Chapter 2: Discovery and Development of The GLP-1s

In the previous chapter I delved into the history of anti-obesity drugs starting around the 20th century. It’s clear that numerous drugs have been developed and used to varying degrees. The general problem with all of them either being limited weight loss or mis-use leading to just enough highly publicized problems to get them banned by the FDA. This is why we can’t have nice things.

I stated at the end of that chapter that most anti-obesity drugs cause perhaps a 5-10% weight loss which, while clinically relevant, is still relatively moderate. This is similar to diet and exercise approaches although as noted they tend to have, at best, moderate success rates (though not as bad as many people claim) as people revert to old patterns and regain the weight that has been lost.

Only bariatric surgery has shown much more potency and relatively more permanent effects, approaching 25-50% weight loss or more in some cases. There are numerous approaches but I don’t know enough about them to really discuss the topic. As well, despite its massive effects, the cost and invasiveness limits its use. I bring it up since one of its mechanisms of actions appears to be through increasing levels of what are called incretins, discussed next.

Incretins

The human body is complex. Like really, really complex. I’m honestly glad I got my degree when I did since we didn’t know anything about anything. There were only like 6 hormones and we were happy! Now the system is so utterly complex that it’s nearly impossible to keep up with every new discovery even though I try. I’d hate to be a brand new university student coming up now having to learn about the zillion different hormone signaling pathways that are known to exist now. It’s overwhelming.

Now we’d known for decades that the gut released various chemicals in response to eating. Cholecystokinin (CCK), Peptide YY (PYY) and others were all involved in the fullness signal that was sent in response to eating. This was along with the well known hormonal response to eating such as changes in insulin and glucagon, both released from the pancreas.

Insulin has a stunning number of roles in the body but basically acts as a storage hormone. It drives glucose and amino acids into muscle cells for storage and, as I imagine many are aware, is part of the storage of fat in fat cells. Glucagon works in the opposite fashion with a primary role (in humans at least) of maintaining blood glucose between meals by stimulating the liver to produce glucose. All you need to remember is that insulin lowers blood glucose and glucagon increases it.

But let’s back up. As early as 1902, it was clear that the gut was releasing compounds after a meal that were impacting on the body’s physiology. And some of them were causing the body to release more insulin from the pancreas. The term “incretin” would be coined to describe them in 1932. But at this point nobody knew what they were or might be.

It would take until the 1970’s, when newer technology allowed for such, for the first incretin to be identified. The first was GIP which originally stood for Gastric Inhibitory Polypeptide (due to its effects in the gut) but was later named Glucose-Dependent Insulinotropic Peptide (due to its effect in increasing insulin secretion when blood glucose was high). By itself GIP didn’t seem to be terribly effective physiologically. It was at best a secondary compound.

But this would set the stage for the discovery, in the 1980’s, of Glucagon-Like Peptide 1 (GLP-1). As I said, glucagon opposes insulin and serves to raise blood glucose. And GLP-1, as its name suggests, is similar in structure to glucagon (hence glucagon “like” peptide). But in this case GLP-1, working in concert with GIP, acts to increase the insulin response to meals, also lowering glucagon itself. All of which served to lower blood glucose.

A zillion pieces of research would look at this and it turns out the GLP-1 and GIP are responsive to nutrients hitting the gut with different nutrients impacting them, err, differently (the same is true for CCK, PYY and others). I can’t even begin to describe it in detail and it’s not important to do so.

As study on the topic increased, the incretins were found to have many other effects than just increasing insulin. They increased heart rate, lowered blood pressure by increasing blood flow to muscle and fat cells, and had effects all over the place. Presumably this was all a coordinated response to eating to facilitate nutrient storage and to prevent blood glucose from going too high.

Later studies, mostly in animals would find that infusion of high doses of GLP-1 blunted appetite and reduced food intake through various means. Many times the infusion was directly into the brain which meant that it was having other effects there, at least under those conditions. There were numerous other effects (again, mostly in rats at this point) including a reduction in the rate at which food leaves the stomach (called gastric emptying).

