The “Weight” for a New Agent Is Almost Over: A Commentary on the Novel Triagonist Retatrutide for Obesity

Abstract

Retatrutide, a hormone receptor agonist targeting glucagon, glucagon-like peptide 1, and glucose-dependent insulinotropic polypeptide, is being developed to treat obesity. A literature review from April 2019 to April 2024 included such terms as “retatrutide,” “LY3437943,” “overweight,” and “obesity.” Phase I proof-of-concept studies led to phase II trials showing up to 24% body weight reduction and nearly 20 cm waist circumference reduction. The most common adverse effects were gastrointestinal. Ongoing phase II and III studies aim to further evaluate the safety and efficacy of retatrutide as a novel triagonist for obesity treatment.

Introduction

The World Health Organization reports that cardiovascular disease is the primary cause of death worldwide. ¹ Poorly controlled diabetes can lead to macrovascular complications that contribute to cardiovascular disease, such as an increased risk of cerebrovascular disease, coronary heart disease, and peripheral vascular disease. Obesity can further complicate diabetes control, leading to an increase in insulin resistance. ² Over the past 50 years, obesity rates have almost tripled, and obesity is a significant contributing factor to increasing cardiovascular risk. ³ Additionally, osteoporosis and certain organ malignancies, including endometrial, breast, ovarian, prostate, liver, gallbladder, kidney, and others, also can be associated with obesity. ⁴ Furthermore, patients who are overweight are at a higher risk for many noncommunicable diseases, and their risk is directly proportional to their body mass index (BMI). ⁴ It is projected that by 2030, nearly half of all adults in the United States will meet criteria for obese classification (BMI = 30–34.9 kg/m²), and almost one fourth will meet criteria for severely obese (BMI ≥ 35 kg/m²). ⁵ Given the link between cardiovascular disease, diabetes, and obesity, the medical community is actively seeking evidence-based treatment options to reduce cardiovascular risk, improve diabetes control, and promote weight loss.

Tirzepatide was the first dual-acting glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist, and it was approved in May 2023. Tirzepatide significantly reduces body weight, decreases hemoglobin A1C, and improves cardiovascular risk factors by lowering blood pressure, triglycerides, and low-density lipoprotein. ⁶ Due to the clinical successes of tirzepatide’s dual mechanism of action, the search for additional evidence-based treatment options continues, with retatrutide, a triple-hormone receptor agonist, currently undergoing phase III clinical studies.

Materials and Methods

A comprehensive literature search was conducted using the PubMed, MEDLINE, and Clinicaltrials.gov databases to gather all relevant studies on the drug retatrutide. The search covered publications from April 2019 to April 2024. The search terms used included “retatrutide,” “LY3437943,” “overweight,” and “obesity.” Studies were included if they were published in English and the efficacy and safety of retatrutide for treating overweight and obesity were evaluated. Studies were excluded if they were not published in English and did not focus on retatrutide as the primary intervention.

Pharmacology: Mechanism of Action

Retatrutide is a triple-hormone receptor agonist that works on GLP-1, GIP, and glucagon receptors. The drug binds to and activates all 3 receptors, enhancing first- and second-phase insulin secretion and reducing glucagon levels. GLP-1 is also a physiologic regulator of appetite and caloric intake by delaying gastric emptying. GIP targets the brain by stimulating satiety within the hypothalamus.^7,8 Glucagon release will help enhance energy expenditure when coupled with GLP-1 and GIP, promoting fat breakdown. ⁹

Pharmacokinetics

The area under the concentration–time curve during 1 dosing interval (AUC_(0–τ)), the maximum observed drug concentration x(C_max), the time at which C_max was observed (T_max), and the half-life associated with the terminal rate constant in the noncompartmental analysis were values that were collected in preclinical studies. The plasma concentration of retatrutide AUC_(0–τ) and C_max were proportional to the dose range studied. The median T_max was 12 to 49 hours after taking the dose. The half-life was ~6 days. ⁶

Clinical Studies

Retatrutide is being studied in participants with several disease states, primarily those with overweight or obesity with or without type 2 diabetes. The current data related to type 2 diabetes and obesity will be discussed here. Additional studies, including patients with kidney disease, osteoarthritis of the knee, and cardiovascular disease, are ongoing.

