What are the beneficial effects of Glucagon-like peptide-1 (GLP-1)?

Beneficial Effects of GLP-1 Receptor Agonists

GLP-1 receptor agonists provide multiple therapeutic benefits including glucose-dependent insulin secretion that minimizes hypoglycemia risk, substantial weight reduction (up to 14.9% with semaglutide 2.4 mg weekly), and proven cardiovascular protection with 13-26% reduction in major adverse cardiovascular events. 1, 2

Glycemic Control Mechanisms

Pancreatic Effects:

• GLP-1 receptor agonists stimulate both first- and second-phase insulin secretion in a glucose-dependent manner, approaching levels seen in healthy subjects, which explains their exceptionally low hypoglycemia risk. 1, 2
• They inhibit glucagon secretion from pancreatic alpha cells only when glucose is elevated, reducing hepatic glucose production without causing hypoglycemia during euglycemia. 1, 3
• Evidence suggests potential preservation of pancreatic beta cell mass through promotion of beta cell proliferation and protection against apoptosis, though this requires further clinical confirmation. 1, 4

Weight Loss and Appetite Regulation

Central Nervous System Actions:

• GLP-1 receptors in the hypothalamus (arcuate nucleus) and brainstem nuclei (area postrema and nucleus tractus solitarius) mediate appetite suppression and induce meal termination. 1, 2
• In non-diabetic overweight/obese patients, weekly semaglutide 2.4 mg produces mean body weight reduction of 14.9%, substantially greater than weight loss seen in diabetic patients. 1

Gastrointestinal Mechanisms:

• GLP-1 delays gastric emptying by inhibiting gastric peristalsis while increasing pyloric tone through vagal nerve pathways, resulting in prolonged satiety. 1, 2
• Short-acting GLP-1 receptor agonists maintain more pronounced effects on gastric emptying than long-acting formulations due to tachyphylaxis with continuous exposure. 1, 3

Cardiovascular Benefits

Major Adverse Cardiovascular Event Reduction:

• The American College of Cardiology recommends liraglutide based on evidence showing 13% reduction in 3-point MACE (cardiovascular death, nonfatal MI, or nonfatal stroke) and 15% reduction in all-cause mortality in patients with type 2 diabetes and established cardiovascular disease. 1
• Semaglutide demonstrated 26% reduction in 3-point MACE in clinical trials. 1

Cardioprotective Mechanisms:

• GLP-1 receptors localized primarily to the sinoatrial node mediate improved myocardial substrate utilization, anti-inflammatory and anti-atherosclerotic effects, reduced myocardial ischemia injury, and lower systemic and pulmonary vascular resistance. 1, 2, 5

Additional Metabolic Benefits

Renal Effects:

• GLP-1 increases natriuresis and diuresis, contributing to blood pressure reduction. 6

Anti-inflammatory Actions:

• GLP-1 decreases systemic inflammation and apoptosis, with potential neuroprotective effects. 6

Important Clinical Caveats

Gastrointestinal Contraindications:

• The American Heart Association recommends avoiding GLP-1 receptor agonists in patients with pre-existing gastroparesis or delayed gastric emptying, as they may exacerbate symptoms through further delay of gastric emptying. 1, 2
• Start at low doses and titrate slowly to minimize gastrointestinal side effects including nausea, which occurs due to delayed gastric emptying and increased gastric volumes. 1

Perioperative Considerations:

• GLP-1 receptor agonists increase risk of gastric stasis and aspiration/regurgitation in the perioperative period, though insufficient evidence exists to guide minimum cessation periods. 7
• This risk must be balanced against worsening glycemic control if discontinued for prolonged duration. 7