Retatrutide

Investigational once-weekly GIP, GLP-1 and glucagon receptor agonist studied for obesity and related metabolic diseases

Retatrutide

Retatrutide
Routes	Subcutaneous injection
Pregnancy category	Safety has not been established
Legal status	Investigational; not FDA-approved

Retatrutide (developmental designation LY3437943) is an investigational, once-weekly injectable peptide being developed by Eli Lilly and Company for the treatment of obesity, overweight and several related cardiometabolic diseases. It is commonly described as a triple-receptor agonist because a single molecule activates the receptors for:

• Glucose-dependent insulinotropic polypeptide (GIP);
• Glucagon-like peptide-1 (GLP-1); and
• Glucagon.

This three-receptor mechanism distinguishes retatrutide from single-receptor GLP-1 receptor agonists such as semaglutide and from the dual GIP/GLP-1 receptor agonist tirzepatide.

Clinical studies have reported substantial average reductions in body weight, improvements in glycemic control and changes in several metabolic risk factors. These findings are promising, but they do not establish that retatrutide is safe or effective for routine clinical use. Regulatory review, peer-reviewed publication of completed Phase 3 studies and longer-term safety evaluation remain necessary.

For medically supervised, currently available weight-management options, patients may visit the W8MD retatrutide and weight-loss information page.

Names and terminology

Retatrutide has been identified by several names:

• Retatrutide – its nonproprietary name;
• LY3437943 – the Eli Lilly developmental code;
• Triple agonist – a reference to its three receptor targets;
• GIP/GLP-1/glucagon receptor agonist – the scientifically descriptive drug class; and
• Triple G – an informal term sometimes used in news and social-media coverage.

Retatrutide is not a “GLP-3” medication. There is no established hormone or receptor class called GLP-3 in this context. The drug acts on three separate receptors: GIP, GLP-1 and glucagon.

Chemical structure

Retatrutide is a synthetic, acylated peptide engineered to retain activity at three metabolically important receptors. Its peptide backbone contains modified amino-acid residues intended to improve stability and receptor activity.

A fatty-diacid side chain promotes reversible binding to albumin. This delays clearance from the circulation and supports the once-weekly administration schedule evaluated in clinical trials. Structural modifications also reduce rapid enzymatic degradation, including degradation associated with dipeptidyl peptidase-4.

Retatrutide should not be described simply as a 31-amino-acid GLP-1 analogue. It is a more extensively engineered peptide whose pharmacologic profile combines GIP-, GLP-1- and glucagon-receptor activity.

Mechanism of action

Retatrutide is designed to influence food intake, glucose regulation and energy metabolism through complementary receptor pathways.

GLP-1 receptor activation

Activation of the GLP-1 receptor may:

• increase glucose-dependent insulin secretion;
• reduce inappropriate glucagon secretion when blood glucose is elevated;
• slow gastric emptying, particularly during early treatment;
• increase satiety;
• reduce hunger and food noise; and
• lower overall energy intake.

Because insulin stimulation is glucose-dependent, GLP-1 receptor activation by itself is generally associated with less hypoglycemia than medications that stimulate insulin independently of glucose. Hypoglycemia may nevertheless occur when incretin-based drugs are combined with insulin or a sulfonylurea.

GIP receptor activation

Glucose-dependent insulinotropic polypeptide is an incretin hormone released after food intake. GIP-receptor activation may contribute to:

• glucose-dependent insulin secretion;
• metabolic signaling in adipose tissue;
• regulation of nutrient handling; and
• interactions with central appetite pathways.

The precise contribution of GIP activity to long-term weight loss remains an area of continuing research.

Glucagon receptor activation

Activation of the glucagon receptor is the principal mechanism that distinguishes retatrutide from tirzepatide. Glucagon-receptor activity may:

• increase energy expenditure;
• promote mobilization and oxidation of stored fat;
• affect liver-fat metabolism; and
• complement appetite reduction produced through GLP-1 and GIP pathways.

Glucagon can also increase hepatic glucose production. Retatrutide was therefore engineered to balance glucagon-receptor activity with the glucose-lowering effects of GIP and GLP-1 receptor activation.

Retatrutide compared with other medications

Medication	Receptor activity	Regulatory status in the United States	Administration
Semaglutide	GLP-1 receptor agonist	FDA-approved formulations are available for specific diabetes, obesity and cardiovascular-risk indications	Weekly injection; an oral formulation is approved for certain diabetes indications
Tirzepatide	GIP and GLP-1 receptor agonist	FDA-approved under different brand names for specific diabetes and chronic weight-management indications	Weekly injection
Retatrutide	GIP, GLP-1 and glucagon receptor agonist	Investigational; not FDA-approved	Weekly injection in clinical trials

Results from separate studies suggest that retatrutide may produce numerically greater average weight reduction than that reported in some trials of semaglutide or tirzepatide. Such cross-trial comparisons have important limitations because the studies may differ in participant characteristics, duration, dose escalation, withdrawal rates and statistical methods.

