Retatrutide for Weight Loss | How Does It Work

For researchers interested in exploring the potential of Retatrutide for weight loss, this guide offers essential insights into this emerging peptide therapeutic.

The peptide is yet to be approved for human use by regulatory bodies such as the United States Food and Drug Administration (FDA), but phase 3 trials are already underway investigating its potential in:

• Weight loss in overweight and obese subjects
• Reduction of liver fat and visceral obesity
• Weight loss and glycemic control in diabetes

Drawing on the latest studies and peer-reviewed literature, we will outline the documented benefits of Retatrutide for weight management, along with considerations for side effects and safety. Additionally, we will discuss underlying mechanisms and recommended dosages.

Finally, this guide provides expert recommendations for purchasing high-quality retatrutide online, enabling qualified researchers to incorporate this peptide into their studies safely and effectively.

What is Retatrutide | Overview

Retatrutide (previously LY3437943) is a synthetic peptide developed by the pharmaceutical giant Eli Lilly. It is a novel triple agonist peptide engineered to address the escalating global challenges of obesity and type 2 diabetes (T2D). 

The peptide distinguishes itself from previous compounds by targeting three key receptors simultaneously: the glucagon receptor (GCGR), glucose-dependent insulinotropic polypeptide receptor (GIPR), and glucagon-like peptide-1 receptor (GLP-1R) [1].

Targeting GIPR and GLP-1R is known to have profound effects on appetite suppression and insulin release, while the addition of GCGR activation is thought to stimulate energy expenditure and further enhance weight loss.

This multi-receptor approach is designed to enhance metabolic outcomes, offering superior weight loss and improved glycemic control compared to single GLP-1R or dual GLP-1R/GIPR agonists [1].

Here is what researchers should know about how retatrutide achieves its potential [2]:

• Retatrutide is a 39-amino acid peptide based on the peptide backbone of the naturally occurring hormone GIP. Therefore, it has the highest affinity for the GIPRs.
• The peptide is engineered with three non-coded amino acid residues for optimized stability and pharmacokinetics while enhancing affinity to the GIPR and GCGR.
• Retatrutide is conjugated to a C20 fatty di-acid moiety which enables albumin binding, extending the half-life to approximately 6 days. This allows for convenient once-weekly dosing and enhances effectiveness by preventing appetite fluctuations.

There already are several phase 1 and phase 2 trials in humans, where it has demonstrated significant dose-dependent weight loss reaching up to 24.2% from baseline, improved insulin sensitivity, and favorable cardiometabolic effects in obese and overweight individuals [3]. 

Currently, retatrutide is under investigation in the phase 3 clinical program TRIUMPH initiated by Eli Lilly, which depending on the results is expected to lead to its approval by the FDA [4].  

Retatrutide is also accessible as a reference material for qualified researchers interested in exploring the therapeutic potential of this triple receptor agonist.

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Retatrutide Side Effects | Overview

Retatrutide is still in phase 3 trials as a part of Eli Lilly’s clinical program that will investigate the peptide’s effectiveness, safety, and side effects in depth.

Nevertheless, the available smaller phase 2 studies have compared retatrutide to other weight loss peptides such as the GLP-1 agonist dulaglutide, which is already approved by the FDA.

Based on one phase 1b trial in T2D patients that lasted for 12 weeks, retatrutide has similar side effects as dulaglutide. More specifically, both compounds primarily led to gastrointestinal side effects. They affected 63% of those on retatrutide, 60% on dulaglutide, and 54% of the placebo cohort [1].

A larger phase 2 trial that incorporated data from 338 subjects without T2D revealed that the most common retatrutide side effects include nausea, diarrhea, and constipation, which are also typical for FDA-approved GLP-1R and GLP-1R/GIPR agonists [3].

These adverse reactions are dose-dependent and were most common in the highest 12mg/weekly group. That group consisted of 62 participants, 92% of whom experienced at least one side effect, including:

• Nausea, affecting 28 participants taking 12mg/weekly (45%)
• Vomiting – 12 (19%)
• Constipation – 10 (16%)
• Loose stools – 9 (15%)
• Allergic reactions and hypersensitivity – 8 (13%)
• Irregular heartbeat – 7 (11%)
• Lack of energy – 6 (10%)
• Increased pancreatic enzymes – 5 (8%)
• Injection site reactions – 5 (8%)
• Hepatic disorder – 2 (3%)
• Pancreatic inflammation – 1 (2%)

About 16% of the participants receiving the highest 12mg/weekly discontinued the retatrutide therapy due to the aforementioned side effects. In comparison, only 6% of the participants in the 1mg/weekly group discontinued the peptide due to side effects. 