Observationally, it was known that individuals with Type II diabetes show an impaired response to GLP-1/GIP. A similarly impaired response is seen in people with obesity suggesting that it may be involved somehow in bodyweight regulation in humans. It’s more difficult to study but some work in humans showed that GLP-1 infusion had at least some (but certainly not all) of the observed effects that had been seen in rat and mouse models.

Finally, as bariatric surgery started to be used more frequently, it was observed that there was often a vast increase in GLP-1 response to the surgery along with an increased release of GLP-1 and GIP after a meal. Both of these occurred long before any meaningful weight loss meaning that it had to do with the effect the surgery had on how food is digested and absorbed into the body. And while somewhat debated, it certainly seemed like the increase in GLP-1 was a big part of the massive appetite suppression that occurred with the surgery. Hmm….

All of this pointed to GLP-1 (along with GIP which again didn’t do much on its own) having some use in obesity treatment and bodyweight regulation. And you might be wondering why it wasn’t used. And the reason has to do with the fact that, in the body, GLP-1 is broken down incredibly rapidly with levels only changing slightly after a meal. And with almost none making it into the general circulation.

Constant infusion worked because it could maintain constantly elevated levels. And the chronically elevated levels seen in bariatric surgery clearly had an effect. A simple injection wouldn’t work since it would be broken down too fast. And an oral form of native GLP-1 would be broken down in the stomach anyhow. In its original form at least, GLP-1 was a non-starter.

As a side note this is why the ignorant stuff you see online about using dietary modifications or most supplements to “naturally mimic GLP-1 drugs” is gibberish. Any effect in increasing GLP-1 is too short-lived to matter. So what happened that got us to where we are now?

A Monster Discovery

In 1990, a researcher named John Eng was using chemical assays to look for new drug compounds which is common in the modern era. Earlier research had shown that the venom of certain snakes and lizards could cause the pancreas to increase in size, suggesting it somehow overstimulated it. Other research had found that the gila monster had the ability to regulate its own blood glucose very well.

So Dr. Eng went looking at gila monster venom (of all things). And in it he found a compound called Exendin-4 that was structurally very similar to GLP-1 (this makes it what is called a GLP-1 agonist meaning it works in the body like natural GLP-1). And like GLP-1 causes the pancreas to release insulin. So why was this interesting? Well unlike GLP-1 which only lasts minutes in the body, Exendin-4 lasted hours before being broken down. This gave it far more potential for use.

Exenatide: The First Step

After the discovery of Exendin-4, the pharmaceutical company Amgen would start a research program in the 1990’s, eventually developing the drug Exenatide (marketed as Bydureon or Byetta). An oral drug taken twice per day, it was shown to lower blood glucose, slow gastric emptying, reduce cardiovascular risk and cause a small weight loss. A once per week injectable version would be developed years later and marketed under the brand name AstraZeneca.

Exenatide was approved in 2005 for the treatment of diabetes although it would take 7 years before it was approved by the FDA for weight loss. However, its effects were limited. Over 82 weeks it caused a small portion of people to lose about 5% bodyweight (I’d estimate this at maybe 0.5 lbs/0.25 kg per month), another portion to lose none and some actually gained weight. So it was kind of a bust so far as actual weight loss was concerned.

But it was an interesting and needed first step, a proof of concept, establishing the potential for GLP-1 drugs to be used for both diabetes and obesity treatment. Perhaps most importantly, it would kick off the race to develop even more effective drugs in the same class. And boy did it.

The Race Begins

Since the initial development of Exenatide, over half a dozen other GLP-1 drugs have been developed although one or two never made it out of the research stage. Perhaps the most impressive fact about these developments is that, with each new drug, the average weight losses are increasing, often in a dose-dependent manner. That is, the higher doses tend to cause more total weight loss. Alternately, more people achieve larger average percentages of weight loss (I’ll come back to this when I talk about non-responders in Chapter 5).

The drugs often differ both in how frequently and how they are taken (i.e. oral or injection). Individuals with diabetes often lose significantly less weight with the GLP-1 drugs than individuals without diabetes but the reasons for this aren’t entirely clear. I’ll discuss this in a little more detail in a later chapter but, to keep things from getting too confusing, I’ll ignore the distinction below.

