"Many people who come to the clinic to seek treatment for obesity will directly ask if they can prescribe this medicine, and there is no need to recommend it, we only have to persuade back." "Not only patients, but also doctors will come to ask if they can help prescribe 'slimming injections', which is also the norm at work."
The "diet shot" in the mouth of endocrinologists refers to an injectable hypoglycemic drug, Semaglutide. However, the reason why it has attracted much attention is more from the efficacy of weight loss.
Recently, the oral version of semeglutide has made new progress. On March 24, 2023, Novo Nordisk announced phase III clinical data for oral version of semeglutide [1], which showed that patients who took 14 mg, 25 mg, and 50 mg orally once daily lost 4.4 kg, 6.7 kg and 8.0 kg, respectively, after 52 weeks (1 year).
Source: Screenshot of Novo Nordisk's official website
Novo Nordisk said the 68-week phase IIIb efficacy and safety trial focused on comparing larger doses (25 mg, 50 mg) of sermeglutide with the previously approved 14 mg dose in the treatment of type 2 diabetes.
Currently, the trial has met the primary endpoint, and at 52 weeks of treatment, oral sermeglutide 25 mg and 50 mg has significantly better reduction and weight loss than the 14 mg dose, and has demonstrated good safety and tolerability.
Hypoglycemic drugs → diet injections
Semeglutide is a GLP-1 receptor agonist (GLP-1RA) hypoglycemic agent. GLP-1 is a type of incretin that promotes insulin secretion in a glucose concentration-dependent manner, inhibits glucagon secretion to lower blood sugar, and also delays gastric emptying.
Because of the collateral effect of "delaying gastric emptying", in addition to completing the hypoglycemic function, semeglutide also has the effect of suppressing appetite, making weight loss its second indication, and therefore exploded as a new phenomenal drug.
Hypoglycemic drugs have been used for weight loss for a long time. Unlike metformin, which is a "random gift", GLP-1RA hypoglycemic drugs have a clear research basis for weight loss. In December 2014, the FDA approved liraglutide for weight loss, and its phase III clinical results suggest that 60% of obese patients lose 5% of their weight after liraglutide injection, and one-third can lose up to 10% [2]. In 2021, the more potent semeglutide was also approved by the US FDA for long-term weight control in patients who are overweight or obese[3].
US FDA approved the indications of semeglutide for weight loss (Source: Reference 3)
In a 2021 systematic review and network meta-analysis of 424 RCTs involving more than 270,000 participants, semeglutide injection showed optimal weight loss in 21 hypoglycemic drugs in 9 categories, including insulin, metformin, SGLT-2i, GLP-1RA, etc.[4]. At the same time, other studies have confirmed that as GLP-1RA drugs, semeglutide also has advantages over liraglutide [5].
On November 2, 2022, NEJM published a double-blind, parallel-group, randomized, placebo-controlled trial of semeglutide demonstrating its effectiveness in weight loss in obese adolescents [6].
NEJM publishes latest results of semeglutide (Source: Reference 6)
The study targeted adolescents (12~18 years old) who were obese (BMI ≥ 95th percentile), overweight (BMI ≥ 85th percentile) and at least one obesity-related chronic disease. Participants received weekly subcutaneous sermeglutide (dose 2.4 mg) or placebo with concurrent lifestyle interventions for 68 weeks.
The results showed that subjects who used semeglutide had significantly better BMI reduction rate and weight loss than placebo, while the semeglutide group showed greater improvement in cardiometabolic risk factors.
At the end of 2017, semeglutide was listed in the United States, listed in China on April 27, 2021, and announced on December 3, 2021 to enter the national medical insurance negotiation catalog.
Indeed, excellent weight loss performance, coupled with the fact that it has been approved abroad, the actual ranking of semeglutide in the selection of clinical drugs for obesity has been advanced. "If the BMI meets the criteria for obesity, I am inclined to choose semeglutide in my heart, because the weight loss effect is indeed obvious to all." Wang Yihan, attending physician of the Department of Endocrinology of a tertiary hospital in central China, talked about his thoughts.
According to domestic guidelines and drug labels, semeglutide is recommended for the treatment of type 2 diabetes mellitus, while there is no clinical recommendation for weight loss. Cui Jin, deputy chief physician of the Department of Endocrinology and Metabolism of Tianjin Medical University General Hospital, introduced: "At present, its weight loss indications have not been approved in China, if you want to use semeglutide to lose weight, even if the BMI meets the diagnostic criteria for obesity, it is also an off-label application, or you need to carefully select and sign the informed consent."
Attracting attention, good medicine also needs to be cautious
According to the Information of the Drug Evaluation Center (CDE) of the State Food and Drug Administration, the indication of oral semeglutide for weight management has obtained implied approval from clinical trials for weight management in adults.
Compared with injection, oral dosage forms are more acceptable to patients and have better promotion advantages.