The phase I proof-of-concept study was designed as a double-blind, placebo-controlled, randomized study with multiple ascending doses of retatrutide. The study included adults with type 2 diabetes diagnosed for at least 3 months, hemoglobin A1C concentration of 7.0% to 10.5%, BMI of 23 to 50 kg/m², and no recent significant weight changes. Participants were randomized 9:3:1 to receive once-weekly subcutaneous injections of retatrutide in 5 ascending dose groups, placebo, or dulaglutide 1.5 mg over 12 weeks. There were 5 cohorts of participants receiving retatrutide. The randomized doses were as follows: 1) 0.5 mg once weekly for 12 weeks, 2) 1.5 mg once weekly for 12 weeks, 3) 3.0 mg once weekly for 12 weeks, 4) 3.0 mg for 4 weeks and then 6 mg for 8 weeks (reported as dose 3/6 mg), and 5) 3.0 mg for 2 weeks, then 6 mg for 2 weeks, then 9 mg for 4 weeks, and 12 mg for 4 weeks (reported as dose 3/6/9/12 mg). The most significant reductions in body weight were seen in the higher-dose retatrutide groups with placebo-adjusted changes of −8.96, –7.83, –4.71, and −2.37 kg for the 3/6/9/12-, 3/6-, 3-, and 1.5-mg groups, respectively. The placebo-adjusted change in body weight for the dulaglutide group was 0.08 kg. Additionally, waist circumference decreased for all treatment groups, with the most considerable placebo-adjusted change in the 3/6/9/12-mg retatrutide group of −6.4 cm (placebo-adjusted changes for the dulaglutide and 1.5-, 3-, and 3/6-mg retatrutide groups were −2.6, –5.9, –5.1 and −1.2 kg, respectively). ⁶

A phase II study was conducted to further examine the safety and efficacy of retatrutide. This study involved adults who were overweight or obese, with no history of diabetes, with a BMI of 30 to 50 mg/kg ² , or a BMI of 27 to 30 mg/kg ² with at least 1 weight-related condition. A total of 388 adults were included and randomized 2:1:1:1:1:2:2 to receive 1 of the 4 maintenance doses of retatrutide (1 and 4 mg with a starting dose of either 2 or 4 mg, 8 mg with a starting dose of either 2 or 4 mg, and 12 mg with a starting dose of 2 mg) or placebo. The primary endpoint of least-squares mean percent change in body weight (kg) at week 24 showed differences of −7.2, –11.8, –13.9, –16.7, –17.9, and −17.5 for retatrutide 1 and 4 mg starting with 2 mg, 4 mg starting with 4 mg, 8 mg starting with 2 mg, and 8 mg starting with 4 and 12 mg compared with −1.6 with placebo. At week 48, the least-squares mean percent changes in body weight (kg) for the same ordered groups were −8.7, –16.3, –17.8, –21.7, –23.9, and −24.2 and −2.1 for placebo. Of note, body weight reductions of at least 5% at week 48 were 100% for the 8- and 12-mg groups and 97% for the 4-mg starting at 4-mg dose group, 87% for 4-mg starting at 2-mg group, and 64% for the 1-mg group. Least-squares mean percent change in waist circumference (cm) from baseline also was evaluated at week 48 with the following results: –6.5, –14.6, –14.9, –18.5, –18.5, and −19.6 for the retatrutide 1-mg group, 4-mg starting with 2-mg group, 4-mg starting with 4-mg group, 8-mg starting with 2-mg group, 8-mg starting with 4-mg group, and 12-mg group, respectively, and −2.6 for placebo. Overall, the study’s results did not show a plateau in weight reduction. Thus, a more prolonged study duration is needed to identify when maximum weight loss peaks with retatrutide. Additionally, retatrutide treatment was linked to improvements in cardiometabolic measures (exploratory endpoints) at weeks 24 and 48, including systolic and diastolic blood pressure and concentrations of glycated hemoglobin, fasting glucose, insulin, and lipids. Within the 48-week treatment period, 41% of individuals in the combined 8-mg group and 30% of participants in the 12-mg group discontinued at least 1 antihypertensive medication due to improvements in blood pressure.^9,10

