What is Retatrutide and How Does it Work?

What is Retatrutide?

Retatrutide is a notable triple-agonist peptide, which means it targets three different hormone receptors: GLP-1 (glucagon-like peptide-1), GIP (gastric inhibitory polypeptide), and glucagon. These hormones play vital roles in regulating blood sugar, appetite, and energy expenditure, making Retatrutide a promising candidate for treating obesity and potentially type 2 diabetes mellitus.

 

The Importance of Insulin

Insulin is a hormone produced by the pancreas, specifically by its beta cells. It plays a critical role in regulating blood glucose (sugar) levels in the body. When we eat, our bodies break down carbohydrates from food into glucose, which enters the bloodstream. Elevated blood glucose levels signal the pancreas to secrete insulin. Insulin facilitates the uptake of glucose into cells throughout the body, where it's used for energy. It also helps store glucose in the liver and muscles for future use and inhibits the body from using fat as an energy source.

The relationship between insulin and Type 2 diabetes is central to understanding the disease. Type 2 diabetes is a chronic condition characterized by insulin resistance and, often, reduced insulin production over time. Insulin resistance occurs when the body's cells do not respond properly to insulin. As a result, more insulin is needed to help glucose enter the cells. The pancreas initially compensates by producing more insulin, but over time, it may be unable to produce enough insulin to maintain normal blood glucose levels.

This disruption in insulin function leads to high levels of glucose in the bloodstream, a hallmark of diabetes. Persistent high blood sugar can cause various health complications over time, including heart disease, kidney disease, vision problems, and nerve damage.

Type 2 diabetes is often associated with lifestyle factors like obesity, physical inactivity, and poor diet, although genetics also play a significant role. Management of the disease typically involves lifestyle changes, such as diet and exercise, and sometimes medication to help improve insulin sensitivity or increase insulin production. In some cases, people with type 2 diabetes may eventually require insulin therapy.

The key to managing Type 2 diabetes is to maintain blood sugar levels within a healthy range, which helps prevent or delay the complications associated with the disease. Regular monitoring of blood sugar levels, along with appropriate medical care, is crucial for people with diabetes.

History of Type 2 Diabetes

Type 2 diabetes is a significant health concern in the United States, affecting a large portion of the population. As of 2021, about 38.4 million Americans, or 11.6% of the population, had diabetes. Among these, approximately 29.7 million were diagnosed, and 8.7 million were undiagnosed. The prevalence of diabetes is particularly high among seniors (aged 65 and older), with 29.2% of this age group having diabetes, either diagnosed or undiagnosed. Additionally, each year, around 1.2 million Americans are newly diagnosed with diabetes.

When it comes to race and ethnicity, diabetes affects certain groups more than others. American Indians/Alaskan Native adults have the highest rate of diagnosed diabetes at 13.6%, followed by non-Hispanic black adults at 12.1%, and Hispanic adults at 11.7%.

The impact of diabetes in the U.S. is not limited to those who have already developed the disease. A substantial number of Americans are in a state known as prediabetes, which is a precursor to type 2 diabetes. As of 2021, an estimated 97.6 million American adults aged 18 and older had prediabetes.

In this context, the development of peptides like Retatrutide is particularly important. Retatrutide, a triple-agonist peptide, is being developed to address obesity, which is a major risk factor for type 2 diabetes. By targeting three different hormone receptors involved in regulating blood sugar, appetite, and energy expenditure, Retatrutide shows promise in aiding weight loss and improving metabolic health. This could be crucial in managing and potentially preventing type 2 diabetes, especially considering the large number of people currently living with or at risk for the disease.

Given the prevalence and impact of type 2 diabetes, advancements in medical treatments like Retatrutide offer hope in combating this widespread health issue. However, it's important to note that lifestyle changes, such as diet and exercise, remain foundational in managing and preventing type 2 diabetes.

How does Retatrutide work?

Retatrutide is an innovative peptide with a complex mechanism of action, making it highly effective for weight loss and diabetes management. It functions primarily through three mechanisms: as a Gastric inhibitory polypeptide receptor (GIPR) agonist, it enhances appetite suppression and prevents fat accumulation by improving the body's response to insulin. As a Glucagon-like peptide 1 receptor (GLP-1R) agonist, retatrutide stimulates insulin release in response to high blood glucose levels, simultaneously reducing the release of glucagon, which helps in balancing glucose metabolism. Finally, its role as a Glucagon receptor (GR) agonist decreases glucagon release, aiding in lowering blood glucose levels and supporting weight loss. These combined actions target different aspects of metabolic and appetite regulation, positioning retatrutide as a superior treatment option in the realms of obesity and diabetes care.