Previously, oral sermeglutide 3 mg, 7 mg, and 14 mg had previously been approved by the FDA for type 2 diabetes. After the release of high-dose oral sermeglutide data, Novo Nordisk expects to apply for regulatory approval in the United States and the European Union in 2023.
Martin Holst Lange, Executive Vice President Development at Novo Nordisk, said, "This trial further demonstrates the benefits of oral semeglutide in patients with type 2 diabetes. If additional blood sugar control or weight loss is required, higher doses of 25mg and 50mg show better results."
In addition to semeglutide, there are also a series of hypoglycemic drugs that have attracted much attention due to their excellent weight loss effect.
For example, Eli Lilly's GIP and GLP-1 dual-receptor agonist tilpotide (Tirzepatide), announced on February 6, 2023 that its Phase III clinical trial in China in obese or overweight adult patients achieved positive results, meeting the primary endpoint and all key secondary endpoints. [7]
Screenshot of Eli Lilly's official website
The patent of liraglutide, which is also developed by Novo Nordisk, has expired in the Chinese market, and many domestic pharmaceutical companies such as East China Pharmaceutical, Tonghua Dongbao, and Hanyu Pharmaceutical are developing domestic liraglutide products.
However, on March 7, 2023, the official website of the Center for Drug Evaluation of the National Medical Products Administration showed that two marketing applications related to obesity indications for liraglutide injection of East China Medicine were suspended.
In this regard, Huadong Medicine said in response to the media that the review of the weight loss indication of liraglutide injection has been extended due to the impact of the epidemic at the beginning of the year, and it is necessary to submit a supplementary requirement report on the test accuracy of the dose, which is the normal process of review. The Company does not expect this suspension to have a significant impact on the eventual approval of this indication.
With the research and development of more and more weight-loss drugs, sharing and dissemination on social media and short video platforms has also made more ordinary people understand this "diet drug". They can inject themselves, the director of the endocrinology department is using, only one injection a week, ten pounds a month thin, etc., driving more and more people to enter the outpatient clinic or seek to buy on behalf of others. This makes specialists often busy dissuading and sometimes compromised.
However, it should be noted that the adverse reactions of these drugs cannot be ignored.
Taking semeglutide as an example, the FDA has reported that the most common side effects of semeglutide include nausea, diarrhea, vomiting, constipation, abdominal pain, bloating, dizziness, headache, dyspepsia, hypoglycemia, gastroenteritis, and gastroesophageal reflux disease [3].
The newly published high-dose study of oral semeglutide also mentioned that 25mg and 50mg showed more common gastrointestinal reactions compared to 14mg doses. A 2022 study published in JAMA confirming that semeglutide was better than liraglutide in weight loss also noted that gastrointestinal adverse events were reported as high as 84.1% in the semeglutide group (82.7% in the liraglutide group) [5].
The prescribing information for semeglutide also contains a contraindication warning indicating the potential risk of thyroid C-cell tumors, as well as the dangers of pancreatitis, gallstones, acute kidney injury, retinal damage, and increased heart rate.
"While semeglutide has a therapeutic effect, the side effects cannot be ignored, including the need to focus on the occurrence of certain tumors and pancreatitis." Cui Jin emphasized, "Semeglutide is a prescription drug that requires an experienced doctor to prescribe treatment, which is also an important power in the hands of doctors."
"Even if it is used for obese patients, these drugs need to be used in conjunction with lifestyle management. Losing weight should not be the only goal, a healthy lifestyle can fundamentally solve the problem." Cui Jin said, "It is a misunderstanding to over-rely on drugs to lose weight and selectively ignore lifestyle management. No matter what causes obesity, it is difficult to lose weight with drugs." (Planner: z_popeye, Yunye|Executive Producer: Gyouza)
Source: Visual China
Bibliography:
[1]https://www.novonordisk.com/news-and-media/news-and-ir-materials/news-details.html?id=165597
[2] HUANG Shijie. Positive results obtained from phase III. clinical trial of liraglutide for weight loss[J].International Journal of Pharmaceutical Research,2014,41(4):428-428.)
[3] FDA Approves New Drug Treatment for Chronic Weight Management, First Since 2014.
[4] Tsapas A，Karagiannis T，Kakotrichi P，et al. Comparative efficacy of glucose-lowering medications on body weight and blood pressure in patients with type 2 diabetes: a systematic review and network meta-analysis[J]. Diabetes， obesity & metabolism. 2021 May 28.
[5] Domenica M. Rubino et al. Effect of Weekly Subcutaneous Semaglutide vs Daily Liraglutide on Body Weight in Adults With Overweight or Obesity Without Diabetes The STEP 8 Randomized Clinical Trial. JAMA，January 11, 2022.
[6] Weghuber Daniel,Barrett Timothy,Barrientos-Pérez Margarita et al. Once-Weekly Semaglutide in Adolescents with Obesity. [J] . N Engl J Med, 2022, undefined: undefined.
[7]https://www.lilly.com.cn/index.html#/?path=new_release&aid=332
[8]https://www.nejm.org/doi/full/10.1056/NEJMoa2206038
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