Skip links

Semaglutide: Mechanism, Questions and Future Discussion Points


It started its life as a diabetes medication. More recently, it’s been referred to as a celebrity weight loss drug. And since NICE – the National Institute of Clinical Excellence – have approved it for NHS prescription, it’s also been the subject of several questions that I’ve received. I am, of course, talking about Semaglutide.

So what do we need to know about Semaglutide? What is it likely to do? Well, let’s start by looking at its mechanism of action. And semaglutide works through the basis of being a GLP-1 agonist. That is to say, it replicates the effects of GLP-1 at the receptor. So GLP-1 is an intestinal hormone and it’s released whenever we consume food. Now, the key thing there is that it has particularly important effects on increasing insulin and decreasing glucagon, something we’re about to touch on. Now, insulin, as most people know, is the storage hormone. It’s released whenever the system senses an excess of energy and helps push that into the cells where it can be used for energy or to fuel metabolic actions or for storage.

In any case, glucagon is the opposing hormone. It’s the management hormone the body uses in order to respond to low energy states. And it not only helps to release energy from storage into circulation to maintain that energy availability between meals, but it also has behavioural effects. That is to say, it induces extra hunger so that we will seek out food and restore the energy that we’ve just lost from the fat cells or liver storage. So this is where it’s particularly relevant when it comes to diabetes, be that Type 1, where there is a lack of insulin production, or Type 2 diabetes, where there is a lack of insulin activity, because when we lack that insulin action, then there’s nothing to suppress the glucagon levels effectively once we actually eat.

And that sees people with diabetes get a double hit of energy each time they eat one from what comes in through the diet, through the intestinal tract, but also a second source of energy being pushed into the circulation, which is that driven by glucagon in the mistaken belief that there’s still a need to support those levels. So this is where we can see unnecessary high rises in blood glucose. And of course, the more glucose there is (in a high insulin state), the more opportunity there is for weight gain. And that’s one of the key factors that see most individuals with Type 2 diabetes actually experience much higher propensity for weight gain.

However, this [Semaglutide] is something that has naturally escaped the realms of simply diabetes alone, primarily because of such stunning results in the trials. And there’s a number of trials, admittedly all done by the same research group, but nonetheless, the results do speak for themselves. Some were conducted over a year, others over two years. But what we’re generally seeing is that, in non-diabetics who are exercising on a regular basis, around about 15% body weight reductions. So, to put that into context, that’s pretty spectacular compared to what we’re often seeing in the results of weight loss trials. So naturally a lot of interest as to whether this is a tool that can be exploited. But of course most people will center on that question of: is this sustainable?

Key thing being that one of the primary mechanisms here is by reducing glucagon we’re reducing appetite in a particularly pronounced manner and thus the participants in the trial ate a lot less. Now, we know from decades and decades of people attempting to lose weight sustainably through calorie counting that by starving the body of calories, yes, you will typically see the body shed some energy in order to meet this energy emergency. But in doing so, you’re also kicking off some of these weight management systems, that is to say, a lowered metabolic rate to conserve energy and increased activity in the fat storage pathways that allow us to maintain an insurance policy against the risk of future starvation. Something that has been confirmed as a legitimate concern through this sustained phase of low energy availability.

And when we look at the research that actually tracks responses for those who finish Semaglutide, we see that those individuals very quickly see a return towards their previous baseline. So not being marketed as something that will alter the metabolism or correct any issues, it is simply a means of stopping individuals consuming the energy necessary to complete this energy management cycle. So knowing that we can’t expect any sustainable results from Semaglutide, is there still any benefit or application that this may be useful for? Well, obviously it does work.

The question being: does this have any place within our arsenal of options when it comes to weight loss management? So this is where it can be really helpful to just get some perspective, comparing it to existing options that we’re more familiar with. In that regard. The one obvious comparison that I would draw would be on some of the results we’ve seen from trials that look at high fat, low carb intake which interestingly enough, when it comes to type two diabetics actually show a very similar outcome, roughly around about 4% for both types of interventions.

And that helps to reframe the discussion. One where it’s less a case of does the miraculous results from Semaglutide call for us to overlook some uncertainties and concerns to one whereby we recognize that perhaps while impressive, there isn’t anything particularly miraculous about the results we’re seeing in a number of patient groups. So that’s where it’s really helpful to put the likely benefits in context. But also it’s important to touch on the disadvantages. And this is where it’s important to state that we can’t really yet know exactly what the side effect profile is going to be because until this is used by populations at large we can only really extrapolate our expectations, made from mechanistic understanding and some of what was picked up in those trials.

In that regard, my main concern would actually be as to the long term effect of suppressing Glucagon. As we mentioned earlier, glucagon is the management hormone for low energy states. So not only does it help encourage us to seek out more food and consume it, we’re also going to see that liberation of energy from storage, particularly glucose. Now, if we take away the role of Glucagon, what is likely going to happen to our blood sugar levels and how is the body going to manage that? Well, they’re not going to be gently supported between meals, as would be the case with glucagon’s activity allowed to occur naturally.

Instead, we’re going to have to rely on the adrenal response, the output of both adrenaline and cortisol in this sympathetic activation that brings in the adrenal axis into action. Now, in itself, not so much of a problem. But what if there is any long term stress on the system? What if there has been long term over activation of that response? Something that’s almost guaranteed in most individuals with any metabolic burden, any energy signalling issues, which of course are the population most interested in this drug.

The problem with that is, if we place excessive demand on that response and do so for too long, we can expect to start losing sensitivity to cortisol. And that means losing its ability to help stabilize blood sugar levels and equally to control inflammation, maintain resilience against stress, which of course is going to have multiple impacts on long term metabolic concerns, brain function, sleep wake cycles, as well as just feeling like shit. So this is where I would have very substantial concerns as to what we can expect from this when deployed over hundreds of thousands of people across the country.

But we can’t know for certain how many are likely to run into problems here and equally how severe those problems will be. What we do know from the trial data is that up to 7% of individuals on the Semaglutide treatment showed severe hypoglycemic episodes versus the controls. Now, that’s obviously only the severe occasions that were recorded, those that required immediate medical treatment, does that account for the moderate hypoglycemic episodes that may have gone repeatedly underreported? We don’t actually know. So an important question that still needs to be answered and can only be done so through observation over the coming months and potentially years. But equally on top of that, we know that glucagon is necessary for getting glucose into the bloodstream during exercise. We know it’s important for optimal formation of ketones. So there’s certainly going to be some impacts on ability to engage in exercise or the opportunities to deploy flexibility with our dietary intake.

There’s also the cost to consider at $1,000 per year for something that doesn’t provide sustainable weight loss. It’s certainly not cheap. And that may well not be a big concern for those receiving it on prescription, but could become relevant very quickly if politics and financial realities would see a U-turn in that NHS policy. In any case, I hope that is a useful overview of Semaglutide, what it is, how it works and the questions we might want to ask.

I don’t think that this ends the conversation on Semaglutide. I think there’s plenty more juicy discussions due in that sphere, not least on one nugget that can be extracted from the trial data, which is the way that those taking Semaglutide – that is to say, those recording an average weight loss of 15% – actually had higher insulin levels than the controls. So perhaps we are going to be able to take something good from these trials regardless and move it one step closer to accepting that maybe insulin isn’t actually the bad guy after all, and that it’s insulin resistance that deserves more of our focus, Perhaps a topic for another day.

Meanwhile, thank you for your attention and see you then.

Leave a comment

This website uses cookies to improve your web experience.