Instead let me run through the quick history of the drugs that have been developed to date along with two in the research stage that are getting close to approval. In looking at each, I’ll look at both the chemical name and commercially branded versions, how it is used along with the average weight losses that it has generated. I’ll summarize all of this below.

Liraglutide was the next drug that was developed. Marketed as Victoza it was available as a once daily oral or injectable for diabetes treatment. Rebranded as Saxenda it was approved for obesity treatment in 2010 but only generated a modest 3-8% weight loss. Increased weight losses of 12-14% were achieved with intensive lifestyle intervention which I will discuss in a later chapter. The once per day injections that were required probably didn’t help with adherence.

In 2016 came dulaglutide, marketed as Trulicity. It was a once per week injectable but also only caused an average 5% weight loss so it wasn’t much of an improvement. I don’t honestly know if dulaglutide is even still in use although liraglutide seems to be the only GLP-1 available in some areas.

Things started to get serious in 2018 with the approval of semaglutide. It was available in two forms, as a daily oral pill called Rybelsus and a weekly injection called Ozempic (this was the drug that had a shortage when 2023 TikTok influencers made it insanely popular for people without overweight to abuse) both of which were for diabetes treatment.

Importantly, with the highest doses, weight losses up to 10-15% of initial weight were seen in some subjects with weekly injections being slightly superior to the daily oral version, called Rybelsus, (the side effects, discussed later, being similar in both). It would be rebranded as Wegovy and approved for weight loss in 2021. You will see Rybelsus mentioned in my chart below since it seems to be used off-label for weight loss.

I’d mention that compounding pharmacies have recently (in 2024) begun offering sublingual semaglutide drops that are put under the tongue for absorption. Given that there are oral versions of the GLP-1 drugs, it seems reasonable that this could work. They claim fewer side effects but I am unaware of any research on this method of administration or its effectiveness.

Let me note that Ozempic has not only (incorrectly) become a general name for this class of drugs but is actually the name of the diabetes version of semaglutide specifically. The weight loss version of semaglutide is sold as Wegovy. I have no idea why the drug has to have a different name for different uses but suspect it has to do with insurance issues and whatever federal guidelines exist for naming.

Regardless, with the development of semaglutide, GLP-1 agonists had equalled or surpassed both earlier anti-obesity drugs and diet and exercise approaches, in terms of the average weight losses that they could achieve. But there was still more to come. Far more.

The most recently approved drug, as I write this in late 2024, is tirzepatide, which was approved for use in 2022 and marketed as Mounjaro for diabetes treatment and Zepbound for weight loss. Also a weekly injectable, tirzepatide represents the next step in the development of this class of drugs in that it is the first dual incretin drug. That is, it is a combination GLP-1/GIP agonist affecting both pathways in the body. Apparently to good effect.

Impressively, tirzepatide was able to achieve an average weight loss of 15-21% over the duration of use eclipsing even the effects of semaglutide at 10-15%. Nobody is quite sure why or how, though. On the one hand, the GLP-1 component binds more weakly (and acts differently) at the GLP-1 receptor than natural GLP-1. The GIP component seems to bind at about the same strength as the body’s own.

It’s thought that it reduces the side effects which allows more of the GLP-1 to be given. It’s also suggested that somehow the activation of GLP-1 and GIP at the same time enhances the metabolic effects but the exact reasons are unclear right now. Given the interaction between GLP-1 and GIP in the body, it may be the combination of the two that is superior. While knowing the exact mechanism would be nice, pragmatically it sort of doesn’t matter in terms of the results.

Even here there is debate over whether or not a GIP agonist or a GIP antagonist would be superior to begin with but my attempts to get to the bottom of it did nothing but give me a throbbing headache. There is a lot of scholarly debate and speculation but it’s exceedingly complicated and I gave up.

Regardless of the underlying physiology, the fact is that tirzepatide generates greater average weight losses than semaglutide. At least some people achieved weight losses that are double previous anti-obesity drugs and 2-4 times what can usually be achieved with diet and exercise. This is a staggering. As with semaglutide, I have seen compounding pharmacies claiming to have oral versions of tirzepatide. Once again I have no idea if these are effective.

