What is the efficacy of sublingual semaglutide (Glucagon-like peptide-1 (GLP-1) receptor agonist) for glycemic control in patients with type 2 diabetes?

Efficacy of Sublingual Semaglutide for Glycemic Control in Type 2 Diabetes

Semaglutide, available in oral formulation, is highly effective for glycemic control in type 2 diabetes, demonstrating among the greatest A1C reductions of all GLP-1 receptor agonists with additional benefits for weight management and cardiovascular outcomes. 1

Glycemic Efficacy

• Oral semaglutide is commercially available as an effective alternative to injectable GLP-1 receptor agonists for patients not achieving glycemic goals 1
• A systematic review and network meta-analysis indicates that semaglutide provides some of the greatest reductions in A1C levels among all GLP-1 receptor agonists 1
• In clinical trials, semaglutide demonstrates dose-dependent efficacy in reducing HbA1c by up to 1.7% from baseline (8.1%) over 12 weeks 2
• Up to 81% of patients achieved an HbA1c level of <7% in phase 2 trials 2

Mechanism of Action

• Semaglutide acts as a GLP-1 receptor agonist that selectively binds to and activates the GLP-1 receptor 3
• It reduces blood glucose through multiple mechanisms:
  • Stimulates insulin secretion in a glucose-dependent manner
  • Lowers glucagon secretion (also glucose-dependent)
  • Delays gastric emptying in the early postprandial phase 3
• These combined effects lead to significant reductions in both fasting and postprandial glucose concentrations 3

Comparative Efficacy

• In trials comparing the addition of injectable GLP-1 RAs, dual GIP and GLP-1 RAs, or insulin in people needing further glucose lowering, the glycemic efficacies of GLP-1 RAs were similar to or greater than that of basal insulin 1
• Semaglutide specifically demonstrates superior efficacy compared to many other GLP-1 RAs, with higher doses providing additional benefits 4
• Dose-response relationship shows that higher semaglutide doses provide modest additional glucose-lowering effects with additional weight loss, though at the expense of more adverse events 4

Additional Benefits Beyond Glycemic Control

• Semaglutide provides significant weight reduction benefits, with clinical trials showing weight loss of up to 4.8 kg over 12 weeks 2
• Cardiovascular outcome trials have demonstrated that semaglutide reduces the risk of major adverse cardiovascular events in adults with type 2 diabetes 3
• The FDA has approved semaglutide to reduce the risk of major adverse cardiovascular events in adults with type 2 diabetes and established cardiovascular disease 3
• It also reduces the risk of sustained eGFR decline, end-stage kidney disease, and cardiovascular death in adults with type 2 diabetes and chronic kidney disease 3

Safety and Tolerability

• The most common adverse events are gastrointestinal disturbances (nausea, vomiting, diarrhea), which are typically mild to moderate and transient 5
• Gastrointestinal side effects can be mitigated by dose escalation 2
• No major episodes of hypoglycemia were reported in clinical trials 2
• Semaglutide increases the risk of biliary disease (cholelithiasis) 5
• Patients at risk for deterioration of existing diabetic retinopathy should be carefully monitored if treated with semaglutide, particularly if also treated with insulin 5

Clinical Application

• For patients without established ASCVD, indicators of high ASCVD risk, heart failure, or CKD, semaglutide should be considered based on its efficacy in supporting individualized glycemic and weight management goals 1
• Due to its potent glucose-lowering effect and favorable cardiovascular and renal outcomes, semaglutide is recommended as a preferred option for individuals requiring potent therapy for glucose management 1
• Cost and tolerability issues are important considerations in GLP-1 RA use, as medication costs can be a major source of stress for people with diabetes 1

Special Populations

• Semaglutide has shown efficacy in patients with chronic kidney disease, with evidence suggesting that GLP-1 RAs reduce albuminuria and slow eGFR decline 1
• In patients with NAFLD/NASH, semaglutide has demonstrated the most robust evidence among GLP-1 RAs for reducing liver fat content and improving liver histology 1
• Preliminary evidence suggests potential benefits in overweight/obese patients with type 1 diabetes, though this remains an off-label use 6

In conclusion, sublingual (oral) semaglutide represents a highly effective option for glycemic control in type 2 diabetes with significant additional benefits for weight management and cardiovascular risk reduction, making it a preferred choice for many patients requiring potent glucose-lowering therapy.