A Comprehensive Guide to GLP-1 Agonists - Semaglutide, Tirzepatide, and Retatrutide

Overview/Introduction

Imagine living in a world where you could improve your health and lose those pesky pounds with only a quick injection. This is the potential of GLP-1 agonists; it is not science fiction. This class of medications has proven to be promising in the fight against obesity. It is a condition that affects millions of people worldwide and has several health hazards. Retatrutide, Semaglutide, and Tirizepatide are the most talked-about in this class for their weight loss benefits. Clinical trials have shown that these drugs, first created to treat type 2 diabetes, considerably lower body weight.

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What is GLP-1?

GLP-1 is a peptide hormone that consists of 30 or 31amino acids. It is released by the intestinal tract, commonly known as the gut. In physiological settings, it increases the release of insulin and decreases the concentration of glucagon. This leads to a decrease in blood glucose levels. This proves to be vital for regulating blood glucose levels. Moreover, GLP-1 causes a delay in gastric emptying time that reduces appetite. The two combined, result in shedding the weight off.

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GLP-1 Agonists

GLP-1 agonists mimic GLP-1 hormone and regulate the blood glucose level. Their primary purpose is in type 2 diabetes, to enhance glycemic control. However, they have been used to treat obesity because of their notable effectiveness in helping patients lose weight. These agents include:

• Exenatide (Byetta) - (Approval; 2005)
• Dulaglutide (Trulicity) - (Approval; 2014)
• Liraglutide (Victoza, Saxenda) - (Approval; 2014)
• Semaglutide (Ozempic, Wegovy) - (Approval; 2017)
• Tirzepatide (Zepbound) - (Approval; 2022)
• Retatrutide - (Clinical trials III stage)

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A Brief History of GLP-1 Agonists

The discovery of the incretin effect brought attention to the role of gut hormones in regulating insulin. This marked the beginning of the voyage of GLP-1 agonists. This class started with the discovery of Exenatide. It was approved in 2005. Semaglutide and Tirzepatide followed FDA approval later on. Retatrutide is the latest addition in this class of agents that is still under clinical trials (stage III).

The journey of Semaglutide GLP-1 single action began with exploring the incretin effect. Semaglutide is a more recent addition to the GLP-1 receptor agonist class. It was developed by Novo Nordisk in 2012. Semaglutide was designed to address the frequent dosing limitations of earlier GLP-1 agonists by having a longer half-life. This allows for once-weekly dosing, improving patient compliance. In 2017, the FDA approved Semaglutide for the treatment of type 2 diabetes. It was marketed under the brand name Ozempic.

The need for more potent therapies for the "twin epidemics" of obesity and diabetes led to the development of Tirzepatide GLP-1 + GIP double action. It was developed by Eli Lilly and Company in 2016. Compared to current medications, it was intended to increase insulin secretion, improve glycemic management, and encourage weight loss.  It was approved by the FDA in 2022. Owing to its success in helping people lose weight, it is now being used off-label to treat obesity. It is marketed as Zepbound.

Eli Lilly and Company is the developer of the investigational drug Retatrutide GLP-1 + GIP + Glucagon receptor agonist triple action. It targets the GLP-1, GIP, and glucagon receptors in a unique way to treat obesity and associated metabolic diseases. It is at the forefront of weight management innovations thanks to its distinctive mechanism. It is still under clinical trials (stage III). It has yet to receive FDA approval.

According to preliminary results from clinical trials, Retatrutide decreases fat, particularly liver fat in diseases like MASLD (Metabolic-Associated Steatotic Liver Disease). However, there is no compelling evidence of excessive muscle loss. Improvements in metabolic indicators including insulin sensitivity and lipid metabolism were connected with the reductions in fat mass. Crucially, in contrast to fat loss, these investigations have not identified muscle breakdown as a noteworthy adverse consequence (Sanyal et al., 2023).

What is the Mechanism of Action?

GLP-1 agonists function similarly to the incretin hormone GLP-1. It decreases food intake, slows stomach emptying, increases insulin production, and suppresses glucagon release. This multimodal strategy significantly reduces hunger and promotes weight loss.

Semaglutide GLP-1 single action

Semaglutide is a GLP-1 analogue. It lowers blood glucose levels and activates GLP-1 receptors (predominantly in the brain, pancreas, and gut). It increases glucose-dependent insulin release in response to GLP-1 receptor activation. This leads to a reduction in blood glucose levels following a meal. Concurrently, it decreases glucagon release. It accelerates the proliferation of pancreatic β-cells, and slows down stomach emptying, all of which lead to a general decrease in appetite. Moreover, Semaglutide may lessen feelings of hunger, reduce cravings for certain foods, and increase feelings of fullness through its interaction with GLP-1 receptors in the brain. These diverse activities support semaglutide's all-encompassing metabolic effects in controlling blood glucose levels and promoting weight loss.

Tirzepatide GLP-1 + GIP double action

Tirzepatide consists of two polypeptides. One is an analogue of GLP-1 and the other is an analogue of GIP. It activates the receptors via binding and replicates the actions of incretins that are found in nature. Specifically, Tirzepatide-induced GLP-1 receptor activation enhances glucose-mediated insulin secretion while reducing glucagon secretion. Tirzepatide activates GIP receptors, supporting the systems that control blood glucose levels. Due to the drug’s additional effects like greater satiety following nutrient consumption and delayed stomach emptying, its use is also linked to decreased food intake and weight loss.

Retatrutide GLP-1 + GIP + Glucagon receptor agonist triple action

Retatrutide is an investigational new drug. It targets the GLP-1, GIP, and glucagon receptors as a triple hormone receptor agonist. The triple agonist strategy of Retratutide seeks to improve metabolic regulation by concurrently activating three important hormone receptors related to glucose metabolism and energy balance. This increases energy expenditure, decreases hunger, and improves insulin sensitivity—all of which will contribute to a notable reduction in body weight.

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Clinical Data

GLP-1 agonists have been shown in clinical trials to cause significant weight loss; in fact, some individuals have lost more than 20% of their body weight.

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Semaglutide

Numerous studies and clinical trials have comprehensively examined the safety and clinical efficacy of Semaglutide. An overview of some of the most important clinical data on Semaglutide is provided below:

Efficacy in Diabetes: The SUSTAIN series is one of the essential clinical trials that assessed the working of Semaglutide to improve glycaemic control in individuals with type 2 diabetes. Doses of 0.5 mg and 1.0 mg once weekly significantly lowered HbA1c levels in comparison to placebo. The reduction was dose-dependent (i.e., a 1.5% reduction in HbA1c levels). A noteworthy weight reduction was also seen as a byproduct.

Cardiovascular Efficacy: Semaglutide significantly decreased the risk of major adverse cardiovascular events (MACE) by 26% as compared to placebo in patients with type 2 diabetes who were at high cardiovascular risk (SUSTAIN trials). This finding was significant in establishing Semaglutide as not only helpful for glycemic control but also beneficial for cardiovascular health.

Administration Route-Based Efficacy: The effectiveness of injectable and oral forms of Semaglutide was examined in the PIONEER trials. Oral Semaglutide effectively lowered HbA1c and body weight. This offers increased patient compliance in the form of an oral route. Although the route-based efficacy of oral Semagutide is comparatively higher, it leads to more gut-based side effects. In case of long-term efficacy, injectable Semaglutide is preferred.

Efficacy in Weight Loss: Significant weight loss has been observed in obese people by the STEP (Semaglutide Treatment Effect in People with Obesity) studies. It showed an average weight reduction of around 14.9% with Semaglutide. The dose was 2.4 mg once weekly compared to placebo. This represented a significant advancement in the alternatives available to people who are obese for weight management.

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Tirzepatide

Numerous clinical trials have studied the safety and clinical efficacy of Tirzepatide. An overview of some of the most important clinical data is provided below:

Efficacy in Diabetes: The efficacy of Tirzepatide in the treatment of type 2 diabetes has been thoroughly assessed by the SURPASS clinical trials. Doses ranging from 5 mg to 15 mg weekly were administered. They significantly lowered HbA1c levels. These outcomes were better than those obtained with a placebo. They frequently outperformed those obtained with other GLP-1 receptor agonists.

Comparative Efficacy: Tirzepatide and Semaglutide were tested in the SURPASS-2 clinical trials. Tirzepatide showed better HbA1c reduction and more weight loss.  It also demonstrated enhancements in both insulin sensitivity and beta-cell function. This adds to its effectiveness in regulating blood sugar levels. Multiple SURPASS experiments have noticed that these benefits were consistent across many ethnic and demographic categories.

Efficacy in Weight Loss: Patients treated with Tirzepatide saw notable weight loss results. It demonstrated greater success in obesity tests, as patients at the 15 mg dosage lost up to 21% of their body weight. This depended on the dose administered (subcutaneous; 5-15 mg). Tirzepatide's effectiveness makes it a dual-purpose medication that treats obesity and diabetes.

Generally speaking, Tirzepatide causes more weight loss than semaglutide—especially at higher dosages. Tirzepatide's improved effect on weight reduction may be attributed to its simultaneous activity on GLP-1 and GIP receptors.

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Retatrutide

Several clinical trials have been to evaluate the clinical efficacy of Retatrutide. Following is the summary of clinical data for Retatrutide, including the most recent studies:

Efficacy in Weight Loss: Based on phase 2 clinical trials published in 2023, participants who received the maximum dose saw an average weight reduction of up to 24.2%. The maximum dose of 12 mg was administered over 48 weeks. These findings focus on the potential of Retatrutide in the treatment of weight loss.

Comparative Efficacy: Retatrutide's triple mechanism provides improved metabolic advantages and appetite suppression. This potentially makes it more effective in weight loss than single or dual GLP-1 agonists.

Efficacy in Diabetes: Patients with type 2 diabetes may benefit from better glycemic control if they take Retatrutide. Improved insulin sensitivity and glucose homeostasis are made possible by the triple agonism. Comprehensive findings from extensive research on the condition are still awaited.

Recent and Ongoing Studies:

• TRIUMPH-1 and TRIUMPH-3 Trials are ongoing clinical trials that aim to study Retatrutide's efficacy and safety in broader populations. It covers those with diseases linked to obesity, such as osteoarthritis in the knee and cardiovascular disease. These trials will yield more thorough information about the advantages and disadvantages of the medication.
• Phase III trials have been started by Eli Lilly to assess Retatrutide's efficacy in treating NAFLD (Non-alcoholic fatty liver disease), obesity, and type 2 diabetes. The purpose of these studies is to verify the drug's long-term safety and effectiveness before regulatory approval is given.
  

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Side Effects & Safety Profile

GLP-1 agonists have a comparatively safe profile in contrast to other weight-loss drugs, with no appreciable rise in serious adverse cardiovascular events.

Semaglutide has demonstrated a stable safety profile in several trials. The side-effect profile of semaglutide may differ between the subcutaneous and oral formulations. Oral dosage forms (tablets) induce more gastrointestinal problems. Such as mild to moderate nausea, vomiting, and diarrhoea. But they tend to go away with time. More serious but rare side effects include pancreatitis and gallbladder issues. Thyroid C-cell tumours may be more common than previously thought, however, the majority of this research has been conducted on rodents.

Tirzepatide has a safety profile similar to other GLP-1 agonist therapies. Common side effects include gut issues like nausea and diarrhoea. Adverse effects like sinus tachycardia, acute renal injury, pancreatitis, and cholecystitis are reported. These can be countered by the discontinuation of therapy.

Retatrutide has been well tolerated. Gastrointestinal side effects like nausea and diarrhoea, are the most commonly reported ones, associated with incretin-based therapy. These side effects are usually transient and decrease in frequency and intensity over time. The drug is still in stage III of clinical trials. Studies are still being conducted to evaluate any possible adverse effects that may impact metabolism and cardiovascular health.

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What Are Some Other Health Benefits of GLP-1 Agonists?

