I previously introduced semaglutide, the “miracle weight loss drug” used by Elon Musk. Two years have passed, and much has changed. For example, a domestically available injectable version for weight loss has been launched, and an oral version for the treatment of type 2 diabetes has been approved. Besides semaglutide, you’ve undoubtedly heard of numerous other peptides used for weight loss. How do these obesity-targeting peptides work? What other new products are worth keeping an eye on? Find out all in this issue.
Most of the peptides you’ve heard of, including semaglutide, are related to glucagon-like peptide-1 (GLP-1).
This natural hormone is primarily released by L cells in the human intestine. Upon activation of its corresponding receptor, the GLP-1R, it subsequently regulates blood sugar by promoting insulin release and other mechanisms.
These receptors are widely distributed in multiple organs and tissues, including the pancreas, brain, heart, gastrointestinal tract, kidneys, lungs, and blood vessels. Therefore, exogenous GLP-1 receptor agonists not only enhance insulin secretion and lower blood sugar, but also delay gastric emptying, promoting a sense of satiety in the brain and achieving weight loss. They are even currently being studied for the treatment of cardiovascular and cerebrovascular diseases and Alzheimer’s disease.
So, these peptides are essentially receptor agonists, synthetic GLP-1 analogs. So, are they all called GLP-1, just different brands?
Of course not. They all undergo molecular modifications to the GLP-1 structure to varying degrees. For example, the amino acid sequences of these four (liraglutide, dulaglutide, semaglutide, and benaglutide) share 97%, 90%, 94%, and 100% identity with human GLP-1, respectively. However, this doesn’t necessarily mean 100% is optimal. For example, the artificial modifications can affect their half-life in the body, which is why some require weekly injections, while others require three injections per day.
A prime example is benaglutide, approved for weight loss in China in 2023. Despite its 100% amino acid homology, its half-life in vivo is only 11 minutes, requiring three injections daily, a significant hassle. Furthermore, data from Phase III clinical trials show an average weight loss of around 6%, making its competitiveness less compelling.
Semaglutide, by contrast, replaces amino acids at position 8 (alanine to α-aminobutyric acid) and position 34 (lysine to arginine) within the GLP-1 molecule, while also modifying lysine at position 26. This makes it resistant to degradation by dipeptidyl peptidase 4 (DPP-4), binds more tightly to albumin, and significantly extends its half-life in vivo, enabling once-weekly dosing.
Official data for semaglutide injections claim an average weight loss of 15%, and its minimal side effects have earned it considerable acclaim in recent years. An oral tablet formulation for obesity has already reached Phase III clinical trials, allowing for a single daily tablet, which is expected to be even more convenient in the future. The patent for semaglutide in China is set to expire in 2026, signaling the arrival of a wave of cheaper domestic generics.
As for liraglutide, it was actually developed earlier, having been approved by the FDA in 2014 for the treatment of obesity. While this product is a long-acting formulation, it still requires a daily injection. Furthermore, Phase III clinical data show that 64% of patients achieved a 5% weight loss, and 33% achieved a 10% weight loss, a significant difference compared to semaglutide.
However, the FDA has lowered the recommended age for liraglutide to 12 years old, making it suitable for children with obesity.
The next peptide is dulaglutide, approved by the FDA in 2014 for once-weekly dosing. However, dulaglutide’s indications have never been expanded to include obesity, focusing instead on type 2 diabetes and hypoglycemia control. Of course, since it’s a GLP-1 inhibitor, those seeking weight loss can still use it beyond the indicated dosage. To be honest, its data is similar to liraglutide, but semaglutide came later. In comparative trials, its weight loss data was over 10 percentage points lower, and it has since gradually lost market share.
Speaking purely of GLP-1s, semaglutide was previously the most effective for weight loss. However, as GLP-1 production runs out, pharmaceutical companies’ R&D directions have begun to shift.
For example, tirzpatide, used for obesity and diabetes, is a dual agonist of the GLP-1/GIP receptors. Dual agonists don’t contain two ingredients; rather, they use a single peptide molecule to target both receptors. In addition to the GLP-1 receptor, tirzpatide also activates the glucose-dependent insulin-releasing peptide (GIP) receptor.
