GLP-1 receptor agonist is a popular type of hypoglycemic drugs with significant weight loss effects. Almost all the dosage methods are subcutaneous injection. In order to make the drug more convenient, oral form of GLP-1 drugs have appeared recently. What are these drugs? What are the effects of weight loss and sugar reduction under oral administration?
Obest is a chronic disease that affects the health of more than 100 million people in China. While diet and exercise are important weight loss methods, most people do not achieve the treatment goals they expect by eating and exercising alone.
In the obesity series introduced in the early stage of this number, glucagon-like peptide 1 (GLP-1) receptor agonist is the most popular 
GLP-1 receptor agonist dosing methods almost are all subcutaneous injection of . The dosing frequency includes liraglutide subcutaneously injected subcutaneously, semegglutide once a week, duragglutide, etc.
Compared with injection methods, many people prefer more convenient oral administration methods. Currently, GLP-1 drugs administered in export-based medication have been developed. Which one is better for weight loss by oral administration or injection administration?
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oral GLP-1 receptor agonist
GLP-1 receptor agonist stimulating insulin secretion with a glucose concentration-dependent mechanism and inhibiting the secretion of glucagon , thereby achieving a glucose-lowering effect. GLP-1 drugs can also inhibit appetite and can also treat diabetes and obesity.
Because has low bioavailability after oral administration of , the weight loss and sugar-lowering effects are often not ideal when GLP-1 drugs are administered orally. After launching the weekly injection of semaglutide (smegglutide), it also launched its oral version Rybelsus in 2019, which is also the first GLP-1 receptor agonist in in the world that can take orally. Rybelsus overcomes the challenge of oral peptide delivery by co-constructing semegglutide with permeation enhancer SNAC.
is similar to subcutaneous injection of semegglutide. The oral dose of Rybelsus is gradually increased from 3 mg once a day to 7 mg or even 14 mg once a day, and it is best to take it at least half an hour before eating. Compared with subcutaneous injection, Rybelsus absorbs significantly faster orally, but has lower bioavailability, with only .8%-1.4% .
In addition to Rybelsus, recently, Pfizer announced the latest clinical trial results of two oral small molecule GLP-1 receptor agonists danuglipron (PF-06882961) and PF-07081532.
Compared with Rybelsus, these two oral GLP-1 drugs of Pfizer are small molecules and are not subject to food or time of use. Moreover, PF-07081532 has a longer half-life.
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GLP-1 oral form of weight loss and sugar-lowering effect?
As the only approved oral preparation for GLP-1 receptor agonist, Rybelsus's glycemic and weight loss effects were widely evaluated in the Phase III clinical trial of PIONEER.
In terms of weight loss effect, Rybelsus is taken orally 14 mg once a day. When is continued for 26 weeks, the weight can be reduced by
-4 kg. is slightly better than subcutaneously injected 1.8 mg of liraglutide daily, but the weight does not continue to lose after 52 weeks. In addition, the weight loss effect of Rybelsus at week 26 and week 52 was not better than orally taking 25 mg engaliflozin per day.
In addition, from the perspective of lowering glycemic effect , the effect of taking 14 mg of Rybelsus orally every day is similar to that of 1 mg of semegglutide subcutaneously once a week, slightly better than engagliflozin and sitagliptin.
Data from Pfizer show that patients with html type 12 diabetes mellitus take PF-07081532 orally once a day, and their weight at the highest dose can decrease from 1 months to 1 and a half months . Take danugligpron twice daily orally, and at 80 mg or 120 mg each time, the weight loss was about 5 kg at 4 months.
Head-to-head study on weight loss and glucose-lowering effects of PF-07081532 and Rybelsus is expected to begin recruiting subjects in November this year.
The safety of the above oral GLP-1 receptor agonist is similar to that of subcutaneous injection. Common adverse events are gastrointestinal reactions, including nausea, diarrhea and vomiting. In addition, after taking oral administration for about one month, the heart rate of generally increased.
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oral preparations have any advantages over subcutaneous injection?
Currently, GLP-1 receptor agonists approved by the U.S. FDA for the treatment of obesity or weight-related combined include Novo Nordisk subcutaneously administered liraglutide once a day and semegglutide once a week.
For obese people who do not suffer from diabetes, liraglutide was injected daily for 3 mg, and the weight loss averaged 8% for 56 weeks, for three years, and the weight loss averaged 5 kg. In comparison, smegglutide has better weight loss effect. 2.4 mg semegglutide was injected subcutaneously every week. When lasted for 20 weeks, the average weight loss was 110.6% .
October 6, 2022, Eli Lilly 's Tirzepatide obtained the U.S. FDA's fast-track designation for the treatment of obesity or weight-related comorbidities to facilitate accelerated review of drugs and fill unmet medical needs.
In the completed SUURMOUNT-1 multi-center, randomized double-blind placebo controlled trial, two-thirds of obese subjects without diabetes lost at least 20% of their weight after receiving a weekly subcutaneous Tirzepatide injection. Tirzepatide became the first GLP-1 receptor agonist to lose more than 20% of the body weight.
Although the weight loss effect of the GLP-1 oral preparation Rybelsus is slightly better than the injection type of liraglutide, the comparison of the weight loss effect of the oral preparation with semegglutide and Tirzepatide has not been reported at present.
More importantly, the weight loss effect evaluation of the above two oral preparations of Rybelsus and Pfizer was from patients with diabetes and obesity, while the weight loss effect evaluation of GLP-1 subcutaneous injection type was from obese subjects without diabetes.
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Summary
(1) GLP-1 receptor agonists are a type of hypoglycemic drugs with clear effects and can take into account weight loss. They are currently a hot topic in the field of weight loss.
(2) Most of the GLP-1 receptor agonists are administered subcutaneously.
(3) Rybelsus (oral form of semegglutide) is the world's first GLP-1 drug that can be administered orally. When taking 14 mg orally every day, your weight can be reduced by 3-4 kg for 26 weeks.
(4) Pfizer's danuglipron and PF-07081532 are two oral GLP-1 drugs that enter the Phase 2 clinical trial. Among them, PF-07081532 can reduce weight by about 5 kg after taking oral 6 weeks.
(5) Liraglutide and semegglutide are two GLP-1 drugs that have been approved for weight loss. Eli Lilly’s Tirzepatide is the first GLP-1 drug to reduce its average weight by more than 20%, and is currently under fast track designation for weight loss treatment.
(6) Judging from the existing clinical trials, the oral preparation of GLP-1 drugs has better glycemic effects than other types of oral antidiabetic drugs, and is not inferior to that of subcutaneous injection of GLP-1. However, the existing data of does not support the better weight loss effect of oral preparations or similar to .
Reference
Rev Endocr Metab Disord. 2022 Oct
Cardiovasc Res. 2022 Aug
N Engl J Med. 2022 Jul
Nat Med. 2021 Jun
Cell Rep Med. 2021
Diabetes Obes Metab. 2020
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