The obesity medicine landscape continues to evolve at a remarkable pace. For patients in Los Angeles exploring their weight loss options, staying informed about emerging therapies is an important part of the journey. One investigational medication generating significant attention in the bariatric community is retatrutide, a novel triple-agonist therapy that recently delivered impressive Phase 3 trial results.
As a Johns Hopkins-trained bariatric surgeon, Dr. Sepehr Lalezari of Lalezari Surgical believes in keeping patients educated about the latest developments in obesity treatment. Here’s what you need to know about retatrutide and the recently published clinical data.
Understanding Retatrutide: A First-in-Class Approach
Retatrutide represents a new class of obesity medication currently under investigation by Eli Lilly. Unlike existing GLP-1 receptor agonists such as semaglutide (Wegovy/Ozempic) or dual-agonist medications like tirzepatide (Zepbound/Mounjaro), retatrutide activates three distinct hormone receptors simultaneously.
This triple-agonist mechanism targets:
- Glucagon-Like Peptide-1 (GLP-1): Reduces appetite and slows gastric emptying
- Glucose-Dependent Insulinotropic Polypeptide (GIP): Enhances insulin secretion and may influence fat metabolism
- Glucagon: Increases energy expenditure and promotes fat breakdown
The theory behind this approach is that engaging all three metabolic pathways simultaneously may produce more substantial effects on body weight than single or dual-agonist therapies. However, it’s important to emphasize that retatrutide remains investigational and has not yet received FDA approval.
The TRIUMPH-4 Trial: Key Findings
In December 2025, Eli Lilly announced positive topline results from TRIUMPH-4, the first Phase 3 clinical trial to complete in the company’s broader TRIUMPH program. This 68-week study enrolled 445 participants with obesity or overweight who also had knee osteoarthritis but did not have diabetes.
The trial evaluated two doses of retatrutide (9 mg and 12 mg) administered via once-weekly subcutaneous injection, combined with healthy diet and physical activity recommendations.
Primary Weight Loss Outcomes
Among participants who remained on the study medication throughout the trial:
- 12 mg Dose: Average weight loss of 28.7% of body weight (approximately 71 pounds)
- 9 mg Dose: Average weight loss of 26.4% of body weight (approximately 64 pounds)
- Placebo Group: Weight loss of just 2.1%
When analyzing all participants regardless of whether they completed the study, the highest dose group still achieved average weight loss of 23.7%. These results represent some of the most significant weight reduction seen in late-stage clinical trials to date.
Beyond the Scale: Additional Health Improvements
The TRIUMPH-4 trial also demonstrated meaningful improvements in several cardiometabolic markers:
- Systolic Blood Pressure: Reduced by up to 14 mmHg at the highest dose
- Non-HDL Cholesterol: Significant reductions observed
- Triglycerides: Notable decreases across treatment groups
- High-Sensitivity C-Reactive Protein (hsCRP): Meaningful reduction, suggesting lower inflammation
For participants with knee osteoarthritis, the trial showed substantial pain relief, with WOMAC pain scores improving by approximately 75%. More than one in eight patients treated with retatrutide reported being completely free of knee pain by week 68.
Side Effects and Safety Considerations
Like other incretin-based therapies, retatrutide’s most common side effects were gastrointestinal in nature:
- Nausea: Reported in approximately 43% of participants
- Diarrhea: Observed in about 33% of participants
- Vomiting: Occurred in roughly 21% of participants
- Constipation and Decreased Appetite: Also frequently reported
These symptoms were generally described as mild to moderate and often improved over time as the body adjusted to the medication.
One notable finding from TRIUMPH-4 was the emergence of a side effect called dysesthesia, an abnormal sensation affecting touch perception that can cause numbness, tingling, or unusual sensitivity. This occurred in 8.8% of participants on the 9 mg dose and 20.9% on the 12 mg dose, compared to just 0.7% with placebo. While these events were typically mild and rarely led to discontinuation, this signal warrants close monitoring in future trials.
Discontinuation rates in the trial ranged from 12% to 18% in the retatrutide groups compared to 4% with placebo. Interestingly, some participants discontinued treatment because they perceived their weight loss as excessive, highlighting the potency of this therapy.
What This Means for Patients
While these results are encouraging for the future of obesity medicine, Dr. Lalezari emphasizes the importance of maintaining realistic expectations. Retatrutide is still an investigational therapy with several important caveats:
- Not Yet FDA-Approved: Regulatory approval, if granted, is not expected before 2027
- More Data Needed: Seven additional Phase 3 trials are expected to complete throughout 2026, evaluating retatrutide in type 2 diabetes, obstructive sleep apnea, cardiovascular outcomes, and other conditions
- Long-Term Effects Unknown: Extended studies are needed to understand the medication’s durability and safety over many years
For Los Angeles patients considering weight loss options today, proven treatments remain available. Medical weight loss programs utilizing FDA-approved medications like semaglutide and tirzepatide continue to offer meaningful results for appropriate candidates. For patients requiring more significant intervention, bariatric surgery procedures such as sleeve gastrectomy, gastric bypass, and endoscopic options provide well-established paths to substantial, sustained weight loss.
The Evolving Treatment Landscape
The retatrutide data underscores an exciting truth: obesity medicine is advancing rapidly. The field has moved far beyond simply recommending diet and exercise, with an expanding toolkit of evidence-based interventions tailored to individual patient needs.
Dr. Lalezari approaches each patient’s weight loss journey with a comprehensive perspective, considering medical history, health goals, and the full spectrum of available treatments. Whether a patient is a candidate for medication, procedural intervention, or bariatric surgery, the goal remains the same: achieving lasting health improvements that enhance quality of life.
As new therapies like retatrutide progress through clinical development, patients can feel confident that their weight loss team is staying current with the science and prepared to incorporate proven advances into their care.
Take the Next Step Toward Your Health Goals at Lalezari Surgical
Navigating the evolving world of weight loss treatment can feel overwhelming. Dr. Sepehr Lalezari and the team at Lalezari Surgical in Los Angeles are here to help you understand your options and develop a personalized treatment plan based on the best available evidence.
Whether you’re interested in learning more about current medical weight loss options, exploring non-surgical procedures, or discussing bariatric surgery, we’re ready to guide you on your journey to better health. Contact Lalezari Surgical today at (213) 545-1656 or schedule your consultation online to get started.
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