The totally speculative reason I won't take GLP-1 "miracle drugs"

Chemical starvation! What's not to like?

Photo by Diana Polekhina on Unsplash

The Fat Loss Miracle?

There’s been a lot of talk recently about these diabetes drugs with a new dual use in fat loss. The reactions are hilariously polarized: some seem to think these are a true miracle, delivering them from The Evil Food Companies. Others think these drugs are immoral for various reasons: making those who don’t take them (or for whom they don’t work) look bad, being unnatural, encouraging “those lazy fat people” to goof off on the couch and eat more donuts, something something big pharma.

I don’t have any moral qualms with these drugs: if you think they are a good idea and you want to lose some weight, be my guest. Should somebody really formulate a drug that made you lose weight with acceptable side effects, I think that’d be great.

In fact, I’d probably get it myself, tell all of you to get it, and close up shop here.

Unfortunately, I don’t think these drugs are it. Let’s take a look at the underlying mechanism of how they work.

Artificial Satiety Signals and our old friend CICO

My understanding is that these drugs act on GLP-1 receptor cells. GLP-1 is usually released in the intestine upon satiety, signaling the brain that we’ve eaten enough.

So you’re basically giving your satiety signal an artificial boost. I’m not quite clear if these artificial signals float around your bloodstream all the time, and thus constantly keep you satiated, or if they intensify the signal of actual GLP-1 after a meal.

The drugs are injected every 14 days, yet from reports, it doesn’t seem like people are satiated around the clock. It seems they just quit eating halfway through a meal. That makes it sound like the normal signal is just boosted.

In a sense, people are inducing artificial cement-truck satiety, no matter the food they eat.

If you believe in CICO, this makes perfect sense:

1. Obesity is caused by eating too many calories

2. Satiety makes you stop eating calories

3. Inducing artificial satiety lowers calorie intake

4. Lower calorie intake reduces obesity

The thing is that I don’t believe in CICO.

What does artificial satiety do if excess calories are not the root cause of obesity?

I think that obesity is fundamentally a nutrient partitioning problem: due to some biochemical lever, the nutrients coming in are (largely) not made available to the body for energy use, and are instead stored as fat. Of course that’s not 100%, but the ratio is bad enough to lead to obesity. In a sense, although you’re eating food, your body is starving on a biochemical level. All the energy from the food you just consumed is stored in your body fat, and isn’t available to fuel you!

So what happens if you have faulty nutrient partitioning, and you induce artificial satiety?

The same thing that happens when you starve, except you don’t notice it. Starvation is actually kind of interesting. There are generally thought to be 3 phases of starvation:

1. Stage I: between meals, the body uses liver glycogen, fatty acids, and proteins, mostly from the blood stream. This lasts for a few hours.

2. Stage II: body fat is metabolized. Depending on circumstances and available body fat, this phase can last weeks or longer. This quickly induces ketosis.

3. Stage III: this is the bad part, what people typically think of when you say “starvation." The body can’t access body fat, e.g. because there isn’t enough left. So it begins breaking down lean body mass. Metabolizing protein is extremely inefficient, which is why the body does it only as a last resort.

If you're chemically starving, repressing the feedback signal likely won't fix it. It’s not impossible - could be that the reduction in your specific intake actually ends up addressing the root cause.

The optimal case

As an example, let’s assume that the root cause of your obesity is eating too many carbs, and you largely eat them in the form of dessert after your meals. You eat a large piece of cake after every meal, three times a day.

In that case, GLP-1 agonists would probably help. You’d get satiated during your main meal, and you wouldn’t be able to stomach the cake after. You’d therefore not eat the sugar/carbs that are the cause of your obesity, and you’d likely lose fat.

But the real reason was that the GLP-1 agonist-induced satiety fixed your nutrient partitioning. In a sense, it was a coincidence.

Short aside: I’ve heard some people describe almost a feeling of disgust that appears very quickly. Those who don’t like these drugs argue that this is a bad thing, because disgust for food is unhealthy or a sign of unhealthy eating behavior.

I’m not so sure. I suspect that a true feeling of satiety can feel almost like disgust. When I hit cement-truck satiety eating heavy cream, I definitely get a sort of short-term disgust for cream. I couldn’t eat another spoon. Next morning in my coffee, I love it again. It’s just a short-term thing that stops me from eating.

It’s probably just that many of us have never felt true satiety all our lives, so any situation in which any food whatsoever isn’t making our mouth water seems alien and abnormal to us

A less optimal case

But what if eating cake after every meal is not the cause of your faulty nutrient partitioning? What if you ate your cake at the beginning of every meal, and now you’d be satiated before you got to much of the protein and fat in the meal?

(I’m not proposing carbs are always the cause of obesity, this is just an example.)

In that case your results would likely be catastrophic. You wouldn’t fix the root cause of your faulty nutrient partitioning. You’re still eating the carbs, and the energy would be stored in your fat. Your body still wouldn’t have a lot of energy to run on.

Therefore, you’d likely quickly end up in Stage III starvation and your body would begin catabolizing your lean tissue. But, your hunger signal would be blunted! So you’re starving and you don’t even notice.

That sounds… pretty bad.

And it probably explains why some people lose a huge amount of lean tissue on these drugs. It’s usually assumed that any weight loss will include a certain percentage of lean tissue loss. After all, even fat cells contain non-fat tissue, and there is likely a lot of structural support material you don’t need when you lose 50lbs, like skin. 25% of weight lost as lean mass is roughly considered normal.

But on these drugs, in one study, people lost an average of 40% of their weight from lean mass.