GIP, discovered before GLP-1, is another natural incretin hormone and accounts for two-thirds of the incretin effect, a larger proportion than GLP-1. This promising drug hasn’t been developed into a successful drug. One problem is that its natural form has a short half-life, making it easily degraded by DPP-4. Another problem is that circulating glucose appears to downregulate GIP receptors, blunting GIP’s effectiveness. Modified receptor agonists, by addressing these two issues, finally allow GIP and GLP-1 to work together to maximize the incretin effect.
In a head-to-head trial, tirzpatide achieved an average weight loss of 20.2% after 72 weeks of treatment, significantly superior to semaglutide’s 13.7%.
Besides targeting GIP, there are also drugs targeting other targets, such as Mazdutide, another dual agonist. Mazdutide has solid research published in the New England Journal of Medicine, BMJ, and Nature Communications, and has been featured numerous times in other internationally renowned journals and conferences. It is a recognized new drug in the industry and has just been approved for marketing in China.
Mazdutide is a modified version of the body’s natural hormone, oxyntomodulin (OXM). In addition to the GLP-1 receptor, it also targets the glucagon (GCG) receptor.
GCG, secreted by pancreatic alpha cells in the pancreas, promotes glycogenolysis and glucose production. It primarily works with insulin in the body to maintain blood sugar levels. GCG receptors are primarily expressed in the liver, promoting fat metabolism and increasing energy expenditure.
We all know that when someone is overweight and undergoes a physical, they are likely to have fatty liver disease, which is essentially an imbalance in the production and distribution of fat in the liver. Approximately 10% to 30% of patients with fatty liver disease will develop steatohepatitis, which can lead to cirrhosis or even liver cancer. Furthermore, patients with fatty liver disease have a risk of cardiovascular disease that is approximately twice that of non-patients.
Mazdutide can address this problem by activating the liver’s GCG receptor. First, it affects key coenzymes in the lipid synthesis pathway, inhibiting de novo lipogenesis in the liver. Second, it reduces hepatic fat deposition by stimulating lipolysis and fatty acid β-oxidation. Furthermore, it affects multiple metabolic pathways, such as reducing liver fat by stimulating fibroblast growth factor 21 (FGF21) secretion.
Simply put, Mazdutide doubles the weight loss and blood sugar reduction rates through its dual receptors. It also reduces liver fat content, inflammation, and fibrosis, directly protecting the liver. Furthermore, it offers a high overall benefit, meaning it can also lower blood lipids, blood pressure, uric acid, and cholesterol, and regulate purine metabolism.
Published clinical data show that 16 mg of Mazdutide can achieve weight loss of up to 21% over 20 weeks, significantly higher than the average weight loss of 20.2% achieved with tirzpatide over 72 weeks in a previous head-to-head study. The 6 mg group achieved an average weight loss of 14.01% over 48 weeks, surpassing semaglutide. It also reduces liver fat by up to 80%, a feat unattainable by other single- and dual-agonist drugs.
Therefore, clinical studies of Mazdutide are particularly well-suited for overweight and obese individuals with numerous comorbidities. For example, many patients suffer from fatty liver disease, while others also have elevated blood lipids, high cholesterol, and gout. High blood lipids and high blood pressure are major contributors to myocardial and cerebral infarctions.
In terms of safety, similar to single-agent GLP-1 agonists, Mazdutide’s primary side effects are nausea and diarrhea, which are mostly mild to moderate and concentrated in the initial stages of treatment. The rate of discontinuation due to side effects in the 6 mg treatment group was only 0.5%, significantly lower than that of similar drugs like semaglutide and tirzpatide.
Currently known contraindications can be found here: acute gallbladder disease, acute pancreatitis, and a personal or family history of medullary thyroid carcinoma (MTC) (low incidence). Patients with these conditions should exercise caution. These contraindications are similar to those of other GLP-1 drugs. Using a concealed needle, it only requires a once-weekly injection, making it relatively convenient and easy. Therefore, individuals with obesity, early-onset type 2 diabetes, and a BMI ≥ 24 should consider this option.
GLP-1 drugs are widely recognized for their excellent glucose-lowering and weight-loss effects. From single-target to dual-target, and potentially even more targets in the future, the development of molecular medicine will further impact modern people’s ability to manage their weight.