GLP-1 agonists are mostly used to treat obesity and type 2 diabetes. Beyond their main purposes, they potentially provide several additional health benefits:

Cardiovascular Benefits

GLP-1 agonists have been linked to cardiovascular advantages such as lowering blood pressure, and prevention of heart failure and stroke. Patients with type 2 diabetes should pay special attention to this since they are more likely to develop cardiovascular illnesses. They lower blood pressure by increasing sodium excretion via urine. Moreover, it causes vasodilation, which also leads to the regulation of blood pressure. GLP-1 agonists reduce inflammation. This mechanism helps lower the risk of heart attacks.

Neuroprotective Benefits

According to recent studies, GLP-1 agonists may have neuroprotective qualities, which could make them useful in treating neurodegenerative diseases like Alzheimer's. Their capacity to lessen oxidative stress and inflammation in the brain is assumed to be the mechanism behind these benefits.

Microdosing

Semaglutide (Ozempic), a GLP-1 agonist, is becoming increasingly popular for treating type 2 diabetes and helping people lose weight. There is a growing trend of "microdosing" Ozempic, wherein lower dosages are utilized to improve cognition and metabolism. Using drugs at sub-therapeutic levels reduces negative effects while maximizing benefits; this technique is known as microdosing. Microdosing for GLP-1 agonists aids in preserving stable blood sugar levels free from sharp swings. Some individuals—including physicians—also use GLP-1 agonists in microdosages to control cholesterol. These medications promote cardiovascular health, lessen inflammation, and lower LDL cholesterol. They are therefore desirable for more extensive metabolic enhancements.

Improved Lipid Profile

GLP-1 agonists have been shown to reduce triglycerides and increase HDL (good cholesterol) in numerous studies. This can lead to improvement in lipid profiles. It may contribute to overall cardiovascular health.

Renal Protection

GLP-1 agonists may have renal protective effects, which is advantageous for diabetic individuals who run the risk of developing kidney disease. The mechanism behind this is the lowering of albuminuria and enhancement of renal haemodynamics.

Pulmonary Benefits

GLP-1 agonists have shown anti-inflammatory qualities that may be advantageous when it comes to respiratory conditions such as asthma and COPD.  GLP-1 agonists may help lessen inflammatory reactions in the lungs by lowering systemic inflammation, which may enhance lung function and lessen exacerbations.

GLP-1 agonists may improve asthma control by lowering eosinophilic inflammation and airway hyperresponsiveness. This implies that GLP-1 receptor activation may have a therapeutic effect in the management of asthma.

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Administration Dose & Guidelines

Following are general administration doses and guidelines.  Consult your prescriber for your specific instructions.

Semaglutide

Semaglutide is available in both injectable and oral forms, primarily used for the treatment of type 2 diabetes and obesity.

Injectable Form: It is administered subcutaneously once a week. Start dose at 0.25 mg once weekly for 4 weeks. Increase the dose every 4 weeks as needed to gain 1-2 pounds per week. If no side effects and no weight loss you may increase the dose at 2-week intervals. Do not increase the dose if weight loss is sufficient. The maximum dose is 2.0 mg.

Oral Form: Typically, the initial dosage is 3 mg daily for 30 days, after which it is increased to 7 mg once a day. Should additional control be required, a maintenance dose of 7-14 mg can be given orally.

Tirzepatide

Tirzepatide is available in the form of a subcutaneous injection. It is used for the management of type 2 diabetes. Start at a dose of 2.5 mg once weekly for 4 weeks. Increase the dose every 4 weeks as needed to gain 1-2 pounds per week. If no side effects and no weight loss you may increase the dose at 2-week intervals. Do not increase the dose if weight loss is sufficient. The maximum dose is 15 mg.

Retatrutide

Retatrutide is currently an investigational new drug only available in the form of subcutaneous injection. The precise dose guidelines for the clinical use of Retatrutide are currently pending because the drug is undergoing clinical testing.

