Retatrutide | A Comprehensive Peptide Overview

Scientists might be interested in an extensive overview of retatrutide and its research applications.

Though the peptide is currently in phase 3 trials for its potential to treat type 2 diabetes and promote weight loss, other potential benefits are also being explored.

Researchers can pursue various avenues in studying retatrutide, such as:

• Chronic weight management in overweight and obesity
• Reducing intraorgan (visceral) fat and improving liver function
• Enhancing glycemic control and other metabolic parameters in type 2 diabetes

To maximize the therapeutic potential of retatrutide, it's crucial for researchers to stay updated on the latest research. Thus, this comprehensive guide aims to provide scientists with valuable insights into retatrutide experimentation.

Read on for an overview of retatrutide structure and mechanisms, information on its potential research applications, and details on the latest published and ongoing trials. 

Additionally, we offer guidance on sourcing research-grade retatrutide to ensure that studies adhere to the highest scientific standards.

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What is Retatrutide

Retatrutide is a synthetic peptide, first publicly identified as a developmental compound by Eli Lilly around 2019 under the code LY3437943 [1]. 

It belongs to a group of peptides known as incretin mimetics, which mimic the function of incretin hormones [2, 3]. 

Incretin hormones, such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are endogenous molecules naturally produced in the human body that stimulate insulin secretion, particularly in response to meals [4]. 

They also play a significant role in the regulation of appetite and peristalsis. Incretin mimetics such as retatrutide exert similar potential.

Retatrutide stands out from most other incretin mimetics because it is a triple agonist, activating GIP, GLP-1, and glucagon (GCG) receptors. This action towards GCG receptors is posited to further influence metabolic rate and support weight management [5].

Here is what researchers should know about retatrutide:

• Structurally, retatrutide is a 39-amino-acid peptide derived from the GIP peptide structure. It is designed to primarily activate the GIP receptors (higher affinity towards GIP) but has also been modified to effectively engage GLP-1 and GCG receptors [6].
• Retatrutide has an enhanced half-life reaching up to several days. This is due to the inclusion of a C20 fatty di-acid modification, which enhances its stability and prolongs its activity in the body, supporting a once-weekly dosing regimen [7].
• The triple action of the peptide is being studied for managing blood glucose levels and promoting weight loss, making it a promising candidate for treating conditions such as obesity and type 2 diabetes (T2D) [5].
• Early clinical trials (phase 1b and phase 2) have shown promising results in terms of pharmacokinetics, safety, metabolic health improvement, and significant efficacy in reducing body weight and improving glycemic control [6, 8, 9, 10].
• Retatrutide is currently undergoing clinical evaluation as part of Eli Lilly’s phase-3 TRIUMPH program. This research focuses on its safety and efficacy in treating obesity in individuals with and without T2D [5].

Although it has not yet received approval from regulatory bodies such as the United States Food and Drug Administration (FDA), retatrutide is available as a reference material for qualified researchers interested in exploring its therapeutic potential further.

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Retatrutide | Breakthrough in Obesity Treatment

Retatrutide development marks a significant breakthrough in obesity research, because it combines the properties of two seemingly counterregulatory endocrine signaling pathways.

GLP-1 and GIP play a major role in increasing insulin secretion and lowering blood sugar following a meal, while GCG works to increase blood sugar levels during fasting [4, 11]. 

Interestingly, the simultaneous activation of these three receptors appears to have potent glucose-lowering effects, similar to other GIP/GLP-1 agonists [9, 10]. 

At the same time, this allows the peptide to stimulate weight loss through a multitude of mechanisms – simultaneously reducing appetite to lower energy intake, and also stimulating metabolism to increase energy expenditure.

