Do retatrutide and survo‑dutide increase glucagon signaling, thereby increasing energy availability for the patient?

Do Retatrutide and Survodutide Increase Glucagon Signaling for Energy Availability?

Yes, both retatrutide and survodutide increase glucagon signaling, which enhances energy expenditure through increased lipolysis and lipid oxidation, though this mechanism contributes to weight loss rather than providing more usable energy for the patient. 1

Mechanism of Glucagon Receptor Activation

Retatrutide (Triple Agonist)

• Retatrutide is a triple agonist that stimulates GLP-1, GIP, and glucagon receptors, distinguishing it from dual agonists 1
• The glucagon receptor component specifically increases lipolysis, lipid oxidation, and energy expenditure 1
• This mechanism works through adenylyl cyclase activation and increased cAMP levels 2
• In clinical trials, retatrutide produced weight loss ranging from 8.7% to 24.2% at 48 weeks depending on dose (1-12 mg), with the glucagon component contributing to this metabolic effect 3

Survodutide (Dual GLP-1/Glucagon Agonist)

• Survodutide is a dual GLP-1-glucagon receptor agonist that similarly activates glucagon signaling 1
• It has shown promising weight-loss effects and preliminary positive histology data in phase IIb trials for metabolic dysfunction-associated steatotic liver disease (MASLD) 1
• The glucagon component provides additional peripheral effects beyond GLP-1 alone, including enhanced fat metabolism 1

Clinical Implications: Energy Expenditure vs. Energy Availability

Important Distinction

The glucagon signaling from these medications increases energy expenditure (burning stored fat) rather than increasing energy availability for patient use 1. This is a critical distinction:

• The glucagon component mobilizes fat stores through increased lipolysis and lipid oxidation 1
• This contributes to the substantial weight loss seen with these agents 3
• Patients may actually feel they have less available energy due to appetite suppression and increased metabolic rate, not more

Glucose Regulation Context

• In euglycemia or hypoglycemia, glucagon receptor activation augments glucagon secretion, which could theoretically increase glucose availability 1
• However, in hyperglycemia, the GIP component inhibits glucagon secretion 1
• The net effect is glucose-dependent and designed for metabolic optimization, not energy supplementation 1

Safety Considerations

Cardiovascular Effects

• Retatrutide increases heart rate by up to 6.7 beats/min, which peaked at 24 weeks then declined 4, 3
• This tachycardia may offset some cardiovascular benefits of weight loss 4
• The drug demonstrates positive inotropic effects in human atrial tissue through cAMP-mediated mechanisms 2

Common Adverse Events

• Gastrointestinal side effects (nausea, diarrhea, vomiting) are dose-related and most common 4, 3
• These were mostly mild to moderate and partially mitigated with lower starting doses (2 mg vs 4 mg) 3

Clinical Bottom Line

These medications do not provide patients with more usable energy—they increase energy expenditure by mobilizing fat stores through glucagon receptor activation 1. The glucagon component is specifically designed to enhance weight loss through increased lipolysis and lipid oxidation, not to make patients feel more energetic 1. Patients should be counseled that while these drugs are highly effective for weight loss (comparable to bariatric surgery), they work by increasing metabolic rate and fat burning, which may actually be perceived as having less energy available, especially combined with appetite suppression 1, 3.