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Contraindications

It is essential to comprehend contraindications for safe and effective drug usage. GLP-1 agonists are contraindicated in the following cases:

• If you are less than 18 years of age.
• If your BMI is less than 27.
• If you have medullary thyroid cancer (MTC) or a family history of MTC.
• If you have multiple endocrine neoplasia syndrome Type 2 (MEN 2) or a family history of MEN 2.
• If you have active cancer or have had chemotherapy/radiation in the last 6 months.
• If you have pancreatitis or diabetes mellitus Type I.
• If you have a serious allergic reaction to desired medications or their compounded components.
• In the case of pregnant women and women who breastfeed.
• If you have any kidney or liver disease (including hepatitis).
• If you suffer from severe gut diseases (e.g. IBD).
• If you suffer from significant eating disorders.
• If you have symptomatic bipolar disorder or symptomatic schizophrenia.
• If you are an active drug user or alcohol misuser.
• If you have active gallbladder disease.
• If you have chronic or persistent hypoglycemia with ranges < 60 mg/dl.
• If you use steroids daily (e.g. Prednisone).

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Cost & Accessibility

GLP-1 agonists are expensive drugs that frequently have gaps in insurance coverage. Despite this, they might be more affordable in the long run, especially for those with cardiovascular disease. Different insurance plans have different copayments and require prior authorization for many patients.

GLP-1 agonists are prescription drugs, therefore using them necessitates a doctor's approval. Patients who do not often have access to healthcare services may find this to be less accessible. The entry of additional GLP-1 agonists into the market may affect prices. Price reductions brought about by more competition might make these drugs more affordable for a larger range of patients. Overall improvement in a person’s general health in the long run and less sickness time also contribute to the benefits of these drugs.‍

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Conclusion

GLP-1 agonists have shown significant benefits for weight loss in addition to improving metabolism, making them useful weapons in the war against obesity. For those who struggle with weight management, they present a promising alternative by decreasing hunger and increasing satiety. To guarantee wider patient access, issues with their high cost and accessibility still need to be resolved despite their efficacy. Further investigation and advancement could enhance their utilization and broaden their suitability in weight reduction treatments. In addition, their potential benefits for other ailments increase their attractiveness.

Future Prospects

With further research examining more applications and better formulations, GLP-1 agonists have solidified their position as a mainstay in the treatment of type 2 diabetes, obesity and potentially many other health conditions. GLP-1 agonists are becoming more and more well-liked because of how well they work to control type 2 diabetes and obesity. If current trends continue, they may be in the top prescribed drug list by 2032. However, given the possibility of breakthroughs in alternative therapies and healthcare policies, it is uncertain to expect them to be the #1 prescribed drug.

1. Wider Range of Therapeutic Uses

GLP-1 agonists are being investigated for applications other than diabetes and obesity. Their potential to treat nonalcoholic steatohepatitis (NASH) (a liver disease frequently linked to obesity and metabolic syndrome) is gaining attention. According to preliminary research, GLP-1 agonists may assist in improving liver function markers and lowering the amount of fat in the liver.

2. Neuroprotective Benefits

GLP-1 agonists may have neuroprotective benefits, according to growing research, which may have consequences for neurodegenerative illnesses including Parkinson's and Alzheimer's. These outcomes are believed to result from their capacity to lessen oxidative stress and inflammation in the brain, pointing to a potential treatment path for these illnesses.

3. Better Drug Delivery Systems

To increase patient adherence and convenience, efforts are being made to improve the delivery of GLP-1 agonists. These efforts include the development of better oral formulations and longer-acting injectables. These developments may increase the usability and accessibility of these treatments, increasing their application across a range of patient populations.

4. Microdosing

A possible method to improve metabolic health with fewer negative effects than full therapeutic doses is to microdose GLP-1 agonists. While sub-therapeutic doses may offer advantages including better blood sugar control, cholesterol management, and reduced inflammation without the typical gastrointestinal problems, standard doses are still beneficial in managing type 2 diabetes, lowering weight, and improving cardiovascular outcomes. Research indicates microdosing could offer gentler, long-term metabolic improvements.

In addition to helping those with diabetes, microdosing may also be beneficial for people at risk for metabolic syndrome or cardiovascular disease. Microdosing is a promising approach because preliminary research indicates that GLP-1 agonists can lower LDL cholesterol and enhance cardiovascular health. To verify its effectiveness and safety for these purposes, more investigation is required.

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REFERENCES

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