How Ozempic (Semaglutide) Works
Ozempic works by mimicking the natural hormone GLP-1, binding to GLP-1 receptors throughout the body to stimulate insulin release, suppress glucagon, delay gastric emptying, and reduce appetite—all in a glucose-dependent manner that minimizes hypoglycemia risk. 1, 2
Core Mechanism of Action
Semaglutide is a GLP-1 receptor agonist with 94% sequence homology to human GLP-1, acting as a selective agonist that binds to and activates GLP-1 receptors—the same targets as native GLP-1 hormone 2. The medication is engineered with albumin-binding modifications (a C18 fatty di-acid chain attached at position 26) and DPP-4 enzyme resistance (modification at position 8), giving it a prolonged half-life of approximately 7 days and enabling once-weekly dosing 2, 3.
GLP-1 receptors are expressed throughout multiple organ systems including the pancreas, gastrointestinal tract, heart, brain, kidney, lung, and thyroid, explaining semaglutide's pleiotropic effects beyond simple glucose control 1.
Glucose-Lowering Mechanisms
Pancreatic Effects
Semaglutide stimulates insulin secretion from pancreatic β-cells only when blood glucose is elevated, making hypoglycemia rare when used as monotherapy 2, 4. Both first- and second-phase insulin secretion are enhanced compared to placebo 2. The medication simultaneously suppresses glucagon secretion in a glucose-dependent manner, reducing fasting glucagon by 8%, postprandial glucagon by 14-15%, and mean 24-hour glucagon by 12% 2.
Critically, during induced hypoglycemia, semaglutide does not impair counter-regulatory glucagon responses or C-peptide decrease, preserving the body's natural protective mechanisms against low blood sugar 2. This glucose-dependent action is what distinguishes GLP-1 agonists from older medications like sulfonylureas.
Gastric Emptying Effects
Semaglutide delays early postprandial gastric emptying, slowing the rate at which glucose enters the circulation after meals 2, 5. In clinical studies, first-hour gastric emptying was reduced by 27% compared to placebo (AUC₀₋₁ₕ treatment ratio: 0.73), though overall 5-hour gastric emptying was not significantly different 5. This delay contributes to lower postprandial glucose spikes and prolonged satiety 5.
The gastric effects are mediated through vagal nerve pathways, with semaglutide inhibiting gastric peristalsis while increasing pyloric tone 1. However, tachyphylaxis (tolerance) to gastric emptying effects can develop with continuous exposure, though weight loss and glucose control persist through other mechanisms 1.
Weight Loss Mechanisms
Central Appetite Suppression
GLP-1 receptors in the hypothalamus and brainstem mediate powerful appetite suppression 1. Semaglutide activates parabrachial neurons that induce meal termination and generates satiety signals through brainstem pathways 1. The medication also activates vagal nerve endings in the intestinal mucosa, creating central nervous system signals that influence both insulin secretion and metabolism 1.
Peripheral Metabolic Effects
Beyond appetite suppression, semaglutide increases energy expenditure and may promote adipose tissue breakdown 1. The delayed gastric emptying leads to prolonged feelings of fullness, reduced phasic gastric contractions, increased fasting gastric volumes, and reduced gastric acid secretion 1.
Cardiovascular and Metabolic Benefits
Semaglutide provides cardioprotective effects through multiple pathways: improved myocardial substrate utilization, anti-inflammatory and anti-atherosclerotic effects, reduced myocardial ischemia injury, lower systemic and pulmonary vascular resistance, and improved lipid profiles 1. In the SUSTAIN-6 trial, semaglutide reduced the composite outcome of cardiovascular death, nonfatal MI, or nonfatal stroke by 26% (HR 0.74,95% CI 0.58-0.95) 1.
The medication improves both fasting and postprandial lipid metabolism 5. In clinical studies, semaglutide reduced fasting glucose by 29 mg/dL (22%), 2-hour postprandial glucose by 74 mg/dL (36%), and mean 24-hour glucose by 30 mg/dL (22%) 2.
Clinical Efficacy Outcomes
Across clinical trials, semaglutide produces HbA1c reductions of 1.5-1.9% after 30-56 weeks of treatment 3. Weight loss ranges from 5-10% of baseline body weight in diabetes trials 3, with higher doses (2.4 mg weekly for obesity) achieving 14.9% weight loss at 68 weeks 1.
Important Clinical Considerations
Common pitfall: The gastric emptying delay creates aspiration risk during anesthesia—retained gastric contents are documented even after extended fasting periods, with 24.2% of semaglutide users showing increased residual gastric content versus 5.1% of controls despite 10-14 day discontinuation and 12-hour fasting 1. For elective surgery, discontinue semaglutide at least 3 weeks (three half-lives) before procedures requiring anesthesia 1.
The medication requires no dose adjustment for renal or hepatic impairment, as pharmacokinetics remain unchanged even in end-stage renal disease 2, 4. Gastrointestinal side effects (nausea, vomiting, diarrhea) are common but typically mild-to-moderate and decrease over time with slow titration 1, 4.
Semaglutide is contraindicated in patients with personal or family history of medullary thyroid cancer or multiple endocrine neoplasia syndrome type 2 (MEN2), based on animal studies showing thyroid C-cell tumors 1, 2.