What are the mechanisms of action of retatrutide, a triple agonist of glucagon‑like peptide‑1 (GLP‑1), glucose‑dependent insulinotropic polypeptide (GIP), and glucagon receptors?

Mechanisms of Action of Retatrutide

Retatrutide is a triple receptor agonist that simultaneously activates GLP-1, GIP, and glucagon receptors, producing synergistic effects on appetite suppression, energy expenditure, insulin secretion, and lipid metabolism that exceed those of dual or single agonists. 1

Triple Receptor Activation

• GLP-1 receptor activation suppresses appetite through hypothalamic pathways (including parabrachial neurons), delays gastric emptying by inhibiting gastric peristalsis and increasing pyloric tone via vagal pathways, and enhances glucose-dependent insulin secretion while suppressing glucagon 2, 1

• GIP receptor activation potentiates the appetite-suppressing effects of GLP-1 through synergistic central nervous system signaling, enhances insulin secretion in a glucose-dependent manner, and promotes adipose tissue breakdown and lipid oxidation 2, 1

• Glucagon receptor activation increases energy expenditure, promotes hepatic fat oxidation and breakdown of adipose tissue, and reduces inappropriate glucagon secretion that drives hepatic glucose production 1, 3

Central Appetite Regulation

• Retatrutide triggers neuronal pathways in the hypothalamus and brainstem that terminate meals early and generate robust satiety signals, with the GIP component enhancing the anorexigenic response beyond what either GLP-1 or glucagon alone can achieve 1, 3

• The combined GIP/GLP-1 activation creates a synergistic appetite-suppressing effect that exceeds the sum of individual receptor stimulation 1

Peripheral Metabolic Effects

• Enhanced insulin secretion and glucagon suppression: The triple agonism yields greater improvements in β-cell function and glucose-dependent insulin release compared with selective GLP-1 agonists, while simultaneously reducing inappropriate glucagon secretion 1, 3

• Increased lipolysis and fat oxidation: Activation of all three receptors promotes breakdown of visceral adipose tissue and hepatic fat, with retatrutide achieving an 82% reduction in hepatic steatosis in clinical trials 1, 4

• Elevated energy expenditure: The glucagon receptor component specifically increases metabolic rate and energy expenditure beyond what GLP-1 or GIP activation alone provides 1, 3

Gastric Emptying and Satiety

• Retatrutide slows gastric emptying through vagal pathways, mechanically prolonging the residence time of food in the stomach and producing prolonged feelings of fullness after eating 1

• This delayed gastric emptying contributes to reduced caloric intake independent of the central appetite-suppression mechanisms 2

Cardiovascular and Cardiometabolic Mechanisms

• Blood pressure reduction: Retatrutide produces clinically meaningful reductions in both systolic (mean difference -9.88 mm Hg) and diastolic blood pressure (mean difference -3.88 mm Hg), mediated through weight loss and broader metabolic improvements 5

• Lipid metabolism improvement: The triple agonism yields superior triglyceride reduction and improved lipid profiles compared with dual or single agonists 1, 5

• Direct cardiac effects: Retatrutide increases force of contraction in human atrial tissue through cAMP-mediated pathways via its cognate receptors, though the clinical significance of this inotropic effect requires further study 6

Comparative Mechanistic Advantages Over Dual Agonists

• Superior weight loss: The addition of glucagon receptor activation to GLP-1/GIP agonism produces mean weight loss of 24.2% at 48 weeks with retatrutide 12 mg, compared with 20.9% for tirzepatide 15 mg (dual GIP/GLP-1 agonist) 1, 5

• Enhanced metabolic effects: Retatrutide achieves greater reductions in HbA1c (mean difference -0.91%), fasting plasma glucose (mean difference -23.51 mg/dL), and waist circumference (mean difference -10.51 cm) compared with placebo 5

• Broader cardiometabolic benefits: The triple agonism produces more comprehensive improvements across multiple metabolic parameters including liver fat, visceral adiposity, blood pressure, and lipid profiles than dual agonists 1, 4

Clinical Efficacy Outcomes

• In adults with obesity, retatrutide achieved mean weight loss of 17.5% at 24 weeks and 24.4% at 48 weeks, approaching the magnitude of weight loss seen with bariatric surgery 1, 3

• In patients with type 2 diabetes, retatrutide produced 16.9% weight loss and 2.2% HbA1c reduction at 36 weeks, with 82% of participants reaching HbA1c ≤6.5% 1

• For metabolic dysfunction-associated steatotic liver disease, retatrutide achieved 82.4% reduction in liver fat at 24 weeks with the 12 mg dose, with 86% of participants achieving normal liver fat (<5%) 4

Safety Profile

• Gastrointestinal symptoms (nausea, vomiting, diarrhea) are the most common adverse events, consistent with the mechanism of delayed gastric emptying shared with other incretin-based therapies 1, 3

• No significant difference in overall adverse events was observed between retatrutide and placebo groups (relative risk 1.11, P=0.24) in meta-analysis of randomized controlled trials 5