Is it a waste of money or is it really effective? Musk tried this popular drug himself

Slimming injections have been popular for a while. With the help of celebrities such as Musk, it is even hard to get one. The Internet is full of claims that one injection can help you lose ten pounds. These slimming injections are all GLP-1 analogs (also known as GLP-1 receptor activators), but there are many types of drugs in this category. The same drug has different names for diabetes or weight loss, and there are many misunderstandings about its specific weight loss effects. Today's article will explain in detail the scientific principles of the slimming injections that Musk supports.

In October 2022, Elon Musk publicly announced on Twitter that he used the weight loss drug Wegovy

Written by Zhou Yebin (PhD, University of Alabama at Birmingham)

01 The origin of blood sugar reduction in weight loss injections

The slimming injections on the market are analogs of the natural hormone secreted by the human body, glucagon-like peptide-1 (GLP-1). GLP-1 is secreted by intestinal cells and is a short peptide composed of 30 or 31 amino acids. Its receptors are widely present in the human body. GLP-1 binds to GLP-1 receptors on different tissues and organs and can produce various metabolic regulating effects.

In drug development, the earliest noticed effect of GLP-1 is that it can stimulate the pancreas to secrete insulin, while inhibiting the production of glucagon, which is the opposite of insulin. This effect is "natural choice" for type 2 diabetes. When the blood sugar level of the human body rises, insulin will be secreted to lower the blood sugar level, and finally maintain the blood sugar at a stable level. However, when faced with the pressure of long-term high blood sugar, the body cannot keep up - the secreted insulin is not enough; or the body is also "tired" of insulin - the blood sugar lowering response after seeing insulin is no longer sharp. This will make it impossible for the human body to maintain normal blood sugar levels, which is the root cause of type 2 diabetes.

GLP-1's pull and pressure on insulin and glucagon are good news for patients with type 2 diabetes and a good candidate for treating diabetes. However, natural GLP-1 is very unstable in the human body and has a very short half-life, so it cannot be used as a drug directly. Whether it is injected or taken as a drug, it is impossible to stabilize blood sugar for a long time.

This gives modern pharmaceutical research and development an opportunity to show its prowess. Many pharmaceutical companies have made multiple drugs that can play the role of GLP-1 by using structures similar to GLP-1 but with improved stability and other characteristics, namely GLP-1 analogs or GLP-1 receptor agonists (GLP-1RA). These drugs have achieved good therapeutic effects on type 2 diabetes. In addition, GLP-1RA drugs are relatively new and are much more expensive than old drugs such as metformin that have long passed the patent period. In recent years, they have become the most profitable business in the diabetes drug market, and many products have been nicknamed "Sugar King".

02 GLP-1RA can also reduce weight

The reason why GLP-1RA drugs are so popular now is definitely not the result of their honest and conscientious work in the field of type 2 diabetes - what everyone is talking about now is the weight loss injection, not the blood sugar-lowering injection.

So how did GLP-1RA become a weight loss tool? Type 2 diabetes is a metabolic disease (type 1 diabetes is an autoimmune disease), which is often associated with obesity, lack of exercise and other factors. Therefore, the subjects recruited for clinical trials of type 2 diabetes drugs are often obese patients, which makes hypoglycemic drugs a "byproduct" in the observation of "weight loss".

However, this does not mean that hypoglycemic drugs will necessarily help you lose weight. In fact, many diabetes drugs will cause you to gain weight. For example, the use of insulin will cause weight gain. The reason is that insulin lowers blood sugar, and the sugar that is squeezed out of the blood has to find a place to go. One way is to store it as fat (insulin itself can promote the conversion of sugar to fat in metabolism). It would be unfair if you don’t gain weight. A type of type 2 diabetes drug that was once widely used - sulfonylurea drugs - also has a weight-gaining effect, with each patient gaining an average of 4-5 pounds. As for metformin, a first-line drug for type 2 diabetes, its effect on body weight is quite satisfactory: it does not cause weight gain, but the weight loss effect is inconsistent in different studies. Some studies have no effect at all, and some studies have shown that the effect is relatively mild.

But GLP-1RA drugs are very different from previous hypoglycemic drugs. We have said that GLP-1 receptors are distributed throughout the body, and GLP-1 binds to receptors on different tissues to produce different effects. It can promote insulin secretion in the pancreas; it can suppress appetite in the brain; and it can inhibit gastric emptying in the stomach. The latter two mechanisms can reduce calorie intake. They cannot help you move your legs, but at least they can make you not want to open your mouth. This lays the mechanistic foundation for weight loss with GLP-1RA drugs.

In clinical trials for type 2 diabetes, multiple GLP-1RA drugs have lived up to expectations, with varying degrees of weight loss in the medication group compared to the control group. For example, the now popular weight loss injection semaglutide, in a clinical trial for type 2 diabetes with an average baseline weight of about 99.3 kg, used a dose of 1 mg per week, and the average weight loss after 40 weeks was 5.7 kg.

