New Kid on the Block - Retatrutide for Obesity Management

Written by Mariana Lopez, PharmD Candidate 2026 and Adenike Atanda-Oshikoya PharmD, BCACP, CDCES, CTTS

Background on Obesity and Comorbidities

Obesity, as defined by the World Health Organization (WHO), is the excessive and unhealthy accumulation of body fat.(1) Severe obesity is strongly associated with comorbid conditions such as type 2 diabetes mellitus (T2DM), cardiovascular disease (CVD), heart failure, chronic liver disease, and reduced life expectancy.(2) In addition to the clinical implications, obesity poses a substantial economic burden. In 2019 alone, obesity-related medical care costs in the United States were estimated at approximately $173 billion.(2)

These widespread health and economic burdens highlight the urgent need for effective obesity management. If left unaddressed, obesity-related comorbidities are likely to progress, further impairing patients' quality of life and increasing mortality risk. Clinical evidence suggests that achieving weight loss of ≥10% of total body weight is associated with significant health benefits, including reductions in hyperglycemia, hypercholesterolemia, and hypertension.(3) Patients may also experience a decreased need for polypharmacy and a lower risk of metabolic syndrome and associated morbidity and mortality.

Historical Overview of Obesity Pharmacotherapy

Pharmacologic treatment for obesity began in 1893 with thyroid hormone extracts, introduced due to their capacity to increase metabolic rate and reduce weight gain.(4) However, they were soon abandoned due to cardiovascular side effects and lack of sustainable results.(4) In 1959, phentermine was approved by the U.S. Food and Drug Administration (FDA). A sympathomimetic agent, phentermine suppresses appetite via norepinephrine release and has demonstrated weight loss of up to 12.6% compared to placebo in a 36-week study.(4) Despite its effectiveness, it remains approved only for short-term use due to cardiovascular risks.

By 2010, newer medications such as orlistat, bupropion/naltrexone, and phentermine/topiramate were approved for long-term use.(5) However, these agents generally failed to achieve a long-term placebo-adjusted mean weight loss exceeding 10% at tolerable doses and were frequently associated with acute or chronic side effects at higher doses.(6)

Modern Developments: GLP-1 Receptor Agonists

A significant milestone occurred in 2014 with FDA approval of liraglutide, the first glucagon-like peptide-1 receptor agonist (GLP-1 RA) for chronic weight management.(6) Clinical trials demonstrated that liraglutide produced 4.5%–6% average body weight reduction after one year of treatment. (7) Liraglutide was also indicated for the management of T2DM and was shown to reduce major adverse cardiovascular events (MACE) in the LEADER trial.(6) Its mechanism includes delayed gastric emptying and suppression of glucagon during hyperglycemia, enhancing satiety and glycemic control.(8) Semaglutide, another GLP-1 RA, received FDA approval in 2021 for chronic weight management in obese adults.(6) It demonstrated a 14.9% reduction in body weight compared to 2.4% with placebo in a 68-week clinical trial and improved cardiovascular outcomes.(6)

While GLP-1 receptor agonists significantly advanced the pharmacologic management of obesity, the introduction of tirzepatide represented a major breakthrough. Tirzepatide combines agonism of the GLP-1 receptor with that of the glucose-dependent insulinotropic polypeptide (GIP) receptor, offering a novel dual-incretin mechanism. GIP, like GLP1 is an incretin hormone and when combined with GLP-1, works synergistically to achieve greater weight reduction than with GLP-1 alone.(9) This approach has led to unprecedented weight loss outcomes, surpassing those observed with both liraglutide and semaglutide, and marking a transformative moment in the treatment of obesity. In the SURMOUNT-5 trial—a head-to-head, open-label, randomized controlled study—tirzepatide (Zepbound®) was compared to semaglutide (Wegovy®) in adults with obesity or overweight and at least one comorbidity (e.g., hypertension, dyslipidemia, obstructive sleep apnea, or cardiovascular disease), but without type 2 diabetes.(11) At maximum tolerated doses over 72 weeks, Zepbound® resulted in a mean weight reduction of 20.3%, compared to 13.2% with Wegovy®.(11) Patients on the highest dose of tirzepatide and semaglutide reported nausea (31%, 14.4%) and diarrhea (23%, 14%).(9)  Tirzepatide is currently the only FDA-approved pharmacotherapy to achieve this level of weight loss. However, ongoing clinical trials for retatrutide—a triple receptor agonist targeting GLP-1, GIP, and glucagon receptors—suggest the potential for even greater long-term weight loss outcomes.

