Description of Retatrutide

Retatrutide is a synthetic peptide that acts as a triple agonist of the glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and glucagon receptors. This combinatorial receptor signaling enables simultaneous modulation of multiple metabolic pathways. In contrast to earlier GLP-1 receptor agonists, which primarily target appetite suppression and glycemic improvement, retatrutide leverages glucagon receptor activation to stimulate lipolysis and elevate basal metabolic rate, thereby contributing to a more pronounced and sustainable reduction in adiposity.

The GLP-1 and GIP receptors play essential roles in augmenting insulin secretion and glucose homeostasis, whereas glucagon receptor engagement elevates circulating glucagon levels, promoting catabolic processes. Through this triagonist mechanism, retatrutide not only reduces caloric intake and improves glycemic control but also enhances energy expenditure. This comprehensive modulation of energy balance represents a novel therapeutic strategy for the management of obesity, type 2 diabetes, and related metabolic disorders.

[1]

Research Confirmed Effects

1. Retatrutide in the Treatment of Obesity

Retatrutide represents a novel generation of anti-obesity and antidiabetic pharmacotherapy, characterized by its unique mechanism of action involving the simultaneous activation of three metabolically relevant receptors: the glucagon-like peptide-1 receptor (GLP-1R), the glucose-dependent insulinotropic polypeptide receptor (GIPR), and the glucagon receptor (GCGR). This triple agonism allows for an integrated modulation of key pathways regulating body weight and metabolic homeostasis. GLP-1 and GIP are incretin hormones that enhance insulin secretion, suppress appetite, and improve glycemic control, while glucagon primarily stimulates lipolysis, increases energy expenditure, and promotes fatty acid oxidation. As a synthetic peptide with an extended half-life, retatrutide consolidates these effects into a once-weekly injectable therapy, potentially improving patient adherence.

The efficacy of retatrutide has been evaluated in several randomized phase 2 clinical trials, demonstrating significant weight reduction. After 48 weeks of treatment, participants receiving 8 mg and 12 mg doses experienced a mean body weight reduction of 22.8% and 24.2%, respectively—an outcome comparable to bariatric surgery. Additional benefits included decreases in body mass index (BMI), waist circumference, fasting plasma glucose, HbA1c, and blood pressure. These effects were dose-dependent and particularly pronounced at higher doses. Notably, retatrutide also exerted a substantial impact on hepatic steatosis, with liver fat volume reduced by up to 82.4% at 12 mg after 24 weeks. A considerable proportion of patients achieved a liver fat content below the threshold for steatosis (<5%), indicating therapeutic promise for metabolic liver diseases such as nonalcoholic steatohepatitis (NASH).

Given the high global prevalence of obesity and its strong association with type 2 diabetes and other chronic diseases, retatrutide emerges as a highly promising therapeutic candidate. Ongoing phase 3 trials aim to further establish its long-term safety and efficacy. If positive, retatrutide may be positioned as one of the most significant pharmacological innovations in obesity treatment in recent decades.

[2] - [5]

2. Retatrutide and Type 2 Diabetes

Recent phase 2 clinical trial data evaluating the efficacy and safety of retatrutide in patients with type 2 diabetes demonstrate its profound effects on both glycemic control and body weight reduction. In one of the studies, patients with a mean baseline body mass index (BMI) of 35.3 kg/m² and an average HbA1c of 8.3% were randomized to receive varying doses of retatrutide (ranging from 1 mg to 12 mg) or placebo over a 36-week treatment period. Retatrutide exhibited a clear dose-dependent reduction in HbA1c, with the highest dose (12 mg) achieving a mean HbA1c reduction of 2.16 percentage points from baseline, compared to only 0.43% in the placebo group—an effect that was statistically highly significant.

In addition to glycemic improvements, a substantial reduction in body weight was also observed. Participants receiving the 12 mg dose of retatrutide experienced a weight loss of up to 16.94%, corresponding to approximately 17.5 kg, while the placebo group showed a reduction of only 3.29%. The weight loss was consistent throughout the study period and showed a continued downward trend beyond week 36, suggesting a potential for sustained long-term efficacy. These findings underscore the dual benefit of retatrutide in patients with type 2 diabetes, combining potent glucose-lowering effects with robust anti-obesity properties—particularly relevant given the strong association between obesity, insulin resistance, and impaired glycemic control.

