drug makers Eli Lilly and Novo Nordisk and dozens of patients, in which it is alleged that patients were not properly warned of serious risks regarding these medications.

Talk of lawsuits have been going on the past few years, but it’s this month where a federal judge in Philadelphia is hearing the lawsuits. Although the lawsuit covers plaintiffs from various states the lawsuits were collected together due to common elements.

The allegations are things that we have heard before such as incidences of gastroparesis (stomach paralysis), ileus (intestinal blockage/paralysis), pancreatitis and even gallbladder removal in some patients.

Those interested in the lawsuits and legalese can read it for themselves through a document contributed by Law&Crime.

I have not read through anything but the first few paragraphs, although to reiterate note again that plaintiffs are alleging that they have not been properly warned of more serious side effects, only being told of minor gastrointestinal issues such as nausea, vomiting and diarrhea, and stomach pain:

In some of these cases plaintiffs allege that their gastrointestinal issues persist even after discontinuing the medications, likely meaning permanent harms related to these medications.

Some of these stories can be found in a recent USA Today article, which includes a woman named Monica Church who began feeling nauseated while using Ozempic. But after her dosage was increased she couldn’t keep food and drinks down even after discontinuing the medication, eventually having to be hospitalized because of gastroparesis.

There’s also a man named Bob Tuttle who seemed to have taken the medication for two years for his diabetes, eventually suffering a severe case of gastroparesis that still persists with morning nausea.

What’s rather striking is the apparent lack of knowledge from many of these doctors, with it appearing that several doctors even continued prescribing these medications and even at higher doses to their patients even though they were experiencing some gastrointestinal-related issues.

Another plaintiff Debbie Kirtz who alleges an H. pylori infection, gastroparesis, and pancreatitis comments that her doctors never warned her of serious side effects in an interview provided by CBS Philadelphia (journalist Stephani Stahl):

Stahl: Did you read the warning label that comes with the drug?

Kirtz: Yeah, I just know that I was going to go through some symptoms, but not halfway die.

Kirtz said the doctor who prescribed Ozempic only talked about the potential for minor side effects. 

"The only thing they would say is you might get nauseous, nauseated or constipation," Kirtz said.

Novo Nordisk and Eli Lilly are, of course, defending themselves against these claims suggesting that the drugs are safe and with known risks and benefits provided on the drug label.

Here’s one response provided to Law&Crime from Novo Nordisk:

Novo Nordisk said in a statement to Law&Crime via email on Friday that the lawsuits “are without merit” and the company intends to “vigorously defend against these claims,” though it was pleased with the decision to coordinate all of the litigation before U.S. District Judge Gene E.K. Pratter. Pratter was appointed by former President George W. Bush.

“Patient safety is our top priority at Novo Nordisk and we work closely with the U.S. Food and Drug Administration to continuously monitor the safety profile of our medicines,” a spokesperson for Novo Nordisk said. “GLP-1 medicines have been used to treat type 2 diabetes (T2D) for more than 18 years, and for the treatment of obesity for 8 years. This includes Novo Nordisk GLP-1 products such as semaglutide and liraglutide that have been on the market for more than 13 years. Semaglutide has been extensively examined in robust clinical development programs, large real world evidence studies and has cumulatively over 9.5 million patient years of exposure. The known risks and benefits of semaglutide and liraglutide medicines are described in their FDA-approved product labeling. Novo Nordisk stands behind the safety and efficacy of all of our GLP-1 medicines when they are used as indicated and when they are taken under the care of a licensed healthcare professional.”

But note that gastroparesis, ileus, and other serious gastrointestinal complications are not noted on Ozempic’s label.

For instance, a 2020-dated label for Ozempic notes the following warnings and precautions, which does include pancreatitis but nothing regarding the gallbladder:

However, a 2022-dated label for Ozempic includes various postmarketing experiences which includes issues regarding the gallbladder including acute gallbladder disease:

And it was only last year that ileus was included on the drug label as another postmarketing experience:

All this to say, it’s very disingenuous for Novo Nordisk to claim that these possible adverse events are listed on their drug label when most of these warnings are recent additions due to patients experiencing them. How would any of these plaintiffs and their doctors be aware of these possible side effects if they were never featured on the label until just two years ago at the very least?

Although these adverse events seem relatively rare it’s important to remember that this isn’t about the frequency of these rare events but whether patients are being properly informed about side effects and what to take heed of when taking these medications.

It’s rather concerning that many doctors appear to continue prescribing these drugs, and at increasing doses even when patients are experiencing side effects, almost as if patients are supposed to just forget about the side effects and to persevere until they go away.

Again, it’s informed consent that is at play here.

And it’s even more shocking that this lawsuit is likely to be overshadowed by Oprah Winfrey’s new special praising these drugs as removing stigma and shame:

So while dozens of people bring forward their lawsuits against these multibillion dollar companies Oprah is parading around touting how great these drugs are and why her thoughts on them have changed (seemingly as Weight Watchers buys a telehealth company to start their own GLP-1 program). Pardon me if this all seems a little too coincidental…

Remember that my intent is not to completely dissuade people from taking these medications, but it’s having an understanding of what they are. Again, it’s informed consent that matters, and one has to ask him/herself how much s/he knows about these medications, and quite frankly how much doctors know about these medications as well.

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Last Friday the FDA gave approval to label GLP-1 RA Wegovy as helping to reduce serious cardiovascular events.

This tacks on another alleged benefit for these drug, and thus further spurs greater interest as the market for these drugs continues to boom. More importantly, it now captures another demographic (those with cardiovascular disease) to which these medications can be prescribed to. Again, the incentives for these drugs continue to grow, leading to articles such as the one below to be released:

All this excitement stems from only one clinical study published in NEJM1 in mid-December called the Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity trial, or better known as the SELECT trial.

In essence, the clinical trial which included over 17,000 patients is argued to show that those who were prescribed Wegovy at the highest dose of 2.4 mg Semaglutide weekly appeared to have a reduction in major acute cardiovascular events (MACE) by about 20%, leading to further increased interest within this class of drugs.

Now, prior to the release of SELECT I covered a previous clinical trial called SUSTAIN-6 which had similar methodologies as SELECT but fewer participants and had both stratified and placebo groups. Readers can look at that article for some of the study outlines and pitfalls that were noticed with SUSTAIN-6.

Because of these similarities in methodology, I won’t go into too much detail regarding SELECT. Note that SELECT skews relatively older (mean age of participants around 62), were predominately male (over 70%), had high BMI’s (low-mid 30s), and generally had a prior history of a cardiovascular event, with a nonfatal myocardial infarction (heart attack) being the predominate event2:

Patients appeared to be properly matched across the characteristics listed. Among those who were prescribed Wegovy a gradual increase in dosing occurred starting with 0.24 mg Semaglutide weekly until patients reached the final dose of 2.4 mg:

The starting dose of semaglutide was 0.24 mg once weekly, and the dose was increased every 4 weeks (to onceweekly doses of 0.5, 1.0, 1.7, and 2.4 mg) until the target dose of 2.4 mg was reached after 16 weeks.

Note that any adverse effect at higher doses led to a more gradual increase in dosage, and that some patients were able to stay at a dosage lower than 2.4 mg weekly as well. It appears that around 77% of Wegovy patients reached the 2.4 mg dosage by the 104-week mark in the study.

Results (and more strange plots)

When looking at the primary endpoint of any cardiovascular event the Wegovy group appears to show a marked decline. Note that the primary endpoint is a composite value considering cardiovascular-related deaths, nonfatal heart attacks, and nonfatal strokes:

Upon first glance this may seem like a very good benefit. It would at least suggest the use of Wegovy may help to reduce cardiovascular-related events by around 20%. However, like the SUSTAIN-6 trial there are a few issues worth noting that makes these results rather complicated to assess.

For one, note that the Wegovy group appeared to show a decline in weight of around 9% original bodyweight whereas the placebo group showed an average weight decline below 1%:

The participants were on average close to 100 kg in each group, meaning that a near 9% weight loss would be close to 20 pounds lost.

Because obesity is related to greater risk of cardiovascular disease one can assume that any weight-loss may help to reduce the risk of a cardiovascular event. In this case, it begs the question if the reduced cardiovascular events within the treatment group may just be a consequence of the weight-loss.

If so, that also begs the question if a medication would be needed in the first place. The study itself doesn’t make mention of the exercise or diets of the participants, and therefore we don’t know if any behavioral changes or lifestyle changes may have occurred during the inclusion into the study. Like SUSTAIN-6 these sorts of studies don’t/can’t separate effects from weight-loss or biochemical/pharmacological effects tied directly to the drug.

What’s also interesting is that the study itself seems to mask some strange occurrences through composite analysis.

For instance, when looking at Figure 1A there’s an obvious gradual separation between the line for the placebo group and the one for the Wegovy group that widens over time, suggesting that the rate of MACE among the placebo group is higher relative to the Wegovy group.

However, when examining the plots separately notice that there is a sudden abrupt change within the last few months (from 36-48 months).

The study complicates much of its numbers, switching between weeks and months at various points.

Note that mean duration of exposure was 33 months for Semaglutide and 35 months for placebo with the mean patient follow-up being near 40 months. There’s a necessary question to consider regarding how many patients continued to be prescribed Wegovy and how many patients were provided placebo.

But what’s important to note here is that the 36-month timepoint onward is essentially a jumping off point, in which participants may have halted their inclusion, may have gotten lost to follow-up, etc.

