What are GLP-1s?

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are a class of medications that mimic the natural GLP-1 hormone in the body, which plays a key role in regulating blood sugar levels, appetite, and digestion. These drugs were originally developed to treat type 2 diabetes but have gained popularity for their effectiveness in promoting weight loss and improving cardiovascular health. GLP-1RAs work by stimulating insulin secretion when blood sugar is high, suppressing glucagon (a hormone that raises blood sugar), slowing gastric emptying, and increasing feelings of fullness. This combination helps control blood sugar levels and reduces overeating, making them particularly useful for managing obesity and diabetes.

Types of GLP-1RAs

There are several GLP-1 receptor agonists available, which differ in their duration of action, dosing frequency, and specific benefits:

1. Short-acting GLP-1RAs:
   1. Exenatide (Byetta): Administered twice daily, primarily lowers post-meal blood sugar levels.
   2. Lixisenatide: Similar to exenatide but with once-daily dosing.
   3. Beinaglutide: Requires multiple daily injections due to its short duration.
2. Long-acting GLP-1RAs:
   1. Liraglutide (Victoza/Saxenda): Injected daily; effective for both diabetes management and weight loss at higher doses.
   2. Exenatide extended-release (Bydureon): A weekly injection with longer-lasting effects compared to Byetta.
   3. Dulaglutide (Trulicity): Once-weekly injection; convenient for patients seeking less frequent dosing.
   4. Semaglutide (Ozempic/Wegovy): Available as a weekly injection or daily oral tablet; highly effective for both diabetes and weight loss. It is also the first GLP-1RA proven to reduce risks of heart attacks and strokes.
   5. PEG-loxenatide: A newer long-acting option with weekly dosing.
3. Dual GLP-1/GIP Agonists:
   1. Tirzepatide (Mounjaro/Zepbound): Combines GLP-1 and GIP receptor activity for enhanced weight loss and blood sugar control. It is injected weekly and has shown superior results compared to other GLP-1RAs in clinical trials.

Retatrutide- In a class of its own

Retatrutide is a novel triple hormone receptor agonist that targets the receptors for glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and glucagon. This innovative drug represents a significant advancement in metabolic therapy, combining the benefits of GLP-1 and GIP receptor agonists with the unique effects of glucagon receptor activation. Retatrutide is administered as a once-weekly subcutaneous injection, making it convenient for patients managing obesity, type 2 diabetes (T2D), and related conditions such as non-alcoholic fatty liver disease (NAFLD).

How Retatrutide Works

Each of the three targeted receptors contributes to retatrutide's therapeutic effects: Together, these actions result in improved glycemic control, significant weight reduction, and reductions in liver fat content. Clinical Benefits Retatrutide has shown remarkable results in clinical trials: How Retatrutide Differs from Other GLP-1RAs Unlike mono-agonists like semaglutide or dual agonists like tirzepatide (which target GLP-1 and GIP), retatrutide adds glucagon receptor activation to its mechanism. This additional pathway enhances weight loss and liver fat reduction beyond what is achievable through GLP-1 or GIP alone. For example, retatrutide’s ability to stimulate hepatic fatty acid oxidation directly addresses liver-related complications such as metabolic-associated steatosis and fibrosis.

Potential Side Effects

Retatrutide’s safety profile is similar to other GLP-1-based therapies but includes mild-to-moderate gastrointestinal symptoms such as nausea, vomiting, diarrhea, and constipation. These side effects are dose-dependent and typically improve over time[3][4]. Rare adverse events include gallbladder issues like gallstones due to rapid weight loss. Unlike some glucagon receptor antagonists that increase hepatic fat, retatrutide’s glucagon activity reduces liver fat effectively.

Future Outlook

Retatrutide is still under investigation but shows promise as a transformative therapy for obesity, T2D, and fatty liver diseases. Its triple-action mechanism offers superior weight loss and metabolic benefits compared to existing GLP-1RAs or dual agonists. Once approved, it could become a leading option for patients seeking comprehensive metabolic health improvements.

