An unexpected discovery in venom gave birth to the "magic drug" for weight loss, semaglutide

The "magic weight loss drug" semaglutide has become a global hit and has caused a weight loss craze on social media. Due to the high demand and the inability to keep up with the production capacity, some places have even imposed purchase restrictions. The reason why people are chasing after it is that it can bring significant weight loss effects without "keeping your mouth shut or moving your legs". However, if you blindly believe in the perfect weight loss method or drug that "you can lose weight by lying down", it may be a bit stupid; if you wantonly exaggerate the weight loss effect and conceal the side effects or harms, it may be a bit bad.

Written by | Mumu

Around 2022, a drug called semaglutide, known as the "magic weight loss drug", gradually became popular around the world and was sought after by many netizens on social media. Many people shared their stories of "losing ten pounds in a month", and even the world's richest man Musk used this drug, and netizens pointed out that he was "a completely different person" since then.

Rationally speaking, "control your mouth and move your legs" is the only way to lose weight. However, when faced with the temptation of delicious food and the ultimate pursuit of "beauty", there will be many irrational factors that affect a person's weight loss decision. Because "if you lose delicious food, what is the meaning of living, but if you gain weight, you don't want to live anymore."

Therefore, in addition to the only way to lose weight, there have emerged some "side roads", "killing one thousand enemies and losing eight hundred of your own", and even "unbelievable" ways to lose weight, such as inducing vomiting after meals, gastric filling surgery, gastrectomy surgery, eating parasites, etc.

We do not question the motivation of people other than those suffering from obesity to lose weight, nor are we surprised by the extreme actions some people take to lose weight. Instead, we try to talk about what a scientific method of weight loss should be like from a scientific perspective, without having to control your mouth or move your legs.

Let's start with blood sugar

Generally speaking, a miracle drug, in addition to its miraculous efficacy, also has a miraculous origin. The story of semaglutide has to start from more than a hundred years ago.

In the early 19th century, Claude Bernard, known as the father of modern physiology, was born in the Beaujolais region of France. It is not known where his talent came from, or what interesting childhood story he had, but in Bernard's career, he was particularly interested in exploring the secrets of metabolism and diabetes.

In 1845, Bernard wrote in his red notebook: "The digestion of carbohydrates takes place in two steps. First, the carbohydrates are converted into glucose. Second, the glucose is 'burned' in the lungs. If the second step of 'burning' does not take place, diabetes will occur."

In order to further study the specific location of glucose "burning" and the cause of diabetes, Bernard designed an experiment. He first fed a dog sweet milk soup, dissected it while the dog was digesting it, and then he detected the presence of sugar in the dog's liver cavity. Therefore, he believed that it was logical to conclude that "all the glucose I found in the veins of this dog came from the sugar that the dog ate."

He then conducted a control experiment, feeding another dog meat, and then dissected it while the dog was digesting the food and checked the glucose content in its liver cavity. He was very surprised to find that even if the dog did not eat any sugar or carbohydrates, there would be a certain amount of glucose in the hepatic vein.

Although Bernard was full of skepticism in this primitive physiological experiment and scientifically set up control experiments, he did not draw any particularly useful conclusions from it given the scientific knowledge at the time, so much so that he wrote in his notebook: "I don't understand anything anymore." (He published these findings in detail in his article "On the Origin of Sugar" in 1848).

Later, Bernard first proposed the concept of "internal environment" and pointed out that blood sugar level can be regulated by the liver, which can keep the organism in a relatively stable state. However, on February 10, 1878, Claude Bernard died in Paris and missed the opportunity to discover insulin (in order to commemorate his pioneering work, the European Diabetes Association established the Claude Bernard Award in his name in 1969 to reward scholars who have made great contributions in the field of diabetes and related metabolic diseases).

In 1922, a story that everyone is familiar with, Frederick Banting and Charles Best discovered insulin, and since then humans have been able to control blood sugar by injecting insulin.

In 1932, Belgian Jean La Barre discovered a hormone in the gastrointestinal tract that stimulates insulin secretion. La Barre named this substance "incretin". Later, with the advancement of newer and more sensitive methods for measuring blood hormone levels, researchers discovered a hormone called glucose-dependent insulinotropic polypeptide (GIP, also known as "gastric inhibitory polypeptide"), which is a major factor in the action of incretin.