It is therefore not scientifically appropriate to claim that retatrutide has been conclusively proven superior to tirzepatide based only on separate trials. The Phase 3 TRIUMPH-5 study is designed to compare retatrutide directly with tirzepatide in adults with obesity.

Clinical development

Phase 2 obesity trial

A randomized Phase 2 trial published in The New England Journal of Medicine evaluated retatrutide in adults with obesity or overweight and at least one weight-related condition, excluding participants with diabetes.

At 48 weeks, reported mean weight changes included:

Study group	Mean body-weight change at 48 weeks
Retatrutide 1 mg	Approximately −8.7%
Retatrutide 4 mg	Approximately −17.1% to −18.1%, depending on escalation regimen
Retatrutide 8 mg	Approximately −22.8%
Retatrutide 12 mg	Approximately −24.2%
Placebo	Approximately −2.1%

Weight loss had not clearly reached a plateau in some higher-dose groups at the end of the 48-week study. The trial was not large or long enough to define uncommon adverse effects or establish long-term clinical outcomes.

Phase 2 type 2 diabetes trial

A separate Phase 2 study in people with type 2 diabetes found reductions in hemoglobin A1c and body weight. The findings supported continued study of retatrutide for glycemic and weight management, but retatrutide remains unapproved for diabetes treatment.

TRIUMPH Phase 3 program

The TRIUMPH clinical-development program evaluates retatrutide in obesity and several obesity-related conditions. Study populations include people with:

• Obesity or overweight with weight-related complications;
• Type 2 diabetes;
• Cardiovascular disease;
• Knee osteoarthritis;
• Obstructive sleep apnea;
• Metabolic dysfunction-associated steatotic liver disease;
• Chronic kidney disease; and
• Obesity-associated chronic low-back pain.

TRIUMPH-1 topline results

In May 2026, Eli Lilly announced topline results from the pivotal TRIUMPH-1 obesity trial. In the efficacy estimand at 80 weeks, the company reported average weight changes of approximately:

Assigned dose	Mean weight change	Approximate mean weight reduction
Retatrutide 4 mg	−19.0%	47.2 lb
Retatrutide 9 mg	−25.9%	64.4 lb
Retatrutide 12 mg	−28.3%	70.3 lb
Placebo	−2.2%	Not applicable

At the 12 mg dose, 45.3% of participants reportedly achieved at least 30% body-weight reduction. In an extension involving participants with a baseline body mass index of 35 or higher, the highest-dose group reportedly achieved an average reduction of approximately 30.3% at 104 weeks.

These results were announced by the manufacturer as topline findings. Interpretation should consider the complete peer-reviewed data, treatment discontinuations, missing-data methods and longer-term safety findings when those details become available.

Effects on body composition and muscle

Weight loss generally consists of reductions in both fat mass and lean body mass. A retatrutide body-composition substudy found a substantial reduction in total fat mass. However, the proportion of weight lost as lean mass was broadly similar to that observed with other obesity treatments.

Retatrutide has not been proven to prevent muscle wasting, treat sarcopenia or selectively preserve skeletal muscle. Claims that it “builds muscle” or prevents muscle loss are not supported by current clinical evidence.

During any substantial medical weight-loss program, clinicians may recommend:

• adequate dietary protein;
• individualized resistance training;
• evaluation for nutritional deficiencies;
• monitoring of strength and physical function;
• assessment of body composition when clinically useful; and
• adjustment of the weight-loss target in older or medically vulnerable patients.

Potential benefits under investigation

Retatrutide is being studied for several possible benefits, including:

• clinically significant weight reduction;
• reduction in waist circumference and visceral fat;
• improved blood glucose and hemoglobin A1c;
• improved insulin resistance;
• reduced liver fat;
• improvement in triglycerides and other cardiometabolic markers;
• improvement in obesity-related sleep apnea;
• reduction in weight-related knee osteoarthritis symptoms; and
• possible cardiovascular and kidney benefits.

A favorable change in a biomarker does not necessarily establish prevention of heart attack, stroke, kidney failure or death. Dedicated outcome trials are needed to evaluate these questions.

Adverse effects

The safety profile of retatrutide is still being established. The most frequently reported adverse effects in clinical trials have involved the gastrointestinal system.

