Retatrutide — Research, Dosing & Price Guide

Retatrutide (LY3437943) is a novel triple-agonist peptide developed by Eli Lilly that simultaneously activates GLP-1, GIP, and glucagon receptors — the first 'triagonist' in its class. In Phase II clinical trials, retatrutide produced unprecedented weight loss of up to 24.2% of body weight at 48 weeks, surpassing all existing anti-obesity medications including semaglutide and tirzepatide. It represents the cutting edge of incretin-based metabolic therapy and is currently in Phase III trials for obesity, type 2 diabetes, and metabolic dysfunction-associated steatohepatitis (MASH/NASH).

Retatrutide is a 39-amino-acid peptide engineered with balanced agonist activity at three metabolic receptors, each contributing distinct and synergistic mechanisms to weight loss and metabolic improvement. **GLP-1 receptor agonism** provides the established incretin backbone: it stimulates glucose-dependent insulin secretion from pancreatic beta cells, suppresses inappropriate glucagon release, delays gastric emptying, and — critically — activates GLP-1 receptors in the hypothalamus and brainstem (arcuate nucleus, nucleus tractus solitarius) to produce potent appetite suppression and satiety. This is the same mechanism underlying semaglutide's efficacy, and it accounts for a significant portion of retatrutide's weight loss. **GIP receptor agonism** adds a layer that distinguishes retatrutide from pure GLP-1 agonists. GIP receptors are expressed on adipocytes, where their activation promotes lipolysis and thermogenesis in brown and beige adipose tissue. GIP receptor activation also enhances the insulin-secretory response beyond what GLP-1 alone achieves (the 'incretin potentiation' effect), improves lipid metabolism, and may have direct neuroprotective effects. The inclusion of GIP agonism is the same approach that makes tirzepatide (a dual GLP-1/GIP agonist) more effective than semaglutide, and retatrutide builds on this foundation. **Glucagon receptor agonism** is the novel third mechanism that sets retatrutide apart from all predecessors. Glucagon receptor activation in the liver increases hepatic energy expenditure through gluconeogenesis, fatty acid oxidation, and amino acid catabolism. More importantly, glucagon receptor signaling stimulates hepatic fat oxidation and reduces hepatic steatosis — making it particularly effective for NASH/MASH. Glucagon also increases resting energy expenditure by 5–10% through thermogenic effects, and promotes lipolysis in adipose tissue. The theoretical concern that glucagon would raise blood glucose is counterbalanced by the concurrent GLP-1 and GIP receptor activity, which provide powerful glucose-lowering effects that more than offset glucagon's glycemic actions. The synergy of these three mechanisms produces: (1) potent appetite suppression exceeding any single agonist; (2) increased resting energy expenditure from glucagon-mediated thermogenesis and GIP-mediated brown fat activation; (3) preferential hepatic fat oxidation addressing fatty liver disease; (4) robust glycemic control despite glucagon's hyperglycemic potential; and (5) improved lipid profiles through multi-receptor metabolic optimization. Retatrutide uses a C20 fatty diacid linker for albumin binding, extending its half-life to approximately 6 days and enabling once-weekly subcutaneous dosing. The peptide is gradually titrated over 24 weeks to the maintenance dose to minimize gastrointestinal side effects.

• Jastreboff et al. (2023) published the Phase II trial results in the New England Journal of Medicine: the 12 mg dose produced 24.2% mean body weight reduction at 48 weeks — the largest weight loss ever reported for any anti-obesity pharmacotherapy in a controlled trial
• At the 12 mg dose, 26% of participants lost ≥30% of their body weight, and 9% lost ≥35%, approaching levels previously only achievable with bariatric surgery
• The Phase II trial showed retatrutide reduced HbA1c by up to 2.02% in participants with type 2 diabetes, with 71% achieving HbA1c <5.7% (normal range) at the 12 mg dose
• A sub-study using MRI showed retatrutide 12 mg reduced liver fat content by 82.4% relative to baseline at 48 weeks, with 86% of participants achieving complete resolution of hepatic steatosis — unprecedented efficacy for fatty liver disease
• Waist circumference decreased by up to 18.3 cm at the 12 mg dose, indicating significant visceral fat reduction
• Cardiovascular risk markers improved significantly: triglycerides decreased by 47%, LDL cholesterol decreased, and HDL cholesterol increased across dose groups
• Retatrutide demonstrated superior weight loss compared to historical data for semaglutide 2.4 mg (~15%) and tirzepatide 15 mg (~20.9%), establishing the triagonist approach as the most potent pharmacological weight loss strategy
• The TRIUMPH Phase III program (initiated 2023) includes trials for obesity, type 2 diabetes, NASH/MASH, and obesity with cardiovascular disease, with projected regulatory submission in 2026