The rate of side effects in the placebo group was 70% and none of the participants in this group discontinued the peptide.

The researchers also reported dose-dependent increases in heart rate that peaked at 24 weeks and declined thereafter. Such reactions have also been observed with previous GLP-1R and GLP-1R/GIPR agonist peptides.

No participants experienced depression or cancer and there were no fatalities linked to retatrutide therapy [3].

How Retatrutide Works for Weight Loss

What sets retatrutide apart from previous therapies is its unique triple mechanism of action, targeting three distinct G-protein-coupled receptors: GCGR, GIPR, and GLP-1R. This may position retatrutide ahead of earlier single and dual agonist therapies [5].

Here is how each of these receptor agonism actions contributes to weight loss:

• GIPR is a receptor found in the pancreas, fat tissue, and brain, amongst other organs. Retatrutide is primarily biased towards GIPR activation which enhances insulin secretion in a glucose-dependent manner and helps regulate blood sugar levels. Additionally, the receptor is crucial to controlling appetite by directly influencing the brain's satiety centers, thereby reducing hunger, cravings, and overall food consumption [6]. 
• GLP-1R activation also enhances glucose-dependent insulin secretion while inhibiting glucagon release, contributing to better glycemic control. Further, this receptor activation has been associated with cardiovascular benefits. But most notably GLP-1R activation is known to promote satiety, reduce appetite, and slow gastric emptying, leading to reduced caloric intake. In combination with GLP-1R agonism, GIPR activation has been shown to synergistically enhance metabolic efficiency and weight loss [7, 8].
• GCGR, primarily associated with increasing blood glucose levels through hepatic glucose production, plays a surprising and significant role in retatrutide weight loss. When activated, it also enhances energy expenditure by promoting lipolysis in white adipose tissue and thermogenesis in beige adipose tissue. Beige fat, also known as “brite” fat, shares characteristics with both white and brown fat. It can burn energy like brown fat but is found within white fat tissue. Beige fat can develop from white fat cells in response to certain stimuli, potentially including GCGR activation. This increases energy expenditure and metabolic rate, which is crucial for effective weight loss. Additionally, GCGR activation is also associated with reduced appetite [9].

The activation of these receptors not only promotes a negative energy balance through increased energy expenditure and reduced food intake but also enhances metabolic health by improving insulin sensitivity and glycemic control [5]. 

This unique combination may provide more significant and sustained weight loss compared to therapies that target only one or two of these receptor pathways.

Benefits of Retatrutide for Weight Loss

As of 2024, one of the retatrutide phase 2 trials has reported the greatest weight loss achieved through a pharmacological agent and published in a peer-reviewed journal [1].

That is the aforementioned 48-week phase 2 study in 338 non-T2D patients, 62 of which received the highest 12mg/weekly dose and achieved a mean -24.2% reduction of their baseline body weight [3].

Here are the most notable findings from this trial after 48 weeks of experimentation:

• the placebo group experienced a -2.1% reduction in baseline body weight
• the 1mg/weekly dose group saw an -8.7% reduction in weight, while the 4mg/weekly group had a -17.1% reduction
• the 8mg/weekly group achieved a -22.8% reduction, while the 12mg/weekly group saw a -24.2% reduction
• both 8mg/weekly and 12mg/weekly led to at least 5% weight loss in all of the treated individuals
• In the 12mg/weekly group, almost everyone lost 10% or more of their baseline weight; nearly two-thirds lost 20% or more, nearly half lost 25% or more, and a quarter lost 30% or more.

Those with higher BMI above 35 experienced the greatest mean percentage weight loss with retatrutide [3]. 

The trial also included a substudy to assess retatrutide effects on the amount of liver fat in patients with metabolic-dysfunction-associated steatohepatitis (MASH) and liver fat higher than 10%. 98 patients with obesity and MASH underwent liver magnetic resonance imaging and had blood biomarkers of liver injury and fibrosis measured. 