Think about that. You lose 50lbs, but 20lbs of it was lean mass, much of it likely muscle. Ouch. How much muscle do you have to spare?

Analogy: Locked up in a cage weight loss

Imagine a crazy alternate society, like they constantly visit in Star Trek and other SciFi shows.

Imagine that this society has completely solved obesity. Their method?

They lock people in cages and throw away the key until they’re thin.

I mean, it might work. For some definition of “work.” But do we think it would be a good idea?

What if they injected them with a chemical, and they didn’t feel they were starving?

That’s pretty much what we’re doing here. I don’t suspect that this cage-based weight loss would be particularly healthy. A lot of the weight lost would be lean mass.

Can the bad effects be prevented?

A lot of proponents argue that these studies are misleading, that they’ve treated patients holistically, prescribing both GLP-1 agonists, but also coaching on diet and strength training. And that the patients on this holistic protocol lose a normal amount of lean mass, e.g. the aforementioned 25%.

But then these aren’t really miracle drugs, are they? If you still have to fix the underlying root cause of the nutrient partitioning problem, I suspect the drug is merely a small booster on top of that.

And if somebody believes in the “miracle drug” idea, and keeps eating in a way that perpetuates the nutrient partitioning problem, he or she will lose a lot of lean mass - and not even get the warning signs of Stage III starvation that would naturally occur!

You still have to solve nutrient partitioning, so just stick to that

I kind of get it if someone is in danger, and taking a massive hit in terms of lean mass is worth it. But I was over 300lbs, and I don’t think 40% lean mass loss would’ve been a good trade off even then. I’ve since lost over 50lbs. Losing 20lbs of that from muscle would be.. scary.

Since you still have to figure out nutrient partitioning, you might as well do that. And if you deal that in right, you can probably lose weight faster than on these drugs. The results aren’t always impressive: in one study, people lost on average 7lbs of fat after 52 weeks of treatment with semaglutide. That’s about the result I’d expect from a very moderate low-carb diet, not even talking keto or anything drastic.

Other studies report better results, but they’re not always mind-blowing:

Eli Lilly just released their SURMOUNT-2 study about Tirzepatide, their new weight loss drug. It’s supposed to be even more powerful than Ozempic. Here’s what they achieved over 72 weeks for their 10mg dose group, 15mg dose group, and a placebo group:

• Average body weight reductions: 12.8% (10 mg), 14.7% (15 mg), 3.2% (placebo)

• Percentage of participants achieving body weight reductions of ≥5%: 79.2% (10 mg), 82.7% (15 mg), 32.5% (placebo)

• Percentage of participants achieving body weight reductions of ≥15%: 39.7% (10 mg), 48.0% (15 mg), 2.7% (placebo)

Of note:

• Even on the highest dose, the reduction in weight wasn’t super crazy. 14.7% over 72 weeks? I lost 21% in half the time.

• While ~80% of participants lost at least 5% of weight, only 40%/50% (10mg/15mg group respectively) lost more than 15%. Clearly, it doesn’t work for everybody. It doesn’t even work to a significant degree for the majority of people.

• The placebo group still had over 30% of people reach the 5% hurdle. That’s because 5% is actually quite low. As I wrote about in the water weight post, I’ve gained 10lbs in a single day (!) when making drastic diet changes. 5% of my initial weight (292lbs) is 14.6lbs. Meaning that this 5% body weight “achievement” is equivalent to 2-3 days of a bad swing. You basically lost the water weight you gained over Christmas.

• 15% is a somewhat significant reduction in body weight, although, personally, I’ve fluctuated more than that over the years. In fact, 15% doesn’t even get you halfway through a BMI category - meaning if you started at the upper end of “Obese” you’d still be smack in the middle of the “Obese” category.

• Only 40-50% (based on dose) of drug recipients achieved this more significant 15% weight loss. The miracle drug doesn’t seem to work for 50-60% of people.

• It would be cool to see the distribution of all weight loss amounts. Is there a small percentage of people who achieve more substantial weight loss? It seems clear that a large percentage doesn’t achieve any weight loss, or no substantial weight loss. This indicates that the root cause is something else, and these drugs don’t fix it.

• It would also really help to see start and end weights. If these people all had six-pack abs at the end of their trials vs. going from morbidly obese to the top end of regular obese, that’d be very different. It’s obviously easier to lose a large percentage if you still have a lot to lose.

Not So Miraculous

Let’s be honest, the average overweight or obese person would probably gladly take a 15%, or even a 5%, weight reduction. But that’s mainly because we’ve been terrible at coming up with any real solutions. The mainstream consensus seems to be that “all diets work well for weight reduction,” which is clearly false, or “no diets work long-term,” which is not exactly.. actionable. Or motivating. So no wonder that a lot of people are looking to weight loss drugs.

But in 50-60% of people, these drugs straight up don’t seem to work - and I suspect it’s because of the nutrient partitioning issue. If you’re one of the “unlucky” ones whose nutrient partitioning root cause doesn’t accidentally get fixed by artificially induced satiety, then not losing any weight is actually a better outcome than ending up in Stage III starvation.

Of course, there could be the worst of both worlds: you recomp in the wrong direction, cannibalizing your lean tissues to fuel your fat stores. To be fair, I haven’t actually seen that in any study yet, but then these always report averages. Could very well be that the 7lbs/year average consisted of a bunch of people losing 50lbs of fat, and some gaining fat at the expense of lean mass.

Maybe I’m missing something, but why would you suppress the feedback your body’s giving you? Clearly something’s awry. Fix the root cause instead. Why shoot the messenger?

But I suppose that’s your brain on CICO.