Peptides: A Brief History of GLP1-s

From Diabetes Management to Obesity Revolution

Introduction

I have been a personal trainer since 2010, and had tens of thousands of people utilize my digital content for fat loss and muscle gain.

My interest in GLP1s is simple; if something can help people with body fat loss and create permanent physiological change, I want to know more about it, and how to use it effectively.

In contrast to the general public, my awareness of GLP1s began years before Ozempic (semaglutide) ever came to market.

The Broscience and biohacker began experimenting with semaglutide in research chemical form back in 2017.

While this may be shocking to some, there is an entire subculture of people who do their own experiments, injections, and research various compounds. These “citizen scientists” are often years and decades ahead of formal medical practice. I am one of them. It is not a small subculture either, there are millions of people in the USA and globally who do this.

That said, I knew Ozempic would be significant when it was finally released, but even I was surprised at the cultural waves it made.

Following Ozempic came Tirzepatide, and soon to come will be Retatrutide.

These GLP1s (as they are referred to generically) have been a legitimate revolution in obesity medicine and popular culture. They are probably responsible for the obesity rate declining in the USA for the first time in decades, and tens of millions of people use them daily.

Glucagon-like peptide-1 (GLP-1) receptor agonists, are transformative class of medications that mimic the effects of the naturally occurring hormone GLP-1.

This hormone, produced in the gut, plays a crucial role in regulating blood sugar levels by stimulating insulin secretion, slowing gastric emptying, and promoting satiety.

GLP1s were initially developed to treat type 2 diabetes, and have have evolved into powerful tools for weight management, which has catapulted them into the premiere medicines for treating the epidemics of diabetes and obesity.

Their mechanism of improving glycemic control and inducing significant weight loss has made them a cornerstone of modern metabolic therapy.

And as of 2025, the GLP-1 market continues to expand.

Not surprisingly, there has been immense media coverage them, with articles both praising and decrying their effects and supposed side effects.

My perspective is to strive towards balance and clear thinking. Mainstream media is not a reliable source of accurate information.

To understand anything, we must know its origins.

What follows is a history of GLP1s. This is not a scientific deep dive into their biochemistry, but a timeline of their discovery.

Contrary to popular misconceptions, GLP1s did not emerge from a black box of unknown science.

The fear mongering on social media is constant

”we have NO IDEA what the side effects are!!”

Yes we do. GLP-1s have been studied for decades with dozens of clinical trials at this point, have been prescribed for 20 plus years, and their effects, potential side effects, and safety are well documented.

Lets begin.

The History of GLP-1s

The story of GLP-1 agonists begins in the mid-20th century with the discovery of incretins, gut hormones that enhance insulin release after meals.

As you will learn fast, they all have long, scientific names. Abbreviations are preferable.

In the 1970s, glucose-dependent insulinotropic polypeptide (GIP) was identified as the first incretin. Incretins are gut peptides that are secreted after nutrient intake. This was interesting, but like most science, exploration does not mean innovation. It wasn't until 1984 that GLP-1 was discovered in porcine gastric extracts, though initial interest was limited. I was research in the late 1980s and 1990s that revealed GLP-1's potent effects on insulin secretion and appetite suppression, but its short half-life (about 2 minutes) due to rapid degradation by the enzyme dipeptidyl peptidase-4 (DPP-4) posed a challenge for therapeutic use.

For a 30 year period, incretins were only in the realm of exploratory science and experiements, but that changed by the turn of millennium.

The breakthrough came in the early 2000s with the development of stable GLP-1 analogs. These analogs lasted much longer than a few minutes, and had therapeutic use for blood sugar control.

1st Generation

Exenatide, derived from the saliva of the Gila monster lizard (synthetic exendin-4), became the first GLP-1 agonist approved by the FDA in 2005 for type 2 diabetes under the brand name Byetta.

This twice-daily injectable marked the dawn of GLP-1 therapy, demonstrating improved glycemic control and modest weight loss.

2nd Generation

Liraglutide followed in 2009 (Victoza for diabetes, later Saxenda for obesity in 2014), offering a once-daily option with enhanced stability through fatty acid acylation.

3rd Generation

By 2010, the class expanded with dulaglutide (Trulicity) and albiglutide (Tanzeum, later discontinued), emphasizing weekly dosing for better patient adherence.

These early drugs were used with diabetics, and while they didnt deliver substantial weight loss, their effects on blood sugar were clinically significant enough to motivate further research.

The 2010s saw GLP-1s pivot toward obesity treatment, driven by clinical trials showing substantial weight reduction.

