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Semaglutide: The Price of Losing Weight
Glucagon-like peptide-1 (GLP-1) agonists are advertised as “game changers” in the treatment of morbid obesity. Originally developed to treat type 2 diabetes, they not only improve HbA1c but also result in significant weight loss. The main reason is due to the increased feeling of satiety and slower gastric emptying.
The GLP-1 agonist liraglutide is made by the pharmaceutical company Novo Nordisk. It is so effective at shedding pounds in the SCALE study that it was approved as a weight-loss drug for non-diabetics throughout the EU in 2016. With the STEP 1 study, the phase 3 data of its successor semaglutide are now available. Which, in contrast to liraglutide, only has to be injected once a week instead of daily.
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Semaglutide seems to be convincing as a weight loss treatment. Studies for more than a year, saw obese non-diabetics had lost around 14.9% weight (BMI: -5.5 kg/m2). These subjects only taking semaglutide plus lifestyle intervention. While the placebo group with lifestyle intervention alone only lost around 2.4 % managed (BMI: -0.9 kg/m2). 32% of the subjects in the semaglutide group achieved a weight loss of more than 20%, compared to only 1.7% in the placebo group.
Compared with liraglutide, the new GLP-1 agonist performs better (-12.4% versus -5.4% weight loss, each compared to placebo). Semaglutide eclipses other weight-loss pharmacotherapies. It’s not just body fat that accounts for most of the weight lost. The metabolically unfavorable visceral fat is also decreased – just slightly by about 270 g comparing to the placebo.
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Nevertheless, this difference was probably already sufficient to reduce the inflammatory activity – measured by the value of the C-reactive protein – under semaglutide. The GLP-1 agonist also improved other parameters such as blood pressure, fasting blood sugar, lipid levels and quality of life. The “older” GLP-1 agonist liraglutide does not seem to come close to semaglutide.
The study is well designed and shows no major weaknesses. What is striking, however, is the minimal weight loss on placebo. Here the suspicion was that the lifestyle intervention had not really been successful – which made the semaglutide group look better. But the data from the recently published study shows that semaglutide is also more effective with a much more intensive diet and exercise program. Here the weight loss was -16% in the semaglutide group versus -6% in the placebo group.
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Against the background of the expected high therapy costs in the event of approval, the question arises as to which patients should receive semaglutide and which should not. Around a quarter of adults in Germany are obese and would in principle be eligible for therapy. “Ideally, every patient should receive semaglutide where we suspect a benefit from a medical point of view,” says Prof. Dr. medical Andreas Birkenfeld, endocrinologist and chief physician at the Department of Endocrinology at the University Hospital in Tübingen, Germany.
The professor thinks in particular of patients who, in addition to obesity, also suffer from its consequences such as joint and cardiovascular diseases and who have already tried in vain to lose weight in the conventional way.
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But there is a problem! Health insurance companies have not yet covered GLP-1 agonists for the treatment of obesity. Simply because it is not been proven that pharmacological weight reduction can also prevent secondary diseases, especially cardiovascular ones. “So far, no drug has managed to do this in the obesity sector,” says Birkenfeld. “If this were to succeed with semaglutide, this would possibly put the Federal Joint Committee (G-BA) under pressure to make this drug reimbursed.” A cardiovascular endpoint study with semaglutide (SELECT study) is already underway and is expected to deliver results by the end of 2023.
But there is also criticism of the new GLP-1 agonists. One of the main problems lies in the necessity of having to administer them for life. Prof. Dr. medical Joachim Spranger, director of the medical clinic with a focus on endocrinology and metabolism at the Charité – Universitätsmedizin Berlin, is therefore cautious: “If you imagine that an obese 30-year-old patient would inject this drug for the next 40 years, then of course we have insufficient experience of what can come.”
In fact, reliable long-term data is still missing. It is accompanied by great uncertainty as to whether the benefits will outweigh the harm in the long run. Some experts also fear a loss of effectiveness over time. However, Spranger does not see this problem in particular: “In the studies, you do not see any diminishing effect as long as the drug is taken. But there is a plateau that is reached after about a year.”
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It is also striking that liraglutide and semaglutide are dosed about twice as high as drugs for weight loss as for diabetes therapy. “The phase 2 studies have shown that even greater weight loss can be achieved with a higher dose while the HbA1c does not fall any further,” argues Birkenfeld. But as is well known, the dose makes a poison, and may be particularly important with regard to cancer risk. In animal models, GLP-1 agonists have been associated with the occurrence of thyroid and pancreatic carcinomas. Although there is no evidence of this in humans. But corresponding endpoint studies are lacking. Birkenfeld sees no danger here. “Actually, we would expect that the pronounced weight loss would be accompanied by a reduction in cancer” says the researcher.