Commonly reported effects

• Nausea;
• Diarrhea;
• Vomiting;
• Constipation;
• decreased appetite;
• abdominal discomfort; and
• indigestion.

Gastrointestinal effects have generally been more frequent at higher doses and during dose escalation.

Other observed or potential concerns

Reported or clinically relevant areas of monitoring include:

• increased resting heart rate;
• altered skin sensation or dysesthesia;
• excessive or overly rapid weight loss;
• dehydration and electrolyte abnormalities;
• loss of lean body mass;
• gallbladder disease;
• possible pancreatitis;
• kidney injury associated with severe vomiting or dehydration; and
• hypoglycemia when combined with insulin or insulin-secretagogue medications.

Because retatrutide is investigational, contraindications, boxed warnings, drug interactions and monitoring requirements have not been finalized in an FDA-approved prescribing label.

Investigational dosing

Clinical trials have evaluated once-weekly subcutaneous doses, generally using gradual dose escalation to improve gastrointestinal tolerability. Target doses in late-stage trials have included 4 mg, 9 mg and 12 mg.

These are research protocols, not prescribing instructions. There is no FDA-approved retatrutide dose, commercial pen, dosing schedule or patient-use instruction. Patients should not attempt to reproduce trial dosing with products obtained online.

Pregnancy and reproductive considerations

Intentional weight loss is generally not recommended during pregnancy. The developmental and reproductive safety of retatrutide has not been established.

People who are pregnant, planning pregnancy or breastfeeding should not use products represented as retatrutide outside an authorized study. Trial participants should follow the study protocol concerning contraception, pregnancy testing and discontinuation.

Availability and legal status

As of August 2026:

• Retatrutide has not been approved by the FDA;
• no FDA-approved retatrutide brand or generic exists;
• authentic retatrutide is legally available only through authorized Eli Lilly clinical trials;
• a clinician cannot prescribe commercial retatrutide;
• retatrutide cannot lawfully be used in compounding under current federal law; and
• products marketed directly to consumers as compounded, generic or research retatrutide should not be assumed to contain authentic retatrutide.

The FDA specifically warns that retatrutide is not a component of an FDA-approved drug and cannot be used in compounding under federal law. The agency has issued warning letters concerning unlawful marketing of products represented as retatrutide.

Clinical-trial access

Patients interested in legitimate retatrutide research may search:

• ClinicalTrials.gov retatrutide studies; and
• Lilly clinical trials.

Trial participation depends on study location, recruitment status and eligibility criteria. Participants may receive retatrutide, placebo or another comparator, depending on the protocol. Enrollment does not guarantee assignment to retatrutide or a specific clinical outcome.

See also

• Anti-obesity medication
• GLP-1 receptor agonist
• Glucose-dependent insulinotropic polypeptide
• Glucagon
• Semaglutide
• Tirzepatide
• Liraglutide
• Orforglipron
• CagriSema
• Obesity
• Type 2 diabetes
• Insulin resistance
• Metabolic syndrome
• Body composition
• Visceral fat
• Sarcopenic obesity
• Medical weight loss
• GLP-1 prior authorization
• Insurance GLP-1 shots
• GLP-1 weight loss shots NYC
• GLP-1 shots Philadelphia

External links

• Eli Lilly: What to know about retatrutide
• ClinicalTrials.gov: Retatrutide studies
• FDA: Concerns with unapproved GLP-1 drugs used for weight loss
• PubMed: Triple-hormone-receptor agonist retatrutide for obesity
• PubMed: Retatrutide in people with type 2 diabetes
• PubMed: Effects of retatrutide on body composition
• ClinicalTrials.gov: TRIUMPH-5 retatrutide versus tirzepatide
• W8MD: Retatrutide information and medical weight-management options

References

1. Jastreboff AM, et al. Triple-Hormone-Receptor Agonist Retatrutide for Obesity. New England Journal of Medicine. 2023.
2. Rosenstock J, et al. Retatrutide, a GIP, GLP-1 and glucagon receptor agonist, for people with type 2 diabetes. The Lancet. 2023.
3. Coskun T, et al. Effects of retatrutide on body composition in people with type 2 diabetes. The Lancet Diabetes & Endocrinology. 2025.
4. Eli Lilly and Company. TRIUMPH-1 Phase 3 topline results. May 21, 2026.
5. U.S. Food and Drug Administration. FDA’s concerns with unapproved GLP-1 drugs used for weight loss. Accessed August 2026.
6. ClinicalTrials.gov. TRIUMPH-5: Retatrutide compared with tirzepatide.
7. Li W, et al. Structural insights into triple agonism at GLP-1R, GIPR and GCGR. Cell Discovery. 2024.