Here is a breakdown of how exactly each of these receptor activations contributes to the overall weight loss effect:

• GLP-1 and GIP receptor activation lower appetite on a central level, acting on the brain’s satiety centers; GLP-1 also slows down gastric emptying [12, 13, 14].
• GIP and GCG receptor activation in fatty tissue may stimulate lipid breakdown and oxidation. GCG-related pathways may stimulate the conversion of white fat into beige fat, also known as “beiging” to mimic the ability of brown fat to actively turn fat into heat [15]. Furthermore, GIP receptors are also posited to actively stimulate the release of fat from fat cells, further augmenting fat loss [16].
• GCG receptor activation, particularly in the liver, is thought to influence liver metabolism, boosting fat breakdown and oxidation, thus increasing metabolic rate [15]. 

Moreover, the data so far suggests that the peptide has a safety profile comparable to previous incretin mimetics, despite its novel triple-agonistic mechanism. 

One of the largest published phase 2 trials reported that the most common side effects include injection-site reactions and gastrointestinal problems such as nausea, vomiting, constipation, and diarrhea [8].

Some of the more serious side effects that are also common with previous incretin mimetics, such as cases of hepatic disorders and pancreatitis were less than 3%. 

The dropout rates ranged from 6% to 16% depending on the dose (between 1mg/weekly and 12mg/weekly), with no dropouts in the placebo group [8].

Retatrutide | Range of Potential Benefits

Retatrutide is under active investigation as a highly effective tool for weight management and therapy in obesity. 

However, the peptide has already shown significant potential in terms of metabolic benefits, blood sugar control, visceral adiposity, and more. 

Below we have detailed the most important studies that researchers should stay aware of as of 2024, as well as when to expect more long-term data to be published.

Weight Management and Obesity Research

Retatrutide is a novel triple-receptor agonist that has already been tested in a couple of studies (phase 1 and phase 2) regarding its potential metabolic effects compared to previous incretin mimetics.

Here is what researchers should know about these notable trials:

• The phase 1 study, conducted in Singapore in 2019, was the initial proof-of-concept investigation for retatrutide. It involved 47 healthy participants with a wide range of BMIs. The peptide was tested in dosages of up to 6mg/weekly for up to 12 weeks and was well tolerated amongst all participants. There was a significant reduction in appetite and improvements in metabolic parameters such as cholesterol levels [6].
• The larger phase 2 trial extended over 48 weeks and included 338 non-diabetic adults with overweight (BMI>27) and obesity (BMI>30). Participants received varying doses from 1mg/weekly to 12mg/weekly.

  Even the lowest dose of 1mg/weekly resulted in an 8.7% reduction in baseline weight, compared to a 2.1% reduction in the placebo group. The 12mg/weekly group saw the highest 24.2% reduction and 100% of the subjects receiving this dose lost at least 5% of baseline body weight.

  Additionally, there were significant reductions in waist circumference, blood pressure, glycated hemoglobin (HbA1c), fasting glucose and insulin levels, and non-HDL cholesterol levels [8].

Other Metabolic Benefits

Researchers have further analyzed the results from the 48-week phase 2 trial with 338 patients with overweight and obesity, to extract further potential metabolic benefits.

98 of those were selected, as they had a diagnosis of metabolic dysfunction-associated steatotic liver disease (MASLD, formerly “non-alcoholic fatty liver disease” or NAFLD) and at least 10% liver fat. Their mean weight was 242.9lb (110.2kg), and their mean BMI was 38.4kg/m².

The researchers had their liver fat reduction measured by magnetic resonance imaging (MRI) at weeks 24 and 48. They also accessed body weight, abdominal fat, metabolic measures associated with improved insulin sensitivity and lipid metabolism, as well as biomarkers of MASLD and fibrosis such as ALT, AST, FIB-4, enhanced liver fibrosis (ELF) score, K-18, and pro-C3.