Essentially, at the 36-month mark it’s likely that a lot of scrambling in patient characteristics may have occurred during the 36-month timepoint and onward as patients continued to drop out.

Note that a drastic decline in the number of participants occurs during this time when looking at the number of at-risk participants:

The study seems to only use the 48-month follow-up assessments as the last timepoint because too many participants dropped out or were lost to follow-up afterwards to make calculations.

It’s likely that patients may have still been properly matched between the two groups, but it nonetheless raises questions of whether the patients lost to follow-up may have biased the cardiovascular events to appear higher among the placebo groups. How many participants continued to take Wegovy during follow-up, and how many who did not return for follow-up would still have a cardiovascular event but not be included in the study?

What’s strange is that the rate of cumulative cardiovascular-related deaths and heart failure (Figure 1B and 1C, respectively) are rather similar between the two groups between the 24–36-month mark. It’s the pairing of the relatively similar lines which suddenly change at the 36-month mark that warrants questioning what may have happened during that timeframe.

And although the study mentions the post 36-month mark as being the follow-up period note that primary and secondary endpoints were calculated based on the time from enrollment until time of last-follow up as mentioned in the footnote for Table 2:

Data are for the full analysis population during the in-trial observation period (from randomization to the final follow-up visit). All end points were analyzed with the use of a Cox proportional hazards model with treatment as a categorical fixed factor. Data from patients without events of interest were censored at the end of their in-trial period. NA denotes not applicable.

Bear in mind that heart failure and death from any cause don’t appear to be factored into the composite primary endpoint.

Nonetheless, the language here would at least suggest that participant data was used for the calculations so long as participants continued to appear for follow-up. Again, what this would suggest (in a hypothetical sense) is that if a participant stopped appearing for follow-ups after the 36-month follow-up but had a cardiovascular event around the 40^th month since trial inclusion, they likely wouldn’t be included within the final calculations irrespective of whether they were within the placebo or the Wegovy group. On the other hand, someone who continues showing up for follow-ups may report their cardiovascular events and thus be included in the calculations.

Again, what exactly is happening near the end of the study?

Overall, this at least suggests that an explanation should be provided for how the results from the tail-end of the study may have affected the calculated hazard ratios. Some information may be found from the Supplementary Appendix but as of now I haven’t been able to gain access to this portion. It’s curious if the placebo patients who continued follow-up were more prone to cardiovascular events or were more likely to report their cardiovascular events to researchers.

If anyone has any thoughts on what may be going on please feel free to ask, but for all intents and purposes it just seems rather strange for the trend to change so drastically, especially during the follow-up period.

In Addition…

There are a few other things worth noting regarding this SELECT study.

• Additionally, note that dropout due to adverse effects were higher among the Wegovy group, predominately due to gastrointestinal issues related to Wegovy:

Adverse events leading to permanent discontinuation of semaglutide or placebo occurred in 1461 patients (16.6%) in the semaglutide group and 718 patients (8.2%) in the placebo group (P<0.001); these events included gastrointestinal disorders in 880 patients (10.0%) in the semaglutide group and 172 patients (2.0%) in the placebo group (P<0.001). Gallbladder-related disorders occurred in 246 patients (2.8%) and 203 patients (2.3%), respectively (P=0.04).

It’s curious how this may have affected the endpoints of this study, and it also follows a pattern seen with other studies and real-world anecdotes regarding the GI issues related with this drug. So even though the authors argue a cardiovascular benefit with the use of Wegovy note that there may be a risk of possible adverse events, especially if one considers a dose-related risk of adverse events.

• Following along, note that Wegovy is the highest dose of Semaglutide available. This raises a question if the cardiovascular benefits may be seen only at higher doses of the drug. This may run the risk of providing a stronger dose of a drug of which there is no longterm safety data that also carries serious risks. Note that the actual dose may be inconsistent in this study depending on if a participant experiences an adverse effect.

• Note that the argued reduction is only around 20%. This may be considered a rather significant number, but it also may not mean much given the possible risk of side effects, cost, and adherence to treatment for patients that come along with these medications. There’s a real question regarding how much this reduction will actually translate into better patient outcomes, and how many clinicians will properly balance risk and benefit.

• Unlike SUSTAIN-6 the authors don’t provide a plot for nonfatal heart attacks and nonfatal strokes even though they are included within the primary endpoint. Again, this may be in the Supplementary Index but it’s strange that no plots are shown for these two measures.

• The units used in this study are also rather unorganized. This may be typical of studies, but it makes it difficult for readers to consider the actual timeline of events. For instance number of people taking the full 2.4 mg of Semaglutide was based on the 104 week (24 month/2 year) mark. This doesn’t tell us what dose patients were taking after the 104-week mark and whether some patients moved to lower doses, which itself raises problems as it may skew the rate of adverse events and interpretations of the endpoints. So the study references various numbers but taken from different timepoints, making the data more difficult to connect together.

For Thought

Many of my thoughts I outlined in the SUSTAIN-6 article are pertinent here so I won’t rehash them again.

That being said, as these medications continue to see more generalized use there should also be a growing concern regarding the need for these medications, and whether there will be any off-ramp- will people be able to stop taking these medications at some point?

But more importantly we should be asking the question of what is happening to native GLP-1. What exactly is happening within the body of these people that an exogenous mimic of an incretin hormone can have such strong effects on the body? Are obese, unhealthy individuals not producing GLP-1 for some reason, and what would that reason be? Do people become tolerant of GLP-1? How much does diet, the microbiome, and other environmental factors affect our production of GLP-1? And why is it that discussion around GLP-1 RAs never seems to also include many of the questions listed above?

It’s as if we are forgetting that we produce these hormones ourselves, because if we produce these hormones ourselves we probably wouldn’t need to rely on exogenous mimics.

This is something that may be explored at a future date. The next article will try to address another factor regarding the effects of GLP-1. That is, the reduction of cardiovascular-related events from taking GLP-1 RAs may not be related to weight loss alone, but may also be related to the agonistic effects these drugs have on the heart and the endothelium, as GLP-1 receptors seem to be found all throughout the body.

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Recently the CDC has provided preliminary analysis regarding the recently released respiratory syncytial virus vaccines and a possible association with the rare neurological condition called Guillain-Barre syndrome, or GBS.

The causes of GBS are not entirely known, but it appears to be a phenomenon in which the immune system may target peripheral nerve cells, generally resulting in the manifestation of muscle weakness as a main symptom.

As for RSV, the virus is seasonal and generally mild disease for most individuals, usually presenting with cold-like symptoms. Although research has been looking into RSV vaccines for decades, it wasn’t until last year that two vaccines against RSV were approved:

• Pfizer’s ABRYSVO (aka RSVPreF)

• GlaxoSmithKline’s AREXVY (aka RSVPreF3+AS01)

As of now the available RSV vaccines have been marketed towards those over the age of 60 predominately as they are argued to be the most at-risk of developing severe illness. And so far over 2 million doses in total appear to have been administered in approved countries. Unlike the COVID vaccines the RSV vaccines available are administered as a single dose.

The comments regarding GBS come after the FDA released preliminary data from a presentation, in which it was noted that both vaccines appear to show a higher than expected rate of GBS cases within 42 days of receiving an RSV vaccine.

Interestingly, the observed events of GBS appear higher among those who received Pfizer’s vaccine. Even though recipients of ABRYSVO make up only 1/3 of RSV vaccine recipients, they also account for more than half of the reported cases of GBS.

Now, the rates of GBS still appear relatively low with overall cases between the vaccines being around the low 20s, but the fact that rates appear elevated nonetheless pose questions as to what may be occurring.

The current evidence is somewhat confounded, as most RSV vaccine recipients are far older than the general population. It’s been suggested that the risk of GBS increases with age which may factor in to the increased risk seen, with age-stratification showing a higher number of reported cases of GBS. How this may relate to the higher possible risk among older population is still left to be determined.

Given that Pfizer’s vaccine shows higher reported cases with fewer vaccines administered, there may be something regarding the formulation of Pfizer’s vaccine which may provide some insights.

However, when comparing the package inserts there doesn’t appear to be egregious differences between Pfizer and GSK’s formulations. Both, for the most part, utilize the surface F glycoprotein of RSV in their formulations, and thus are protein subunit-based vaccines.

Pfizer’s vaccine appears to use F glycoproteins from two different strains of RSV. As for GSK the source of the F glycoprotein isn’t as clear.

A greater description for the two vaccines are as follows (derived from corresponding vaccine package inserts):

Pfizer’s ABRYSVO

ABRYSVO (Respiratory Syncytial Virus Vaccine) is a sterile solution for intramuscular injection. The vaccine is supplied as a vial of Lyophilized Antigen Component that is reconstituted at the time of use with a Sterile Water Diluent Component. The antigen component contains recombinant RSV preF A and RSV preF B.

The RSV preF A and RSV preF B recombinant proteins are expressed in genetically engineered Chinese Hamster Ovary cell lines grown in suspension culture using chemically-defined media, without antibiotics or animal-derived components. The recombinant proteins are purified through a series of column chromatography and filtration steps followed by formulation, filling into vials, and lyophilization.

After reconstitution, each dose of ABRYSVO is approximately 0.5 mL. The vaccine is formulated to contain 120 mcg of RSV stabilized prefusion F proteins (60 mcg RSV preF A and 60 mcg RSV preF B) per 0.5 mL. ABRYSVO also contains the following buffer ingredients: 0.11 mg tromethamine, 1.04 mg tromethamine hydrochloride, 11.3 mg sucrose, 22.5 mg mannitol, 0.08 mg polysorbate 80, and 1.1 mg sodium chloride per 0.5 mL. ABRYSVO is a sterile, clear, and colorless solution.