According to the research, Retatrutide has been shown to aid in:

1. Weight reduction

2. Improving blood sugar levels

3. Improving blood pressure

Retatrutide and Weight Reduction Research:

Retatrutide has been showing promising results in aiding weight reduction, especially in the context of obesity and related conditions, according to clinical trial data available up to my last update in April 2023. In these trials, participants receiving retatrutide exhibited significant weight loss compared to those on placebo or other weight loss medications, highlighting its effectiveness.

Moreover, retatrutide has demonstrated a positive impact on various metabolic parameters, including cholesterol levels, blood pressure, and glycemic control, which is beneficial for patients with obesity-linked conditions such as type 2 diabetes and hypertension. A key factor in retatrutide's success in weight management is its ability to regulate appetite. By targeting specific receptors, it reduces hunger and increases satiety, leading to a decrease in calorie intake and consequent weight loss.

Additionally, there's evidence to suggest that retatrutide influences fat distribution and accumulation, potentially improving overall metabolic health and reducing risks associated with fatty liver disease and cardiovascular issues. In comparative studies, retatrutide often outperforms existing weight loss treatments, marking it as a significant advancement in obesity management.

Retatrutide and Blood Sugar Research:

            Retatrutide plays a pivotal role in improving blood sugar levels, primarily through its dual action on the hormone’s insulin and glucagon, which are crucial for maintaining glucose homeostasis. As a GLP-1 (Glucagon-like peptide-1) agonist, retatrutide enhances the release of insulin from the pancreas. Insulin is a hormone that lowers blood sugar levels by facilitating the uptake of glucose by cells, thus reducing its concentration in the bloodstream. At the same time, as a Glucagon Receptor (GR) agonist, retatrutide effectively reduces the release of glucagon, a hormone that typically increases blood sugar levels by stimulating glucose production in the liver. The reduced release of glucagon complements the insulin-enhancing effect of retatrutide, leading to a more balanced and effective control of blood sugar levels.

This dual mechanism is particularly beneficial for individuals with diabetes, where the regulation of blood sugar is a critical aspect of disease management. By simultaneously boosting insulin release and suppressing glucagon secretion, retatrutide ensures a more stable and healthier blood sugar level, which is essential in reducing the risk of diabetes-related complications and improving overall metabolic health.

Retatrutide and Blood Pressure Research:

Retatrutide's role in improving blood pressure is closely linked to its effectiveness as a weight loss drug, primarily by addressing obesity, a key factor in hypertension. By decreasing energy intake and increasing energy expenditure, retatrutide facilitates significant fat loss, a process that is directly associated with the reduction of blood pressure. Obesity often leads to increased strain on the cardiovascular system, and reducing body weight can alleviate this strain, thereby lowering blood pressure. The mechanism through which retatrutide promotes weight loss involves both the suppression of appetite and the enhancement of metabolic efficiency. As individuals lose weight, there's a corresponding decrease in the workload on the heart and blood vessels, leading to improved blood pressure readings. This is particularly crucial for individuals with obesity-related hypertension.

The connection between weight loss and blood pressure reduction is well-established, and the effectiveness of retatrutide in facilitating this weight loss positions it as a potentially beneficial treatment for people with hypertension. This dual benefit of managing weight and concurrently improving blood pressure levels highlights retatrutide's potential as a comprehensive treatment option in the broader context of cardiovascular health and metabolic diseases.

Research Example 1:

Retatrutide, a GIP, GLP-1 and glucagon receptor agonist, for people with type 2 diabetes: a randomized, double-blind, placebo and active-controlled, parallel-group, phase 2 trial conducted in the USA.

Background

According to current consensus guidelines for type 2 diabetes management, bodyweight management is as important as attaining glycemic targets. Retatrutide, a single peptide with agonist activity at the glucose-dependent insulinotropic polypeptide (GIP), GLP-1, and glucagon receptors, showed clinically meaningful glucose-lowering and bodyweight-lowering efficacy in a phase 1 study. We aimed to examine the efficacy and safety of retatrutide in people with type 2 diabetes across a range of doses.

Methods

In this randomized, double-blind, double-dummy, placebo-controlled and active comparator-controlled, parallel-group, phase 2 trial, participants were recruited from 42 research and health-care centers in the USA. Adults aged 18–75 years with type 2 diabetes, glycated hemoglobin (HbA1c) of 7·0–10·5% (53·0–91·3 mmol/mol), and BMI of 25–50 kg/m2 were eligible for enrolment. Eligible participants were treated with diet and exercise alone or with a stable dose of metformin (≥1000 mg once daily) for at least 3 months before the screening visit.