4th Generation, The Introduction of Semaglutide

Semaglutide emerged as a game-changer in the GLP-1 landscape, developed by Novo Nordisk through innovative peptide engineering. Its development drew from liraglutide's success but addressed limitations like daily injections.

Semaglutide features a longer half-life (about a week) achieved via albumin-binding fatty acid chains and amino acid substitutions to resist DPP-4 degradation.

What does that mean?

It means the peptide doesnt get broken down very fast due to it chemical structure being harder to break apart. Hence the longer half life.

Preclinical studies in the early 2010s demonstrated superior glucose control and weight loss compared to existing GLP-1s.

The FDA approved semaglutide in December 2017 as Ozempic, a once-weekly subcutaneous injection for type 2 diabetes. Clinical trials, including the SUSTAIN series, showed A1C reductions of up to 1.8% and weight loss of 4–6 kg over 30–56 weeks, outperforming comparators like exenatide and dulaglutide. Its cardiovascular benefits were confirmed in the SUSTAIN-6 trial, reducing major adverse events by 26%.

In 2021, the higher-dose formulation Wegovy gained FDA approval for chronic weight management in adults with obesity or overweight with comorbidities, marking semaglutide's shift to obesity therapy. The STEP trials reported average weight loss of 15–17% over 68 weeks, far exceeding prior options. By 2023, an oral version (Rybelsus) was approved for diabetes, broadening accessibility. Semaglutide's success fueled shortages and off-label use, highlighting its dual role in metabolic health. As of 2025, ongoing research explores its potential in heart failure and Alzheimer's.

Tirzepatide: The Dual Agonist Breakthrough

Tirzepatide, developed by Eli Lilly, represented the next generation of incretin mimetics as a dual GLP-1 and GIP receptor agonist. GIP, another incretin hormone, complements GLP-1 by enhancing insulin secretion and potentially improving lipid metabolism. This dual action addresses GLP-1 monotherapy limitations, as some people did not respond well to it.

Preclinical development began in the 2010s, with tirzepatide engineered as a unimolecular peptide biased toward GIP activity but with balanced GLP-1 effects. The FDA approved it in May 2022 as Mounjaro for type 2 diabetes, following the SURPASS trials that showed A1C reductions of up to 2.5% and weight loss of 7–11 kg, superior to semaglutide.

In November 2023, Zepbound (same molecule) was approved for obesity, achieving up to 21% weight loss in the SURMOUNT-1 trial.

Tirzepatide's once-weekly dosing and side effect profile (primarily gastrointestinal, similar to GLP-1s) have made the frontrunner. Recent studies, like SURMOUNT-5 in 2024, confirmed its edge over semaglutide in weight reduction.

As of 2025, it's approved in over 50 countries, with ongoing trials for heart disease and sleep apnea. Its innovation lies in harnessing GIP's synergistic effects, potentially resetting metabolic setpoints more effectively.

Retatrutide: Pioneering Triple Agonism

Retatrutide (LY3437943), also from Eli Lilly, pushes boundaries as a triple agonist targeting GLP-1, GIP, and glucagon receptors. Glucagon, traditionally linked to raising blood sugar, paradoxically aids weight loss by boosting energy expenditure and fat oxidation when combined with incretins. Glucagon therapy has existed for many years to treat hypoglycemia in diabetics. Glucagon stimulates the liver to release glucose.

Interestingly, when combined with GLP1 and GIP actication, Glucagon also potentiates body fat loss.

Phase 2 trials of Reta were published in 2023, and showed remarkable 24% weight loss over 48 weeks in obese adults, outpacing tirzepatide's 20%. It also improved liver fat and insulin sensitivity in nonalcoholic steatohepatitis (NASH) patients.

As of mid-2025, retatrutide remains in phase 3 trials for obesity and diabetes, with FDA approval anticipated by 2026–2027. There are current ongoing studies explore its role in cardiovascular and hepatic diseases. Side effects are similar to its predecessors but include potential glucagon-related issues like mild heart rate elevation during the early stages of usage.

Retatrutide will undoubtably be a "game changer" when its the approved by the FDA.

As of today, its the most popular fat loss peptide in biohacker world, and is purchased as a research chemical. There are tens of thousands of reports of experimentation and its remarkable effects.

How do GLP1s Work though? What about side effects? Are they just appetite suppressants, or do they work in other ways?

More to come in the next chapter.

For those interested in biohacking and doing your own research, Id encourage you to join my free telegram group.