ABRYSVO contains no preservatives. Each dose may also contain residual amounts of host cell proteins (≤0.1% w/w) and DNA (<0.4 ng/mg of total protein) from the manufacturing process.

GlaxoSmithKline’s AREXVY

AREXVY (Respiratory Syncytial Virus Vaccine, Adjuvanted) is a sterile suspension for intramuscular injection. The vaccine is supplied as a vial of lyophilized recombinant respiratory syncytial virus glycoprotein F stabilized in pre-fusion conformation (RSVPreF3) as the antigen component, which must be reconstituted at the time of use with the accompanying vial of AS01E adjuvant as the adjuvant suspension component.

The RSVPreF3 antigen is expressed by culturing genetically engineered Chinese Hamster Ovary cells in media containing no antibiotics or animal-derived proteins. The RSVPreF3 protein is purified by several chromatographic and filtration steps, formulated with excipients, filled into vials, and lyophilized.

The AS01E adjuvant is composed of 3-O-desacyl-4’-monophosphoryl lipid A (MPL) from Salmonella minnesota and QS-21, a saponin purified from plant extract Quillaja saponaria Molina, combined in a liposomal formulation. The liposomes are composed of dioleoyl phosphatidylcholine (DOPC) and cholesterol in a phosphate-buffered saline solution containing disodium phosphate anhydrous, potassium dihydrogen phosphate, sodium chloride, and water for injection.

After reconstitution, each 0.5-mL dose is formulated to contain 120 mcg of the recombinant RSVPreF3 antigen, 25 mcg of MPL, and 25 mcg of QS-21. Each dose also contains 14.7 mg of Trehalose, 4.4 mg of sodium chloride, 0.83 mg of potassium dihydrogen phosphate, 0.26 mg of dipotassium phosphate, 0.18 mg of polysorbate 80, 0.15 mg of disodium phosphate anhydrous, 0.5 mg of DOPC, and 0.125 mg of cholesterol. AREXVY contains no preservative. '

Each dose may also contain residual amounts of host cell proteins (≤2.0%) and DNA (≤0.80 ng/mg) from the manufacturing process.

One distinction could relate to the use of a saponin in GSK’s vaccine formulation which appears similar to that of Novavax’s SpikeVax COVID vaccine, in which case it may suggest that GSK’s vaccine presents the F glycoprotein on the surface of liposomes likely mimicking the structure of an RSV virion.

This may suggest that presentation of F glycoprotein may be different between the two RSV vaccines, and thus may be related to the increased risk of GBS among Pfizer recipients, although this is merely a speculation.

Thus, although GBS appears rather rare in both vaccines their higher-than-expected incidences nonetheless raise questions regarding what may be influencing this increased risk. Given that both vaccines utilize protein subunits the answer for the differences in reported adverse events may lie somewhere else in the formulation or purification of these products, although there are likely to be differences among the subunits used as well.

And so more important than the fact that GBS cases are being reported is the explanation for why this may be higher among Pfizer vaccine recipients, and what differences in formulation or patient demographics may help to provide more context.

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Not all weight-loss is the same, and a recent article published in The Atlantic helps point out some of the issues regarding the use of GLP-1 RAs to the extent that some patients may lose weight derived from muscle along with fat.

As these GLP-1 RAs become more popular and more prescribed there should be growing concerns over possible side effects related to taking these medications.

However, in this case it’s not necessarily a side effect of the drug, but instead it’s possible that the appetite-suppressing nature of GLP-1s and changes in dietary intake may unfortunately lead to muscle loss as the body scours for whatever source of calories it can find when in a deficit. As people begin to eat less they may source fewer protein-rich foods, which may also contribute to loss in muscle.1

This effect may not be severe in average adults, but in people who may be more susceptible to muscle loss or may already be weak (such as the elderly) the effects can be rather detrimental.

The Atlantic provides the following remarks:

The newest and much-hyped obesity drugs are, at their core, powerful appetite suppressants. When you eat fewer calories than you burn, the body starts scavenging itself, breaking down fat, of course, but also muscle. About a quarter to a third of the weight shed is lean body mass, and most of that is muscle.

Muscle loss is not inherently bad. As people lose fat, they need less muscle to support the weight of their body. And the muscle that goes first tends to be low quality and streaked with fat. Doctors grow concerned when people start to feel weak in everyday life—while picking up the grandkids, for example, or shoveling the driveway. Taken further, the progressive loss of muscle can make patients, especially elderly ones who already have less muscle to spare, frail and vulnerable to falls. People trying to slim down from an already healthy weight, who have less fat to spare, may also be prone to losing muscle. “You have to pull calories from somewhere,” says Robert Kushner, an obesity-medicine doctor at Northwestern University, who was also an investigator in a key trial for one of these drugs.

In this case, there’s a concern that the rapid muscle loss, a phenomenon named sarcopenia, may lead to fatigue and difficulty engaging in strenuous activity. For instance, a survey conducted with Japanese elderly2 who were on GLP-1 RAs noted a higher risk of falling as compared to those who weren’t on these medications, suggesting a possible heightened risk of harm in the elderly and more feeble.

In one article cited by The Atlantic3 they also make the following remarks:

Weight loss with semaglutide and tirzepatide is accompanied by favorable reductions in body fat [1••, 2••]. However, it is also accompanied by reduced lean body mass [1••, 2••, 45, 69, 70], which may influence factors that contribute to body weight regulation and other health outcomes. Lean body mass (LBM) is considered a significant driver of metabolic rate, with a reduction in lean tissue partially contributing to reduced daily energy expenditure [34]. The reduction in LBM may also influence the tonic drive to eat, which may further contribute to influences on body weight regulation [71]. Reduced LBM may be of additional clinical importance given its association with decreased bone mineral density and increased risk of fractures, as well as its relation to metabolic function (e.g., insulin sensitivity) and aerobic capacity [72, 73]. Adults 65 years and older are at increased risk of sarcopenia, characterized by an age-related decrease in skeletal muscle mass, with accompanying losses of strength and physical function [74, 75].

Again, muscle loss may be a typical consequence of various weight-loss processes. It’s also worth noting that the role of GLP-1 RAs and lean mass loss is not clear, as some evidence suggests a protective role against muscle wasting and sarcopenia in select mouse models and human studies.4

However, what may surprise readers is that doctors appear to be offering a solution in case of muscle loss- eat more protein and engage in resistance training:

Doctors currently offer two pieces of standard and unsurprising advice to protect people taking obesity drugs against muscle loss: Eat a high-protein diet, and do resistance training. These recommendations are perfectly logical, but their effectiveness against these drugs specifically is unclear, John Jakicic, a professor of physical activity and weight management at the University of Kansas Medical Center, told me. He is now surveying patients to understand their real-world behavior on these drugs.

This comment is extremely bizarre since, for all intents and purposes, wouldn’t a better diet and resistance training already help with weight management? As in, if you were to make these changes wouldn’t you also lose weight anyways? It’s quite strange how often recommendations for GLP-1 RAs tend to come with factors that would already be critical in weight management.

For now, the mixed evidence should suggest that we should be more on the lookout for clear evidence of muscle wasting and sarcopenia related to GLP-1 RAs, but raise concerns that those who are more affected by GLP-1 RAs may be more at risk of detrimental effects after taking these drugs.

And of course, it seems as if there is already a possible solution in the making to help with some of these side effects- by pairing GLP-1 RAs with other treatments that can help protect from muscle wasting:

Meanwhile, drug companies are already thinking about the next generation of weight-loss therapies. “Wouldn’t it be great to have another mechanism that's moving away from just appetite regulation?” Haines said. Companies are testing ways to preserve—perhaps even enhance—muscle during weight loss by combining Wegovy or Zepbound with a second muscle-boosting drug. Such a combination could, in theory, allow patients to lose fat and gain muscle at the same time.

[…]

Pairing bimagrumab with an existing obesity drug could potentially maximize the weight loss from both. Losing weight tends to get harder over time; as you lose muscle, your body burns fewer calories. A drug that minimizes that muscle loss—or even flips it into muscle gain—could help patients boost the amount of energy their body expends, while Wegovy or Zepbound suppresses calories consumed. The mechanisms of how this might actually work in the body still need to be understood, though. Previous studies of bimagrumab found that patients grew more muscle, but they didn’t necessarily become faster or stronger. Haines, who is planning a small study of her own with bimagrumab, is most interested in how the combination affects not the structural but the metabolic functions of muscle.

The solution to a possible pharma side effect is, of course, more drugs!

I’m not sure how well this will map our as it seems that this is a mere hypothesis, but it speaks greatly to how pharmaceutical companies perceive the common people and how willing they are to take as many medications as possible.

Consider that comments were made at the end of 2023 that obese patients should be provided both GLP-1 RAs as well as bariatric surgery for even better weight-loss possibilities:

Remember that weight-loss is not something that should happen by an “any means necessary” approach. How and what weight is being loss are just as important than the mere act of weight-loss.

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Recently the FDA has issued warnings to manufacturers of a rather new form of cancer therapy called CAR-T therapy with concerns that this new therapy may be associated with possible secondary T-cell malignancies.