With the development of genetic technology, scientists have discovered another incretin that can stimulate insulin secretion, glucagon-like peptide 1 (GLP-1), and have proven that GLP-1 can stimulate the pancreas to secrete insulin at a concentration of 1/100 of GIP.

At this point, what really excites scientists is not weight loss, but the blood sugar lowering effect of GIP and GLP-1. Since natural GIP and GLP-1 are metabolized too quickly in the body, if a stable drug can be found to replace the blood sugar lowering effect of GIP and GLP-1, then the feat of "conquering" diabetes will definitely leave an important mark in the history of medicine.

If nothing unexpected happens, science will also have surprises

In the 1980s, John Pisano, a biochemist who was "enthusiastic" about venom research, and Jean-Pierre Raufman, a gastroenterologist, began studying the venom of a Gila monster. Later, they and other colleagues accidentally discovered a hormone-like molecule, Exendin-4, from the venom.

The amazing thing is that Exendin-4 molecules can act on the same receptors as GLP-1 to stimulate insulin secretion. And the key is that Exendin-4 is relatively stable and has a relatively long metabolic cycle in the human body, so it is very likely to become a diabetes treatment drug.

However, pharmaceutical companies at the time seemed reluctant to develop drugs using the venom of a Gila monster and provide them to patients. Later, Pierre Laufman and his colleagues persuaded a small startup called Amylin Pharmaceuticals to develop the drug. Amylin Pharmaceuticals soon proved that synthetic Exendin-4 could quickly normalize blood sugar in mice with type 2 diabetes, and subsequent clinical trials also proved the safety and effectiveness of Exendin-4 on humans.

In 2005, the U.S. Food and Drug Administration (FDA) officially approved the drug Exenatide for the treatment of type 2 diabetes, under the trade name Byetta.

Well, here comes the point! What surprised the scientists even more was that they found that many patients treated with exenatide experienced sustained weight loss while reversing their diabetes symptoms! The average weight loss was 5%, and some people experienced a significant weight loss of far more than 5%.

In a short-term exenatide treatment trial in non-diabetic obese women, scientists found that the average weight loss of subjects treated with exenatide was 2.49±0.66 kg, and 30% of the subjects lost more than 5% of their weight.

Scientists soon realized that GLP-1 drugs could be used to treat obesity.

Here we also need to explain why GLP-1 can lead to weight loss when it is used to stimulate insulin secretion. In fact, there were various controversies at the beginning, until people later discovered that there are GLP-1 receptors in the brain. Because GLP-1 binds to the GLP-1 receptors in the brain, it suppresses appetite, so weight loss will occur after receiving GLP-1 drug treatment. It is indeed the only way to lose weight. If you can't control your appetite, you can rely on taking medicine to suppress your appetite.

The evolution of miracle drugs

As an international pharmaceutical giant with a leading position in the field of diabetes, Novo Nordisk has not only paid attention to the huge potential of GLP-1 for weight loss very early on, but also began to try to develop a longer-acting GLP-1 drug since the 1990s to better act on the GLP-1 receptors in the brain and achieve the goal of weight loss.

In 2010, the US FDA approved a new GLP-1 drug from Novo Nordisk, liraglutide, trade name Victoza, which has a more significant weight loss effect than Byetta, with the average weight loss of subjects being 10%.

But there is one downside to liraglutide, which is that it still needs to be injected every day (GLP-1 drugs are large polypeptide molecules, so they cannot be taken orally and must be injected). Obviously, for the purpose of losing weight, one injection a day seems less attractive than forgoing it, and the key is that choosing the latter saves money.

In order to better benefit human health, scientists later developed a longer-acting drug, semaglutide (also known as semaglutide), which further enhances the targeting of GLP-1 receptors in the brain. Not only is the weight loss effect more significant, but it only requires one injection per week.

In 2017, semaglutide injection (1 mg) was officially approved for marketing under the trade name Ozempic, which is used to treat type 2 diabetes and reduce the risk of cardiovascular events in patients with type 2 diabetes and cardiovascular disease. Although the indication is still for the treatment of diabetes, it must be said that semaglutide's weight loss effect is really amazing.

A study published in Nature Medicine evaluated the long-term weight loss effect of semaglutide in non-diabetic obese or overweight adults. The results showed that once-weekly subcutaneous injection of 2.4 mg of semaglutide, combined with lifestyle changes, can reduce weight by approximately 33.7 pounds (15.3 kg).