Although still in the research stage, one of the drugs next closest to achieving approval is retatrutide. It currently has no commercial name but might be up for approval by 2025-2027. Retatrutide goes a step further than tirzepatide in that it is the first triple incretin drug, acting on GLP-1, GIP and glucagon receptors (glucagon isn’t technically an incretin but I’ll keep using that term).

In the one 48 week study published to date, average weight losses of 12-24%, 2.5 times more than previous anti-obesity drugs have been seen with some losing up to 30% of their total bodyweight. Impressively, no plateau was seen at the 48 week mark so more might have been lost.

I’d also mention another still in the research stage but nearing approval drug called CagriSema. This actually combines two different compounds, semaglutide and cagrilintide. The latter of which mimics amylin, a hormone that makes insulin work better.

Early short-term research demonstrated an impressive 16% average weight loss over 20 weeks in individuals with obesity. Data published at the very end of 2024 showed a 22% weight loss (with some losing up to 25%) over 68 weeks which puts it slightly above tirzepatide and right in the realm of retatrutide in terms of it’s weight loss effects.

As I write this, and will address later, a stunning number of new drugs are currently in development by various pharmaceutical companies with new ones being announced seemingly weekly. But they are years away. The chart on the page below provides a partial list of past and current GLP-1s.

For each I’ve given the drug name along with its trade name, the type of drug that it is, how it’s used and the dosing schedule. I’d note that the doses used for the treatment of diabetes are often different than what I listed above (i.e. semaglutide is typically capped at 1 mg) but I’m not entirely sure why. Since the topic of this book is only about the issue of weight loss, I’ve only shown the weight loss brand name along with the dosing schedule.

I’ve also shown the average percentage weight loss along with estimated absolute weight losses for a hypothetical 220 lb (100 kg) person. I would note that the highest weight losses generally occur with the highest doses of the compound but there is a huge amount of variability between any two people.

As I mentioned earlier in the chapter, people with Type II diabetes often lose significantly less weight than people without it although the reasons why are unclear. I’ll discuss both topics in a later chapter.

Drug	Trade Name	Type	How Used	Dosing Schedule	Average Weight Loss	Wt Loss for 220 lb/100 kg person
Exenatide	Bydureon	GLP-1	Twice daily oral	Who Cares	Meh	Meh
Exenatide	Astrazeneca	GLP-1	Weekly injection	Who Cares	Meh	Meh
Dulaglutide	Trulicity	GLP-1	Weekly injection	Who Cares	Meh	Meh
Liraglutide	Saxenda	GLP-1	Daily injection	0.6 mg, 1.2 mg, 1.8 mg, 2.4 mg, 3.0 mg	3-8%	6.6-17.5 lbs (3-8 kg)
Semaglutide	Rybelsus	GLP-1	Daily oral	3 mg, 7 mg,14 mg	12-14%	26.4-30 lbs (12-14 kg)
Semaglutide	Wegovy	GLP-1	Weekly injection	0.25 mg, 0.5 mg, 1 mg, 1.7 mg, 2.4 mg	10-15%	22-35 lbs (10-15 kg)
Tirzepatide	Zepbound	GLP-1+GIP	Weekly injection	2.5 mg, 5 mg, 10 mg, 15 mg	15-21%	33-46 lbs (15-21 kg)
Retatrutide	In development	GLP-1+ GIP + Glucagon	Weekly injection	2 mg, 4 mg, 8 mg, 12 mg	12-24%* 30% (max)	12-24 kg (30 kg) 26.5-52.8 lbs (66 lbs)
Cagrilintide +Semaglutide	CagriSema	Amylin + GLP-1	Weekly injection	.25 mg, .5 mg, 1.0 mg, 1.7 mg, 2.4 mg of both drugs in a single pen	22%	44 lbs (22 kg)

* Retatrutide has only been studied over 48 weeks.

I’ll discuss the use of the drugs in a later chapter but, for now I’d mention that the drugs are always started at the lowest doses and gradually increased. Doses of injectable liraglutide are increased weekly, reaching a maximum after 5 weeks. The others are generally dose escalated every four weeks.