A phase IIb study is underway, including ~120 adults with chronic kidney disease and overweight or obesity. Participants may or may not have diabetes and will be randomized to receive retatrutide or placebo. The primary outcome will measure change from baseline on the glomerular filtration rate. Results are anticipated in November 2025. ¹¹

The phase III Training in Urban Medicine and Public Health (TRIUMPH) program will evaluate the safety and efficacy of retatrutide on chronic weight management, obstructive sleep apnea (OSA), and knee osteoarthritis in people with obesity and overweight. TRIUMPH-1 has an estimated completion date of May 2026 and is expected to include 2100 participants without type 2 diabetes who are obese or overweight to receive retatrutide or placebo. The study will consist of participants with OSA and knee osteoarthritis with a primary outcome of a percent change in body weight from 3 doses of retatrutide compared with placebo. ¹² TRIUMPH-2 will compare 3 doses of retatrutide with a placebo with ~1000 participants who are obese or overweight with type 2 diabetes. TRIUMPH-2 also will have a subset of participants with OSA and a primary outcome of percent change in body weight. TRIUMPH-2 is expected to be completed in May 2026. ¹³ The TRIUMPH-3 study will investigate retatrutide compared with placebo in participants with severe obesity (BMI ≥ 35 kg/m²) and established cardiovascular disease. Participants will receive 1 of 2 doses of retatrutide or placebo, with the primary outcome being a change in body weight. TRIUMPH-3 is expected to enroll 1800 participants and conclude in February 2026. ¹⁴ The TRIUMPH-4 study is actively recruiting participants with obesity or overweight and knee osteoarthritis. Participants will be randomized to 1 of 2 doses of retatrutide or placebo and evaluated for 2 primary outcomes: percent change from baseline in body weight and change from baseline in the Osteoarthritis Pain Subscale Score Index. ¹⁵ TRIUMPH-OUTCOMES is the phase III outcomes study set to be completed in February 2029. This study anticipates including 10,000 participants who are overweight with atherosclerotic cardiovascular disease, with or without chronic kidney disease, to receive retatrutide in an ascending dose titrated to a maximum tolerated dose compared with a placebo. This study aims to identify whether retatrutide can lower the incidence of severe cardiovascular events or prevent the worsening of kidney function. ¹⁶

Adverse Events

In the phase I study, treatment-emergent adverse events occurred with greater frequency in the dulaglutide and retatrutide groups compared with placebo (60%, 63%, and 54%, respectively). Nausea and diarrhea were the most frequently reported gastrointestinal adverse events, most mild to moderate. Of note, the 3/6/9/12-mg retatrutide group did have participants experiencing treatment-emergent adverse events at a higher proportion than the lower-dose retatrutide groups. Of the 6 serious adverse events reported, none of them were related to the study drug. ⁶

Similar to the phase I study, gastrointestinal adverse events were most common in the phase II study. The adverse events of nausea, diarrhea, constipation, and vomiting were more common in the retatrutide groups than in the placebo group. They were more commonly reported during the dose-escalation phase of treatment. Serious adverse events occurred in 4% of participants in the placebo group and 4% of participants in the retatrutide group. ⁹ Based on the data from these 2 completed studies, the side-effects profile of retatrutide looks very similar to that of the currently available GLP-1 receptor agonists and GLP-1/GIP dual agonists.

Drug Interactions

Because retatrutide has yet to undergo phase III studies, drug interactions can be speculated to match those of other GLP-1 and/or GIP receptor agonists. Regarding retratrutide’s actions as a glucagon receptor agonist, data regarding drug interactions via this mechanism are lacking. Caution should be exercised when using retatrutide with other antihyperglycemic medications or other medications that may enhance its glucose-lowering effects (eg, beta-blockers and androgens). Similar to tirzepatide, there may be a reduction in the efficacy of oral hormonal contraceptives due to delayed gastric emptying. ¹⁷ However, based on available evidence, this has not been confirmed, and patients may be advised to switch to a nonoral contraceptive method or add a barrier method.

Precautions/Contraindications

As retatrutide goes through phase III studies, precautions/contraindications will be further defined. However, given the exclusion criteria used in the clinical studies thus far and similarity to GLP-1 receptor agonist/GIP backbone agents, the contraindications potentially will include

• Family or personal history of medullary thyroid carcinoma,

• Family or personal history of multiple endocrine neoplasia syndrome type 2, and

• History of pancreatitis.