Table 1: Average percent change in body weight(10,11)

*On-treatment results evaluated for at least 12 months

The Future

Retatrutide is the first investigational agent to combine triple receptor agonism: GLP-1, GIP, and glucagon receptor activation.(13) While GLP-1 and GIP contribute to appetite suppression and delayed gastric emptying, glucagon receptor activation introduces complementary metabolic effects. Glucagon receptors are primarily found in hepatic tissue and stimulate glucose production through gluconeogenesis and glycogenolysis during hypoglycemia.(14) Additionally, glucagon modulates appetite via vagal signaling from the liver to the central nervous system, enhances energy expenditure, and promotes lipolysis and ketogenesis.(14)

Efficacy and Safety Outcomes

The triple receptor agonism of retatrutide has shown promising outcomes in weight loss, A1C reduction, fatty liver disease and improved lipid profiles in phase II trials. A 48-week, randomized, double-blind, placebo-controlled Phase II trial investigated the safety and efficacy of retatrutide in 338 adults with a BMI ≥30, or ≥27 with at least one comorbidity: cardiovascular disease, dyslipidemia on lipid lowering medication or LDL ≥160 mg/dL, hypertension on blood pressure lowering medication or blood pressure of ≥130/≥80 mmHg. (13) Participants were assigned to placebo or varying doses of retatrutide (1 mg, 4 mg, 8 mg, or 12 mg). Results showed significant dose-dependent weight reductions at 24 and 48-weeks from randomization. Retatrutide was found to be superior to placebo in reduction of weight from baseline to 24 and 48 weeks.(13) Fourteen patients had a decrease in BMI to 22 or lower. Table 2 summarizes the results from the trial.

Table 2: Results of a 48-week retatrutide phase II trial(9)

ID - Initial dose

During the trial period about 94% of patients reported side effects while on retatrutide with most of them occurring in the 8mg and 12mg treatment groups and mostly during dose escalation.(13) These side effects were on average mild to moderate and included nausea (27%), diarrhea (13%), vomiting (10%), constipation (9%) and fatigue (7%). These side effects were expected, because GLP-1/GIP receptor agonists have a similar side effect profile.

Conclusion

Retatrutide’s novel triple agonist mechanism offers a promising new avenue in the pharmacologic management of obesity and its comorbidities. With substantial weight loss demonstrated in Phase II trials and an acceptable safety profile, retatrutide may emerge as a leading treatment option pending Phase III trial results and FDA approval, anticipated in 2026.

While the weight loss efficacy of retatrutide—up to 24.2% within less than a year—is promising, further research is essential to evaluate the long-term safety and overall health implications of such rapid reductions. As healthcare professionals, it is critical to distinguish between effective treatment and the potential for overtreatment, ensuring that therapeutic benefits consistently outweigh associated risks. Ongoing investigation is needed to clearly define the threshold between safe and excessive weight loss. Additionally, although the adverse effect profile of retatrutide is similar to agents such as tirzepatide and semaglutide, current data indicate a higher frequency of gastrointestinal side effects (27% nausea, 13% diarrhea). These tolerability concerns may significantly influence patient adherence and willingness to initiate or maintain therapy, even in the setting of substantial clinical benefit.

Pharmacists and healthcare providers are integral to patient education, medication adherence, and side effect management. As retatrutide approaches market availability, clinicians should remain informed on updates to treatment guidelines and emerging best practices in obesity management.

