What is retatrutide
Retatrutide is an experimental peptide drug developed by Eli Lilly. It is a triple receptor agonist: it activates three hormonal receptors involved in metabolism and appetite regulation:
- GLP-1 receptor (Glucagon-Like Peptide-1),
- GIP receptor (Glucose-Dependent Insulinotropic Polypeptide),
- Glucagon receptor (GCGR).
The idea is that combining signaling through these three receptors can yield greater weight loss and metabolic benefit than targeting one or two alone. New England Journal of Medicine+2PubMed+2
It has a pharmacokinetic profile that supports once-weekly dosing. New England Journal of Medicine+1
Mechanism of action — how it helps with weight loss
Here are the major ways retatrutide is thought to drive weight loss and metabolic improvements:
- Reduced appetite / food intake
GLP-1 and GIP receptor activation (as with other incretin drugs) tend to reduce appetite, slow gastric emptying, and increase satiety. People taking retatrutide report decreased feelings of hunger, lower prospective food consumption, etc. PubMed+2PubMed+2 - Increased energy expenditure
Activation of the glucagon receptor component can increase basal metabolic rate (or energy use), helping burn more calories even at rest. This is not as strong as the appetite effect but may provide additional “push.” New England Journal of Medicine+1 - Improved metabolic parameters
Better control of glucose, insulin, lipids, body-fat distribution, etc., which often accompany weight loss but also may be independently beneficial. New England Journal of Medicine+2PubMed+2 - Behavioural / appetite changes
Higher doses are associated with greater suppression of hunger, less disinhibition (e.g. less likelihood of overeating), and increased dietary restraint. These subjective effects are correlated with greater weight loss. PubMed
What the clinical trials show
Several key studies have examined retatrutide. Here are findings from Phase 1, Phase 2, and systematic reviews as of mid-2024:
| Study / Trial | Population | Duration | Dose(s) | Weight Loss Results | Other Findings / Notes |
|---|---|---|---|---|---|
| Phase 2 trial in obesity/overweight without diabetes (NCT04881760) | 338 adults with obesity or overweight (no type 2 diabetes) New England Journal of Medicine+2PubMed+2 | 48 weeks | 1 mg, 4 mg, 8 mg, 12 mg weekly doses (with some dose-escalation schemes) New England Journal of Medicine+1 | At 24 weeks: mean weight change from baseline: −7.2% (1 mg) to ~−17.5% (12 mg). At 48 weeks: up to −24.2% with the 12 mg dose. New England Journal of Medicine+2Lilly Investor Relations+2 | Dose-dependent side effects (mainly GI), heart rate increases peaked around 24 weeks then declined. Participants hadn’t fully plateaued at 48 weeks, suggesting longer durations might yield even more weight loss. Improvements in metabolic markers (blood pressure, lipids, glucose, etc.). New England Journal of Medicine+2Lilly Investor Relations+2 |
| Phase 1b / type 2 diabetes proof-of-concept | People with type 2 diabetes, BMI 23-50 kg/m², etc. PubMed+1 | 12 weeks | Ascending multiple doses (e.g. up to 12 mg) PubMed | In the highest dose group, placebo-adjusted weight loss ~10% (≈8.96 kg) at 12 weeks. New England Journal of Medicine+1 | Also improvements in glycemic control, safety tolerability similar to other incretin-based therapies. PubMed |
| Appetite / eating behaviour sub-study (in T2D) | Adults with type 2 diabetes, at various retatrutide doses, placebo, or comparison with dulaglutide PubMed | 24-36 weeks | 0.5, 4, 8, 12 mg vs placebo or dulaglutide PubMed | Higher doses (≥4 mg) showed greater reductions in self-reported appetite, hunger, and prospective food consumption; greater disinhibition; greater dietary restraint at higher doses. Weight loss correlated with these appetite / behaviour changes. PubMed | Provides insight into psychological appetite control mechanisms, not just physical hormonal effects. |
| Meta-analysis | 3 RCTs, 640 patients (510 on retatrutide) with overweight, obesity and/or T2D ScienceDirect | Up to ~48 weeks in included trials | Once-weekly, various doses | On average, ~10.66 kg weight loss vs placebo; BMI and waist circumference also significantly reduced. Large increases in the proportion achieving ≥5, ≥10, ≥15, ≥20% weight loss compared to placebo. ScienceDirect | Side effects mostly mild to moderate, especially gastrointestinal. Some hypersensitivity. Longer-term safety and head-to-head comparisons with other agents still pending. |
Safety profile & adverse effects
Retatrutide so far appears to have a safety and side-effect profile broadly similar to GLP-1 and dual agonist drugs (like GLP-1/GIP), with some considerations:
- Gastrointestinal (GI) side effects are the most common: nausea, vomiting, diarrhea, constipation. These are often dose-related and more frequent during dose escalation. New England Journal of Medicine+1
- Increase in heart rate: There are dose-dependent increases in heart rate, peaking around mid-trial (~24 weeks) then declining somewhat. The long-term cardiovascular implications are still under study. New England Journal of Medicine+1
- Other metabolic effects are generally favorable (improved glucose / lipid markers), but potential off-target or longer-term effects (on liver, pancreatic function, potential for hypoglycemia, etc.) need monitoring.
- Inter-individual variability: Not everyone responds equally. Factors like baseline BMI, sex, perhaps genetics, and other comorbid conditions may influence responsiveness. New England Journal of Medicine+1
How retatrutide compares with other weight loss treatments
While direct head-to-head trials are still limited, some comparisons can be made indirectly:
- The weight losses seen in the Phase 2 retatrutide trial (up to ~24-25% at 48 weeks in highest doses) are higher than many GLP-1 monotherapy trials (often ~15% or less over comparable durations) and even dual agonists in many cases. New England Journal of Medicine+1
- Retatrutide’s triple agonist action (adding glucagon receptor activation) may allow additional benefit in energy expenditure, not just suppression of appetite.
- However, effectiveness must be balanced with tolerability, patient preference, cost, route of administration, etc.
What is still unknown / uncertain
Here are key areas where more data are needed:
- Long-term safety
Effects over multiple years, especially cardiovascular, hepatic, pancreatic, gallbladder, etc., are not yet fully characterized. - Durability & plateauing
In the Phase 2 trial, weight loss was still ongoing at 48 weeks (i.e. did not fully plateau) in many participants; but how long that continues, and when/if weight regain occurs, is being studied. New England Journal of Medicine - Effect in various populations
How well it works (and safety profile) in people with type 2 diabetes, different ethnic groups, older age, kidney/liver impairment, etc. Some data already there, but not comprehensive. - Head-to-head comparisons
Particularly vs established weight loss medications like semaglutide, tirzepatide, etc. To know relative efficacy, side-effects, and cost/benefit. - Optimal dosing, titration / escalation regimens
The Phase 2 trial used multiple dose levels and different starting doses. Figuring out the best way to start, increase, and possibly maintain dose will matter for tolerability and maximizing benefit. - Real-world effectiveness
Clinical trial populations are selected and closely managed. What happens in broader clinical practice, adherence, insurance coverage, etc., will influence how useful it becomes.
Key references for further reading
Here are some important studies / reviews on retatrutide, many available on PubMed:
- Triple-Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial., NEJM, 2023. DOI: 10.1056/NEJMoa2301972 — PubMed entry: [pmid 37312005] New England Journal of Medicine
- LY3437943, a novel triple agonist peptide at GCGR, GIPR, and GLP-1R: from discovery to clinical proof of concept. — PubMed: [pmid 35985340] PubMed
- Phase 1b trial in people with type 2 diabetes. — PubMed: [pmid 36354040] PubMed
- Appetite, eating attitudes, and eating behaviours during treatment with retatrutide in adults with type 2 diabetes. — PubMed: [pmid 40916752] PubMed
- Retatrutide showing promise in obesity (and type 2 diabetes) — expert opinion / review article. PubMed