This news has hit six companies which have approved CAR-T therapies on the market, with the FDA alerting manufacturers that they must place a warning label on their products for these alleged malignancies.

One example of these letters can be seen below, which was sent to Kite Pharma, Inc. who produces TECARTUS. The most pertinent paragraph is the last one, and for those interested a list of all 6 letters can be found on the FDA’s website, although be aware that the body of the letters are the same aside from approval date, manufacturer, and the intended recipient of the letter.

And following these concerns the FDA noted that the following warning labels must be included with these products:

All of these remarks follow comments made by the FDA in November raising concerns over reports of these malignancies in those who have been provided CAR-T therapy:

With the summary made at the time providing the following remarks:

The Food and Drug Administration (FDA) has received reports of T-cell malignancies, including chimeric antigen receptor CAR-positive lymphoma, in patients who received treatment with BCMA- or CD19-directed autologous CAR T cell immunotherapies.  Reports were received from clinical trials and/or postmarketing adverse event (AE) data sources.

FDA has determined that the risk of T-cell malignancies is applicable to all currently approved BCMA-directed and CD19-directed genetically modified autologous CAR T cell immunotherapies.  T-cell malignancies have occurred in patients treated with several products in the class.   Currently approved products in this class (listed alphabetically by trade name) include the following:

Abecma (idecabtagene vicleucel)

Breyanzi (lisocabtagene maraleucel)

Carvykti (ciltacabtagene autoleucel)

Kymriah (tisagenlecleucel)

Tecartus (brexucabtagene autoleucel)

Yescarta (axicabtagene ciloleucel)

Although the overall benefits of these products continue to outweigh their potential risks for their approved uses, FDA is investigating the identified risk of T cell malignancy with serious outcomes, including hospitalization and death, and is evaluating the need for regulatory action.

Now, these warnings have created a large stir-up among mainstream news outlets as well as among scientists, as noted by an article published in Science after these remarks from the FDA:

But before covering some of these concerns it’s worth briefly summarizing what CAR-T therapy is.

CAR-T Therapy Background

CAR-T therapies are a rather new method of fighting cancer and comes after a long list of other cancer therapies.

Because cancer cells are by all accounts like our own cells the targeting of cancer cells has been rather difficult, with early chemotherapy treatments relying on the idea that cancer cells divide far more rapidly than noncancerous cells as a method of killing the cancer.

This led to the development of various nucleoside analogs that are intended to inhibit DNA replication by relying on the faster rate of cancer cell replication to hopefully uptake these drugs at a higher rate as compared to uncancerous cells, resulting in the cancer’s destruction. Unfortunately, this method of treatment didn’t target only cancer cells, but also targeted any cells that undergo rapid division, thus leading to serious side effects such as hair loss, skin issues, brittle nails, and GI dysfunction for recipients of these treatments.

Afterwards cancer therapy moved towards the direction of immunotherapy which included antibodies that can bind to regions on the surface of cancer cells and direct immune responses. This provided a more targeted approach and helped to overcome some issues regarding cancer’s ability to avoid destruction by the immune system.

However, this research still had limitations, especially when it comes to cancers related to B-cells in which there are still challenges in alerting the immune system to target these cancerous cells.

This eventually would lead to the development of CAR-T as a method of targeting several forms of leukemias and lymphomas by way of genetically modifying autologous (i.e. your own T-cells) so that they can target receptors on the surface of B cells and lead them to their death.

In this case, the two main receptors targeted by CAR-T therapies are CD19 and B-cell maturation antigens (BCMA); the former is a critical component of signaling for B cells1 whereas the latter is involved with survivability/longevity of B cells.2

Many cancerous B cells express at least one of these receptors on their surface, and therefore have made them prime targets for cancer therapy, leading to development of ways to target these receptors and kill off these cells.

Now, this is where the CAR portion of CAR-T comes in, and it stands for Chimeric Antigen Receptor, and is a method in which T-cells can target CD19 and BCMA.

CAR is chimeric in nature; in that it comprises a synthetic receptor with one portion derived from monoclonal antibodies as well as another portion derived from T-cell receptors. Essentially, this chimeric receptor was constructed with the intent of providing both binding capabilities to either CD19 or BCMA while also inducing an intracellular T-cell response to help kill off these cancerous cells.

The conceptualization of this process may be rather difficult (and I certainly am not doing it justice in my explanation), but this chimeric structure is depicted in the following figure3:

Note here that the blue, extracellular portion of CAR is the antibody-like portion which binds to either CD19 or BCMA while the orange portion is involved with T-cell activation. Additional modifications are being made to CAR which include the addition of domains that may help with stimulation.

Now, CAR cannot operate on its own, but rather relies on a patients own T-cells in order to present CAR and target cancer cells (hence the T portion of CAR-T). Put another way, CAR must be inserted into a patient’s T-cell so that the patient can express CAR, and this is where genetic modification comes in.

Essentially, a patient’s T-cells are isolated and have the gene for CAR inserted into the cells, usually by way of utilizing a lentivirus or retrovirus that can incorporate the CAR gene. The T-cells are then proliferated and eventually added back into the patient where, hypothetically speaking, these CAR-expressing T-cells can kill off the cancer.

The process is outlined below (taken from NCI):

Is there serious concern with T-cell malignancies?

So with the background out of the way we should examine these concerns with a rational approach. What generally appears confusing about these FDA remarks is that they appear rather aggressive given their otherwise lackadaisical approach when it comes to other therapies.

In some ways, the FDA’s remarks have caught a lot of researchers off-guard as there didn’t seem to be a strong basis for these claims, as noted in the Science article from November:

The CAR-T community was taken aback by FDA’s announcement. Although CAR-T therapy comes with documented side effects, T cell cancers have rarely been associated with treatment in the past. “We have not seen any such event in our patients at MSK,” where hundreds have been treated, Sadelain says.

“We are all completely in the dark regarding the basis for the new concern,” adds Crystal Mackall of Stanford University, who like Sadelain is a pioneer in the field.

Researchers say it’s tough to assess these cancer risks because FDA’s announcement was light on the details.

Granted, remarks about the safety and efficacy of any drug should be taken with some degree of skepticism. As of now there doesn’t appear to be any clear explanation for these incidences of T-cell malignancies.

One concern appears to relate to the use of viral vectors in order to help with integration of the CAR gene into patient T-cells, as there appears to be a possibility that the CAR gene integration process may lead to other alterations in the T-cell genome that can result in cancer development.

The growing process of CAR-T cells may also unwillingly include cells predisposed to cancer development. In this case, selection of T-cells from patients may unfortunately select for cells bearing unwanted mutations, which may then propagate substantially as a consequence of the CAR-T growing process.

There is also the issue of radiation therapy which may induce mutations. Radiation and other chemotherapy treatments may be deployed in order to remove some of the CAR-T patient’s immune cells, making room for more of the CAR-T cells while reducing their need to compete for immunogenic signals, thus making the activity of CAR-T cells more pronounced. Patients undergoing CAR-T therapy may also have undergone chemotherapy and other standards of care beforehand, which carry risk of secondary cancers as well. These processes may unfortunately increase the risk of secondary cancers through DNA damage, and is an unfortunate general consequence of cancer therapies.

All of this suggests possible ways in which T-cell malignancies may occur, but it’s important to note that there again doesn’t appear to be a clearly defined relationship between these therapies and these reports of T-cell malignancies. Bear in mind that CAR-T therapy is also usually provided as a last means when other cancer treatments don’t appear effective. Patients also tend to lean older with other comorbidities which can also contribute to the increased risk of cancer.

What’s interesting is that the insertion of the CAR gene provides clinicians with a way to screen for possible cancerous T-cells by assessing for CAR gene positivity as well as expression of CAR through assays. As of now there doesn’t appear to be enough evidence to argue for or against CAR gene and protein expression and its relationship with these malignancies. This doesn’t mean that there is no relationship, but suggests more research should be conducted in order to examine for possible relationships.

Is this fear warranted?

It is part of this Substack to point out egregious issues when it comes to the FDA’s approval process as I have listed with several recent Alzheimer’s immunotherapies, as well as the growing discussion regarding these GLP-1 RAs. That is to say, I’m generally one who encourages more scrutiny of approvals and more robust assessment for adverse events.

But this is also one of the reasons why the current predicament regarding these CAR-T therapies warrants scrutiny. As of now it’s suspected that over 30,000 patients have received CAR-T therapies. On one hand, this number can be considered rather large within the scheme of overall cancer therapies. On the other hand, this number may pale in comparison to the number of people who have received COVID vaccines, Alzheimer’s immunotherapies, and GLP-1 RAs, and yet there doesn’t appear to be as large as a sweeping concern for these other, more widely used medications.

It also doesn’t help that recipients of CAR-T therapies are usually given this option after standard care fails, suggesting that outcomes and risk of secondary cancer may already be relative high among these individuals. It’s also worth noting that the FDA’s warning appears standard for all 6 approved CAR-T therapies, even though several of them utilize different viral vectors, CAR, and are provided for different B-cell malignancies to different demographics.

In essence, the FDA’s sweeping warning doesn’t provide any information as to whether certain CAR-T therapies pose a greater increased risk relative to others, or which reported cases of T-cell malignancies are attributed to which CAR-T therapy, making these warnings even more confusing given how ambiguous they seem to appear.

Again, note that the phrasing of the FDA’s letter, which is the same for all 6 manufacturers, makes it out as if there is evidence that each product may be associated with T-cell malignancies, suggesting that there may be evidence of these T-cell malignancies for all 6 products even though no clear evidence has been provided.