After 48 weeks of treatment with the two highest doses of retatrutide, 90% of participants had normalization of liver fat levels (under 5%). Inflammation markers, liver enzymes, triglyceride levels, and insulin resistance markers also improved [10].

Previous studies in subjects with T2D have also shown significant weight loss:

• In a phase 1b trial involving 72 T2D patients, retatrutide, when titrated up to 12mg/weekly, resulted in a mean weight loss of -19.7lb (8.96kg) and a 1.6% reduction in HbA1c over just 12 weeks. These improvements surpassed those seen with both placebo and FDA-approved GLP-1 agonists like dulaglutide [11].
• Additionally, a phase 2 trial involving 281 T2D patients found that 12mg/weekly retatrutide led to a mean -2.16% reduction in HbA1c levels over 36 weeks. Participants also experienced a -16.94% decrease in their baseline weight and saw greater reductions in triglycerides and non-HDL cholesterol compared to both the placebo and dulaglutide groups [12].

Retatrutide Dosage for Weight Loss

 

To ensure the safety and efficacy of retatrutide in weight loss studies, researchers are advised to follow specific dosing guidelines. 

The dosing regimen as reported in phase 2 trials begins with a low dose of 2mg/weekly, which is gradually increased over the study period to minimize potential side effects [3, 12]. 

The dose may be increased every four weeks, allowing sufficient time for patient adaptation and monitoring of potential side effects. The recommended titration framework suggests reaching the maximum dosage of 12mg/weekly over a minimum period of 12 weeks.

It is important to note that faster titration is not recommended due to the increased risk of side effects. 

However, the titration process can be slowed based on individual patient response and tolerability. For example, some researchers may consider initiating with an even lower dose of 1mg/weekly, and then following the standard dosing protocol for a total of 16 weeks.

Retatrutide's extended half-life allows for once-weekly subcutaneous administration, which can be done at any time of day, with or without meals. The preferred injection site, based on clinical trials, is the abdomen, specifically at least 2 inches (5cm) away from the belly button, to minimize the risk of bruising, reddening, infection, or irritation.

Below is a comprehensive dosing regimen based on existing research data:

• Initial Dose: Researchers start with 2mg/week dosage for the first four weeks.
• Dose Increase: Researchers increase to 4mg/weekly during weeks five to eight, 8mg/weekly during weeks nine to twelve, and finally 12mg/week dosage from the thirteenth week onward.
• Frequency: Researchers administer retatrutide weekly via subcutaneous injection.
• Study Duration: Research on retatrutide has extended up to 48 weeks.
• Additional Notes: Researchers conduct dosage adjustments necessary based on individual responses, but the dosage must not exceed 12mg/week. If a dose is missed, it should be administered within five days or omitted entirely. Subsequent doses should continue according to the original schedule.

Clinical studies on retatrutide dosing protocols have extended for up to 48 weeks, which indicates that retatrutide can be safely administered over an extended period without requiring cycling on and off the peptide [3, 12]. 

Continuous administration is crucial for maximizing the therapeutic benefits of retatrutide in weight management and improving metabolic health.

Longer-duration phase 3 studies as part of the TRIUMPH program are ongoing, with the first results expected as early as 2026. Specifically, there are 4 TRIUMPH trials with the longest one (TRIUMPH-3) expected to last 113 weeks [13, 14, 15, 16].

Where to buy Retatrutide online? | 2024 Edition

Many online vendors offer retatrutide, providing researchers with numerous options.

However, not all vendors are legitimate, To ensure you receive high-quality retatrutide, it is recommended to use only vetted sources.

Our peptide review team has evaluated multiple vendors by purchasing retatrutide, and the following consistently meets high standards for peptide purity, delivery, and customer support.

Polaris Peptides

 

Polaris Peptides is a newer peptide source supplying high-quality peptides designed exclusively for research and development endeavors of professionals. The vendor offers several key benefits, including:

• Purity and Precision: Polaris retatrutide for sale is crafted with the utmost precision, ensuring a purity level of over 99%.

• Transparency: Detailed lab results accompany every Polaris peptide for sale, providing you with the assurance of retatrutide’s quality and integrity. 

• Customer Support: Team Polaris is dedicated to providing personalized support and fast shipping, ensuring a seamless purchasing experience.