03 Why did GLP-1RA become a weight loss star?

Several GLP-1RA drugs have shown weight loss effects in clinical trials of type 2 diabetes. For example, semaglutide can help people lose more than ten pounds at once, which has led some doctors to use some GLP-1RAs off-label (that is, beyond the approved drug indications) to help people lose weight or control their weight. However, some GLP-1RAs can be transformed into weight loss injections today, not only because they can lower blood sugar.

Although there are numerous health products and nutritional supplements that claim to help lose weight, such as Pu'er tea, which was popular at the time, which was also under the banner of fat removal, it is very difficult to make a drug that can clearly help lose weight. It is basically a graveyard for new drug research and development. On the one hand, it is not easy to make it effective, and on the other hand, the safety standards for weight loss drugs are very high.

Obesity is a high-risk factor for many diseases, including cardiovascular disease and diabetes. Even some cancers have a higher incidence rate in obese people. But the problem is that facing the risk of multiple diseases does not mean that obese people are "fat". An obese person can also be very healthy and have no particularly urgent dangerous diseases that need to be treated. Therefore, serious weight loss drugs, that is, drugs that only treat obesity, are close to drugs used in healthy people, and the safety factor must be very high. In the history of weight loss drugs, there have been malicious incidents such as fen-phen (fenfluramine/phentermine) that were removed from the shelves after being launched due to toxicity issues. Pharmaceutical companies and regulatory agencies are highly cautious.

Now when people look at GLP-1RA drugs, their focus is on how effective these drugs are in reducing weight. In fact, pharmaceutical companies dare to develop these drugs as weight-loss drugs, and regulatory agencies such as the FDA dare to approve them. One thing that cannot be ignored is that the safety of these drugs is incredibly outstanding.

Glucose-lowering drugs generally need to worry about a side effect: hypoglycemia. People who use insulin to treat diabetes often keep some candy and chocolate around to deal with hypoglycemia. The great thing about GLP-1RA drugs is that there is no risk of hypoglycemia when used alone. Although GLP-1 promotes insulin secretion, this only occurs when blood sugar in the body is too high. That is, the hypoglycemic effect of GLP-1RA depends on blood sugar concentration. If the concentration is not high, blood sugar will not drop, avoiding the possibility of causing hypoglycemia.

The weight loss drug fen-phen mentioned above was removed from the shelves because it has cardiovascular toxicity. In the history of diabetes drug development, there have been precedents in which some thiazolidinediones were found to increase the risk of cardiovascular disease after they were put on the market. Considering the problems with thiazolidinediones, the FDA directly issued a restriction order on hypoglycemic drugs in 2008: new diabetes drugs must not only show the ability to lower blood sugar, but also have clinical trials to prove that they do not increase the risk of cardiovascular disease. Why did the FDA take such a harsh approach to hypoglycemic drugs? Because one of the biggest hazards of high blood sugar is an increased risk of cardiovascular disease, the primary purpose of lowering blood sugar is to reduce the threat of cardiovascular disease. If hypoglycemic drugs increase the risk of cardiovascular disease, then what is the point of taking the drugs? This is why the FDA attaches great importance to the increase in cardiovascular risk caused by hypoglycemic drugs.

This means that after 2008, diabetes drugs had to complete a cardiovascular disease clinical trial before they could be marketed in the United States. This trial requires a much larger number of subjects than a clinical trial to confirm the hypoglycemic effect, and it takes longer. Many pharmaceutical companies have reduced their investment in hypoglycemic drugs because of the increased difficulty in the development of hypoglycemic drugs (the FDA updated the relevant regulations in 2020 and no longer simply required cardiovascular risk verification). On the other hand, this nitpicking also made the hypoglycemic drugs that were later launched on the market extremely awesome (safe). For example, GLP-1RA drugs not only exclude cardiovascular toxicity due to the relevant FDA regulations, but also actually show a protective effect in reducing the risk of cardiovascular disease in diabetic patients.

In summary, GLP-1RA is a glucose-lowering drug that has been shown to have cardiovascular protective effects in diabetic patients and does not even pose a risk of hypoglycemia when used alone. Because of such a good safety foundation, the weight loss effect of this type of drug can be singled out for research and development in the direction of weight loss.

04 Switching to weight loss and making a big splash

Almost no one disagrees that losing weight is difficult, but making an effective weight loss drug is no less difficult than losing weight. Orlistat, a widely used weight loss drug, is a lipase inhibitor that can inhibit the absorption of fat. It has been verified in multiple clinical trials that after one year of use, the subjects lost 2-3 kg more than the control group. It should be noted that the subjects who take weight loss drugs often have a BMI of more than 30, and a weight of 100 kg is considered average. To be honest, the difference of 2-3 kg is something that can only be seen with a magnifying glass.