Here is what the researchers reported [17]:

• The benefits were dose-dependent and the highest dose of 12mg/weekly retatrutide led to a mean -82.4% reduction in liver fat within 24 weeks, compared to no change in the placebo group. 86% of those receiving the maximum dosage achieved normal liver fat levels (<5%).
• There were significant reductions in fasting insulin, C-peptide, fasting triglycerides, and increases in adiponectin, and HOMA2-IR with higher doses.

• Liver fat reduction is strongly correlated with reductions in body weight, ASAT, VAT, and improvements in insulin sensitivity.

Blood Glucose Control

Researchers have already conducted phase 1b and phase 2 trials to investigate the potential of retatrutide’s benefits in T2D, primarily measuring glycated hemoglobin (HbA1c) as a marker of long-term glycemic control. 

The phase 1b trial lasted for 12 weeks and involved 72 adults aged 20-70 with T2D. The following findings were reported [9]:

• Participants had starting HbA1c levels between 7.0% and 10.5% and received retatrutide, dulaglutide (an FDA-approved GLP-1 agonist), or a placebo. Retatrutide and dulaglutide are both incretin mimetics that increase insulin synthesis in a glucose-dependent manner and help normalize blood sugar levels.
• By week 12, the group receiving the highest dose of retatrutide (12mg/weekly) experienced a significant HbA1c reduction of up to 1.6%. Additionally, participants in this group lost up to 19.7 pounds (8.96kg), achieving significantly better results than those on dulaglutide or placebo.
• Further studies on this phase 1b trial indicated that retatrutide can significantly slow gastric emptying, which also contributes to better glycemic control by slowing carbohydrate digestion.
• Although this effect is subject to tachyphylaxis (development of tolerance), researchers found that the time course of tachyphylaxis for gastric emptying delay may be longer with retatrutide compared to previously studied incretins [18].

The phase 2 trial was considerably larger, conducted over 36 weeks with 281 patients with T2D. Key results from the study include [10]:

• Participants received up to 12mg/weekly and had a notable decrease in HbA1c levels by up to -2.02% (22.07 mmol/mol) at 24 weeks and -2.16% (23.59 mmol/mol) at 36 weeks, compared to baseline. The placebo group didn’t experience any reduction.
   
• Moreover, 12mg/weekly retatrutide improved lipid profiles, including reductions in triglycerides and non-HDL cholesterol compared to both baseline and placebo.
• On a side note, there was a dose-dependent weight reduction, with the highest dose group (12mg/weekly) losing 16.94% of their initial body weight within 36 weeks, compared to a 3.00% reduction in the placebo group.

Long-Term Health Benefits

Long-term weight management, achieved through means such as incretin mimetics, has been associated with numerous health improvements including improved cardiovascular health, better glycemic control, and reduced risk of obesity-related complications.

Currently, data on the long-term potential of retatrutide remains limited, as the longest trials have lasted up to 48 weeks (11 months). However, Eli Lilly is actively exploring retatrutide's potential against obesity in long-term trials spanning 77 to 113 weeks.

This research is being conducted through the TRIUMPH phase-3 clinical program, which includes four ongoing trials. Researchers plan to enroll over 5,000 participants across these studies. The trials are as follows:

• TRIUMPH-1: This trial is aimed at evaluating the effectiveness of 89 weeks of therapy in individuals with overweight or obesity who do not have T2D and have had at least one unsuccessful attempt at dietary weight loss [19].
• TRIUMPH-2: This study aims to assess the effectiveness of 89 weeks of therapy in individuals with T2D who are also obese or overweight and have previously failed in attempts to lose weight [20].
• TRIUMPH-3: This trial is aimed at Investigating the effectiveness of 113 weeks of therapy in individuals with overweight or obesity who have a history of heart attack, stroke, or peripheral arterial disease [21].
• TRIUMPH-4: This trial is aimed at examining the effectiveness of 77 weeks of therapy in individuals with obesity or overweight issues who also have knee osteoarthritis [22].

As of 2024, all these trials are in the participant recruitment stage, with the first results expected to be published as soon as 2026.

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.