An article explains various types of weight loss injections: Don't rush to try, more options are still to come

In the previous article "Is it an IQ tax or is it really effective? Musk personally tried this internet-famous drug", we introduced the blood sugar-lowering antecedents of the currently popular weight loss injections - GLP-1RA (glucagon-like peptide-1 (GLP-1) receptor agonists), and why they turned to obesity treatment after becoming the "sugar king". However, there are many varieties of weight loss injections. Liraglutide and semaglutide are both called weight loss injections. What is the difference between them? Some people search for weight loss injections and find that there are multiple brands of semaglutide, which makes them start to wonder if they have encountered fakes. This year, we will sort out the GLP-1RA drugs on the market.

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

01 The first generation of weight loss injection - liraglutide

GLP-1RA drugs are the hottest new drugs in metabolic diseases, and the result is that there are multiple drugs and multiple dosage forms mixed in the market, which can be confusing. Fortunately, after a number of GLP-1RA drug battles in the past decade, this field has become a three-way competition between Novo Nordisk and Eli Lilly. Whether the remaining pharmaceutical companies are eating melons or watching covetously depends on whether the securities analyst you ask is short or long, but there are currently no other companies' listed products to confuse us.

Currently, Novo Nordisk and Eli Lilly each have only two GLP-1RA drugs on the market, which further facilitates us to clarify the weight loss injection products on the market.

Both GLP-1RA drugs

They can be considered as two generations of drugs. Let’s first look at Novo Nordisk’s: liraglutide and semaglutide. Semaglutide is the most popular weight loss injection on the Internet and is Novo Nordisk’s new generation of GLP-1RA drugs; liraglutide is the previous generation and its patent has expired. China has also recently approved a biosimilar drug (similar in structure and action to liraglutide).

Figure: Liposuction, the first blood sugar lowering/weight loss injection approved in China.

Liraglutide can be regarded as the first GLP-1 receptor agonist that combines blood sugar lowering and weight loss. However, it should be noted that the dosages used for blood sugar lowering and weight loss are different. For this reason, the same substance is made into two products. The product used for blood sugar lowering and targeting diabetes is called Victoza; the product used for weight loss is called Saxenda.

Why is this so? Because the main purposes of blood sugar reduction and weight loss are different. The former is for diabetic patients, and the main treatment goal is to control blood sugar. Taking A1C (glycosylated hemoglobin), a key indicator of diabetes, as an example, in the clinical trials conducted by Novo Nordisk, the daily use of 1.2mg or 1.8mg of liraglutide can reduce the average A1C of patients with a baseline of 8.4%-8.5% by 1.2% or 1.5%. You must know that A1C above 6.5% is diabetes, and the blood sugar reduction level of the above dose is already good, so Novo Nordisk made Victoza, a product for diabetes, at this dose. Patients first use a dose of 1.2mg, and if further blood sugar reduction is necessary, the dose can be increased to 1.8mg.

Figure: Novo Nordisk's diabetes injection Victoza, which contains liraglutide

In diabetic patients with a baseline weight of approximately 94 kg, the use of 1.2 mg of liraglutide per day can reduce an average of 2.7 kg, and the use of 1.8 mg can reduce weight by 3.3 kg. This is already a significant weight loss, but if used alone for weight loss, there is still room for improvement in the degree of weight loss, and the most direct way to increase it is to increase the dosage. In the clinical trial of weight loss, liraglutide finally achieved a dose of 3 mg, which can make subjects with an average baseline weight of 106 kg lose 7.4% in a year, a loss of nearly 8 kg. Therefore, liraglutide used for weight loss uses a 3 mg dose, and also has a separate packaging and product name-Saxenda.

Figure: Novo Nordisk's first-generation weight loss injection Saxenda, which contains liraglutide

02 Contemporary weight loss injection - semaglutide

Liraglutide was once very popular, but it was approved by the FDA for glucose reduction (Victoza) in 2010 and weight loss (Saxenda) in 2014. Its core patent will expire in 2023. Even the best innovative drugs will no longer be new. When the patent is about to expire, liraglutide will fall into this state of being old and weak. Pharmaceutical companies often prepare for this and make the next better product. Liraglutide can be improved in two directions. One is the extent of glucose reduction and weight loss, that is, some work can be done on "effectiveness"; the other is that liraglutide is injected once a day. This frequency is fine for oral medication, but it is a bit frequent for injectable drugs. If the injection frequency can be reduced, it will be much more convenient to use.

