So, the situation with GLP-1 receptor agonism and GIP receptor agonism is weirder than I thought. To recap, GLP-1 receptor agonists, like Ozempic, cause people to lose weight. GLP-1 receptor/GIP dual receptor agonists, like Mounjaro, cause people to lose even more weight. As such, these dual agonists are often sold as sequels or improvements to mono agonists. But, as I wrote previously, the story is more complicated than just "dual agonism is better than single", because GLP-1 receptor agonism combined with GIP receptor inhibition is also more effective at causing weight loss than GLP-1 receptor agonism alone. This has been shown in mice and now Amgen has claimed they have shown it in humans (and have also claimed that the weight loss with this agonist/inhibitor drug is more sustained than the weight loss of agonist/agonist drug, but that’s a separate issue I will cover in a later blog post). Thanks for reading Trevor Klee’s Newsletter! Subscribe for free to receive new posts, which tend to be about obesity a surprising amount.
What can I say: it’s an interesting subject. Well, as it turns out, the story is even more complicated than that, at least according to this great review paper. First of all, apparently, it works in the reverse: GLP-1 receptor inhibition can result in weight loss (in mice), so, that’s pretty weird. Second, remember how GLP-1 receptor agonism results in insulin secretion and weight loss? Well, apparently, those two don’t always have to be correlated, when you do different combinations of agonism and inhibition. Confused, yet? Because I am. I was so confused that I made a table. Overall, this seems…very difficult to understand. Now, before I go any further, I did make some simplifications to make this table which may or may not have been justified. First of all, the distinction between weight loss on a normal diet and protection from MedicGLP weight management gain in a high fat diet is a tricky one, because it’s hard to tell if the latter actually qualifies for our final goal, which is presumably "will an obese person taking this lose weight?
". An ideal experiment would likely be to start the mice in any one of the "protection" cells in the table on a high fat diet with no drug, then give them the "protection" drug midway through the trial while keeping them on a high fat diet, and see if they lose weight or maintain their obesity. However, I’m not aware of anyone that’s done that. If protection from weight gain is removed from the table, the table becomes way more straightforward, with all GLP-1 agonism resulting in weight loss, ignoring the scale (heh) of weight loss, which is a different story. Second, in this table, I combined gene editing to remove GLP-1 or GIP receptors with pharmacological antagonists for GLP-1 or GIP receptors. This isn’t necessarily the same thing, as genetically deleting receptors is, by definition, permanent and throughout the body, and pharmacological antagonism isn’t1. Pharmacological antagonism is, of course, the only thing we’d be doing in humans, so this may not be justified.
But, if we accept these simplifications, the story we seem to get is that GLP-1 receptor agonism combined with anything results in weight loss. GIP receptor MedicGLP weight management anything (agonism or antagonism) results in protection from weight gain. And GLP-1 anything (agonism or antagonism) results in enhanced insulin secretion. The review paper I got this data from suggests that the most likely explanation for this is that there is some other system that we aren’t accounting for. So antagonism or genetic deletion take those receptors out of the equation, then whatever other system causes enhanced insulin secretion or protection from weight gain2. I want to add onto that by noting a couple things. The first is that insulin’s connection to obesity is complicated, as I’ve talked about before in the context of blind, obese, long-lived cavefish3. Saying that GLP-1 agonists and antagonists cause enhanced insulin secretion is all well and good, but the quick connection of increased insulin to less glucose in the bloodstream to less body fat can’t be made so quickly.