What is the mechanism of Ozempic (semaglutide) and its effects on blood sugar, insulin, and weight loss?

Mechanism of Ozempic (Semaglutide) and Its Effects on Blood Sugar, Insulin, and Weight Loss

Ozempic (semaglutide) is a GLP-1 receptor agonist that works by binding to and activating GLP-1 receptors, stimulating insulin secretion and suppressing glucagon in a glucose-dependent manner, while also delaying gastric emptying and suppressing appetite through central nervous system action, leading to improved glycemic control and significant weight loss.

Mechanism of Action

• Semaglutide is a human GLP-1 analog with 94% sequence homology to human GLP-1 that selectively binds to and activates the GLP-1 receptor 1
• The peptide backbone is produced by yeast fermentation, with modifications that protect against degradation by DPP-4 enzyme and facilitate albumin binding, resulting in its long half-life of approximately one week 1
• GLP-1 receptors are expressed in multiple organs, including the pancreas, gastrointestinal tract, heart, brain, kidney, lung, and thyroid, explaining semaglutide's pleiotropic effects 2

Effects on Blood Sugar

• Semaglutide reduces blood glucose through multiple mechanisms:
  • Stimulates insulin secretion in a glucose-dependent manner when blood glucose is high 1
  • Lowers glucagon secretion, also in a glucose-dependent manner 1
  • Delays gastric emptying in the early postprandial phase 1
• In patients with type 2 diabetes, semaglutide 1 mg reduces fasting glucose by 29 mg/dL (22%), 2-hour postprandial glucose by 74 mg/dL (36%), and mean 24-hour glucose concentration by 30 mg/dL (22%) compared to placebo 1
• The glucose-dependent nature of insulin stimulation and glucagon suppression explains the low risk of hypoglycemia with semaglutide 2

Effects on Insulin

• Semaglutide enhances both first- and second-phase insulin secretion in patients with type 2 diabetes 1
• It promotes β-cell proliferation and protects against apoptosis, potentially preserving pancreatic function 2
• The insulin secretion rate in patients with type 2 diabetes treated with semaglutide becomes similar to that of healthy subjects 1
• During induced hypoglycemia, semaglutide does not impair the counter-regulatory responses, maintaining safety 1

Effects on Weight Loss

• Semaglutide produces substantial weight loss through multiple mechanisms:
  • Acts on GLP-1 receptors in the hypothalamus and brainstem nuclei to suppress appetite and increase satiety 3
  • Delays gastric emptying, contributing to reduced food intake 3
  • Affects the central nervous system to regulate energy intake and expenditure 3
• Weight loss is significantly greater in individuals without diabetes (mean weight loss 6.1–17.4%) compared to those with diabetes (4–6.2%) 3, 2
• In the STEP 1 trial, semaglutide 2.4 mg weekly led to a mean weight loss of 14.9% at 68 weeks (compared to 2.4% with placebo) 3
• After cessation of semaglutide, significant weight regain occurs (11.6% of lost weight regained after 52 weeks), highlighting the need for long-term use 3

Additional Metabolic and Cardiovascular Benefits

• Semaglutide has demonstrated cardioprotective effects through multiple mechanisms:
  • Improved myocardial substrate utilization
  • Anti-inflammatory and anti-atherosclerotic effects
  • Reduced myocardial ischemia injury
  • Lower systemic and pulmonary vascular resistance
  • Improved lipid profiles 3, 2
• In the SUSTAIN 6 trial, semaglutide reduced the primary outcome of cardiovascular death, non-fatal myocardial infarction or stroke compared with placebo (HR 0.74,95% CI 0.58–0.95) 2

Common Side Effects and Safety Considerations

• The most common adverse effects are gastrointestinal:
  • Nausea, vomiting, diarrhea, dyspepsia, constipation, and abdominal pain 3, 2
  • These effects are typically mild-to-moderate, dose-dependent, and often transient, occurring mainly during dose escalation 2, 4
• Semaglutide increases the risk of gallbladder disease (cholelithiasis) 2, 4
• It is contraindicated in patients with personal or family history of medullary thyroid cancer or multiple endocrine neoplasia syndrome type 2 2
• Due to its potent glucose-lowering effect, patients with existing diabetic retinopathy should be carefully monitored, particularly if also treated with insulin 2, 4

Clinical Applications

• Semaglutide is available in both injectable (Ozempic) and oral formulations, though the oral form is currently only approved for diabetes management, not obesity 2
• For patients requiring treatment intensification after oral therapy or as add-on to insulin, semaglutide provides effective glucose lowering and weight loss with low risk of hypoglycemia 5, 6
• When used in combination with basal insulin in type 2 diabetes, semaglutide significantly reduces HbA1c (MD: -1.17%), body weight (MD -5.99 kg), and fasting blood glucose (MD -1.08%) compared to placebo or other active treatments 6