Is weight loss with GLP-1 (Glucagon-like peptide-1) receptor agonists, such as semaglutide (semaglutide) and liraglutide (liraglutide), primarily due to appetite suppression?

Weight Loss Mechanisms of GLP-1 Receptor Agonists

Weight loss with GLP-1 receptor agonists is NOT primarily due to appetite suppression alone—these medications work through multiple complementary mechanisms including delayed gastric emptying, central nervous system effects on satiety, and metabolic changes that together produce their substantial weight reduction effects. 1, 2

Multiple Mechanisms Beyond Appetite Suppression

Delayed Gastric Emptying as a Primary Mechanism

• Much of the glucose-lowering and weight loss effects of GLP-1 receptor agonists are due to their effects on gastric emptying, rather than their effect on the pancreatic islets alone. 1
• GLP-1 receptor activation delays gastric emptying by inhibiting gastric peristalsis while increasing pyloric tone, mediated through the vagus nerves. 1
• This delayed gastric emptying is documented even with long-acting formulations like semaglutide using scintigraphy (the gold standard), showing persistent effects despite some tachyphylaxis development. 1
• The delayed gastric emptying leads to prolonged feelings of fullness and reduced phasic gastric contractions, increased fasting gastric volumes, and reduced gastric acid secretion. 1, 3

Central Nervous System and Appetite Regulation

• GLP-1 and GIP receptors located in the hypothalamus and brainstem nuclei mediate appetite, satiety, energy intake and expenditure—this represents the appetite suppression component. 1, 2
• GLP-1 receptor agonists induce meal termination through parabrachial neurons and hypothalamic suppression, generating powerful satiety signals through central nervous system pathways. 2
• These medications activate vagal nerve endings in the intestinal mucosa, generating central nervous system signals that influence both insulin secretion and metabolism. 2
• GLP-1 receptors are also found in the hippocampus, neocortex, spinal cord and cerebellum, explaining broader neurological effects beyond simple appetite suppression. 1

Metabolic and Hormonal Effects

• Tirzepatide's dual-receptor action provides enhanced metabolic benefits including delayed gastric emptying, suppressed appetite, improved insulin secretion, decreased glucagon secretion, and increased energy expenditure. 2
• GLP-1 receptor agonists promote β-cell proliferation and protect against apoptosis, potentially preserving pancreatic function—this represents a metabolic benefit beyond weight loss. 2
• The glucose-dependent nature of insulin stimulation and glucagon suppression contributes to metabolic improvements that facilitate weight loss. 2

Evidence of Tachyphylaxis and Adaptation

• A critical nuance: the effects on gastric emptying show tachyphylaxis with continuous exposure, suggesting autonomic nervous system adaptation. 1
• Acute and intermittent infusions of GLP-1 receptor agonists have more pronounced effects on delaying gastric emptying than continuous infusion, as demonstrated by scintigraphy studies. 1
• Two studies using long-acting semaglutide (12-20 weeks) showed no delay in gastric emptying using paracetamol absorption tests, suggesting tachyphylaxis had developed, though this test is now considered suboptimal. 1
• Despite tachyphylaxis to some gastric emptying effects, patients still experience significant weight loss, indicating that multiple mechanisms continue to operate effectively. 1

Comparative Efficacy Reflecting Multiple Mechanisms

• Semaglutide 2.4mg produces 14.9% weight loss at 68 weeks, while tirzepatide achieves 20.9% weight loss—these substantial effects cannot be explained by appetite suppression alone. 2, 4
• Weight loss is greater in non-diabetic patients (6.1-17.4%) compared to those with diabetes (4-6.2%), suggesting metabolic factors and insulin resistance influence treatment response through mechanisms beyond appetite. 2

Clinical Implications

• The combined effect of delayed gastric emptying, central appetite suppression, and metabolic improvements produces early satiation and reduced food consumption. 3
• Patients should understand that these medications work through multiple pathways, not just "making you less hungry"—this helps explain why they are so effective compared to older weight loss medications. 1, 2
• The peri-operative aspiration risk from delayed gastric emptying (documented even after extended fasting periods) demonstrates that gastric effects persist independently of appetite suppression. 1, 2