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# GLP-1 peptides: classification, characteristics and systematic review

Glucagon-Like Peptide-1 (GLP-1) is an incretin hormone secreted by intestinal L cells. It regulates blood sugar, suppresses appetite and improves pancreatic β-cell function by activating GLP-1 receptor (GLP-1R). In recent years, GLP-1 receptor agonists (GLP-1 RAs) have become the core drugs for the treatment of type 2 diabetes (T2DM) and obesity. This article will systematically explain the diversity and scientific value of GLP-1 peptides from the aspects of structural classification, physicochemical properties, clinical applications and future development directions.

## 1. Classification and characteristics of GLP-1 peptides

### 1. **Natural GLP-1 analogs**

**Representative drugs**: Exenatide, Lixisenatide

**Structural features**:

- Exenatide is derived from Exendin-4 in the saliva of the Gila monster and has 53% homology with human GLP-1.

- Resistance to dipeptidyl peptidase-4 (DPP-4) is enhanced by replacing the amino acid residues of natural GLP-1 (such as glycine at position 2 → glutamic acid).

**Physical and chemical properties**:

- Molecular weight: Exenatide is 4,186 Da, and the isoelectric point (pI) is about 5.5.

- Solubility: Easily soluble in water, stable under pH 4.5-7.0.

- Color: Lyophilized powder is white or off-white, and the injection is a colorless and transparent liquid.

**Advantages**:

- Short half-life (2-4 hours), requires 2 injections per day, suitable for patients who need rapid blood sugar control.

- Low risk of hypoglycemia, and has weight loss effect (average weight loss 2-3 kg).

### 2. **Long-acting GLP-1 analogs (fatty acid modified)**

**Representative drugs**: Liraglutide, Semaglutide

**Structural features**:

- Extended half-life through fatty acid side chains (such as C16 or C18) binding to albumin.

- Liraglutide is connected to C16 fatty acid at lysine 26; semaglutide introduces C18 diacid chain at α-aminobutyric acid at 8.

**Physical and chemical properties**:

- Molecular weight: Liraglutide is about 3.75 kDa, and semaglutide is about 4.1 kDa.

- Stability: Fatty acid modification enhances resistance to enzymatic degradation and can be stored at room temperature (such as semaglutide injection).

- Color: The lyophilized powder is white, and the pre-filled pen syringe contains a colorless or light yellow solution.

**Advantages**:

- The half-life is significantly extended (13 hours for liraglutide and 7 days for semaglutide), enabling once-daily or once-weekly dosing.

- Stronger hypoglycemic effect (HbA1c decreases by 1.5-2.0%) and significant weight loss effect (average weight loss of 15% for semaglutide).

### 3. **Oral GLP-1 analogs**

**Representative drugs**: Oral semaglutide (Rybelsus®)

**Structural features**:

- Based on the semaglutide molecule, absorption enhancers (such as SNAC) are added to resist gastric acid degradation.

- SNAC promotes drug transcellular absorption by locally increasing the pH value in the stomach.

**Physicochemical properties**:

- Molecular weight: consistent with semaglutide for injection (4.1 kDa).

- Formulation: tablets, containing micronized drug particles to improve bioavailability (about 1%).

- Color: white to off-white film-coated tablets.

**Advantages**:

- Breakthrough the bottleneck of oral absorption of peptide drugs and improve patient compliance.

- The clinical effect is equivalent to that of injection, and HbA1c is reduced by 1.5-1.8%.

### 4. **Dual-target or multi-target GLP-1 analogs**

**Representative drugs**: Tirzepatide, Retatrutide

**Structural features**:

- Tirzepatide is a GLP-1/GIP dual receptor agonist, containing 39 amino acids, with a C20 fatty acid connected to the C-terminus.

- Retatrutide (GLP-1/GIP/Glucagon triple targets) achieves synergistic effects through multiple modifications.

**Physical and chemical properties**:

- Molecular weight: about 4.8 kDa for telportide and about 5.3 kDa for retatrutide.

- Solubility: Depends on the length of the fatty acid chain and requires a specific buffer system to maintain stability.

- Color: The injection is usually colorless or slightly yellow.

**Advantages**:

- Multi-target synergistic enhancement of metabolic regulation (e.g., telportide HbA1c reduction of 2.4%, weight loss of 12-15 kg).

- Potential cardiovascular and liver protective effects.

### 5. **GLP-1 compound preparations**

** Representative drugs**: IDegLira (insulin degludec + liraglutide), GLP-1/SGLT-2 inhibitor compound

** Structural features**:

- Combination of GLP-1 RA with other glucose-lowering mechanisms (e.g., insulin or SGLT-2 inhibitors).

**Physical and chemical properties**:

- The stability of each component needs to be maintained separately (e.g., insulin requires an acidic environment, and GLP-1 RA requires a neutral buffer).

- Color: The compound injection may show slight opalescence (such as insulin suspension).

**Advantages**:

- Synergistic hypoglycemic effect, reducing the number of injections.

- IDegLira can reduce the risk of hypoglycemia, and the HbA1c reduction can reach 1.9-2.0%.

## 2. Physical and chemical stability and formulation challenges of GLP-1 peptides

### 1. **Temperature and pH sensitivity**

- GLP-1 analogs are prone to aggregation or degradation (such as deamidation) at high temperatures or extreme pH.

- Long-acting preparations require the addition of stabilizers (such as mannitol, polysorbate 80).

### 2. **Light stability**

- Most GLP-1 drugs need to be stored away from light, and light may cause oxidation or disulfide bond rupture.

## 3. Future development direction

1. **Ultra-long-acting preparations**:

- Research monthly preparations (such as Novo Nordisk's CagriSema), with a half-life extended to 1 month.

2. **Non-injection routes of administration**:

- Inhalants (such as Pfizer's PF-06882961), transdermal patches, etc.

3. **AI-assisted design**:

- Use AI to predict peptide structure and receptor binding mode to optimize efficacy and safety.

## 4. Conclusion

GLP-1 peptides continue to break through the boundaries of treatment through structural innovation. From short-acting injections to oral dual-target drugs, the balance between their physical and chemical properties and clinical advantages is the core of research and development. In the future, with the advancement of formulation technology and multi-target strategies, GLP-1 drugs are expected to play a wider role in the field of metabolic diseases.