This is due to the fact that the drugs take 4 weeks to build up in the system to a stable level. It also helps to limit side effects, discussed in a later chapter. Finally it’s good for study control. When I look at actually using the GLP-1s, I’ll discuss a better way to dose escalate the drugs.

You can see that with each new drug the amount of weight loss is increasing with the amounts of weight loss being seen with the newest drugs being startlingly impressive. I have “joked” that these things are going to put me out of a job. But it’s no joke.

Retatrutide at 24% (and 30% in some cases) total weight loss is approaching the lowest levels of bariatric surgery (ranging from 25-50% or so) and all three of the most recent drugs exceed not only all previous obesity drugs but also lifestyle intervention approaches (which usually stop working after perhaps 5-10% total weight loss). And these drugs are utterly changing how we approach weight loss and the treatment of individuals with overweight and obesity.

For perspective, Weight Watchers, arguably the longest lasting (and in my opinion best) weight loss programs in the US has fully embraced the GLP-1 drugs as part of their overall approach. They realize that the drugs represent a powerful new tool in the treatment of overweight and obesity and that it would be foolish to ignore them. If only fitness industry hardheads would do the same.

Other Health Effects of GLP-1 Drugs

I want to briefly (very briefly) mention that, although the GLP-1 based drugs have been mostly studied for their roles in diabetes and obesity treatment, there has been recently emerging evidence that they may play other roles in improving health. Studies have shown a decrease in cardiovascular risk, stroke risk, PCOS (Poly-Cystic Ovary Syndrome, the most common reproductive disorder in women) and the progression of diabetes itself. Limited research suggests a benefit for both Parkinson’s and Alzheimer’s.

Other papers, and they come out almost weekly, suggest other potential benefits of the drugs such as reducing depression and so many others. Others in the field are suggesting even more far reaching benefits. Along with this is constant research examining the potential mechanisms, almost exclusively in animal models, and why they might be occurring.

This is an area of research that is both very new, rapidly changing and to my mind confusing. By that I wonder why GLP-1 receptors would even be found in many of the tissues of interest since they would never have been exposed to GLP-1 under most conditions.

I also find it odd that a meal released compound like GLP-1 which has literally none of these effects when released acutely (well not in humans) would cause them when maintained at chronic levels. In many cases the supposed chronic effects of the GLP-1s are the opposite of what meal stimulated GLP-1 does in the body.

This is especially true when a majority of the supposed benefits of the GLP-1 can probably be explained, at least in the majority, by nothing more than the weight loss itself. That is, weight loss per se improves cardiovascular disease risk, stroke risk, PCOS, etc. Of course the GLP-1s do this. The question being whether the GLP-1s have an effect above and beyond the weight loss.

My confusion and questions notwithstanding, the purpose of this book is about optimizing nutrition and training when using the GLP-1 based drugs. The above, while interesting is beyond the scope of what I want to talk about and I mention it only for (partial) completeness.

A Very Quick Summary

Since the initial discovery of GIP and GLP-1 along with the critical discovery of Exendin-4, the development of GLP-1 based drugs has exploded. From liraglutide to semaglutide to tirzepatide to retatrutide (with CagriSema in the pipeline) each new drug has improved upon the previous one. Who knows what the future holds.

Excepting the improvement from liraglutide to semaglutide, the newer drugs have all achieved greater effects by adding other compounds to the base of GLP-1. Tirzepatide added GIP, with retatrutide adding a glucagon component on top of that while CagriSema went a different direction combining a GLP-1 compound with amylin. I suspect that all future compounds, regardless of what else they do or do not add, will also be based on GLP-1.

But they all have GLP-1 as a base. And for that reason, primarily for clarity of writing, I will refer to the entire class of drugs as GLP-1s or GLP-1 drugs throughout this book. It’s arguably not technically correct but neither is calling glucagon or amylin an incretin. And I’m going to do that, too. Some researchers contend that the current definition of an incretin is too limiting. Others vigorously disagree.

That debate is not relevant to the topic of this book so I’ll leave it to the scholars. Rather, I’ll just call them all GLP-1s (or incretin based drugs) and leave it at that. So let me now move to how the GLP-1s actually work in the body to cause weight loss.

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