Novo Nordisk has managed to do both things well and launched a successor to liraglutide, semaglutide. The biggest highlight of the upgrade is that semaglutide only needs to be injected once a week.

Similar to its predecessor, semaglutide is also used in different doses for hypoglycemic and weight loss. In terms of hypoglycemic, the 1mg and 2mg doses reduced the baseline A1C of 8.8% and 8.9% by 1.9% and 2.1% in clinical trials. With such a high A1C baseline (A1C below 5.6% is normal), 56% of the 1mg group and 64% of the 2mg group reached the target, controlling A1C at 7%. Semaglutide can be said to be an A1C killer. It should be noted that semaglutide is not only more effective than liraglutide, but also achieves this with a once-a-week injection. Because the 1mg and 2mg doses have a good hypoglycemic effect, semaglutide uses these two doses for diabetes (1mg is not enough and can be increased to 2mg, but this is FDA-approved, and China has only approved the 1mg dose at present), and the product name is Ozempic.

Similar to liraglutide, the dose of semaglutide used for weight loss is larger than that used for hypoglycemic treatment. The obesity clinical trial of semaglutide used a dose of 2.4 mg per week. The subjects with an average weight of 105 kg lost 14.9% of their weight after 68 weeks, exceeding 15 kg. As a result, 2.4 mg semaglutide became the standard for weight loss, and also had a product name different from the diabetes indication - Wegovy.

In addition, the dosage of GLP-1RA drugs is not in place at one time, but rises step by step to the final stable dose. For example, we say that the dosage of Wegovy is 2.4mg, but in actual use, patients will start from 0.25mg, go through 0.5mg, 1mg, 1.7mg, and finally 2.4mg. The doses before 2.4mg are all transitional doses-use it for four weeks and then go to the next dose until it reaches the final dose. Because liraglutide is used every day, the syringe is designed with a scale. When using it, the patient adjusts the dose by himself, changing a pillow each time until all the medicine in the syringe is used up. Semaglutide is injected once a week, so the syringe is simply designed to be disposable, and syringes of different doses also have different colors, so that users can put together a colorful row.

Figure: Gradual dosage of semaglutide injection

03 Are you afraid of injections? You can also take it orally

As shown in the illustration above, the syringes for GLP-1RA drugs look like pens, similar to insulin pens; indeed, these drugs are injected subcutaneously, not intravenously. Subcutaneous injections are easier and do not require professional help. You can do it yourself. Moreover, the subcutaneous injection of GLP-1RA drugs is so easy that you can't even see the needle. For example, the following is the design of the authentic weight loss injection Wegovy:

Figure: Schematic diagram of the design of the disposable Wegovy slimming needle

Wegovy's syringe is in the form of a pen - hence the name "slimming pen" - the needle is hidden inside the pen and cannot be seen at all. When using it, just press it on the injection point, such as the abdomen, thigh or outer arm (this position requires help from others), and the injection is automatically completed. Not only can you not see the needle during the whole process, you don't even need to push the syringe to inject. In reality, slimming injections can be sent directly to the user's home by pharmacies on a regular basis.

However, compared with oral administration, the threshold for use of injections is always higher.

I have to admit that many people get chills just hearing about "injection". Novo Nordisk did something that seemed simple but was actually amazing: it made semaglutide into an oral version. Like all GLP-1RA drugs, semaglutide is a polypeptide, which is a macromolecular drug. When taken orally, it will be directly digested and degraded into amino acids in the stomach, so the macromolecular drugs we see are all injectable. However, Novo Nordisk has made an oral version of semaglutide through innovation in formulation, and also brought the third product of this molecule - Rybelsus.

Figure: Three different doses of the oral semaglutide product Rybelsus

Currently, Rybelsus is only approved for the treatment of type 2 diabetes, with a daily dose of 7 mg or 14 mg. Note that these are also final doses. Similar to injected GLP-1RA drugs, Rybelsus also has a transition dose, which starts with 3 mg for one month and then rises to 7 mg. If it is necessary to increase the dose, 7 mg will be used for at least one month before switching to 14 mg. In clinical trials of diabetic patients, the 14 mg group of Rybelsus was close to liraglutide in A1C control; the weight loss effect was also similar: the baseline weight was 92.5 kg, and the average weight loss was 4.4 kg at 26 weeks. The control group of 1.8 mg liraglutide injection was 95 kg and the baseline weight was reduced by 3.1 kg.

