Is Ozempic already on the out?

Research for another Type II diabetes/ weight-loss drug is underway that appears to lack the side effects of typical GLP-1RAs including nausea and vomiting.

Most of my articles remain free to allow for open access to the information provided. However, given that Substack is the main way I am supporting myself (for the time being) I release occasional posts for paid members to encourage support. Please consider becoming a paid member or supporting me through my ko-fi in order to help support the work that I put out. Note that ko-fi donations do not provide access to paywalled content on Substack.

However, if you wish to unsubscribe from being a paid member please note that Substack has an autorenewal policy, and so please be aware if your autorenew is coming up in case you would like to unsubscribe.

Note: Like with all posts the following is not an endorsement of the drug described below, but is intended to provide more information on the subject matter.

Cover image from Freepik

---

As quickly as Ozempic has made waves and controversies another drug appears to be under development, and one that has a better safety profile than the GLP-1RAs on the market so far.

In the prior post I overlooked many of the side effects of Semaglutide in favor of focusing on its mechanism of action.

It would appear that the side effects of these GLP-1RAs are inherently a consequence of the these drugs’ mechanisms of action.

Remember that GLP-1 receptors are located within our central nervous system which, when bound by receptor agonists, help to signal a sense of fullness and satiety.

If we consider the flow of signaling response, GLP-1 is first released when food is eaten to help control the increase in blood sugar. However, as nutrient and food consumption continue the levels of circulating GLP-1 may become high enough to translocate into the CNS, bind to GLP-1 receptors there, and begin to signal a sense of fullness to alert an individual to stop eating.

But what would happen if someone keeps eating? Well, we may infer that GLP-1 will continue to be released, binding to receptors within the CNS and inducing a signaling effect until the signal becomes so strong that it actually produces a serious side effect of nausea.

Essentially, your body is telling you you’ve eaten too much and to stop, but if that threshold is surpassed even further then the feedback may signal to relieve excess food out of you in any way possible such as through vomiting or through diarrhea.

This is merely a speculation, but from an evolutionary standpoint this side effect would make sense as a feedback mechanism that prevents over consumption.

Some evidence has suggested a correlation between symptoms of nausea and weight loss, although these results appear mixed (Smits, M. M., & Van Raalte, D. H.¹):

Finally, although nausea and vomiting are perhaps unwanted effects, they may also be partly responsible for aspects of the drug’s efficacy as indicated above. As such, in some studies, nausea induced by GLP-1RAs is linked to weight loss (51, 52). For example, obese subjects treated with high-dose liraglutide who experienced (transient) nausea had on average 2.9 kg (95%-CI 0.5–5.3) more weight loss compared to those without GI events (51). In a mediation analysis of the SUSTAIN 1 to 5 trials, a small component (0.07 to 0.5 kg) of the total treatment difference in weight loss was explained by nausea or vomiting (52). In contrast, when combining data from SUSTAIN 3, 7 and 10, the occurrence of nausea and vomiting was not associated with superior weight loss (53). Whether this route plays a role in the beneficial effects of GLP-1RA on body weight needs further studying.

I did come across a Reddit post in which someone on Ozempic commented that as soon as the nausea went away the hunger came back. Unfortunately, I can’t find that post anymore but it’s a rather interesting piece of anecdote.

Remember that these GLP-1RAs are essentially acting as a hormone, artificially telling the body that it is not hungry even if nothing has been consumed.

The difference in side effects across individuals could likely be contributed to the type of GLP-1RA taken (limited data suggest higher molecular weight forms may not readily pass the blood-brain barrier and thus may not trigger that feeling of fullness/nausea). This may also stem from higher GLP-1 receptors in select individuals who may become far more sensitive to these drugs.