Can Rybelsus (semaglutide) cause hypoglycemia?

Rybelsus (Semaglutide) and Hypoglycemia Risk

Rybelsus (oral semaglutide) has minimal risk of causing hypoglycemia when used as monotherapy due to its glucose-dependent mechanism of action. 1, 2

Mechanism of Action and Hypoglycemia Risk

• Semaglutide is a GLP-1 receptor agonist that stimulates insulin secretion and lowers glucagon secretion in a glucose-dependent manner, meaning it primarily acts when blood glucose levels are elevated 1
• During induced hypoglycemia, semaglutide does not alter the counter-regulatory responses of increased glucagon compared to placebo, maintaining the body's natural defense against low blood sugar 1
• GLP-1 receptor agonists, including oral semaglutide, have minimal risk for hypoglycemia when used alone 2, 3

Risk Factors for Hypoglycemia with Rybelsus

• The primary risk of hypoglycemia occurs when Rybelsus is used in combination with insulin or insulin secretagogues (such as sulfonylureas) 2, 3
• In these combination scenarios, the glucose-lowering effect of Rybelsus can potentiate the hypoglycemic effects of these other medications 3
• Patients with advanced age or compromised kidney function may potentially be at higher risk for adverse effects, though no dose adjustment is required for renal impairment 1

Clinical Evidence on Hypoglycemia Risk

• According to the 2025 American Diabetes Association Standards of Care, GLP-1 receptor agonists including semaglutide are categorized as having "No" hypoglycemia risk when used as monotherapy 3
• This contrasts with insulin and sulfonylureas which are associated with significant hypoglycemia risk 3
• The FDA label for semaglutide confirms that it works in a glucose-dependent manner, stimulating insulin secretion only when blood glucose is high 1

Special Populations and Considerations

• For patients fasting during Ramadan, a panel of experts recommends titrating the dose of Rybelsus to at least 7 mg approximately 2–3 weeks before Ramadan to ensure therapeutic efficacy and patient tolerance 3
• No dose adjustment is required for patients with renal or hepatic impairment, though clinical monitoring is always prudent 1
• In patients with a history of bariatric surgery, semaglutide has actually been reported to help reduce reactive hypoglycemia related to dumping syndrome 4

Management of Hypoglycemia Risk

• When prescribing Rybelsus with medications that increase hypoglycemia risk (insulin or sulfonylureas), consider:
  • Using lower doses of the insulin or insulin secretagogue 2
  • Educating patients on recognizing and managing hypoglycemia symptoms 2
  • Advising patients to monitor blood glucose more frequently 2
• For patients experiencing hypoglycemia while on combination therapy, use glucose tablets or carbohydrate-containing foods or beverages for immediate treatment 2

Clinical Practice Recommendations

• Rybelsus can be safely used as monotherapy or in combination with other non-insulin secretagogue medications without significant hypoglycemia concerns 3, 5
• When adding Rybelsus to a regimen containing insulin or sulfonylureas, consider proactively reducing the dose of these medications to prevent hypoglycemia 2
• Patients should be educated about proper administration of Rybelsus (taking on an empty stomach with a small amount of water and waiting 30 minutes before eating) to ensure optimal absorption and efficacy 5
• The low risk of hypoglycemia with Rybelsus makes it an appropriate option for patients where hypoglycemia avoidance is a priority 6