Semaglutide’s Surprisingly Unexamined Effects

Semaglutide’s Surprisingly Big Research Gap

GLP-1 receptor agonists like Ozempic, Wegovy, and other semaglutide drugs. are fast becoming a health industry standard go-to tool in the weight loss toolbox. When it comes to recommending that patients lose weight, “Have you considered Ozempic?” is the common refrain.

Sometimes, this may be a mere case of kicking the can down the road with regard to some other treatment that it can be argued (sometimes even truthfully) would go better after some weight loss:

How weight bias in health care can harm patients with obesity: Research

…which we also covered in fewer words in the second-to-last item here:

Shedding Some Obesity Myths

But GLP-1 agonists work, right?

Yes, albeit there’s a litany of caveats, top of which are usually:

• there are often adverse gastrointestinal side effects
• if you stop taking them, weight regain generally ensues promptly

For more details on these and more, see:

Semaglutide For Weight Loss?

…but now there’s another thing that’s come to light:

The dark side of semaglutide’s weight loss

In academia, “dark” is often used to describe “stuff we don’t have much (or in some cases, any) direct empirical evidence of, but for reasons of surrounding things, we know it’s there”.

Well-known examples include “dark matter” in physics and the Dark Ages in (European) history.

In the case of semaglutide and weight loss, a review by a team of researchers (Drs. Sandra Christenen, Katie Robinson, Sara Thomas, and Dominique Williams) has discovered how little research has been done into a certain aspect of GLP-1 agonist’s weight loss effects, namely…

Dietary changes!

There’s been a lot of popular talk about “people taking semaglutide eat less”, but it’s mostly anecdotal and/or presumed based on parts of the mechanism of action (increasing insulin production, reducing glucagon secretions, modulating dietary cravings).

Where studies have looked at dietary changes, it’s almost exclusively been a matter of looking at caloric intake (which has been found to be a 16–39% reduction), and observations-in-passing that patients reported reduction in cravings for fatty and sweet foods.

This reduction in caloric intake, by the way, is not significantly different to the reduction brought about by counselling alone (head-to-head studies have been done; these are also discussed in the research review).

However! It gets worse. Very few studies of good quality have been done, even fewer (two studies) actually had a registered dietitian nutritionist on the team, and only one of them used the “gold standard” of nutritional research, the 24-hour dietary recall test. Which, in case you’re curious, you can read about what that is here:

Dietary Assessment Methods: What Is A 24-Hour Recall?

Of the four studies that actually looked at the macros (unlike most studies), they found that on average, protein intake decreased by 17.1%. Which is a big deal!

It’s an especially big deal, because while protein’s obviously important for everyone, it’s especially important for anyone trying to lose weight, because muscle mass is a major factor in metabolic base rate—which in turn is much important for fat loss/maintenance than exercise, when it comes to how many calories we burn by simply existing.

A reasonable hypothesis, therefore, is that one of the numerous reasons people who quit GLP-1 agonists immediately put fat back on, is because they probably lost muscle mass in amongst their weight loss, meaning that their metabolic base rate will have decreased, meaning that they end up more disposed to put on fat than before.

And, that’s just a hypothesis and it’s a hypothesis based on very few studies, so it’s not something to necessarily take as any kind of definitive proof of anything, but it is to say—as the researchers of this review do loudly say—more research needs to be done into this, because this has been a major gap in research so far!

Any other bad news?

While we’re talking research gaps, guess how many studies looked into micronutrient intake changes in people taking GLP-1 agonists?

If you guessed zero, you guessed correctly.

You can find the paper itself here:

Dietary intake by patients taking GLP-1 and dual GIP/GLP-1 receptor agonists: A narrative review and discussion of research needs

What’s the main take-away here?

On a broad, scoping level: we need more research!

On a “what this means for individuals who want to lose weight” level: maybe we should be more wary of this still relatively new (less than 10 years old) “wonder drug”. And for most of those 10 years it’s only been for diabetics, with weight loss use really being in just the past few years (2021 onwards).

In other words: not necessarily any need to panic, but caution is probably not a bad idea, and natural weight loss methods remain very reasonable options for most people.

See also: How To Lose Weight (Healthily!)

Take care!