However, compared with the injectable version of semaglutide, the oral version is obviously less effective. In a clinical trial of diabetic patients with an average baseline weight of 93 kg, a low-dose (1 mg) injectable version of semaglutide can reduce weight by 4.7 kg in 30 weeks.

Perhaps because the current oral dose is not as effective as the injectable version in terms of weight loss, Rybelsus did not apply for obesity treatment with the current dose version, but is still testing the therapeutic effect of higher doses. In March 2023, Novo Nordisk announced some clinical trial results of 25mg and 50mg oral semaglutide in patients with type 2 diabetes, showing that at 68 weeks, subjects with an average weight of 96.4 kg lost 4.5 kg using the marketed 14mg oral semaglutide, while the 25mg group and 50mg group lost 7.0 kg and 9.2 kg, respectively.

In a clinical trial, 2 mg of the injectable version of semaglutide reduced the weight of diabetic patients with a baseline weight of 99.3 kg by 6.4 kg in 40 weeks. It can be said that the high-dose oral version of semaglutide is no longer inferior to the injectable version.

In May 2023, Novo Nordisk announced the results of a Phase III clinical trial of high-dose oral semaglutide in obese people. In the clinical trial code-named OASIS1, 50 mg of Rybelsus achieved a 17.4% weight loss effect at 68 weeks for subjects with a baseline weight of 105.4 kg, which is comparable to Wegovy. Novo Nordisk also announced that it expects to submit an application for high-dose oral semaglutide for weight loss indications in Europe and the United States this year, making no secret of its ambition to move from weight loss injections to weight loss pills.

04 Dulaglutide is not effective enough for weight loss

In addition to Novo Nordisk's liraglutide and semaglutide, the GLP-1RA drug market also has two drugs from Eli Lilly - dulaglutide and tirzepatide. These two drugs can also be regarded as two generations of products, dulaglutide is the previous generation, and tirzepatide belongs to the new generation. However, both of them are now only approved for hypoglycemic purposes, not for the treatment of obesity. In other words, all weight loss drugs (injections and oral drugs) officially marketed for the treatment of obesity are products of Novo Nordisk.

Why did Eli Lilly give up the weight loss market? It was not voluntary. Tesiparatide has just been launched, and the Phase III clinical trial for the treatment of obesity will not be announced until 2022, and it is still waiting for approval. And its previous generation product dulaglutide is really not that effective in reducing weight.

Dulaglutide is injected once a week, the same frequency of use as semaglutide, and more convenient than liraglutide's one injection a day. However, in a head-to-head clinical trial among diabetic patients with a baseline weight of about 94 kg, 1.8 mg of liraglutide was used for 26 weeks to reduce weight by 3.6 kg, while 1.5 mg of dulaglutide was used to reduce weight by 3.96 kg. (Head-to-head studies are "non-placebo-controlled" trials, which use clinically used therapeutic drugs or treatments as controls for clinical trials, aiming to conduct more detailed research and comparison of the efficacy or safety of drugs.)

Of course, dulaglutide can also improve the weight loss effect by increasing the dose. In clinical trials of diabetic patients, 3mg and 4.5mg doses can reduce weight more than 1.5mg doses. However, the results of these high-dose dulaglutide trials were published in 2021, and the overall weight loss level did not surpass the competitor's previous generation product liraglutide. The even more amazing semaglutide also received FDA approval for the treatment of obesity in 2021. All this made Eli Lilly realize that it is not meaningful to pursue the direction of weight loss with dulaglutide.

Therefore, dulaglutide is still only used as a diabetes drug, with only one brand, Trulicity. However, some doctors still prescribe dulaglutide to patients beyond the indication for use, for weight loss or control.

Figure: Eli Lilly's type 2 diabetes injection Trulicity, which contains dulaglutide

05 Challenges from Tesiparatide

Eli Lilly does not expect dulaglutide to impact the obesity market, but that does not mean it has given up on the huge potential weight loss market. You should know that the Wegovy version of semaglutide for obesity was only approved by the FDA in 2021, and its annual sales in 2022 have exceeded US$900 million. If it were not for the shortage of supply, it would have exceeded the 1 billion mark without any suspense. The shortage of Wegovy even caused Novo Nordisk to voluntarily suspend advertising in the United States and restrict some pharmacies from selling low-dose versions for new patients.

