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This article comes from the official account of Wechat: back to Park (ID:fanpu2019), author: Zhou Yebin

Weight loss needles have been popular for some time, and with the help of celebrities such as Musk, there is even a phenomenon that it is difficult to get a single needle, and the Internet is full of people who lose ten jin per stitch. These weight loss needles all refer to GLP-1 analogues (also known as GLP-1 receptor activators), but there are many kinds of these drugs, the same drug has different names for diabetes or weight loss, and there are many misunderstandings about the specific weight loss effect. Today's article will interpret in detail the scientific principle of the weight loss needle on Musk platform.

In October 2022, Elon Musk publicly used the weight loss drug Wegovy on Twitter. Zhou Yebin (PhD, University of Alabama, Birmingham, USA)

The slimming needle on the market is an analogue of the natural hormone secreted by the human body, glucagon-like peptide-1 (GLP-1). GLP-1, secreted by intestinal cells, is a short peptide composed of 30 or 31 amino acids, and its receptor exists widely in human body. GLP-1 binds to GLP-1 receptors in different tissues and organs and can regulate metabolism.

In drug development, GLP-1 was first noticed that it can stimulate the secretion of insulin from the pancreas and inhibit the production of glucagon opposite to insulin. This effect is a "natural choice" for Ⅱ diabetes. When the body's blood sugar increases, it secretes insulin to reduce blood sugar levels, eventually keeping blood sugar at a stable level. But in the face of long-term high blood sugar stress, the body can't catch up with it-it doesn't secrete enough insulin; or the body is "tired" of insulin-the hypoglycemic response to insulin is no longer sharp. This makes it impossible for the body to maintain normal blood sugar levels, which is the root cause of Ⅱ diabetes.

The pull and pressure of GLP-1 on insulin and glucagon happens to be the good news for patients with type Ⅱ diabetes and is a good candidate for the treatment of diabetes. However, natural GLP-1 is very unstable in the human body, and its half-life is so short that it is impossible to make medicine directly-no matter when it is taken as medicine, it is impossible to stabilize blood sugar for a long time.

This gives modern pharmaceutical research and development a great opportunity. Many pharmaceutical companies make use of the structure similar to GLP-1, but improve the stability, to make a number of drugs that can play the role of GLP-1, that is, GLP-1 analogues or GLP-1 receptor agonists (GLP-1RA). These drugs have achieved good results in the treatment of Ⅱ diabetes. In addition, GLP-1RA drugs are relatively new, and their prices are much higher than those of old drugs such as metformin, which have long been out of patent. In recent years, they have become the most profitable business in the diabetes drug market, and a number of products are jokingly called "sugar kings."

02. GLP-1RA can also lose weight GLP-1RA drugs are as popular as they are now, which is by no means the result of being honest and responsible in the one-third of an acre of Ⅱ diabetes.

So how did GLP-1RA become a weight loss tool again? Ⅱ diabetes is a metabolic disease (Ⅰ diabetes is an autoimmune disease), which is often related to obesity, lack of exercise and other factors. As a result, clinical trials of Ⅱ diabetes drugs tend to recruit subjects who are obese, making it easy for hypoglycemic drugs to observe "weight loss".

However, this is not to say that hypoglycemic drugs are bound to lose weight, in fact, many diabetes drugs will gain weight. Use of insulin, for example, can lead to 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 out is to store it as fat (insulin itself can promote the conversion of sugar to fat in metabolism), which makes no sense not to gain weight. Sulfonylureas, a class of Ⅱ diabetes drugs that have been widely used, also have weight gain, with an average weight gain of 4-5 jin per patient. As for metformin, a first-line drug for Ⅱ diabetes, the effect on weight is moderate: no weight gain, but weight loss varies from study to study, some not at all, and some slightly at all.

But GLP-1RA drugs are very different from previous hypoglycemic drugs. We said that the receptors of GLP-1 are distributed throughout the body, while GLP-1 binds to receptors in different tissues to produce different effects. It boosts insulin secretion in the pancreas, suppresses appetite in the brain, and suppresses gastric emptying in the stomach. The latter two mechanisms can reduce calorie intake, can not help you open your legs, at least so that you do not want to open your mouth, which lays the foundation for GLP-1RA drugs to lose weight.