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1. Obesity and overweight. World Health Organization. March 1, 2024. Accessed April 9, 2025. https://www.who.int/news-room/fact-sheets/detail/obesity-and-overweight.

2. Cawley J, Biener A, Meyerhoefer C, et al. Direct medical costs of obesity in the United States and the most populous states. J Manag Care Spec Pharm. 2021;27(3):354-366. doi:10.18553/jmcp.2021.20410.

3. Brown JD, Buscemi J, Milsom V, Malcolm R, O'Neil PM. Effects on cardiovascular risk factors of weight losses limited to 5-10. Transl Behav Med. 2016;6(3):339-346. doi:10.1007/s13142-015-0353-9.

4. Bray GA, Purnell JQ. An Historical Review of Steps and Missteps in the Discovery of Anti-Obesity Drugs. In: Feingold KR, Ahmed SF, Anawalt B, et al., eds. Endotext. South Dartmouth (MA): MDText.com, Inc.; July 10, 2022.

5. Aaseth J, Ellefsen S, Alehagen U, Sundfør TM, Alexander J. Diets and drugs for weight loss and health in obesity - An update. Biomed Pharmacother. 2021;140:111789. doi:10.1016/j.biopha.2021.111789.

6. Müller TD, Blüher M, Tschöp MH, DiMarchi RD. Anti-obesity drug discovery: advances and challenges. Nat Rev Drug Discov. 2022;21(3):201-223. doi:10.1038/s41573-021-00337-8.

7. Pi-Sunyer X, Astrup A, Fujioka K, et al. A Randomized, Controlled Trial of 3.0 mg of Liraglutide in Weight Management. N Engl J Med. 2015;373(1):11-22. doi:10.1056/NEJMoa1411892.

8. Collins L, Costello RA. Glucagon-Like Peptide-1 Receptor Agonists. In: StatPearls. Treasure Island (FL): StatPearls Publishing; February 29, 2024.

9. Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide Once Weekly for the Treatment of Obesity. N Engl J Med. 2022;387(3):205-216. doi:10.1056/NEJMoa2206038.

10. Tak YJ, Lee SY. Long-Term Efficacy and Safety of Anti-Obesity Treatment: Where Do We Stand?. Curr Obes Rep. 2021;10(1):14-30. doi:10.1007/s13679-020-00422-w.

11. Rodriguez PJ, Goodwin Cartwright BM, Gratzl S, et al. Semaglutide vs Tirzepatide for Weight Loss in Adults With Overweight or Obesity. JAMA Intern Med. 2024;184(9):1056–1064. doi:10.1001/jamainternmed.2024.2525.

12. Marso SP, Bain SC, Consoli A, et al. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med. 2016;375(19):1834-1844. doi:10.1056/NEJMoa1607141.

13. Jastreboff AM, Kaplan LM, Frías JP, et al. Triple-Hormone-Receptor Agonist Retatrutide for Obesity - A Phase 2 Trial. N Engl J Med. 2023;389(6):514-526. doi:10.1056/NEJMoa2301972.

14. Al-Massadi O, Fernø J, Diéguez C, Nogueiras R, Quiñones M. Glucagon Control on Food Intake and Energy Balance. Int J Mol Sci. 2019;20(16):3905. Published 2019 Aug 11. doi:10.3390/ijms20163905.

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Mariana Lopez

Doctor of Pharmacy Candidate 2026

University of North Texas

Health Science Center College of Pharmacy

Fort Worth, TX

Dr. Adenike Atanda-Oshikoya PharmD, BCACP, CDCES, CTTS

Assistant Dean of Pharmacy Student Success and Academic Performance - Office of Pharmacy Student Success

Director of Introductory Pharmacy Practice Experiences - Office of Experiential Education

Associate Professor of Pharmacotherapy

University of North Texas

Health Science Center College of Pharmacy

Fort Worth, TX