Retatrutide Side Effects: What the Clinical Data Shows

Overview

Retatrutide (LY3437943) is an investigational triple-agonist peptide targeting GIP, GLP-1, and glucagon receptors. As with other incretin-based therapies, gastrointestinal side effects represent the most frequently reported adverse events in clinical trials. The Phase 2 trial data published in 2023 provides the most detailed safety information currently available, though ongoing Phase 3 trials (the TRIUMPH program) will offer a more comprehensive picture of retatrutide's long-term safety profile. Because retatrutide activates three hormone receptors rather than one or two, its side effect profile shares features with existing GLP-1 agonists while also introducing considerations unique to glucagon receptor activation — particularly regarding hepatic metabolism and energy expenditure. This article summarizes what the published clinical evidence shows about retatrutide safety and tolerability, organized by system and severity.

Common Gastrointestinal Side Effects

Gastrointestinal adverse events were the most frequently reported side effects across all retatrutide dose groups in the Phase 2 obesity trial. Nausea occurred in approximately 16–34% of participants depending on the dose level, making it the single most common complaint. Diarrhea was reported in 16–22% of participants, vomiting in 9–19%, and constipation in approximately 12–16%. Decreased appetite — which is both a therapeutic effect and a reported adverse event — was also common across dose groups. These GI symptoms were most frequent during the dose titration phase, when the body is adjusting to increasing levels of receptor activation. In most participants, GI side effects tended to diminish in frequency and severity as the maintenance dose was reached and sustained. This pattern is consistent with the tolerability profile observed with other GLP-1 receptor agonists such as semaglutide and tirzepatide, though retatrutide's top-dose GI rates appear slightly higher — possibly reflecting the additional glucagon receptor activation. It is worth noting that the majority of GI events were classified as mild to moderate in severity, and relatively few participants discontinued treatment solely because of gastrointestinal symptoms.

Side Effects by Dose Group

The Phase 2 trial evaluated retatrutide at maintenance doses of 1 mg, 4 mg, 8 mg, and 12 mg, revealing a clear dose-dependent pattern in adverse event rates. The 4 mg dose group experienced lower rates of GI side effects overall, with nausea and vomiting rates closer to the lower end of the reported ranges. The 8 mg group showed moderate GI event rates, while the 12 mg group — which also produced the greatest weight loss — had the highest incidence of gastrointestinal symptoms. Treatment discontinuation due to adverse events was approximately 6% in the 12 mg group compared to roughly 4% in the placebo arm. This dose-dependent relationship supports the clinical rationale for gradual titration: the Phase 2 protocol started all participants at 0.5 mg weekly and increased the dose monthly, allowing the body to acclimate before reaching higher maintenance levels. For individuals and clinicians considering retatrutide (pending regulatory approval), these data suggest that slower titration schedules may meaningfully reduce the burden of side effects, particularly at the higher doses associated with the greatest efficacy.

Cardiovascular Considerations

Phase 2 trial data showed a small mean increase in resting heart rate of approximately 2–4 beats per minute among retatrutide-treated participants. This finding is consistent with the GLP-1 receptor agonist drug class as a whole — semaglutide and tirzepatide have both shown similar modest heart rate elevations in their respective trials. Blood pressure, by contrast, tended to decrease in retatrutide-treated groups, which is generally considered a favorable metabolic signal associated with weight loss and improved insulin sensitivity. No major adverse cardiovascular events (MACE) were identified as a safety signal in the Phase 2 data. However, it is important to note that Phase 2 trials are not powered to detect rare cardiovascular events — the sample sizes and treatment durations are too limited for definitive conclusions about cardiovascular safety. The ongoing Phase 3 TRIUMPH program, with its larger participant pools and longer follow-up periods, will be critical for establishing retatrutide's cardiovascular risk-benefit profile. Individuals with pre-existing cardiac conditions should discuss these considerations with a healthcare provider.