In the clinical trial of Ⅱ type diabetes, a number of GLP-1RA drugs also lived up to expectations, and the treatment group showed varying degrees of weight loss compared with the control group. In a clinical trial of Ⅱ diabetes in which subjects' average baseline weight is about 99.3kg, a weekly dose of 1mg, like the popular slimming needle, lost an average of 5.7kg after 40 weeks.

03. Why is there a weight loss star in GLP-1RA? several GLP-1RA drugs have shown weight loss in clinical trials of Ⅱ diabetes, such as Smegeluppin, which has led some doctors to exceed the label (that is, beyond the approved drug indications) to use part of GLP-1RA to help people lose weight or control weight. However, some GLP-1RA can be turned into weight-loss needles today, not just because it can reduce sugar.

Despite the fact that there are so many health products and nutrients that can lose weight, such as Pu'er tea, it is also under the banner of scraping oil. But serious weight loss drugs are very difficult to do, and it is basically a graveyard for new drug research and development. On the one hand, it is not easy to make effectiveness, on the other hand, it is because the safety standards of weight-loss drugs are very high.

Obesity, including cardiovascular disease, diabetes and other high-risk factors, even some cancers have a higher incidence in obese people. But the problem is that facing the risk of multiple diseases does not mean that obese people are sick. An obese person can also be healthy and there are no particularly urgent dangerous diseases that need to be treated. Therefore, serious weight loss drugs, that is, drugs that only treat obesity, are similar to those used in healthy people, and the safety factor must be very high. In the history of weight-loss drugs, there have also been vicious events such as fen-phen (fenfluramine / fentamine) that have been removed from the shelves because of toxic problems, and drug companies and regulators have been highly cautious.

Now we look at GLP-1RA drugs, the focus is how much weight loss of this kind of drugs, in fact, drug companies dare to use this kind of drugs as weight loss drugs, FDA and other regulatory agencies dare to approve, can not be ignored is that the safety of this kind of drugs is surprisingly excellent.

Hypoglycemic drugs generally need to worry about one side effect: hypoglycemia. People who treat diabetes with insulin tend to keep candy chocolates with them in case of hypoglycemia. The powerful thing about GLP-1RA drugs is that there is no risk of hypoglycemia when used alone. Despite the fact that GLP-1 promotes insulin secretion, this only happens when the blood sugar in the body is too high, that is, the hypoglycemic effect of GLP-1RA depends on the blood sugar concentration, which is not high, and the blood sugar does not fall, avoiding the possibility of causing hypoglycemia.

The weight-loss drug fen-phen was removed from the shelves because of its cardiovascular toxicity. In the history of diabetes drug research and development, there have been precedents in which thiazolidinediones have been found to increase the risk of cardiovascular disease. Also considering the problem of thiazolidinediones, the FDA imposed a direct restriction on hypoglycemic drugs in 2008: new diabetes drugs should not only be shown to reduce blood sugar, but also be shown in clinical trials that do not increase the risk of cardiovascular disease. Why would FDA do this to hypoglycemic drugs? Because one of the biggest hazards of hyperglycemia is to increase the risk of cardiovascular disease, the primary purpose of reducing blood sugar is to reduce the threat of cardiovascular disease. If hypoglycemic drugs increase the risk of cardiovascular disease, what's the point of taking them? This is why FDA attaches great importance to hypoglycemic drugs to increase cardiovascular risk.

This means that diabetes drugs will have to complete a clinical trial of cardiovascular disease before they can be marketed in the United States after 2008, which requires far more subjects than clinical trials that confirm hypoglycemic effects and takes longer. Many pharmaceutical companies have reduced their investment because of the sharp increase in the difficulty of developing hypoglycemic drugs (FDA updated the rules in 2020 to no longer simply criticize cardiovascular risk verification), but on the other hand, this nitpicking has also made the later hypoglycemic drugs a mess. For example, GLP-1RA drugs, not only because the relevant regulations of FDA exclude cardiovascular toxicity, but also show a protective effect of reducing the risk of cardiovascular disease in patients with diabetes.

To sum up, GLP-1RA is a hypoglycemic drug that has a cardiovascular protective effect in patients with diabetes and is used alone without the risk of hypoglycemia. Because of such a good safety basis, the weight loss effects of these drugs can be taken out alone for research and development in the direction of weight loss.