Participants were randomly assigned (2:2:2:1:1:1:1:2) using an interactive web-response system, with stratification for baseline HbA1c and BMI, to receive once-weekly injections of placebo, 1·5 mg dulaglutide, or retatrutide maintenance doses of 0.5 mg, 4 mg (starting dose 2 mg), 4 mg (no escalation), 8 mg (starting dose 2 mg), 8 mg (starting dose 4 mg), or 12 mg (starting dose 2 mg). Participants, study site personnel, and investigators were masked to treatment allocation until after study ended. The primary endpoint was change in HbA1c from baseline to 24 weeks, and secondary endpoints included change in HbA1c and bodyweight at 36 weeks. Efficacy was analyzed in all randomly assigned, except inadvertently enrolled, participants, and safety was assessed in all participants who received at least one dose of study treatment. The study is registered at ClinicalTrials.gov, NCT04867785.

Findings

Between May 13, 2021, and June 13, 2022, 281 participants (mean age 56·2 years [SD 9·7], mean duration of diabetes 8·1 years [7·0], 156 [56%] female, and 235 [84%] White) were randomly assigned and included in the safety analysis (45 in the placebo group, 46 in the 1·5 mg dulaglutide group, and 47 in the retatrutide 0·5 mg group, 23 in the 4 mg escalation group, 24 in the 4 mg group, 26 in the 8 mg slow escalation group, 24 in the 8 mg fast escalation group, and 46 in the 12 mg escalation group). 275 participants were included in the efficacy analyses (one each in the retatrutide 0·5 mg group, 4 mg escalation group, and 8 mg slow escalation group, and three in the 12 mg escalation group were inadvertently enrolled). 237 (84%) participants completed the study and 222 (79%) completed study treatment. At 24 weeks, least-squares mean changes from baseline in HbA1c with retatrutide were –0·43% (SE 0·20; –4·68 mmol/mol [2·15]) for the 0·5 mg group, –1·39% (0·14; –15·24 mmol/mol [1·56]) for the 4 mg escalation group, –1·30% (0·22; –14·20 mmol/mol [2·44]) for the 4 mg group, –1·99% (0·15; –21·78 mmol/mol [1·60]) for the 8 mg slow escalation group, –1·88% (0·21; –20·52 mmol/mol [2·34]) for the 8 mg fast escalation group, and –2·02% (0·11; –22·07 mmol/mol [1·21]) for the 12 mg escalation group, versus –0·01% (0·21; –0·12 mmol/mol [2·27]) for the placebo group and –1·41% (0·12; –15·40 mmol/mol [1·29]) for the 1·5 mg dulaglutide group.

HbA1c reductions with retatrutide were significantly greater (p<0·0001) than placebo in all but the 0·5 mg group and greater than 1·5 mg dulaglutide in the 8 mg slow escalation group (p=0·0019) and 12 mg escalation group (p=0·0002). Findings were consistent at 36 weeks. Bodyweight decreased dose dependently with retatrutide at 36 weeks by 3·19% (SE 0·61) for the 0·5 mg group, 7·92% (1·28) for the 4 mg escalation group, 10·37% (1·56) for the 4 mg group, 16·81% (1·59) for the 8 mg slow escalation group, 16·34% (1·65) for the 8 mg fast escalation group, and 16·94% (1·30) for the 12 mg escalation group, versus 3·00% (0·86) with placebo and 2·02% (0·72) with 1·5 mg dulaglutide.

For retatrutide doses of 4 mg and greater, decreases in weight were significantly greater than with placebo (p=0·0017 for the 4 mg escalation group and p<0·0001 for others) and 1·5 mg dulaglutide (all p<0·0001).

Mild-to-moderate gastrointestinal adverse events, including nausea, diarrhea, vomiting, and constipation, were reported in 67 (35%) of 190 participants in the retatrutide groups (from six [13%] of 47 in the 0·5 mg group to 12 [50%] of 24 in the 8 mg fast escalation group), six (13%) of 45 participants in the placebo group, and 16 (35%) of 46 participants in the 1·5 mg dulaglutide group. There were no reports of severe hypoglycemia and no deaths during the study.

Interpretation

In people with type 2 diabetes, retatrutide showed clinically meaningful improvements in glycemic control and robust reductions in bodyweight, with a safety profile consistent with GLP-1 receptor agonists and GIP and GLP-1 receptor agonists. These phase 2 data also informed dose selection for the phase 3 program.