Hepatic Effects

One distinguishing feature of retatrutide compared to GLP-1-only or GIP/GLP-1 dual agonists is its activation of the glucagon receptor, which plays a significant role in hepatic lipid and glucose metabolism. In the Phase 2 trial, retatrutide demonstrated substantial reductions in liver fat content — up to approximately 81% in participants with metabolic dysfunction-associated steatotic liver disease (MASLD, formerly known as NAFLD). This hepatic fat reduction is thought to be driven in part by glucagon-mediated increases in hepatic lipid oxidation and energy expenditure. Liver enzyme levels (ALT and AST, which can serve as markers of hepatic stress) generally improved or remained stable throughout the trial in retatrutide-treated participants. These findings are considered encouraging, as elevated liver fat and liver enzymes are common comorbidities in individuals with obesity and type 2 diabetes. That said, glucagon receptor activation has theoretical potential to affect hepatic function in ways that may not be fully captured in a 48-week Phase 2 trial. Ongoing Phase 3 studies are monitoring for rare hepatic adverse events, and long-term data will be necessary to confirm the favorable liver safety profile suggested by early results. Individuals with existing liver conditions should consult a healthcare provider before considering any investigational therapy.

Strategies to Minimize Side Effects

The most effective strategy for reducing retatrutide side effects, based on the Phase 2 trial design and clinical experience with the GLP-1 agonist class, is slow and consistent dose titration. The Phase 2 protocol used a monthly escalation schedule starting at 0.5 mg, which allowed participants to gradually adjust to increasing receptor activation before reaching their target maintenance dose. Beyond titration, several practical approaches may help manage GI symptoms — these are general strategies commonly recommended for individuals using incretin-based therapies and are not specific to retatrutide.

• Follow a gradual dose titration schedule — the Phase 2 trial escalated doses monthly (e.g., 0.5 mg → 1 mg → 2 mg → 4 mg → 8 mg → 12 mg), and skipping steps may increase GI side effect risk
• Administer the injection at the same time each week to maintain consistent drug levels
• Eat smaller, more frequent meals rather than large portions, which can exacerbate nausea and fullness
• Stay well hydrated throughout the day, particularly if experiencing diarrhea or vomiting
• Avoid lying down immediately after eating, as this may worsen nausea and acid reflux symptoms
• Reduce intake of high-fat and fried foods during the titration phase, as these can amplify GI discomfort
• If side effects are persistent or severe, discuss dose adjustment timing with a healthcare provider — a longer titration interval may be appropriate

Serious and Rare Adverse Events

As with all GLP-1 receptor agonists, retatrutide carries class-wide precautions for several serious but rare adverse events. While no confirmed cases of the following were reported in the Phase 2 trial, the sample size and duration were insufficient to rule them out, and they remain important safety considerations for ongoing Phase 3 evaluation.

• Pancreatitis — Acute pancreatitis is a recognized class-wide precaution for GLP-1 receptor agonists. No confirmed cases of pancreatitis were reported in the retatrutide Phase 2 trial, but participants with a history of pancreatitis were excluded from enrollment. Vigilance for this potential risk continues in Phase 3 studies.
• Medullary thyroid carcinoma (MTC) — GLP-1 receptor agonists carry a boxed warning based on thyroid C-cell tumor findings in rodent studies. Whether this risk translates to humans remains uncertain, and no thyroid malignancies were reported in the retatrutide Phase 2 data. Retatrutide is expected to carry the same class-wide warning if approved.
• Gallbladder events — Rapid weight loss from any cause can increase the risk of gallstones and cholecystitis. GLP-1 agonists as a class have been associated with gallbladder-related adverse events, and the significant weight reduction observed with retatrutide may carry a similar risk.
• Hypoglycemia — Retatrutide monotherapy has a low risk of hypoglycemia in non-diabetic individuals. However, when combined with insulin or sulfonylureas in people with type 2 diabetes, the risk of hypoglycemia may be increased. Dose adjustments of concomitant glucose-lowering medications may be necessary.

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References

1. Triple-Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial (2023) — PubMed
2. Retatrutide, a GIP, GLP-1 and Glucagon Receptor Agonist, for People with Type 2 Diabetes: A Randomised, Double-Blind, Placebo and Active-Comparator Controlled, Parallel-Group, Phase 2 Trial (2023) — PubMed
3. A Phase 2 Trial of the GIP/GLP-1/Glucagon Receptor Agonist Retatrutide and Liver Fat Reduction in MASLD (2024) — PubMed
4. Pharmacology of GIP/GLP-1/Glucagon Receptor Triple Agonism and Metabolic Implications (2023) — PubMed