How do Glucagon-like peptide-1 (GLP-1) receptor agonists work, is it just appetite suppression?

How GLP-1 Receptor Agonists Work

GLP-1 receptor agonists work through multiple complementary mechanisms beyond just appetite suppression—they simultaneously enhance glucose-dependent insulin secretion, suppress glucagon release, delay gastric emptying, and activate central nervous system pathways that control satiety and energy expenditure. 1, 2

Multi-System Mechanisms of Action

Pancreatic Effects

• GLP-1 receptor agonists stimulate glucose-dependent insulin release from pancreatic β-cells, meaning insulin secretion only occurs when blood glucose is elevated, which explains the low hypoglycemia risk 1, 3
• They suppress glucagon secretion in a glucose-dependent manner, preventing inappropriate glucose production by the liver 1, 4
• Evidence suggests these agents may promote β-cell proliferation and protect against β-cell apoptosis, potentially preserving pancreatic function long-term 5

Gastrointestinal Effects

• Delayed gastric emptying is a major contributor to glucose control, not just a secondary effect—this slows the rate at which glucose enters the bloodstream after meals 5, 6
• The gastric emptying delay is mediated through GLP-1 receptors on the myenteric plexus and requires intact vagal nerve function (patients with vagotomy do not experience this effect) 5
• Tachyphylaxis (tolerance) can develop to the gastric emptying effects with continuous long-acting exposure, though scintigraphy studies still demonstrate measurable delays even with chronic use 2, 5
• GLP-1 also inhibits gastric acid and pancreatic exocrine secretion, functioning as part of the "ileal brake" mechanism 7, 6

Central Nervous System Effects

• GLP-1 receptors in the hypothalamus and brainstem nuclei directly suppress appetite and increase satiety signals, working in concert with other satiety hormones like PYY and CCK 2, 5
• These central effects reduce food intake and influence energy expenditure, not merely through feeling full from delayed gastric emptying 8, 6
• GLP-1 is expressed in hypothalamic neurons and appears to be a physiological regulator of feeding behavior 7

Cardiovascular and Metabolic Effects

• Cardioprotective effects occur through improved myocardial substrate utilization, anti-inflammatory and anti-atherosclerotic actions, reduced myocardial ischemia injury, and lower systemic and pulmonary vascular resistance 5
• Meta-analyses demonstrate that GLP-1 receptor agonists decrease cardiovascular disease events in adults with overweight or obesity, even without diabetes 1

Pharmacokinetic Advantages

Semaglutide achieves its prolonged once-weekly action through albumin binding, which decreases renal clearance and protects against metabolic degradation by the DPP-4 enzyme 5. This is critical because endogenous GLP-1 is extremely rapidly metabolized—inactivated by DPP-4 even before leaving the gut—which is why native GLP-1 has a half-life of only minutes 6.

Clinical Implications of Multiple Mechanisms

• The combined effect of all these mechanisms produces weight loss of 14.9% in non-diabetic patients with obesity, a degree previously only achieved with bariatric surgery 1, 5
• Patients without diabetes experience substantially greater weight loss (6.1-17.4%) compared to those with diabetes (4-6.2%), suggesting metabolic factors influence response 2
• Much of the glucose-lowering effect comes from delayed gastric emptying rather than pancreatic effects alone, which explains why these agents work differently than traditional diabetes medications 5

Important Caveats

• Weight regain occurs after discontinuation, indicating these medications must be used long-term for sustained benefit 1, 2
• The incretin effect is diminished in proinflammatory, insulin-resistant states common in obesity due to increased GLP-1 degradation by DPP-4 2
• Gastrointestinal side effects (nausea, vomiting, diarrhea) result from the delayed gastric emptying mechanism and can lead to treatment discontinuation 1, 2
• For patients with BMI >35 kg/m², GLP-1 receptor agonists may provide insufficient weight loss alone, and bariatric surgery may eventually be needed 2