Retatrutide, as a triple agonist targeting GLP-1, GIP, and glucagon receptors, holds significant promise as a therapeutic agent in the management of type 2 diabetes—not only through its ability to improve glycemic parameters but also via its substantial impact on weight reduction. Its efficacy in diabetic populations approaches outcomes observed in individuals with obesity without diabetes, indicating its potential as a next-generation treatment option. These results pave the way for a more individualized therapeutic strategy in patients with diabetes and metabolic syndrome, especially in those with significant overweight or obesity contributing to worsened prognosis.

[6], [7]

3. Retatrutide and Its Liver Impact

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), is the most prevalent chronic liver disorder worldwide, with an increasing incidence driven by the global rise in obesity and metabolic syndrome. Pathophysiologically, MASLD is strongly associated with insulin resistance, leading to hepatic lipid accumulation, inflammation, and in advanced stages, fibrosis and cirrhosis.

Retatrutide, a novel triple agonist of the GIP, GLP-1, and glucagon receptors, has demonstrated significant hepatoprotective effects in individuals with MASLD. In a phase 2 substudy that included participants with hepatic fat content ≥10%, 48-week treatment with retatrutide resulted in a robust, dose-dependent reduction in liver fat. At doses of 8 mg and 12 mg, participants achieved a mean relative reduction in hepatic fat content of 81.4% and 82.4%, respectively, at week 24 (versus +0.3% in the placebo group), with normalization of liver fat content (<5%) observed in 79% and 86% of patients. These effects were sustained at week 48, with 89% and 93% of participants maintaining hepatic fat levels below the steatosis threshold. Additionally, liver volume decreased significantly, and improvements were observed in biomarkers of hepatic injury and inflammation, suggesting potential antifibrotic and anti-inflammatory actions.

The hepatic benefits of retatrutide are likely mediated by multiple mechanisms. Most prominently, the substantial reduction in total and visceral adiposity is tightly linked to improved insulin sensitivity—a core pathophysiological determinant of MASLD. Enhanced insulin action decreases the influx of free fatty acids to the liver and suppresses hepatic de novo lipogenesis. Moreover, treatment with retatrutide resulted in favorable changes in metabolic parameters including glycemia, lipid profile, and inflammatory markers. Given the current lack of approved pharmacotherapies for metabolic dysfunction-associated steatohepatitis (MASH)—the progressive form of MASLD characterized by hepatocellular injury and fibrosis—retatrutide emerges as a highly promising candidate. Its multifaceted mechanism of action, encompassing weight reduction, metabolic normalization, and marked hepatic fat clearance, underscores its potential role in the comprehensive management of metabolic liver diseases.

[4]

References

1. „Retatrutide (LY3437943): A Novel Tri-agonist Peptide for Metabolic Disease Treatment“, 2025.
2. Alaa Abdrabou Abouelmagd et al., „Efficacy and safety of retatrutide, a novel GLP-1, GIP, and glucagon receptor agonist for obesity treatment: a systematic review and meta-analysis of randomized controlled trials“, 2025.
3. Coskun T, Urva S, Roell WC, et al. LY3437943, a novel triple glucagon, GIP, and GLP-1 receptor agonist for glycemic control and weight loss: from discovery to clinical proof of concept. Cell Metab. 2022;34(9):1234–1247.e9. doi: 10.1016/j.cmet.2022.07.013. [DOI] [PubMed]
4. Sanyal AJ, Kaplan LM, Frias JP, et al. Triple hormone receptor agonist retatrutide for metabolic dysfunction-associated steatotic liver disease: a randomized phase 2a trial. Nat Med. 2024;30(7):2037–2048. doi: 10.1038/s41591-024-03018-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
5. 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. [DOI] [PubMed]
6. Rosenstock J, Frias J, Jastreboff AM, et al. Retatrutide, a GIP, GLP-1 and glucagon receptor agonist, for people with type 2 diabetes: a randomised, double-blind, placebo and active-controlled, parallel-group, phase 2 trial conducted in the USA. Lancet. 2023;402(10401):529–544. doi: 10.1016/S0140-6736(23)01053-X. [DOI] [PubMed]
7. Urva S, Coskun T, Loh MT, et al. LY3437943, a novel triple GIP, GLP-1, and glucagon receptor agonist in people with type 2 diabetes: a phase 1b, multicentre, double-blind, placebo-controlled, randomised, multiple-ascending dose trial. Lancet. 2022;400(10366):1869–1881. doi: 10.1016/S0140-6736(22)02033-5. [DOI] [PubMed]