Retatrutide | Side Effects, Complications, and Risk Profile

Retatrutide side effects are a major focus for researchers due to its unique properties and potential applications, in various research settings. 

Understanding the possible adverse effects of retatrutide is essential for ensuring the safety of future research in areas such as:

• Chronic weight management

• Glycemic control

• Visceral obesity management

This guide will cover the main side effects of retatrutide as identified in current research. We also provide detailed information on correct dosing and administration to reduce risks during experiments.

Continue reading to find our recommended source for purchasing research-grade retatrutide online.

What is Retatrutide | Overview 

Retatrutide, also known by its developmental code LY3437943, is a promising investigational peptide-based compound developed by Eli Lilly and Company. It is currently undergoing clinical trials to evaluate its efficacy and safety in obesity and type 2 diabetes (T2D) [1].

The peptide is composed of 39 amino acids, engineered from a glucose-dependent insulinotropic polypeptide (GIP) peptide backbone. GIP is a naturally occurring hormone that alongside another natural hormone called glucagon-like peptide-1 (GLP-1) acts as an “incretin” to induce insulin release after food intake [2].

Retatrutide is modified to achieve triple agonist activity, primarily activating the GIP receptors, but also activating the GLP-1 receptors and the receptors for the hormone glucagon (GCG) [3].

This multi-receptor activation is thought to enhance the therapeutic potential of retatrutide, providing synergistic benefits in glucose control, weight reduction, and lipid metabolism [4]:

• GIP receptor activation stimulates insulin secretion, complementing the effects of GLP-1. It potentially enhances beta-cell function and survival, which is beneficial for T2D and may suppress appetite, reducing food intake and body weight [5].
• GLP-1 receptor activation promotes insulin secretion in a glucose-dependent manner, slows gastric emptying, inhibits glucagon release, reduces hepatic glucose production, and suppresses appetite with the latter aiding in weight loss [6, 7].
• GCG receptor activation may enhance energy expenditure by promoting lipolysis and thermogenesis. It helps in maintaining glucose homeostasis during fasting states and contributes to weight loss through its catabolic effects on adipose tissue [8].

The peptide backbone sequence of retatrutide includes three non-coded amino acid residues at positions 2 (α-amino isobutyric acid), 13 (α-methyl-L-leucine), and 20 (α-amino isobutyric acid) to enhance stability against dipeptidyl peptidase-4 (DPP4) cleavage and optimize glucagon and GIP activity [2].

Additionally, the backbone is conjugated to a C20 fatty di-acid moiety via a linker at position 17 lysine residue. This conjugation enables albumin binding, which extends the peptide's half-life up to six days to allow once-weekly administration [9].

Although not yet approved by the United States Food and Drug Administration (FDA), retatrutide is actively investigated in Eli Lilly’s phase 3 clinical program TRIUMPH [1]. The peptide is also accessible as a reference material for qualified researchers.

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Benefits of Retatrutide | Overview

Retatrutide has been studied in phase 1 and phase 2 clinical studies which showcase a wide range of benefits for research participants with metabolic conditions like glycemic control in T2D, obesity, and metabolic dysfunction–associated steatotic liver disease (MASLD). 

In particular, glycemic control in T2D is assessed by measuring the levels of glycated hemoglobin (HbA1c) which showcases the average glucose levels for the last 3-4 months. 

Further, MASLD (formerly known as NAFLD or NASH) severity is assessed by measuring the levels of liver fat, as this type of visceral fat can significantly impede its function and contribute to metabolic diseases. 

Below we have listed the most important retatrutide benefits and related research trials that researchers should note:

• Weight loss in T2D: A phase 1b trial in 72 T2D patients reported that retatrutide, titrated up to 12mg/weekly, led to -19.7lb (8.96kg) weight reduction and HbA1c reduction by -1.6% within just 12 weeks. The improvements were greater than both placebo and FDA-approved GLP-1 agonists like dulaglutide [9].
• Glycemic control in T2D: A phase 2 trial reported that 12mg/weekly retatrutide led to a mean -2.16% reduction in HbA1c levels in 281 T2D patients within 36 weeks. The subjects also lost -16.94% of their baseline weight, and reduced their triglyceride and non-HDL cholesterol to a greater extent than both the placebo and dulaglutide groups [10].
• Weight loss in overweight/obesity: Another phase 2 trial in 338 non-diabetic patients reported that 48 weeks of retatrutide therapy led to significant, dose-dependent weight loss. Both 8mg/weekly and 12mg/weekly led to at least 5% weight loss in all of the treated individuals. More specifically, the 8mg/weekly group had a -22.8% reduction and the 12mg/weekly group had achieved a -24.2% reduction compared to just -2.1% for the placebo [11].
• MASLD improvement: The aforementioned 48-week phase 2 trial investigated the effect of the peptide in a subset of 98 patients who had at least 10% liver fat (measured via MRI) and a diagnosis of MASLD. The 12mg/weekly retatrutide led to a mean reduction of 82.4% in liver fat within the first 24 weeks, compared to no change in the placebo group, and 86% of the patients achieved normal liver fat (<5%). Inflammation markers, liver enzymes, triglyceride levels, and insulin resistance markers also decreased [12].