04, the war to lose weight is a blockbuster, it is difficult to lose weight, which almost no one has an objection to, but the difficulty of being an effective weight loss drug is no lower than losing weight at all. A widely used weight loss drug orlistat (orlistat), as a lipase inhibitor, can inhibit the absorption of fat, in several clinical trials verified, a year of use, the subjects also lost 2-3 kilograms compared with the control group. It is important to know that subjects with weight-loss drugs tend to have a BMI of more than 30 and weigh 100kg on average. 2-3kg is really the difference that can only be seen with a magnifying glass.

In medicine, there is a "clinically significant weight loss" standard: 5% weight loss. 5% does not seem like much, but it is a mountain that many weight-loss drugs cannot be crossed by most obese patients under the addition of exercise and diet control.

GLP-1RA itself is safe, and many subjects have received significant weight loss in clinical trials of type 2 diabetes mellitus (Ⅱ). As a result, some of the more prominent GLP-1RA drugs for weight loss are being sent to the weight loss battlefield-directly recruiting obese patients without Ⅱ diabetes for clinical trials to see if the weight loss drugs work well regardless of diabetes.

The first person to test the effect of weight loss was liraglutide, and the result was a blockbuster. A clinical trial published in the Lancet in 2009 showed that subjects in BMI30-40, in the context of exercise and diet control, were injected with 1.2pm 1.4max 3.0mg of lialutide a day (different groups), and lost an average of 4.8pm 6.37.2 kg at 20 weeks, compared with 2.8kg in placebo. The aforementioned orlistat lost 4.1 kilograms.

And the percentage of subjects who achieved a clinically significant weight loss-- that is, a 5% weight loss-- was 30% in the placebo group and 44% in orlistat. How much is 3mg liralutide? 76%!

These are data from 20 weeks of treatment, and subsequent studies have shown the ability to lose weight over a longer period of time. A clinical trial of more than 3000 people (with a baseline average weight of about 106kg) followed for 56 weeks (more than one year), showing that 62.3% of 3mg Lilarutide users lost more than 5% of their weight, 33.9% of them lost more than 10%, and an average of 9.2%.

With its amazing weight loss effect and good safety, in 2014, FDA approved liralutide to help obese patients lose or control weight, the first weight loss needle on the market. (note: the original drug was approved for diabetes in China in 2011, only one year later than FDA, but so far there is no indication of obesity in China; the original drug entered medical insurance in 2017, and the patent has expired; on March 30 this year, the first domestic biological analogue of rilarutide was approved, what is interesting is that in the absence of weight loss indications of the original drug, this biological similar drug approved weight loss indications recently.)

Despite the fact that Lilarutide rubbed predecessors of weight-loss drugs such as orlistat on the floor, its effect was nothing compared to the next generation of GLP-1RA drugs. Today's online celebrity weight loss injection Simigeluppin, in the third-phase clinical trial to study the effect of weight loss, the average weight loss was 14.9% in 68 weeks, more than 80% of the subjects lost more than 5% weight, and 30.9% of the subjects lost more than 20% of their weight.

It's not over. Lilaru peptide and Simiguelu peptide are both developed by Novo Nord, and there is also a prominent pharmaceutical company in the field of GLP-1RA-Eli Lilly. In July 2022, Lilly announced the results of a phase III clinical trial of its new generation of GLP-1RA drug, tirzepatide, in the treatment of obesity. The three doses, 5mg and 15mg, followed for 72 weeks, the baseline weight was about 105kg, and the average weight loss was 15%, 19.5% and 20.9%, respectively-towards an average of 20%. Weight loss surgery such as gastric bypass surgery has only achieved an average weight loss of 25-30% in 1-2 years. More than 1/3 of the subjects in the high-dose group lost more than 25% of their weight, which is comparable to weight-loss surgery.

Unlike their predecessors, Ticipapeptide is a biagonist, not only an analogue of GLP-1, but also similar to another hormone, GIP. The drug is currently approved by the FDA only for diabetes, but should be approved for obesity treatment this year.

At this point, many people may wish to get an injection themselves, not to ask for a 20% reduction, a reduction of 5% is also good. Friends with this idea may be dumbfounded when they look it up on the Internet. It seems that there are many weight loss needles, such as Lilaru peptide and Simeglu peptide. How to distinguish these? Even if you choose the most popular Smegler peptide to prevent mistakes, you will find several different brands and doses. How did the simple GLP-1RA drugs in principle become so complicated in the real world? Who on earth is the weight loss needle? Let's listen to the next decomposition.

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

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