In addition, semaglutide is also superior to dulaglutide in the field of diabetes, and the convenience of the oral version has gained a considerable market share (in 2022, sales of Rybelsus, which was approved for diabetes alone, doubled from the previous year to $1.7 billion). Continuing to rely on dulaglutide to compete with semaglutide will obviously be passive everywhere.

How to make a GLP-1RA drug that is stronger than semaglutide? This has become a difficult problem that pharmaceutical companies such as Eli Lilly that have ambitions in the field of metabolism must overcome. In 2022, Eli Lilly handed over the answer-tirzepatide. Unlike predecessors such as semaglutide, liraglutide and dulaglutide, tirzepatide is a dual agonist. Structurally, it resembles both GLP-1 and another hormone GIP (Gastric inhibitory peptide). The latter can also stimulate insulin secretion, inhibit gastric acid secretion, and delay the movement of food in the gastrointestinal tract. This gives GIP and GLP-1 potential synergistic effects. As an analog of GLP-1 and GIP, tirzepatide also has the hope of achieving better blood sugar and weight loss effects than a single GLP-1 analog.

In clinical trials, tesiparatide has indeed surpassed semaglutide. First, in diabetic patients, tesiparatide controls A1C levels better than semaglutide (5 mg, 10 mg or 15 mg tesiparatide vs. 1 mg semaglutide per week). Secondly, in terms of weight loss, the 40-week weight loss rates of diabetic patients with a baseline weight of approximately 93 kg in the 5mg, 10mg and 15mg dose groups were 8.2%, 10% and 11.8%, respectively, which were significantly higher than the 6.2% weight loss effect of 1mg semaglutide.

In May 2022, the FDA officially approved tesiparatide for the treatment of type 2 diabetes. This is also the first GLP-1 and GIP dual-target drug, with a trade name of Mounjaro. But as we introduced before, although GLP-1RA can lose weight and lower blood sugar at the same time, obesity and diabetes are still two independent indications, and the clinical trials of the two are also different. Clinical trials for obesity must be targeted at patients without type 2 diabetes, and obesity standards such as BMI are also higher. For example, in clinical trials for type 2 diabetes, the average weight of the subjects is 90-95 kg, and the average weight of the subjects in clinical trials for obesity will be around 105 kg.

Figure: Tesiparatide Type II Diabetes Injection Mounjaro

Therefore, although tesiparatide is better than semaglutide in the treatment of diabetes, if you want to make a weight loss injection, you must start again. Of course, referring to the stable performance of GLP-1RA drugs in previous clinical trials of diabetes and obesity, tesiparatide is still quite stable in the field of weight loss. The results of the Phase III clinical trial of tesiparatide for obesity published in the New England Journal of Medicine in July 2022 also confirmed this: Among obese patients with an average weight of 104.8 kg, the three groups of patients who received weekly injections of 5 mg, 10 mg and 15 mg of tesiparatide had a 72-week weight loss of 15.0%, 19.5% and 20.9%, respectively.

Since semaglutide increased the weight loss rate to 15%, tesiparatide has become the first weight loss injection to achieve a 20% weight loss rate, which is comparable to gastric reduction surgery. Although tesiparatide is only a one-year-old hypoglycemic drug, it should be approved by the FDA this year and become the third weight loss injection to be launched.

06 The battle of slimming injections, new players on the way

As mentioned earlier, the patent period of liraglutide has expired, and Novo Nordisk is pushing for semaglutide to replace it. Eli Lilly is also actively promoting tesiparatide, replacing dulaglutide, which is obviously not strong enough in the field of hypoglycemics, and waiting for tesiparatide to be approved for the treatment of obesity, so as to compete with semaglutide.

Of course, in the "weight loss" blue ocean market with unlimited imagination, GLP-1RA drugs have become a must-win for many pharmaceutical companies. How can they be willing to give it to Novo Nordisk and Eli Lilly? Therefore, we can also see other pharmaceutical companies layout in this field. Many are really unoriginal copies, but some are trying to do something "something".