All of the aforementioned experiments also reported significant improvements in waist circumference, lipid profiles, fasting glucose, and insulin levels with retatrutide, when compared to placebo. 

Currently, retatrutide is studied in four phase 3 trials as part of the TRIUMPH clinical program. All trials are in the participant recruitment stage, with the first results expected to be published as soon as 2026. The trials are:

• TRIUMPH-1: An 89-week study evaluating therapy effectiveness in overweight or obese individuals without type 2 diabetes (T2D) who have failed dietary weight loss attempts [13].
• TRIUMPH-2: An 89-week study assessing therapy effectiveness in overweight or obese individuals with T2D who have previously failed weight loss attempts [14].
• TRIUMPH-3: A 113-week study investigating therapy effectiveness in overweight or obese individuals with a history of heart attack, stroke, or peripheral arterial disease [15].
• TRIUMPH-4: A 77-week study examining therapy effectiveness in overweight or obese individuals with knee osteoarthritis [16].

Side effects of Retatrutide

As shown in phase 1 and phase 2 trials, retatrutide appears to have a similar safety profile and side effects as previous GLP-1 agonists and dual GLP-1/GIP mimetics.

One of the phase 2 trials which compared retatrutide to dulaglutide reported that within 36 weeks of therapy, 12mg/weekly retatrutide led to side effects in 76% of subjects, compared to 67% for the GLP-1 agonist. The incidence of serious side effects was also similar [10]. 

Thus, researchers may assume that there do not appear to be any additional risks associated with retatrutide’s mechanisms of a triple-agonist.

Below, we have outlined the most common side effects as reported by the available data, as well as all reported serious reactions, additional risks, and considerations

Common Side Effects

The largest published retatrutide trial, which was the aforementioned phase 2 trial in 338 non-diabetic individuals, reported that the most common side effects associated with retatrutide were gastrointestinal problems [11]. 

Such complaints, including nausea, diarrhea, and constipation have also been reported by GLP-1 agonists and their occurrence is dose-dependent. 

Concurrently, retatrutide trials report the highest rate of gastrointestinal adverse reactions and overall discontinuation rate (16%) in the subgroup receiving the maximum dose of 12mg/weekly. In comparison, the lowest dosage (1mg/weekly) had only 6% dropout, while there was no discontinuation in the placebo group. 

Specifically, the 62 participants receiving the maximum dosage reported the following complaints:

• Nausea – 28 participants (45%)
• Vomiting – 12 (19%)
• Constipation – 10 (16%)
• Diarrhea – 9 (15%)
• Allergic reactions and hypersensitivity – 8 (13%)
• Cardiac arrhythmia – 7 (11%)
• Fatigue – 6 (10%)
• Increased lipase levels – 5 (8%)
  
• Injection site reactions – 5 (8%)

There were dose-dependent increases in heart rate that peaked at 24 weeks and declined thereafter. Such reactions have also been observed with previous incretin mimetic peptides [11].

Serious Side Effects

As derived by the largest phase 2 trial on retatrutide, the incidence of serious side effects was as low as 4% amongst both the retatrutide and the placebo groups. 

The most notable serious side effects in the highest dosage 12mg/weekly retatrutide group as reported by the researchers included:

• Hepatic disorder – 3% (2 participants)
• Pancreatitis – 2% (1 participant)

In addition to the case of pancreatitis, there were several patients with increases in amylase and lipase levels, which were asymptomatic. 

There were no cases of depression or other mental disorders in any of the treatment groups. Any deaths occurring during the trial, specifically one case of drowning, were determined to be unrelated to the study [11].

General Risks and Complications

GLP-1 agonists and GLP-1/GIP agonists have been under scrutiny due to potential safety concerns, particularly the risk of medullary C-cell carcinoma of the thyroid gland. 

