Retatrutide

Authors:

Arun J. Sanyal, Axel Haupt, Bram Brouwers, Charles Harris, Juan P. Frias, Kieren J. Mather, Lee M. Kaplan, Mark L. Hartman, Melissa K. Thomas, Nanette C. Schloot, Qiwei Wu, Yu Du

Findings:

Once-weekly subcutaneous retatrutide (1, 4, 8, or 12 mg) administered for 48 weeks significantly reduced liver fat in participants (N=98) with MASLD and ≥10% liver fat compared to placebo. At 24 weeks, the mean relative change from baseline in liver fat was -42.9% (1 mg), -57.0% (4 mg), -81.4% (8 mg), -82.4% (12 mg) versus +0.3% for placebo (all P < 0.001). Retatrutide also led to significant reductions in body weight, abdominal fat (visceral and subcutaneous), and improvements in metabolic measures including insulin sensitivity, lipid metabolism, K-18, and pro-C3.

Participants:

N=98 participants with metabolic dysfunction-associated steatotic liver disease (MASLD) and ≥10% liver fat (LF), selected from a larger phase 2 obesity study. Overall, 46 (46.9%) participants were female, 98.0% were white, and 41.8% identified as Hispanic or Latino. At baseline, participants had a mean age of 46.6 years, mean weight of 110.2 kg, and mean body mass index (BMI) of 38.4 kg m−2. Patients with type 2 diabetes (T2D) were excluded.

Dosage:

Once-weekly subcutaneous retatrutide at doses of 1 mg, 4 mg, 8 mg, or 12 mg, or placebo, for 48 weeks. A dose-escalation scheme was used.

Study Quality Assessment:

Randomized, double-blind, placebo-controlled, multicenter (all in the United States) phase 2a substudy (N=98). Liver fat assessed by magnetic resonance imaging proton density fat fraction (MRI–PDFF). Primary objective: mean relative change from baseline in liver fat at 24 weeks. ClinicalTrials.gov registration: NCT04881760. Limitations acknowledged: relatively small sample size of the MASLD substudy, geographic and racial homogeneity (United States only and majority white), exclusion of patients with T2D, absence of liver histology, lack of enrichment for MASH or significant fibrosis, lack of multiplicity control for statistical assessments, and absence of 48-week MRI data for 56.1% of participants. The study sponsor (Eli Lilly and Company) designed, executed the trial, and was involved in data collection, data analyses, data interpretation, and writing of the report.

All Effects:

Authors:

Laiba Imran, Muhammad Naeem, Umm E Salma Shabbar Banatwala

Findings:

This correspondence concludes that retatrutide, a novel triple agonist (GCGR, GIPR, GLP-1R), is expected to result in significant weight loss among individuals who are obese or overweight, potentially revolutionizing pharmacotherapy. Clinical trials reviewed show retatrutide demonstrated dosage-dependent weight reduction (e.g., up to 24.2% mean weight loss at 48 weeks with 12mg dose in one trial), improved cardiometabolic measures (HbA1c, fasting blood glucose, insulin, blood pressure, lipids), and a favorable safety profile with mild/moderate, dose-dependent gastrointestinal issues (nausea, vomiting, diarrhea, constipation) being the predominant adverse events. Further research, including ongoing phase 3 trials with diverse populations, is deemed imperative to assess long-term impacts, safety, and effectiveness.

Participants:

Participants in the clinical trials reviewed in this correspondence included: adults who were obese or overweight (N=338, 51.8% men in one phase 2 trial); 72 individuals diagnosed with type 2 diabetes mellitus (in a phase 1 trial); and 281 people recruited for another phase 2 trial (categorized by baseline BMI and HbA1c levels). Ongoing phase 3 trials (Triumph trials) are evaluating retatrutide in obese, overweight, or type 2 diabetic individuals.

Dosage:

Retatrutide was administered as weekly subcutaneous injections in the reviewed trials. Dosages in one phase 2 trial included 1 mg, 4 mg (starting at 2 mg or 4 mg), 8 mg (starting at 2 mg or 4 mg), and 12 mg (starting at 2 mg). A phase 1 trial in type 2 diabetics used weekly 12 mg injections, and also tested 3, 6, 9, 12 mg doses. Another phase 2 trial used varying retatrutide dosages (e.g., 4 mg and greater, 12 mg). Retatrutide demonstrates dosage-dependent pharmacokinetics and a half-life of nearly 6 days, enabling weekly administration.

Study Quality Assessment:

This correspondence article is an open access publication under a Creative Commons license. The authors declare no conflict of interest, and the lead author affirms the manuscript is an honest, accurate, and transparent account. The correspondence reviews several clinical trials of retatrutide: a randomized, double-blind, placebo-controlled phase 2 study (N=338, conducted for nearly 11 months); a phase 1 randomized clinical trial (N=72); and another randomized, double-blind phase 2 trial (N=281, results at 36 weeks), all conducted in the United States. The correspondence highlights limitations of these reviewed trials, including relatively small sample sizes, geographically homogeneous populations (United States), insufficient duration to evaluate longer-term effects, and lack of long-term safety profiles and efficacy data.

All Effects:

Findings:

Retatrutide treatment for 48 weeks in adults with obesity led to substantial, dose-dependent reductions in body weight (e.g., -24.2% with 12 mg vs -2.1% with placebo at 48 weeks). The most common adverse events were dose-related gastrointestinal issues, mostly mild to moderate. Dose-dependent increases in heart rate were observed, peaking at 24 weeks and declining thereafter.

Participants:

N=338 adults who had a body-mass index (BMI) of 30 or higher or who had a BMI of 27 to less than 30 plus at least one weight-related condition. 51.8% were men.

Dosage:

Subcutaneous retatrutide (1 mg, 4 mg [initial dose, 2 mg], 4 mg [initial dose, 4 mg], 8 mg [initial dose, 2 mg], 8 mg [initial dose, 4 mg], or 12 mg [initial dose, 2 mg]) or placebo once weekly for 48 weeks.

Study Quality Assessment:

Phase 2, double-blind, randomized, placebo-controlled trial involving 338 adults, conducted for 48 weeks. Primary endpoint: percentage change in body weight from baseline to 24 weeks. Safety assessed. Funded by Eli Lilly. ClinicalTrials.gov number, NCT04881760.

All Effects: