Retatrutide (LY3437943) is an experimental peptide drug that stimulates three hormone receptors – GLP-1 (glucagon-like peptide-1), GIP (glucose-dependent insulinotropic polypeptide), and glucagon receptors – all involved in energy balance. Early human trials have found that retatrutide causes large weight losses in people with obesity pubmed.ncbi.nlm.nih.gov. For example, in a 48-week study of obese adults, the highest retatrutide dose (12 mg weekly) led to an average 24.2% body‑weight reduction versus ~2% with placebo pubmed.ncbi.nlm.nih.gov. We review the drug’s mechanism, major clinical trials, benefits (weight loss and metabolic improvements) and known risks (gastrointestinal side effects, heart effects, etc.) for a general audience, citing up-to-date research.

Mechanism of Action and Preclinical Findings

Retatrutide’s mechanism is based on combining three natural hormones. GLP-1 and GIP are gut-derived “incretin” hormones that enhance insulin secretion after meals and also act on the brain to suppress appetite. Glucagon is a pancreatic hormone that normally raises blood sugar by stimulating the liver, but it also increases energy expenditure and fat burning. By activating all three receptors at once, retatrutide reduces how much people eat and increases how many calories they burn.

In laboratory animals, this triple agonist effect proved powerful. In obese mice, a single dose of retatrutide (LY3437943) caused significant weight loss and better blood sugar control. Importantly, adding the glucagon activity to a GLP-1/GIP backbone boosted energy expenditure: “body weight loss was augmented by GCGR-mediated increases in energy expenditure” on top of the calorie-reducing effects of GLP-1 and GIP pubmed.ncbi.nlm.nih.gov. Animal studies also show retatrutide delays gastric emptying – it makes the stomach empty food more slowly – which helps people feel full longer pmc.ncbi.nlm.nih.govpmc.ncbi.nlm.nih.gov. For instance, in mice given retatrutide daily, stomach emptying slowed dose-dependently and food intake dropped sharply (greater than with semaglutide alone) pmc.ncbi.nlm.nih.gov.

On a molecular level, retatrutide is a stabilized peptide with strong activity at all three receptors (especially GIP receptors) pmc.ncbi.nlm.nih.gov. It has a long half-life (about 6 days) so it can be given once weekly and is mainly broken down by the liver pmc.ncbi.nlm.nih.gov. In short, preclinical data suggest retatrutide combines the effects of GLP-1 agonists (satiety and insulin release) with glucagon’s calorie-burning boost, leading to larger weight loss than previous drugs pubmed.ncbi.nlm.nih.govpmc.ncbi.nlm.nih.gov.

Human Clinical Trials

Phase 2 Obesity Trial (Jastreboff et al., NEJM 2023)

A landmark 48-week phase 2 trial in people with obesity (BMI ≥30, or ≥27 with weight-related conditions) tested retatrutide versus placebo pubmed.ncbi.nlm.nih.gov. This randomized, double-blind trial enrolled 338 adults and compared several weekly doses of retatrutide (1, 4, 8, or 12 mg) to placebo. The primary endpoint was percent change in body weight at 24 weeks; 48-week results were also reported.

The results were striking: at 48 weeks, average weight loss was about –8.7% (1 mg dose), –17.1% (4 mg), –22.8% (8 mg), and –24.2% (12 mg), compared to –2.1% with placebo pubmed.ncbi.nlm.nih.gov. Over 90% of people on 4 mg or higher lost at least 5% of their weight, and roughly 75–83% lost ≥15% (versus only 2% on placebo) pubmed.ncbi.nlm.nih.gov. These are among the largest weight losses ever seen in drug trials.

Importantly, metabolic markers improved alongside the weight loss. Many participants had reductions in waist size, blood pressure, triglycerides, and blood sugar. In fact, a separate analysis of the same study’s patients with fatty liver disease showed that liver fat was dramatically reduced (see below), and that insulin and triglyceride levels fell significantly nature.comnature.com. Overall, the trial concluded “substantial reductions in body weight” with retatrutide pubmed.ncbi.nlm.nih.gov.

Phase 2 Diabetes Trial (Rosenstock et al., Lancet 2023)

Another phase 2 study in adults with type 2 diabetes (average age ~56, mean BMI ~34) compared weekly retatrutide to placebo and to dulaglutide (1.5 mg, a GLP-1 drug) over 24–36 weeks pubmed.ncbi.nlm.nih.govpubmed.ncbi.nlm.nih.gov. Participants had diabetes for about 8 years and were on diet/exercise (with or without metformin). They received doses up to 12 mg retatrutide weekly (titrated up from 2–4 mg) or control treatments.

Retatrutide again showed dose-dependent benefits. At 24 weeks, higher doses lowered HbA1c (a measure of blood sugar) by about –1.9 to –2.0 percentage points (versus ~–0.01% with placebo) pubmed.ncbi.nlm.nih.gov. By 36 weeks, body weight fell up to –16.9% (for the 12 mg group) compared to only –3.0% with placebo pubmed.ncbi.nlm.nih.gov. These reductions significantly exceeded those seen with dulaglutide. In plain terms, many patients lost 10–17% of their body weight on retatrutide, a level of weight loss that also drove the larger improvements in blood sugar.

Adverse effects in this trial were largely gastrointestinal and mild-to-moderate. About 35% of retatrutide-treated patients reported nausea, vomiting, diarrhea or constipation (similar to 35% on dulaglutide) versus 13% with placebo pubmed.ncbi.nlm.nih.gov. There were no cases of severe hypoglycemia or deaths among retatrutide users in the study pubmed.ncbi.nlm.nih.gov. Overall, investigators noted “clinically meaningful improvements in glycaemic control and robust reductions in bodyweight” with retatrutide pubmed.ncbi.nlm.nih.gov, with a safety profile similar to existing GLP-1 drugs.

Fatty Liver (MASLD) Trial (Sanyal et al., Nat. Med. 2024)

Retatrutide’s effects on liver fat and related markers were tested in patients with obesity and metabolic-associated steatohepatitis (MASLD). In a substudy of the above obesity trial, 98 adults with ≥10% liver fat were randomized to 48 weeks of retatrutide (1, 4, 8, or 12 mg) or placebo pubmed.ncbi.nlm.nih.gov. The main goal was change in liver fat at 24 weeks, measured by MRI.

Results showed dramatic liver improvements. At 24 weeks, mean liver fat fell by –42.9% (1 mg), –57.0% (4 mg), –81.4% (8 mg), and –82.4% (12 mg) versus essentially no change (+0.3%) with placebo pubmed.ncbi.nlm.nih.gov. In other words, most of the fat was gone. By that time, 86% of the 12 mg group and 79% of the 8 mg group achieved normal liver fat (<5%) pubmed.ncbi.nlm.nih.gov. These improvements were strongly linked to weight loss: nearly maximal liver fat reductions occurred once body weight had dropped by ~20% nature.com.

Retatrutide also produced broad metabolic benefits in this study. Patients treated with ≥4 mg had much lower fasting insulin and C-peptide (markers of insulin resistance) at 24 and 48 weeks nature.com. Insulin resistance scores (HOMA-IR) fell by over 50–70% on higher doses nature.com. Blood triglycerides and the hormone leptin dropped, while adiponectin (a beneficial fat hormone) rose nature.com. These changes reflect healthier metabolism: better insulin sensitivity and improved lipid profiles accompanied the weight loss. Importantly, retatrutide caused no liver toxicity in these patients over 48 weeks nature.com. In summary, retatrutide not only greatly reduced weight but also cleared fat from the liver and improved blood sugar and fat markers in people with fatty liver disease pubmed.ncbi.nlm.nih.govnature.com.

Observed Benefits

Across studies, retatrutide’s benefits are clear. The main advantage is large, sustained weight loss – averaging 15–25% of body weight on the higher doses (weeks-months) pubmed.ncbi.nlm.nih.govpubmed.ncbi.nlm.nih.gov. This loss exceeds that seen with earlier drugs (for example, semaglutide and tirzepatide produce ~15–20% in similar trials). In addition, retatrutide consistently improved metabolic health: lowering blood pressure, blood sugar (HbA1c), and fasting insulin, and improving cholesterol and triglycerides nature.comnature.com. Patients’ waist sizes shrank and body fat (both visceral and subcutaneous) was greatly reduced in imaging studies nature.comnature.com. In practice, many subjects moved from obese to overweight categories or even normal BMI, and patients with fatty liver often returned to normal liver fat content pubmed.ncbi.nlm.nih.gov.

Other observed benefits include improved markers of liver and kidney health. For example, in animal studies retatrutide reduced signs of liver inflammation and steatohepatitis pmc.ncbi.nlm.nih.gov. In the clinical trials, liver enzymes (ALT/AST) tended to fall (reflecting less fatty liver stress), and in a mouse model of diabetic kidney disease, retatrutide improved kidney markers more than liraglutide or tirzepatide pmc.ncbi.nlm.nih.gov. These findings suggest that besides weight loss, retatrutide may help reverse obesity‑related organ damage.

For a layperson, the key takeaway is that retatrutide has shown unprecedented weight-loss effects in trials, along with major improvements in blood sugar, blood fats, and liver fat. It acts on appetite centers to reduce hunger and slows digestion (like GLP-1 drugs) while also increasing metabolic rate (via the glucagon effect), so it tackles obesity on multiple fronts pubmed.ncbi.nlm.nih.govpmc.ncbi.nlm.nih.gov.

Risks and Side Effects

No medication is without side effects, and retatrutide’s safety profile largely mirrors that of other drugs in its class, with some unique considerations. The most common side effects are gastrointestinal. Many patients experience nausea, vomiting, diarrhea, or constipation, especially after dose increases pubmed.ncbi.nlm.nih.govpubmed.ncbi.nlm.nih.gov. These symptoms tend to be mild or moderate and often lessen over time or with dose adjustments. For example, the obesity trial reported that GI events were dose-dependent and “mostly mild to moderate in severity”, and starting at a lower dose helped reduce them pubmed.ncbi.nlm.nih.gov. In the diabetes trial, about one-third of patients on retatrutide reported nausea or similar issues (comparable to rates on dulaglutide) pubmed.ncbi.nlm.nih.gov. Some people may discontinue treatment due to these effects (for context, clinical experience with GLP-1 drugs shows up to 20–50% drop-out in the first year).

A small heart rate increase is another known effect. Retatrutide tends to raise pulse by a few beats per minute in a dose-related way pubmed.ncbi.nlm.nih.gov. In the obesity study, heart rate increases peaked around 24 weeks and then decreased, and no dangerous arrhythmias were reported. This mild tachycardia is a class effect of GLP-1 agonists and is generally not considered harmful in healthy patients. (In fact, weight loss itself usually lowers blood pressure and improves overall heart health nature.com.)

Because retatrutide contains a glucagon component, there was theoretical concern about blood sugar spikes or ketoacidosis, but trials have not seen serious problems. No patients on retatrutide had severe hypoglycemia pubmed.ncbi.nlm.nih.gov, and rises in ketone bodies (β-hydroxybutyrate) were noted but no cases of diabetic ketoacidosis were reported nature.com. Liver safety appears good: extensive testing during the trials showed no evidence of drug-induced liver injury after nearly a year of treatment nature.com.

Some less common issues noted include temporary elevations in liver enzymes (ALT/AST) and minor injection-site reactions or skin sensitivity pmc.ncbi.nlm.nih.gov. There was a report of a few serious adverse events (two people in the liver study had serious events), but these were rare and not clearly related to the drug. Overall, the safety profile is “consistent with GLP-1 receptor agonists”pubmed.ncbi.nlm.nih.gov: mainly gut symptoms and small vital-sign changes, with no new alarms.

An important long-term risk to consider (inherited from the GLP-1 drug class) is gallbladder disease. Rapid weight loss can lead to gallstones, and GLP-1 agonists have been linked to a 1.3–2.3-fold higher risk of gallbladder problems (stones, cholecystitis) in trials pubmed.ncbi.nlm.nih.gov. Retatrutide’s potent weight loss suggests a similar risk. Patients starting this therapy should be aware of gallstone symptoms (pain after fatty meals) and doctors may monitor gallbladder health.

Lastly, all new weight-loss drugs carry theoretical long-term unknowns. For GLP-1–based drugs, animal studies showed thyroid C-cell tumors (in rodents), so use is contraindicated in people with medullary thyroid cancer or MEN2 syndrome. No cases have been seen in humans yet, but retatrutide shares the GLP-1 and glucagon pathways, so regulatory agencies will watch for any rare effects with extended use. Current trials did not last long enough to detect very rare events, so ongoing phase 3 trials (TRIUMPH program) will further evaluate safety.

In summary, common risks of retatrutide include gastrointestinal upset and a slight heart rate increase pubmed.ncbi.nlm.nih.govpubmed.ncbi.nlm.nih.gov. These are generally manageable and similar to those of existing drugs for obesity. There were no deaths or severe hypoglycemias in trials pubmed.ncbi.nlm.nih.gov. Less common risks include gallstones (a known class effect) pubmed.ncbi.nlm.nih.gov and transient liver enzyme rises pmc.ncbi.nlm.nih.gov. Overall, the adverse effects must be weighed against the substantial benefits; according to the trials, “retatrutide showed clinically meaningful improvements in glycaemic control and robust reductions in bodyweight, with a safety profile consistent with GLP-1 receptor agonists”pubmed.ncbi.nlm.nih.gov.

Conclusion

Retatrutide is a promising new obesity treatment that works by activating three hormone pathways to reduce appetite and boost metabolism. In phase 2 clinical trials, it produced unprecedented weight loss (up to ~25% of body weight) and marked improvements in blood sugar, blood fats, and liver fatpubmed.ncbi.nlm.nih.govpubmed.ncbi.nlm.nih.gov. These effects could translate into major health gains for people with obesity and diabetes. The side effects appear generally similar to existing GLP-1 drugs – mostly gastrointestinal and mild – though careful long-term study is still needed. If future phase 3 trials confirm these benefits and clarify safety, retatrutide could become a powerful tool against obesity. As always, patients and doctors should balance the benefits of weight loss against the known risks, and continue to monitor for any emerging issues with this novel therapy.

Sources: Published human trials and studies of retatrutide and related drugs pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov nature.com pubmed.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov, as well as reviews of GLP-1/GIP/glucagon triple agonists. All findings are drawn from peer-reviewed medical literature and official trial reports.