All of this adds further criticism towards the FDA’s rulings on safety and efficacy, as it raises serious questions why the FDA has focused so closely on these CAR-T therapies when there are concerns about other products on the market with clear safety issues.

As a caveat, note that the business of CAR-T therapies is rather lucrative, with some treatments costing upwards of nearly half a million dollars, in which case there would be a strong incentive for companies to downplay possible causal roles between CAR-T and these reported T-cell malignancies.

Hopefully the FDA provides clearer evidence for their concerns that makes them more warranted, but this adds to the growing fact that the FDA continues to be inconsistent in the battles they choose and how they gauge the actual safety and efficacy of therapies on the market.

Thus, these cases of T-cell malignancies should be taken seriously, but so should all adverse reactions reported to the FDA.

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Following behind European regulators it appears the FDA is looking into reports of several adverse events related to individuals taking GLP-1 RA medications, with the most notable adverse event being suicidal ideation.

This comes from a quarterly report from the months of July-September 2023 based upon reports to the FDA’s adverse event reporting system (FAERS):

Included in the quarterly report are case reports of alopecia and aspiration related to GLP-1s as well, and adds to a growing list of concerning adverse events associated with these medications.

This report also comes months after European regulators have reported that they were investigating possible suicidal ideations as well based on some of their own data:

So far the range of FAERS reports associated with these medications appears to range around the low hundreds, with some articles suggesting that Semaglutide reports of suicidal ideation near 200 case reports alone. When checking the FAERS dashboard for “Semaglutide” and narrowing down the Reactions to “Suicidal Ideation”, there appears to be 159 serious cases and 2 deaths associated with Semaglutide specifically.

It’s important to remember that FAERS reports can’t tell of any causative relationship between these drugs and the reports of suicidal ideation, but it’s interesting that these reports have begun to raise serious concerns, and adds to the growing list of other adverse events. And although these reports may be minimal so far, as more people begin to take these medications we may begin to see even more adverse events being reported of all different types and numbers.

This also follows as Eli Lilly, the makers of GLP-1 RAs Tirzepatide (Brand name Mounjaro and Zepbound) have come out stating that they will now help their Tirzepatide users with direct access to telehealth services, which can provide these medications directly to patients’ homes, becoming one of the first pharmaceutical companies to promote a direct-to-consumer approach in drug accessibility. This follows after companies such as Weight Watchers just released their own telehealth services.

So as there appears to be a growing number of concerning adverse events it doesn’t appear that these drugs are seeing any reservation in their prescriptions, and instead it seems like the approach is to make these drugs more accessible while long-term effects continue to be unknown.

Bear in mind it’s quite possible that these reports are not related to GLP-1 RAs in particular, however why is it that precautions are not taken to warn people of possible side effects to look out for, or why they should show some degree of hesitation before immediately jumping into taking these drugs?

Rather, the narrative around these drugs have pushed a “safe and effective” ideation, and in fact are now considered the norm for weight-loss in many circles.

This doesn’t help that a retrospective study released just today1 seems to suggest that there doesn’t appear to be elevated risk of suicidal ideation associated with Semaglutide when compared to other medications used for obesity or diabetes, although many outlets seem to hide the fact that this retrospective study was a comparative study to other medications. Instead, headlines like the ones below may make it appear that Semaglutide may actually reduce suicidal ideation when compared to the overall population, leading to a narrative that these drugs may help to treat depression:

More importantly, these articles obfuscate possible associations between incretin hormones such as GLP-1 and their relationship to other signaling systems. For instance, there appears to be some evidence that GLP-1 expression is inverse that of cannabinoid responses. In some individuals in which cannabis was administered there appeared to be reduced expression of insulin and GLP-1.2 This also follows from the fact that many obesity medications in use and in development appear to target cannabinoid receptor type-1 (CB1) by acting as antagonists/blockers or inverse agonists.

One example from the Wang, et al. study notes the drug Rimonabant, which was pulled from trials after high reports of suicidal ideation. Rimonabant acts as a CB1 inverse agonist, although the drug was later found to be a nonselective binder to other receptors.

In contrast, the active ingredient in cannabis is THC which acts as a CB1 agonist and induces the feelings of hunger (aka “the munchies”) after administering cannabis. This points to further possibility of some cross-talk between these agents in dictating feelings of hunger and satiety. As of now some animal studies have come out pairing CB1 antagonists with GLP-1 agonists to see their effects on obesity, with evidence noting greater loss of weight with dual therapies as compared to monotherapies.3

All this suggests that there may be some intimate relationship between GLP-1 and neuropsychology that have yet to be elucidated. Thus, it may be early and rather ignorant to assume that these drugs may not have some relationship with depression and other mental health diseases. As I mentioned in my previous article “And now suicidal ideation?” GLP-1 appears to be related to release of neurotransmitters and therefore may provide some insights into the suicidal ideation that can be seen with some SSRIs.

And so maybe all of these concerns may be a nothingburger, but with how common these medications have become there needs to be some degree of caution taken rather than alleging that these drugs are purely safe. It requires that these reports be taken seriously and investigated in order to see if there is some relationship between these GLP-1 RAs and possible suicidal ideation.

More restraint and better information can help the public make informed decisions without being influenced by influencers and pharmaceutical representatives.

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On Thursday the popular weight-loss/lifestyle company Weight Watchers began launching their new initiative titled the “GLP-1 Program”. The new program deviates heavily from the prior intents of Weight Watchers, which focused on balancing eating habits through their points system (along with other lifestyle changes) with a focus geared more towards the use of pharmaceutical interventions to help individuals lose weight.

This new program focuses predominately on individuals taking GLP-1s, with the program allowing customers to connect with doctors who can prescribe these medications, along with a slew of other supposed benefits at a steeper price, as noted by a CNN article on this program:

The company has started advertising the clinic on its website. The support program is included in the company’s $23 monthly membership. For additional access to clinicians who can prescribe weight loss medications, members will pay a $99 monthly fee – excluding the price of the medication. Customers can also receive a prescription from their primary care physician if they prefer.

Interesting- customers are expected to pay a higher premium in order to gain access to some of this access to clinicians. Also, make note that the program seems to refer to all forms of GLP-1 RAs and not Semaglutide alone.

And this shouldn’t come as a surprise. A few months ago Weight Watchers bought the telehealth company Sequence with a focus on providing GLP-1 RA medications virtually. This came as a sign of the company’s changing intentions to focus follow the now rampant trend of miracle weight-loss with pharmaceuticals. It also follows with this strange approach of Weight Watchers to chastise “diet culture” as I mentioned in a prior post:

Again, Weight Watchers seems to be a exemplar in following cultural trends, all with the intent of making money and remaining relevant as other companies such as Jenny Craig shut down.

The website itself comes with this following screen, making the new program appear flashy and exciting:

Learn more? Don’t mind if I do! Well, I actually do mind, as the link doesn’t provide much learning aside from more pitches for the greatness of this program. It even comes with this tagline of saying how they will help you on your “GLP-1 journey”:

What I find rather interesting is this constant use of “GLP-1” rather than “GLP-1 RA” in all of the marketing (and even the name of this program) as GLP-1 RA is the proper designation for these drugs. Something tells me that this is intentionally done to obfuscate the fact that these medications are synthetic and act differently than native GLP-1, and instead the use of GLP-1 is intended to draw likeness to something naturally produced in our body. Although they both bind to GLP-1 receptors, these receptor agonists last far longer in the body, and on the surface I suspect that some of the adverse events being reported may be aligned with the longer half-life and higher binding of these drugs to these GLP-1 receptors compared to native GLP-1. It’s likely that this stronger effect may inducing a greater-than-expected effect on the body, such as going from reduced stomach emptying to gastroparesis and ileus, as well as a whole growing list of possible adverse events that are being investigated:

But let’s turn back to this “learning”. The website provides a link to information on “GLP-1”, which again makes allusions GLP-1 while playing down what these GLP-1 RAs are.

Here’s a excerpt from an “expert” on what GLP-1 agonists do for weight-loss (emphasis mine):

“GLP-1 agonists activate the receptors in the body that respond to GLP-1,” says Kushner. In other words, they act like the body’s GLP-1. By activating receptors in the pancreas, they’re able to regulate insulin and control blood sugar. But they also activate receptors in the brain to curb appetite and in the gut to slow stomach emptying.

That’s why, notes Kushner, “when a person uses a GLP-1 agonist, they may feel less hungry, have less cravings and thoughts of food, and feel more full after a meal and between meals.” They may also raise your resting metabolism.

Again, these drugs are activating similar receptors as native GLP-1, but that doesn’t necessarily mean that such activation is not without its drawbacks. It’s a bit disingenuous to say that these are just like our own natural GLP-1. These drugs aren’t even administered when eating, so it’s not as if they are being administered at timepoints similar to when our natural GLP-1 would be released anyways.

The explanation for what GLP-1 agonists are is even worse, as it doesn’t even provide any explanation for what differences these drugs have relative to native GLP-1:

GLP-1 (which stands for glucagon-like peptide) is a gut hormone released by specialized cells in your intestinal tract after you eat. “When you consume carbohydrates, GLP-1 boosts the amount of insulin the body makes in order to bring your blood sugar back to normal,” says Dr. Robert Kushner, M.D., professor of medicine and medical education at Northwestern University Feinberg School of Medicine in Chicago. It does this in two ways: by triggering extra insulin, a hormone that helps lower blood sugar levels, and by inhibiting glucagon, a hormone that raises blood sugar levels.