In medicine, there is a standard for "clinically significant weight loss": 5% weight loss. 5% may not seem like much, but it is a mountain that many weight loss drugs cannot overcome for most obese patients even with exercise and diet control.

GLP-1RA itself is very safe, and in clinical trials for type 2 diabetes, many subjects have also achieved significant weight loss. Therefore, some GLP-1RA drugs with better weight loss effects have begun to be sent to the weight loss battlefield - directly recruiting obese patients without type 2 diabetes for clinical trials to see if they work as weight loss drugs regardless of diabetes.

The first drug to be tested for its weight loss effect was liraglutide, and the results were amazing. A clinical trial published in The Lancet in 2009 showed that subjects with a BMI of 30-40, who were all exercised and had a controlled diet, received daily injections of 1.2/1.8/2.4/3.0 mg of liraglutide (different groups), and lost an average of 4.8/5.5/6.3/7.2 kg in 20 weeks. In contrast, the placebo only lost 2.8 kg, and the aforementioned orlistat lost 4.1 kg.

Moreover, the proportion of subjects who achieved clinically significant weight loss, that is, a 5% weight loss, was 30% in the placebo group, 44% in the orlistat group, and how much was 3 mg of liraglutide? 76%!

These are data from 20 weeks of medication, and later studies have shown the weight loss ability of liraglutide over a longer time frame. A clinical trial of more than 3,000 people (average baseline weight of about 106 kg) followed for 56 weeks (more than a year) and showed that 62.3% of 3 mg liraglutide users lost more than 5% of their weight, 33.9% lost more than 10%, and the average weight loss was 9.2%.

With its amazing weight loss effect and good safety, the FDA approved liraglutide in 2014 to help obese patients lose or control their weight. It is also the first weight loss injection on the market. (Note: The original liraglutide was approved for diabetes in China in 2011, only one year later than the FDA, but it has not been approved for obesity indications in China so far; the original drug began to enter the medical insurance in 2017, and the patent has expired; on March 30 this year, the first biosimilar of liraglutide was approved in China. What's interesting is that recently, when the original drug had no weight loss indication, this biosimilar was approved for weight loss indications)

Although liraglutide has crushed orlistat and other weight loss drug predecessors, its effect is not a big deal compared to the new generation of GLP-1RA drugs. In the phase III clinical trial of the current popular weight loss injection semaglutide, the average weight loss was 14.9% in 68 weeks, and more than 80% of the subjects lost more than 5%, and 30.9% of the subjects lost more than 20%.

This is not over yet. Both liraglutide and semaglutide were developed by Novo Nordisk. There is another pharmaceutical company in the field of GLP-1RA that also has a prominent position-Eli Lilly. In July 2022, Eli Lilly announced the results of its Phase III clinical trial of its new generation of GLP-1RA drug tirzepatide for the treatment of obesity. There were three doses, 5mg, 10mg and 15mg, with a follow-up time of 72 weeks, a baseline weight of about 105 kg, and an average weight loss of 15%, 19.5% and 20.9%, respectively-this is heading towards an average of 20%. The weight loss effect achieved by bariatric surgery such as gastric bypass surgery is only an average weight loss of 25-30% within 1-2 years. More than one-third of the subjects in the high-dose group of tirzepatide lost more than 25%, which is comparable to bariatric surgery.

Unlike predecessors such as tesiparatide and semaglutide, it is a dual agonist, not only an analog of GLP-1, but also similar to another hormone, GIP. This drug is currently only approved by the FDA for diabetes, but it should be approved for obesity treatment this year.

After reading this, many people may be eager to get an injection themselves, not to lose 20%, but 5% is good. Friends with this idea may be dumbfounded when they search the Internet. There seem to be many weight loss injections, liraglutide, semaglutide, how to distinguish them? Even if you choose the most popular semaglutide to prevent mistakes, you will find that there are several different brands and doses. How did the GLP-1RA drug, which is simple in principle, become so complicated in the real world? Who is the weight loss injection? Let's wait for the next time to analyze it.

References

1.https://www.ncbi.nlm.nih.gov/books/NBK551568/

2.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6520185/

3.https://www.novomedlink.com/diabetes/products/treatments/ozempic/efficacy-safety/ozempic-and-weight.html

4. https://www.ahajournals.org/doi/full/10.1161/CIRCULATIONAHA.119.041022

5.https://pubmed.ncbi.nlm.nih.gov/19853906/

6.https://www.novomedlink.com/obesity/products/treatments/wegovy/efficacy-safety/clinical-trial-1-results.html

7. https://www.nejm.org/doi/full/10.1056/NEJMoa2206038

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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