For example, Amgen is also working on a dual-target drug for GLP-1 and GIP. Does it look very similar to tesiparatide? However, tesiparatide stimulates the receptors of GLP-1 and GIP at the same time. Amgen has a different idea. Its molecule stimulates the GLP-1 receptor while inhibiting the GIP receptor. From a scientific point of view, it is worth paying attention to what kind of results this different mechanism of action will achieve. In addition, Amgen's drug is injected once every four weeks, which is more convenient than the weekly injection of GLP-1RA drugs on the market today. Reducing the frequency of medication and facilitating patients is also a major development direction of GLP-1RA drugs.

As mentioned earlier, no matter how convenient injections are, many people think they are not as convenient as taking medicine. Pfizer is also testing new oral GLP-1RA drugs, with the goal of making the best oral GLP-1RA drug. Moreover, Pfizer's idea is different from Novo Nordisk's. It wants to make a small molecule GLP-1RA drug. Even if it is made into an oral version, semaglutide is still a large polypeptide molecule drug, and the production cost and difficulty are higher. Once the small molecule GLP-1RA represented by Pfizer is successful, the production capacity can benefit more audiences.

Even GLP-1 players such as Eli Lilly and Novo Nordisk, which already have mines in their hands, are not idle. In late June 2023, Eli Lilly published two Phase 2 clinical trial papers in the New England Journal of Medicine, showing that its small molecule GLP-1 agonist orforglipron and GLP-1/GIP/GCG triple-target peptide agonist retatrutide respectively achieved weight loss of 14.7% and 17.5% at 26 and 24 weeks in the treatment of obesity.

Of course, these new drugs have not yet completed phase III clinical trials, and they are still several years away from being put on the market. With the popularity of weight loss injections, some new drugs have also frequently appeared in the news, making many people itchy and wondering if they can give it a try, but we should note that there are always various uncertainties in the development of new drugs. For example, Pfizer previously had two GLP-1 small molecule drugs in phase II clinical trials, of which lotiglipron had the side effect of elevated transaminase in the trial, so it had to be abandoned in June this year. Now only danuglipron is left to move forward.

Just looking at the GLP-1RA drugs we encounter in life, we can refer to the following table to distinguish them:

After distinguishing the various GLP-1RA peptides, many people may also wonder if they can try the Internet celebrity weight loss injection. But we should note that, as shown in the table above, various GLP-1RA drugs such as semaglutide have not been approved for weight loss in China. Recently, only the biosimilar drug of liraglutide has obtained the domestic weight loss indication, but the specific application has not yet been announced. The weight loss injection version of semaglutide, the high-dose oral version, and tesiparatide are also undergoing phase III clinical trials for obese people in China. Only after these trials are completed and approved by the drug regulatory authorities can they meet with everyone. At present, semaglutide has only been approved for diabetes applications in China, which means that the dosage of "weight loss injections" sold on various domestic platforms or even illegally is different from the real weight loss injections.

In the past two years, there has been a frequent shortage of GLP-1RA drugs such as semaglutide, which is probably due to too many people wanting to try weight loss injections. But are these drugs suitable for everyone? Are there any contraindications when using them? Are there any side effects worth paying attention to? Can one injection really help you lose ten pounds? How should we rationally view and reasonably use weight loss injections? Let's wait for the next time to find out.

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/victoza/about/efficacy-safety.html

4. https://www.novomedlink.com/obesity/products/treatments/saxenda/efficacy-safety/significant-weight-loss.html 5. https://www.novomedlink.com/diabetes/products/treatments/ozempic/efficacy-safety/ozempic-and-weight.html

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

7. https://www.novomedlink.com/diabetes/products/treatments/rybelsus/dosing-administration/dosing-and-prescribing.html

8.https://www.novonordisk.com/content/nncorp/global/en/news-and-media/news-and-ir-materials/news-details.html?id=165597

9. https://www.fiercepharma.com/pharma/novos-rybelsus-comes-its-own-wegovy-shakes-2022-supply-constraint

10. https://www.mounjaro.com/hcp/a1c-weight#mounjaro-a1c

11. 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.

Special Tips

1. Go to the "Featured Column" at the bottom of the menu of the "Fanpu" WeChat public account to read a series of popular science articles on different topics.

2. Fanpu provides a function to search articles by month. Follow the official account and reply with the four-digit year + month, such as "1903", to get the article index for March 2019, and so on.

Copyright statement: Personal forwarding is welcome. Any form of media or organization is not allowed to reprint or excerpt without authorization. For reprint authorization, please contact the backstage of the "Fanpu" WeChat public account.