• Phase II trial protocol (titration schedule): Start at 0.5 mg weekly SC for 4 weeks → 1 mg weekly for 4 weeks → 2 mg weekly for 4 weeks → 4 mg weekly for 4 weeks → 8 mg weekly for 4 weeks → 12 mg weekly (maintenance) — total titration period of 24 weeks
• The 12 mg once-weekly dose produced the highest efficacy (24.2% weight loss at 48 weeks) in Phase II
• Lower maintenance doses (4 mg, 8 mg weekly) also showed significant weight loss (17.5% and 22.8% respectively)
• Inject subcutaneously in the abdomen, thigh, or upper arm — rotate injection sites weekly
• Administer on the same day each week for consistent pharmacokinetics
• Slow titration is mandatory — rapid dose escalation dramatically increases GI side effects
• If a dose is missed, administer as soon as possible if within 3 days, then resume the regular schedule
• For type 2 diabetes: the same titration schedule applies; glucose-lowering effects emerge early in titration
• Not yet FDA-approved — Phase III trials (TRIUMPH program) are ongoing with results expected 2025–2026
• Dietary modifications (reduced fat intake, smaller meals) significantly reduce GI side effects during titration

Known Side Effects

• Nausea — the most common adverse event, reported in 25–45% of participants depending on dose; most prominent during dose escalation and generally improves with continued use
• Diarrhea — reported in 15–30% of participants; usually mild-moderate and improves over the titration period
• Vomiting — dose-dependent, occurring in 10–20% of participants; typically during the first 1–2 weeks at each new dose level
• Decreased appetite — significant and sustained, which is therapeutic but can become excessive; adequate protein intake (1.2–1.6 g/kg/day) should be prioritized to preserve lean mass
• Constipation — reported by approximately 10–15% of participants, likely related to delayed gastric emptying
• Injection site reactions — mild erythema, pruritus, or pain at the injection site
• Dyspepsia and acid reflux — reported by some participants, manageable with dietary modifications (smaller, lower-fat meals)
• Increased heart rate — mean increase of 2–4 bpm observed in clinical trials, consistent with other incretin agonists; clinical significance uncertain

Safety Profile

Retatrutide's safety profile from Phase II trials is encouraging but still being fully characterized in the ongoing Phase III program. The gastrointestinal side effect profile is consistent with the GLP-1 agonist class but may be somewhat higher due to the triple-agonist mechanism. The slow 24-week titration schedule was specifically designed to mitigate GI tolerability. The glucagon receptor component raised theoretical concerns about hyperglycemia, but the Phase II data showed robust glucose-lowering despite glucagon agonism, suggesting the GLP-1 and GIP components provide adequate glycemic counterbalance. Cardiovascular safety is being assessed in dedicated trials — the heart rate increase is a class effect of incretin agonists and not unique to retatrutide. Thyroid C-cell tumor warnings (boxed warning) apply as with all GLP-1 receptor agonists based on rodent findings, though human relevance is uncertain. Pancreatitis is a theoretical risk of the incretin class; no signal was detected in Phase II but monitoring continues. Contraindications include personal/family history of medullary thyroid carcinoma (MTC) or Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Patients should maintain adequate nutrition and protein intake to minimize lean mass loss during rapid weight reduction.

Weeks 1–4 (0.5 mg): Minimal weight loss (1–2 lbs). Mild GI adjustment — nausea is possible but generally manageable. Appetite may begin to decrease slightly. This introductory phase establishes tolerability. Weeks 5–12 (1–2 mg): Weight loss accelerates to 0.5–1.5 lbs/week. Appetite suppression becomes pronounced. Portion sizes naturally decrease. GI side effects may recur briefly at each dose increase but typically resolve within 3–5 days. Blood glucose improvements are measurable. Weeks 13–24 (4–8 mg): Weight loss is now rapid and consistent — typically 1–2 lbs/week. Total weight loss of 10–15% from baseline is common by week 24. Users report dramatically reduced food cravings, improved energy, and better blood work across metabolic markers. Clothing sizes drop noticeably. Liver fat is declining significantly. Weeks 24–48 (8–12 mg maintenance): Weight loss continues at a steady pace. At 48 weeks, the Phase II trial showed average total weight loss of 24.2% at 12 mg — for a 250 lb individual, that's approximately 60 lbs. Body composition shifts are dramatic. Metabolic parameters normalize. Many users with type 2 diabetes achieve remission-level HbA1c values. Energy and physical function improve substantially as the weight burden decreases. Beyond 48 weeks: Long-term maintenance data is still being generated. Based on the GLP-1 agonist class, continued treatment is likely necessary to maintain weight loss, as discontinuation typically leads to partial weight regain.

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