While GLP-1 naturally occurs in the body, it only lasts about two to three minutes upon release. But the drug form of GLP-1, known as GLP-1 agonists, can last up to 14 hours in your body. And that means the effects last a lot longer too.

Although this article was from February, it’s important to note that there’s some easy-to-spot misinformation here for how long these GLP-1 RAs last within the body.

In this case I’m not sure where exactly the “14 hours in your body” value came from, as Semaglutide has a half life of around 168 hours, or over a week. Intuitively, we can infer this given the fact that this and other GLP-1 RAs are administered weekly. Loosely, remember that drugs are administered based upon their half-lives. Or put another way, the more frequently a drug needs to be administered in a day/week the shorter the half-life of that drug is. In this case, a half life of 168 hours means that it takes nearly up to a week before half of a dose of Semaglutide gets eliminated from the body (this doesn’t take into account the multitude of variables that would influence individual differences in half-lives). Therefore, it’s a bit of a stretch to allege that these drugs last only 14 hours in the body, otherwise most of it would likely be eliminated by the time a patient receives the second dose.

But what about adverse reactions? The websites provides an all-too familiar description in which the most minor of adverse reactions are listed:

Since most GLP-1 agonists such as Wegovy and Saxenda (and the soon-to-be-approved Mounjaro, which combines a GLP-1 agonist with something called a GIP) are taken via injection, a little irritation or discomfort wherever you inject is fairly common. Beyond that, though, side effects tend to be limited to the gastrointestinal system, where these medications work by changing gut hormones. “The most commonly reported side effect is nausea, which feels like motion sickness or morning sickness,” says Dr. Sarah Fishman, M.D., a professor of medicine, endocrinology, diabetes, and bone disease at Icahn School of Medicine at Mount Sinai in New York City. Also on the list? Constipation and diarrhea, as well as some abdominal discomfort and bloating. Research indicates these effects could result from slower stomach emptying.

However, “these side effects are often intermittent, mild, and short-lived,” she says. They usually happen when you first begin taking the drugs, a period when you are steadily increasing your dosage. As a result, “they usually resolve within a few days of the injection, and within a few weeks of longer term use,” says Fishman.

Intermittent, mild, and short-lived? Sounds a bit familiar…

On one hand this article is from June and may have based the information around the available information at the time. On the other hand, if were to start a program titled “GLP-1 Program” I would probably update my articles to reflect some of the adverse events being examined today.

So not only do these articles fail to outline the proper extent of what these GLP-1 RAs are they also seem to lack any information on serious adverse events being reported. The article does note medullary thyroid cancer and these medications, but that portion of the article seems to be confusing more than anything:

And if you’ve heard that GLP-1s can increase your risk of thyroid cancer, don’t be alarmed. “There is a theoretical increased risk of medullary thyroid cancers, but it’s not clear how likely this is to actually happen in people,” says Fishman, who along with Vash stresses that the link has only ever been studied in animals.

Saying that it’s not clear how likely this will happen in people isn’t evidence that this wouldn’t happen. Again, absence of evidence is not evidence of absence.

Apologies to readers who may be bored by the Ozempic and GLP-1 RA coverage, but I find it important to highlight that this is the direction that the pharmaceutical industry is taking. This is the new bread and butter of Big Pharma in a post-COVID vaccine world.

And because of this the pharmaceutical industry, the medical industry, and even the diet and lifestyle industry is getting in on finding ways to entice people to become dependent upon these medications.

The fact that Weight Watchers of all companies is getting in on the Ozempic craze should tell us a lot about how profit-driven many of these companies are, and quite frankly how often they are willing to give up any semblance of integrity if it means following cultural trends and making a quick buck.

And let’s not forget that Oprah Winfrey, the highest-profile individual to be the face of Weight Watchers, has come out detailing her use of the drug.

Is it really any surprise that she would now promote this medication? Someone who is the face and investor of a company? Talk about conflicts of interest…

The USA Today article is something else as well, because it doesn’t raise any concerns about ethics and persuasion from Big Pharma, but instead enforces this idea that willpower and steady lifestyle changes aren’t enough to lose weight (emphasis mine):

Winfrey said it wasn't until this year that she added weight-loss medication to her health regimen, which also includes hiking, eating her last meal at 4 p.m. and drinking a gallon of water a day. She also serves as an investor and board member for WW, formerly WeightWatchers, which announced in March it would add weight loss drugs like Wegovy to its program.

"I was actually recommending it to people long before I was on it myself," Winfrey told People. "I had an awareness of medications, but felt I had to prove I had the willpower to do it. I now no longer feel that way."

She added: "Obesity is a disease. It's not about willpower — it's about the brain."

“Your obesity is outside of your control and only medications with unknown side effects and high costs can provide you the help you need”.

Now, let me be clear and state that I am not downplaying the difficulties in losing weight or denigrating those who take these medications. I am simply pointing out that pharmaceutical companies are finding more ways to prey on the public, and targeting the obesity epidemic in such underhanded ways is the new norm.

The article goes on to state how Oprah’s transparency in her use of these drugs will remove the “shame” in people who may want to seek out these medications but may not feel like they can do so:

"A lot of people look up to Oprah as a source of mentorship, inspiration and guidance," he says. "If Oprah speaks about a medication and shines light about it, then a lot of people will not only look at it more favorably, but they would also research it more on their own, get more information and learn more about it."

After looking into the science behind the medication, Winfrey said she "released my own shame about it" and consulted her doctor, who prescribed it to her. Vazirnia emphasizes these medications can cause side effects and should only be taken under medical supervision.

"The fact that there's a medically approved prescription for managing weight and staying healthier, in my lifetime, feels like relief, like redemption, like a gift, and not something to hide behind and once again be ridiculed for," Winfrey said. "I'm absolutely done with the shaming from other people and particularly myself."

There’s a lot to say about the language in this excerpt, but I can’t help but feel like this is some pitch from pharmaceutical executives, using celebrities and high-profile individuals as a way of marketing these drugs. It’s also strange that the era that has enforced such ridiculous notions such as “fat shaming” are now trying to remove “Ozempic shaming”. Heaven forbid we criticize a move to medicalizing society even more than it already is.

In any case, this is a sign of things to come and a reason for people to remain vigilant against cultural trends and influences.

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In another hit to Pfizer and its investors the pharmaceutical giant saw a 5% decline to their stocks on December 1st.

This came after Pfizer reported that they would no longer progress their own GLP-1 RAs to further clinical trials after noticing high patient dropout and a concerning number of side effects such as nausea and vomiting. In this case, one potential drug named Danuglipron has been halted and seeing possible reformulations coming down the line in the near future. This comes months after Pfizer halted clinical trials for another potential GLP-1 RA Lotiglipron due to concerningly elevated levels of liver enzymes within blood of patients from the treatment group, suggesting possible hepatotoxicity related to this drug.

Pfizer includes the following within their press release published yesterday regarding their discontinuation of Danuglipron:

While the most common adverse events were mild and gastrointestinal in nature consistent with the mechanism, high rates were observed (up to 73% nausea; up to 47% vomiting; up to 25% diarrhea). High discontinuation rates, greater than 50%, were seen across all doses compared to approximately 40% with placebo. No new safety signals were reported and treatment with danuglipron was not associated with increased incidence of liver enzyme elevation compared to placebo. Data from this study will be presented at a future scientific conference or published in a peer-reviewed journal.

I have covered this new generation of medications previously as it appears that this is the direction that pharma companies are taking. Unlike the current iterations of GLP-1 RAs on the market these new medications are expected to be easier to administer and cheaper to produce, making them highly sought out by companies attempting to pivot towards a new market as COVID vaccines and treatment interest continue to decline.

Please take a look at the prior article and note the differences in structure between GLP-1 RAs already on the market and ones that make up this new generation:

It appears that Pfizer may have hoped to enter into this burgeoning market topped by other companies such as Novo Nordisk, which is now considered the largest company in Europe’s stock markets due to the success of their GLP-1 RAs Ozempic and Wegovy:

As of now Pfizer doesn’t appear as if they will halt their attempts at releasing their own GLP-1 RAs, with talks suggesting that Pfizer may be attempting to alter the release rate of Donuglipron, with the hope that a a slower release may attenuate some of the side effects:

“We believe an improved once-daily formulation of danuglipron could play an important role in the obesity treatment paradigm, and we will focus our efforts on gathering the data to understand its potential profile,” said Mikael Dolsten, MD., PhD., Chief Scientific Officer & President, Pfizer Research and Development. “Results from ongoing and future studies of the once-daily danuglipron modified release formulation will inform a potential path forward with an aim to improve the tolerability profile and optimize both study design and execution.”

But as more and more people take interest into these alleged weight-loss drugs we are seeing additional side effects that were not normally reported (or at least overlooked) such as stomach and intestinal paralysis, with possible suicidal ideation being the newest possible side effect being investigated:

Given these increasing concerns over safety it begs the question if these newer generations of medications will be safer.

As I remarked in my prior post these drugs are attempting to mimic the agonistic effects of a hormone that induces widespread effects throughout the body. This includes inducing insulin secretion from the pancreas, signaling the stomach and intestines to slow down digestion, and can bind to various neurons within the CNS to possibly induce a feeling of fullness- the latter mechanism now being looked at as a possible explanation for GLP-1 and these drugs appearing to reduce the need for addictive substances.