This risk has been observed in murine studies, prompting similar concerns for newer agents such as retatrutide. 

However, it is noteworthy that, despite the extensive use of GLP-1 agonists over the past decade and the ongoing development and approval of dual and triple agonists for human use, no cases of this type of thyroid cancer have been reported in humans.

Another area of concern is the potential risk associated with the activation of GLP-1 receptors during pregnancy and lactation. Animal studies have suggested that this could pose risks, although these findings have yet to be confirmed in human studies. 

Consequently, the use of peptides like retatrutide is generally discouraged during pregnancy and lactation.

Retatrutide is currently being evaluated in clinical trials under the TRIUMPH program, which aims to generate comprehensive data on its efficacy and safety. This program will support further scientific research and potential clinical application of retatrutide [17].

Recommended dosage for Retatrutide

Retatrutide’s pharmacokinetic properties allow for once-weekly dosing, enhancing patient compliance and minimizing the frequency of administration.

In clinical studies, retatrutide is typically initiated at a low dose of 2mg/weekly. This conservative approach is adopted to mitigate the risk of adverse effects, particularly gastrointestinal disturbances commonly associated with peptide therapies. 

The initial dose serves as a foundation upon which subsequent titration can be safely built. The titration of retatrutide follows a structured and gradual protocol. 

The dose may be increased every four weeks, ensuring adequate time for patient adaptation and monitoring of potential side effects. The maximum dosage recommended within this titration framework is 12mg/weekly, which should be achieved over a minimum period of 12 weeks [10]. 

In regards to research duration, current clinical trials involving retatrutide have spanned up to 48 weeks [11, 12].

It is important to note that faster titration than the described schedule is not recommended due to the heightened risk of side effects. However, the titration process can be adjusted to a slower pace based on individual patient response and tolerability. 

Therefore, researchers are also advised to experiment with a lower starting dose of 1mg/weekly to further minimize the risk of side effects, and extend the titration phase to 16 weeks. Below is a sample dosing guide with these considerations in mind:

• Initial Dose: Researchers begin administering retatrutide at 1mg/weekly for the first four weeks of the study period.
• Dose Escalation Protocol: weeks 5-8 – 2mg/weekly; weeks 9-12 – 4mg/weekly; weeks 13-16 – 8mg/weekly; week 17 and beyond – 12mg/weekly.
• Frequency: Injections are given once a week subcutaneously, typically in the abdomen, maintaining a distance of at least 2 inches from the navel.
• Study Duration: As of 2024, published studies have extended up to 48 weeks.
• Important Notes: It is critical that the dosage does not exceed 12mg/weekly. 

Longer-duration studies are in progress, with some expected to extend up to 113 weeks. Results from these extended trials are anticipated to be published in 2026, offering a more comprehensive understanding of the long-term effects of retatrutide.

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:

• Transparency: Detailed lab results accompany every Polaris peptide for sale, providing you with the assurance of retatrutide’s quality and integrity. 
• Purity and Precision: Polaris retatrutide for sale is crafted with the utmost precision, ensuring a purity level of over 99%.
• Customer Support: Team Polaris is dedicated to providing personalized support and fast shipping, ensuring a seamless purchasing experience.

Side effects of Retatrutide | Overall

As of 2024, retatrutide has not been approved for any human use, and its safety is still being assessed in phase 3 trials. 

However, data from phase 1 and phase 2 trials indicate that the peptide is generally well-tolerated, with side effects similar to those of FDA-approved incretin mimetics like dulaglutide, suggesting a comparable safety profile.

These include gastrointestinal side effects such as nausea, vomiting, diarrhea, constipation, and potential risks for hepato-pancreato-biliary issues.

The TRIUMPH phase 3 program aims to provide detailed data on the efficacy and safety of retatrutide, offering a more comprehensive understanding of its safety and effectiveness. 

Until this data is available, researchers must carefully consider the risks of using retatrutide in laboratory settings and ensure professional oversight in its handling and experimental use.

Risk Score

Our risk score is estimated based on the extent of peptide research and the reported safety/side effects, including data from:

• animal studies data
• phase 1 data if available
• phase 2 data if available
• phase 3 data if available
• any reports of mild/moderate reactions
• any reports of serious/permanent side effects
• any reports of fatalities
• current status by regulatory bodies

Based on these criteria, the risk score of retatrutide can be estimated as relatively low, at 3.5/10. 

The reason this score is not even lower is because the peptide is still undergoing phase 3 trials and doesn’t have any regulatory approval, while the available phase 2 studies report mild-moderate side effects.