Spranger sees it similarly. But even if GLP-1 agonists turn out to be completely safe, the question remains: are patients even willing to inject themselves once a week for the rest of their lives just to lose weight? “Injections are indeed still a certain obstacle” reports Spranger from his clinical experience. However, Novo Nordisk already has a solution ready and could soon offer Semaglutide in the EU as a tablet. Oral semaglutide has already been approved in the United States.
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Other pharmaceutical companies such as Eli Lilly are also working on oral GLP-1 agonists. Birkenfeld finds this idea very interesting from a biotechnological point of view: “For the first time, it has been possible to make peptides available orally.” Nevertheless, he is skeptical as to whether the drugs will prove themselves in practice. With strict rules to be observed when taking them, for example they have to be taken with a certain amount of water and half an hour before any other medication. “For me, compared to the injections, there is currently a greater likelihood of taking errors. Practice will show to what extent this plays a clinical role,” says Birkenfeld.
Gastrointestinal symptoms are among the troublesome and common side effects of GLP-1 agonists, which is why they must be dosed carefully. Nausea, vomiting, diarrhea and constipation also occur significantly more frequently under liraglutide and semaglutide. Even if these symptoms often decrease over time, around half of the patients are affected. Some therefore ask whether this might be the reason for the strong weight loss (3, 8, 9, 10). “We know that weight loss from GLP-1 agonists is independent of nausea. Initially, however, it will contribute to this,” says Birkenfeld.
Biliary problems, especially gallstones, occur around twice as often with liraglutide and semaglutide. For example, 2.6% with semaglutide and 1.2% with placebo. It is not uncommon for side effects to lead to discontinuation of therapy, in 6% to 7% of subjects in the approval studies. “We also see a similar dropout rate in clinical practice” says Spranger.
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GLP-1 agonists such as semaglutide are a new tool in the repertoire of individualized obesity therapy. But because of their side effects and the need for lifelong therapy, they’re not a miracle cure. You can Buy Peptides for Weight Loss Research here today. We supply a range of fat burning peptides for study. Ranging from Adipotde, AOD-9604, 5-Amino-1MQ Capsules, Tesofensine capsules, GlP-1, liraglutide and semaglutide, we sell them all!
How much Weight can you Lose with Peptide Therapy?
A lot of people talk about peptide therapy in the current world of obesity. What can you really expect from this type of diet? What are the results, if any? Does peptide therapy really work for the obese person?
We will answer the question of how much weight can you lose with peptide therapy in the body. To answer the question about the efficacy of peptide therapy in the body, let’s look at the results in the previous weight-loss studies.
Peptide therapy, first of all, can be divided into two branches, namely, peptide hydrolysates and injectable peptides. Peptide hydrolysates are obtained by hydrolyzing peptide molecules. Injectable peptides are peptides that have been isolated. There are many ways of obtaining these types of peptides. It is a very complex process, which begins from a living organism, followed by the digestion of proteins into smaller molecules, and finally leads to the isolation of peptides.
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The main function of peptides is to stimulate the metabolism. The body requires peptides for a number of biological functions. The digestion of proteins in the gastrointestinal tract is the first step in peptide therapy. Digestion of protein is carried out by the proteolytic enzymes. Proteolytic enzymes are one of the four enzymes in the digestive tract. In the human body, there are four proteolytic enzymes. They are amylases, chymotrypsin, trypsin and pepsin. Among them, amylases are most widely used for peptide therapy. As we know, amylases are mainly used for the hydrolysis of carbohydrates, which are the main part of protein, into disaccharides and trisaccharides.
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It has been proven that amylase will reduce the rate of obesity to a certain extent. But what is its exact mechanism? After hydrolyzing the carbohydrates, there are some oligosaccharides remaining on the intestinal wall, which have a certain function in fat digestion. Oligosaccharides are macromolecular carbohydrate polymers. They consist of two monosaccharide units linked by a glycosidic bond. These oligosaccharides can reduce fat absorption, and therefore act as inhibitors in the digestive tract.
In addition, these oligosaccharides, in the intestinal wall, can stimulate the body to release the fat and increase the oxidation in the body. Therefore, in obese people, more oligosaccharides will remain in the digestive tract, and consequently, the absorption of fat will decrease. In other words, the more oligosaccharides left in the digestive tract, the less fat the body absorbs.
So, if there are some oligosaccharides remaining in the digestive tract, the absorption of fat will be reduced. That is the reason why a lot of fat patients benefit from amylase when they use diet pills. If the amount of oligosaccharides in the digestive tract is not increased, the fat absorption will not be reduced and hence the efficacy will not be better. But if there are not many oligosaccharides in the digestive tract, the fat absorption will increase, and then the efficacy will be better.