All this to say that the effects of these drugs are not one-to-one. They are not only reducing weight or feelings of hunger. Rather, they are likely inducing widespread effects throughout the body. This tells us that there’s a lot more that’s going on, and certainly a lot more than is being reported by these companies. Again, these drugs are intended to mimic the effects of an endogenous hormone.

And this may be the likely reason why we aren’t close to having a miracle weight-loss drug, and in reality may be the reason why we should be careful of wishing for such a medication if it were to ever appear. The body is far more complex than we make it out to be, and when science takes a reductive approach that focuses only on dealing with symptoms or a specific problem we may lose sight of the forest for the trees.

The growing evidence suggests that there’s a lot more going on with GLP-1, and so we should expect the same for these medications which have far longer half-lives and may be more bioactive.

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As more people hop onto the GLP-1 RA bandwagon with drugs such as Wegovy or Ozempic more reports of concerning safety issues are making their way into the media, with the next big concern being possible suicidal ideation and self-harm in those taking these drugs.

So far, the reports provided are anecdotal and relegated to adverse events reporting systems. Nonetheless, the signal appears to be enough that several agencies are looking into these reported safety signals.

For instance, the European Medicines Agency listed both Liraglutide (sold as Victoza and Saxenda) and Semaglutide (Wegovy/Ozempic) as a topic of discussion for their July pharmacovigilance agenda:

As the EMA reports in a November article, the emerging safety signal was brought on by initial reports to Iceland’s medicine agency, which eventually led to over 150 documented reports by the EMA:

EMA’s safety committee, the PRAC, is reviewing data on the risk of suicidal thoughts and thoughts of self-harm with medicines known as GLP-1 receptor agonists,¹ including Ozempic (semaglutide), Saxenda (liraglutide) and Wegovy (semaglutide). These medicines are used for weight loss and for treating type 2 diabetes.

The review was triggered by the Icelandic medicines agency following reports of suicidal thoughts and self-injury in people using liraglutide and semaglutide medicines. So far authorities have retrieved and are analysing about 150 reports of possible cases of self-injury and suicidal thoughts.

Liraglutide and semaglutide medicines are widely used, with an exposure of over 20 million patient- years² to date. It is not yet clear whether the reported cases are linked to the medicines themselves or to the patients’ underlying conditions or other factors.

Note that there’s a strong relationship between obesity, diabetes, and depressive symptoms, and so one has to consider the fact that underlying suicidal thoughts may be derived from factors that would lead one to seek out these GLP-1 RA medications, and may not be directly related to the actual drug.

The EMA is expected to provide a report this month in regards to their investigation.

In the meantime, the question remains why suicidal ideation would even be a factor in a possible weight-loss medication.

As several readers have mentioned, one clear thing worth considering is the fact that these GLP-1 RAs are not just typical, one-action drugs, but rather are acting as hormone mimetics for native GLP-1.

As GLP-1 shows widespread effects on the body it may not come as a surprise that a drug that not only binds to GLP-1 receptors, but does so more strongly with reduced metabolism relative to native GLP-1, may also elicit other unwanted effects.

This can be seen in reports of stomach paralysis in some individuals taking these drugs, which may suggest an overexaggerated response otherwise not produced by native GLP-1:

Which is further corroborated by the FDA including intestinal paralysis on Ozempic’s label:

And due to the fact that Ozempic-like drugs are being examined for their possible role in helping treat addiction:

Indeed, it does appear that there may be a relationship between GLP-1 and depression, which has led researchers to wonder if GLP-1 RAs may aid in treating depressive symptoms.

A review from Detka, J., & Głombik, K.1 notes some of these possibilities, which includes reduction of neuroinflammation, restoration of the gut-brain axis, and other benefits that may come from GLP-1 RAs:

Again, keep in mind that obesity, poor diet, and microbiome dysfunction may play causative roles in depression, and so it’s quite possible that GLP-1 RAs may help to restore homeostasis that may have been lost.

Another review from Laurindo, et al.2 notes that GLP-1 RAs may help to improve neurogenesis (production of neurons) and production of neurotransmitters:

The neurotransmitter imbalance (serotonergic, dopaminergic, and noradrenergic dysfunctions) is directly related to neuroinflammation and can lead to behavioral changes and behavioral impairment. The stimulation of GLP-1 receptors in the cerebral cortex and hippocampus is related to the modulation of serotonin, dopamine, gamma-aminobutyric acid, and glutamate. Additionally, GLP-1 stimulates dopamine turnover in the amygdala due to its actions on dopamine receptor 2. Due to these effects as a neurotransmitter release supporter, GLP-1 can be related to the amelioration of depressive behavioral signals and symptoms [84,85,88].

Depression is related to impairments due to neurogenesis, principally in the hippocampus, as well as neuronal atrophy and a decreased volume of several neuronal areas, such as the hippocampus, cortex, and limbic lobe regions of the brain. These regions are related to emotion and cognition in the normal brain. Decreased hippocampus volume and hippocampus atrophy are related to depressive episodes in patients affected by depression. Past studies demonstrated that the stimulation of neurogenesis in the hippocampus influences emotional regulation and depression, acting as an anti-depressant molecule due to increased serotonin receptors’ increased activity and reduced neuronal loss by neuronal replacement. GLP-1 can stimulate neurogenesis by several different pathways. Studies with human neuronal cells could demonstrate that GLP-1 increases cell proliferation, and studies with animal models could indicate the stimulation of the neuronal cells by GLP-1 and by the activation of GLP-1 receptors. In rodent models, liraglutide promoted neurogenesis in the hippocampus. In mouse models, neurogenesis was activated by the GLP-1 stimulations of cAMP/PKA and Akt/GSK3 cellular signaling pathways [84,85,88]. Figure 9 shows some effects of GLP-1 in the pathophysiology of depression.

Overall, the proposed mechanisms of treating depression with GLP-1 RAs, aside from reductions in diabetes and obesity, seem to be rather multifaceted. So far clinical trials have been limited, with most trials of GLP-1 RAs as antidepressants being conducted in people with Type-II diabetes and therefore may be confounded by the direct actions of GLP-1 RAs on diabetes management. Nonetheless, there’s growing interest in figuring out many different uses of GLP-1 RAs. Some recent systematic reviews/meta-analyses have raised further considerations into this avenue of research as well.3

Unfortunately, with all this being said, we are still left with a curious question of why exactly suicidal ideation may be related with the use of these GLP-1 RAs.

Hopefully we get more answers in the future, but for now I’m curious if these drugs may be inducing effects similar to antidepressants such as selective serotonin reuptake inhibitors (SSRI), which are known to increase the risk of suicidal ideation in susceptible individuals (albeit this hypothesis is also seen as controversial).

To that extent, it’s possible that these reports of suicidal ideation may be the same as all of these other adverse events being reported. That is, there may be such a thing as too much of a good thing when it comes to these GLP-1 RAs, such that a subset of the population may hyper respond to these drugs which may lead to these reported adverse events.

It’s curious if some people may experience suicidal ideations at higher doses of GLP-1 RAs, or even if these drugs induce too strong of a release of neurotransmitters or synaptic function, thus leading to suicidal ideation.

More research needs to be conducted in order to figure out if these reports are clear signals or noise related to other circumstances, and more research will be needed to find mechanistic explanations for these adverse events.

But more importantly, more awareness needs to be made that these drugs are not merely antidiabetic or weight-loss drugs, but that these drugs are acting as hormones (and strong ones at that). There is plenty we have yet to uncover about native GLP-1, so who’s to say that more adverse events may not be reported as these drugs become more and more popular.

More awareness, more research, and more hesitancy should be practiced when looking at these, and other medications.

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In following a post earlier in the week noting ileus, or intestinal paralysis, being included in the FDA’s label for Ozempic, a recent study published in JAMA1 seems to provide further evidence that these highly popularized and sought after drugs may not be as safe as they appear to be.

Published Thursday, the study looked at a random sampling of over 16 million patients between the years 2006 and 2020 for their use of GLP-1 RAs Semaglutide or Liraglutide and compared incident rates to those of a comparator drug bupropion-naltrexone (brand name Contrave) which has been used for weight-loss for several years.

Because of the timeframe in which the study was conducted researchers limited their inclusion criteria to those who both did not have diabetes and also were not taking anti-diabetes medications, while also having evidence of obesity up until inclusion into the study:

We used a random sample of 16 million patients (2006-2020) from the PharMetrics Plus database (IQVIA), a large health claims database that captures 93% of all outpatient prescriptions and physician diagnoses in the US through the International Classification of Diseases, Ninth Revision (ICD-9) or ICD-10. In our cohort study, we included new users of semaglutide or liraglutide, 2 main GLP-1 agonists, and the active comparator bupropion-naltrexone, a weight loss agent unrelated to GLP-1 agonists. Because semaglutide was marketed for weight loss after the study period (2021), we ensured all GLP-1 agonist and bupropion-naltrexone users had an obesity code in the 90 days prior or up to 30 days after cohort entry, excluding those with a diabetes or antidiabetic drug code.

For those curious Contrave is an oral therapy comprised of Bupropion (aka Wellbutrin), which exerts its effect by inhibiting the reuptake of neurotransmitters such as dopamine and norepinephrine. There are a few other effects on the CNS as well, but the general intent is that bupropion eventually leads to appetite suppression.