It is important to note that recent evidence suggests that GLP-1 receptor agonist use is not associated with an increased risk of thyroid cancer, but more studies are needed to make this conclusion. ¹⁸

Dosage, Administration, and Cost

With a half-life of ~6 days, retatrutide enables the achievement and maintenance of significant steady-state exposure following once-weekly subcutaneous treatments. Starting doses, treatment doses, and maximum doses have not been finalized at this time. The pricing of retatrutide has not yet been determined, but following current trends for other recently approved weight loss medications, the cost may be close to about $1000 for a 30-day supply. ¹⁹

Discussion

Using retatrutide for weight management entails a nuanced evaluation of its clinical implications, featuring both positive and negative aspects. On the positive front, retatrutide exhibits notable enhancements in weight loss and metabolic parameters, including reductions in blood pressure and concentrations of blood glucose, triglycerides, and LDL cholesterol. However, retatrutide is also associated with a transient increase in heart rate that can occur for up to 24 weeks. Whether this transient effect on heart rate represents a clinically significant issue compared with the long-term metabolic benefits will be up to providers and patients to determine individually. Further research on the safety implications of this phenomenon may be warranted.

In the context of the phase II study, all participants received lifestyle interventions consisting of counseling sessions delivered by a dietitian or qualified healthcare professional in alignment with current weight loss guidelines such as the Dietary Guidelines for Americans.^9,20 Lifestyle interventions to the extent exhibited by this study may not be feasible for patients depending on their level of health literacy, access to specialists such as dieticians, and time available for counseling sessions. Therefore, the real-world efficacy of retatrutide when used for weight loss may be less than reported in clinical studies if patients cannot co-initiate effective lifestyle modifications. This, in turn, may represent a burden on providers due to the need for increased time spent on additional counseling. Additionally, the cost of the drug likely will pose an additional accessibility challenge for uninsured and underinsured patients or patients whose insurance companies do not cover retatrutide.

At the time of this writing, multiple recent changes to GLP-based medications used for weight loss have affected both cost and availability. Simply existing as an alternative option for weight loss likely will enhance the use of retatrutide in the market because all other injectable medications are facing manufacturing and availability issues. However, given the successive cost increase from single-acting GLP agents to dual-acting agents, it is likely that retatrutide will similarly be unaffordable for many patients. Insurance coverage is currently unavailable for most anti-obesity medications unless the patient has diabetes, and coupons or discounts are highly variable.

One could assume in the development of this medication within a market saturated with medication of similar mechanisms that it would pursue additional benefits outside of weight management for it to be competitive within the market (eg, cardiovascular outcomes). These additional uses and potential indications likely will be further explored in phase III testing. Current studies are constrained by small sample sizes and brief durations, necessitating comprehensive investigations, particularly those employing more robust comparators such as tirzepatide, to elucidate the actual value of retatrutide in weight management.

Conclusion

Retatrutide, a novel GIP, GLP-1, and glucagon receptor agonist, has promising safety and tolerability results, with an overall profile similar to GLP-1 receptor agonists approved for obesity treatment. As a next step, the TRIUMPH phase III program will evaluate the safety and efficacy of retatrutide for chronic weight management, OSA, and knee osteoarthritis in people with obesity and overweight. These ongoing studies will explore the efficacy and safety of retatrutide further prior to Food and Drug Administration approval.

List of Abbreviations

Definition	Abbreviation
Area under the concentration–time curve	AUC (0–τ)
Body mass index	BMI
Clearance	CL
Centimeter	cm
Glomerular filtration rate	GFR
Glucagon	GCG
Glucagon-like peptide 1	GLP-1
Glucose-dependent insulinotropic polypeptide	GIP
Kilogram	kg
Low-density lipoprotein	LDL
Maximum drug concentration	Cmax
Medullary thyroid carcinoma	MTC
Multiple endocrine neoplasia syndrome type 2	MEN-2
Obstructive sleep apnea	OSA
Serious adverse events	SAEs
Half-life	t 1/2
Time at which Cmax was observed	T max
Treatment-emergent adverse events	TEAEs