In 2021, the FDA also approved this higher dose of semaglutide injection specifically for the treatment of obesity, under the trade name Wegovy.

As written at the beginning, the road to the godhood of semaglutide was also blessed by Musk's traffic. In October 2022, a netizen asked Musk on social media what his secret to weight loss was. Musk replied: fasting and Wegovy, and said that he had successfully lost 30 pounds.

As a result, semaglutide became a global hit and triggered a weight loss craze on social media. According to statistics, the three semaglutide products launched in 2023 had a combined sales of more than $20 billion. Due to insufficient production capacity, Novo Nordisk had to restrict the supply of drugs in many places.

More possibilities and some risks

To be honest, semaglutide is indeed a miracle drug for diabetes, and the evolution of miracle drugs is still in the ascendant, for example:

In addition to semaglutide injection, there are also semaglutide oral tablets;

In addition to GLP-1 drugs, there are also GIP-type glucose-lowering and weight-loss drugs;
In addition to controlling blood sugar and promoting weight loss, GLP-1 drugs appear to reduce the risk of heart problems, such as heart failure, stroke, and kidney disease, as well as improve blood pressure and cholesterol levels in people who take them;

In February 2021, semaglutide injection was approved for marketing in China. On January 26 this year, oral semaglutide tablets were also approved for marketing in China. It is also expected that Wegovy, a drug for weight loss indications, will also be approved for marketing in China this year.

Although semaglutide has significant and definite effects in controlling blood sugar and losing weight, any one-sided statement of “although” without mentioning “but” is a hooliganism. At least so far, there are still some known or unknown risks of semaglutide, such as:

First, semaglutide is a prescription drug approved by regulatory authorities. In China, semaglutide (whether injection or oral tablet) that has been approved for marketing has not been approved for weight loss indications. However, off-label abuse is common nowadays. Many people buy it online or through unknown channels for weight loss, and it has frequently become a hot topic on social media.

Secondly, even if the FDA approves semaglutide injection (Wegovy, 2.4 mg, once a week) for obesity indications, obesity here has a strict definition. According to the FDA official website, Wegovy can be used for chronic weight management of obese or overweight adults with at least one weight-related disease (such as high blood pressure, type 2 diabetes, or high cholesterol). More specifically, for this drug, the applicable population is patients with a BMI ≥ 30 kg/m2, or patients with a BMI ≥ 27 kg/m2 but with at least one combined weight-related disease.

Then, there are the possible side effects or adverse reactions of any drug. Looking through the clinical trial papers and instructions of semaglutide, it can be seen that its most common adverse reactions are gastrointestinal diseases, including nausea, diarrhea, vomiting and constipation, as well as headaches, fatigue, etc. It also contains risk warnings for pancreatic inflammation, gallstones, acute kidney injury, diabetic retinopathy, increased heart rate and suicidal impulses. In addition, there are also laboratory studies that link the use of these drugs to the occurrence of thyroid tumors in animals, but the risks to humans are currently unclear.

Finally, there is one more thing that is quite heartbreaking. After stopping semaglutide, many people's weight usually rebounds significantly...

So, from a scientific point of view, there is no panacea.

I want to eat delicious food, so I don't want to control my mouth; I'm lazy (tired) and don't want to move, so I can't move my legs; I want to eat delicious food, but I don't want to move, and I don't want to get fat, so I choose to take some diet pills that may have side effects. No matter how a person chooses, there is no right or wrong in essence, so everyone should make rational judgments and make their own choices.

But it may be a bit stupid to blindly believe in the perfect weight loss method or medicine that "can lose weight by lying down"; and it may be a bit bad to wantonly exaggerate the weight loss effect and conceal the side effects or hazards.

References

[1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3712027/

[2] https://theconversation.com/the-rise-of-ozempic-how-surprise-discoveries-and-lizard-venom-led-to-a-new-class-of-weight-loss-drugs-219721

[3] https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021773_byettatoc.cfm

[4] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3241299/

[5] https://www.fda.gov/news-events/press-announcements/fda-approves-new-drug-treatment-chronic-weight-management-first-2014

[6] https://www.nature.com/articles/s41591-022-02026-4

This article is supported by the Science Popularization China Starry Sky Project

Produced by: China Association for Science and Technology Department of Science Popularization

Producer: China Science and Technology Press Co., Ltd., Beijing Zhongke Xinghe Culture Media Co., Ltd.

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