Naltrexone (brand name Revia) is an opioid antagonist and has generally been used for those dealing with alcohol and opioid dependency. It’s alleged that blocking of opioid receptors reduces the euphoric effects of opioids such as heroin, and hopefully results in reductions in opioid dependency. The use of Naltrexone for obesity appears to relate to its dampening of reward systems in the brain- use of Naltrexone is argued to reduce food cravings because it reduces the pleasurable, reward feelings one may get from eating.2

Patient data was measured from time of first use of a drug up until any reported incident:

Patients were observed from first prescription of a study drug to first mutually exclusive incidence (defined as first ICD-9 or ICD-10 code) of biliary disease (including cholecystitis, cholelithiasis, and choledocholithiasis), pancreatitis (including gallstone pancreatitis), bowel obstruction, or gastroparesis (defined as use of a code or a promotility agent). They were followed up to the end of the study period (June 2020) or censored during a switch.

Note that matching didn’t appear to occur in this study. Patients within the Bupropion/Naltrexone group were predominately male. Patients within the Semaglutide group also had higher rates of hyperlipidemia, although the researchers conducted a sensitivity analysis excluding this variable in order to see if it played a role in the outcomes.

The final number of patients included 4144 Liraglutide, 613 Semaglutide, and 654 Bupropion/Naltrexone users.

When comparing incident rates based on incidents in patient groups there appeared to be elevated rates of pancreatitis and gastroparesis among GLP-1 RA users. Note that biliary disease appeared to be slightly lower in Semaglutide users when compared to Bupropion/Naltrexone users. There also didn’t appear to be any incidences of bowel obstruction among the Semaglutide group included, with the Liraglutide group showing the highest incidence rate of bowel obstruction:

When comparing hazard ratios, with Buproprion/Naltrexone acting as a comparator reference, there was notably increased risk of an incident with respect to use of GLP-1 RAs relative to Buproprion/Naltrexone even when hyperlipidemia was excluded:

Note that the hazard ratio used above collected GLP-1 RAs together, and so different risks between Semaglutide and Liraglutide will be masked. This is an issue given that Hyperlipidemia occurred in more than half of all Semaglutide patients who had an incident. Bowel obstruction appears to occur predominately within the Liraglutide group as well. Keep in mind that, although both Semaglutide and Liraglutide operate as GLP-1 RAs, minor molecular differences may lead to other, more nuanced differences between the two drugs which need to be considered within the context of adverse reactions.

Note also that the use of Bupropion/Naltrexone as a comparator control means that the hazard ratios calculated are relative to incidence rate of those taking another medication, and therefore doesn’t provide any background comparison for people who may be obese but not taking any medications.

The patient information also doesn’t provide any time from first use of medication to first incident. Because of the possible long-term use of GLP-1 RAs for weight loss there should be a considerable concern over prolonged use of these drugs and increased risk of adverse reactions. There also isn’t any information on dosage (Semaglutide may refer to different doses, with Wegovy having the highest dose of Semaglutide) which we may argue may correlate with increased risk of adverse reactions. Lack of BMI data for patients is also a problem. BMI assumptions appear to have been done based on patient codes that infer an obese BMI. It would be interesting to consider if BMI differences were noticeable across the groups.

Overall, I take this study more as a point of interest. It suggests that there may be more things going on than nebulous announcements that these GLP-1 RAs are “safe and effective”. It warrants further investigations, especially as interest in these drugs continue to grow.

Note that, although the risk of these adverse reactions are considered rare, the risk will likely occur in a larger population the more people take these medications. It warrants understanding who may be at risk, and why it’s necessary to do research into the things we put into our bodies.

Or maybe, it’s another reminder that we should take the old-fashioned way in losing weight before turning to medications.

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On September 22nd the FDA added an additional warning to Ozempic’s label, this time noting ileus, or intestinal paralysis, as a post-marketing adverse reaction, suggesting that these adverse reactions may not have been found or noticed during clinical trials, but have now been reported, especially as these drugs gain in popularity.

This also comes months after reports of stomach paralysis (gastroparesis) in a few individuals, raising growing concerns that these popularized-by-celebrities GLP-1 RA drugs may not be as safe as they are made out to be.

The effect here may be similar to gastroparesis, to the extent that GLP-1 RAs may slow down peristalsis ( contractions/relaxations that move digested food through the gastrointestinal tract), so too may GLP-1 RAs slow down movement of digested material through the intestines, possibly as a mechanism to slow down eating and control insulin spikes (my assumption, at least).

Strangely, this effect was noticed even back in 20171 with the drug Liraglutide (Brand name Victoza) through a study which utilized capsule endoscopy to see the transit time of the endoscope through both the stomach and intestines of Type II Diabetes patients.

The authors noted that, relative to transit time prior to Liraglutide administration, patients provided up to 0.9 mg Liraglutide showed noticeable increases in both gastric and intestinal transit time, suggesting a slowing of bowel movements:

The present study performed capsule endoscopy before and after liraglutide administration and quantitatively evaluated the effects of liraglutide on motility in the gastrointestinal tract.

Liraglutide exhibited gastric-emptying delaying effects, as reported previously. However, the drug also inhibited duodenal and small bowel movements at the same time.

The study was very small, and there were some widely varied results such as a few patients who showed fast transit times following Liraglutide administration, which may be related to diarrhea (this symptom was noted, although considered not severe and not distinctly related to any patient).

That being said, this provides at least some evidence that this slowing down of bowel movements is something that has been documented in prior years. Although it doesn’t explain the phenomena of gastroparesis or ileus in particular2, it does at least suggest a possible risk for these events, especially for those who may be more sensitive to these drugs and therefore may experience stronger responses in reduced bowel movements.

The authors suggest, citing one of their prior studies, that this effect may be related to GLP-1RA activation of the sympathetic nervous system, which may result in a slowing of peristalsis:

Previously, our team reported that the long-acting GLP-1RA liraglutide promotes sympathetic nervous system activity for 24 h [16]. This 24-h promotion of sympathetic nerve activity can activate the greater splanchnic nerve (Th5–9), lesser splanchnic nerve (Th10–11) and sympathetic nerve branch of Auerbach's plexus. Such activation would result in an inhibitory effect of the sympathetic nervous system on intestinal peristalsis, which may extend not only gastric-emptying time, but also duodenal–small bowel-emptying time.

And in 2022 a review of the FDA’s AERS database3 for GLP-1RA-related adverse events noted an unexpected signal for ileus.

Unfortunately, I don’t have access to this study. The Results note the following based on the Abstract (emphasis mine):

A total of 71,515 records involving GLP-1RA monotherapy were submitted to the database, of which 16,350 records were GLP-1RA/IME pairs. Significant disproportionality emerged in five SOCs: 'gastrointestinal disorders' (n = 13,104; lower end of the 95% confidence interval (CI) of the IC [IC₀₂₅] = 1.34), 'investigations' (n = 6889; IC₀₂₅ = 0.64), 'metabolism and nutrition disorders' (n = 2943; IC₀₂₅ = 0.44), 'neoplasms benign/malignant' (n = 1989; IC₀₂₅ = 0.01), and 'hepatobiliary disorders' (n = 1497; IC₀₂₅ = 0.38). The most common AEs were pancreatitis, nausea, and weight decrease. Unexpected significant AEs were detected, such as ileus, osteomyelitis, renal cell carcinoma, nephrolithiasis, and drug-induced liver injury.

The actual number of ileus-related events are not provided, but are likely to be low relative to other adverse events.

That being said, the main issue with these adverse events reports is that it notes a severe side effect that many in the public may not be aware about. It certainly undermines the constant announcements that these drugs are safe and effective, and raises a serious question for determining who may be harmed by the use of these drugs, especially as they gain popularity.

It’s worth noting that other GLP-1RAs such as Mounjaro (from Eli Lilly) as well as Wegovy, a higher dosage of Semaglutide than Ozempic, also carry this warning label, and so this actually doesn’t seem out of the ordinary when it comes to this class of drugs, and may be in line with the mechanisms proposed by above.

In a CNN report following the ileus addition to Ozempic’s label, it’s reported that Novo Nordisk, the maker of Ozempic, doubled down on suggesting that Ozempic is safe and effective if used correctly:

“Novo Nordisk stands behind the safety and efficacy of Ozempic® and all of our medicines when used consistent with the product labeling and the approved indications,” the company said.

Strangely, Novo Nordisk also remarks that the slowing down of digestion is something that is commonly known:

“Gastrointestinal (GI) events are well-known side effects of the GLP-1 class,” Novo said in a statement. “For semaglutide, the majority of GI side effects are mild to moderate in severity and of short duration. GLP-1’s are known to cause a delay in gastric emptying, as noted in the label of each of our GLP-1 RA medications. Symptoms of delayed gastric emptying, nausea and vomiting are listed as side effects.”

This fact is a mischaracterization given that most people who are now taking these drugs are unaware of these side effects. This may be due to clinicians who may not be aware of these side effects, or may not even bother to alert patients to their possibility. Patients may also ignore labels on medications, and unless they experience the side effects themselves or see them reported in a mainstream outlet may be none the wiser to these risks.

Sure, the pharmaceutical manufacturers may be aware of these risks, but it certainly doesn’t mean the public are. This is an indication of a clear lack of dissemination of medical information, where recorded knowledge may not be publicly-known knowledge.

As these drugs gain in popularity we may see far more of these adverse reactions. It’s important that people know what they are taking, how they work, and what risks to look out for rather than rely on a nebulous statement of “safe and effective”.

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