• Tirzepatide (Mounjaro/Zepbound): Combines GLP-1 and GIP receptor activity for enhanced weight loss and blood sugar control. It is injected weekly and has shown superior results compared to other GLP-1RAs in clinical trials.

1. GLP-1 receptor activation helps lower blood sugar by stimulating insulin secretion, suppressing glucagon release, and slowing gastric emptying. It also reduces appetite, aiding in weight loss.
2. GIP receptor activation enhances insulin secretion and may improve fat metabolism, complementing GLP-1’s effects.
3. Glucagon receptor activation promotes fat breakdown by stimulating hepatic fatty acid oxidation and reducing liver fat accumulation. This mechanism is particularly beneficial for conditions like NAFLD.

• In people with obesity, it achieved a weight reduction of up to 24% after 48 weeks at higher doses, surpassing the weight loss seen with other therapies like semaglutide or tirzepatide.
• It demonstrated substantial improvements in glycemic control for individuals with T2D, lowering HbA1c levels significantly.
• In patients with NAFLD, retatrutide reduced liver fat content by more than 80% at higher doses, with many participants achieving complete resolution of steatosis (defined as <5% liver fat).

Benefits

GLP-1RAs are highly effective at lowering HbA1c (a measure of long-term blood sugar control) and promoting weight loss. For example, semaglutide can reduce body weight by nearly 6 kg on average, while tirzepatide offers even greater reductions. These medications also help lower cardiovascular risks, making them valuable for patients with diabetes or obesity-related heart conditions.

Potential Side Effects

While GLP-1RAs are generally well-tolerated, common side effects include nausea, vomiting, diarrhea, constipation, and mild abdominal discomfort. These issues often improve over time as the body adjusts to treatment. Rare but serious side effects include pancreatitis or gallbladder problems like gallstones. Some drugs may also carry risks related to thyroid tumors, though this is primarily based on animal studies.

Choosing the Right GLP-1RA

The choice of medication depends on individual needs such as dosing preferences (daily vs. weekly), specific health goals (e.g., weight loss vs. glycemic control), and tolerance to side effects. For example, semaglutide may be preferred for patients seeking significant weight loss, while dulaglutide offers convenience with once-weekly injections. Tirzepatide is ideal for those requiring enhanced efficacy through dual hormone action.

In summary, GLP-1 receptor agonists have revolutionized the treatment of type 2 diabetes and obesity by offering effective glycemic control, weight loss benefits, and cardiovascular protection. However, patients should work closely with their healthcare provider to select the most suitable option based on their health profile and lifestyle preferences.

Sources

[1] Long Acting GLP-1 Receptor Agonist Drugs Lists and Overview https://www.biochempeg.com/article/226.html

[2] Switching Between Glucagon-Like Peptide-1 Receptor Agonists https://diabetesjournals.org/clinical/article/38/4/390/35426/Switching-Between-Glucagon-Like-Peptide-1-Receptor

[3] Comparison of the efficacy and safety of 10 glucagon-like peptide-1 ... https://pmc.ncbi.nlm.nih.gov/articles/PMC10493284/

[4] GLP-1 Agonist List: An Overview of Common Brands & Uses https://www.joincalibrate.com/resources/glp-1-agonist-list

[5] Research shows GLP-1 drugs are effective but complex https://www.uchicagomedicine.org/forefront/research-and-discoveries-articles/2024/may/research-on-glp-1-drugs

[6] Ozempic and Mounjaro Aren't the Same. Here's How Weight-Loss ... https://www.scientificamerican.com/article/mounjaro-and-ozempic-arent-the-same-heres-how-weight-loss-drugs-compare/

[7] Comparing Ozempic, Wegovy and Other GLP-1 Drugs - GoodRx https://www.goodrx.com/classes/glp-1-agonists/glp-1-drugs-comparison

[8] Comparative effectiveness of GLP-1 receptor agonists on glycaemic ... https://www.bmj.com/content/384/bmj-2023-076410