Can Rybelsus (semaglutide) cause hypoglycemia?

Rybelsus (Semaglutide) and Hypoglycemia Risk

Rybelsus (oral semaglutide) by itself has minimal risk of causing hypoglycemia due to its glucose-dependent mechanism of action, but the risk increases significantly when combined with insulin or insulin secretagogues like sulfonylureas. 1

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
• This glucose-dependent mechanism provides a built-in safety feature that minimizes hypoglycemia risk when used as monotherapy 2
• Semaglutide works by selectively binding to and activating the GLP-1 receptor, which is the target for native GLP-1, a physiological hormone with multiple actions on glucose metabolism 1

Clinical Evidence on Hypoglycemia Risk

• According to the American Diabetes Association's Standards of Care (2025), GLP-1 receptor agonists including semaglutide have "No" hypoglycemia risk when used alone 3
• The FDA label for semaglutide confirms that it lowers blood glucose through a mechanism where it stimulates insulin secretion and lowers glucagon secretion, both in a glucose-dependent manner 1
• During induced hypoglycemia studies, semaglutide did not alter the counter-regulatory responses of increased glucagon compared to placebo, maintaining normal physiological protection against hypoglycemia 1

High-Risk Scenarios for Hypoglycemia

• Combination therapy with insulin or insulin secretagogues (sulfonylureas) significantly increases hypoglycemia risk 2
• Patients with renal impairment may be at higher risk for medication-related adverse effects, though semaglutide itself doesn't require dose adjustment for renal function 1
• Fasting states, such as during Ramadan, may require careful consideration when using Rybelsus to ensure therapeutic efficacy and patient tolerance 3

Management Recommendations

• When prescribing Rybelsus with medications that increase hypoglycemia risk (insulin or sulfonylureas), consider:

  • Lower doses of the insulin or insulin secretagogue 2
  • More frequent blood glucose monitoring 2
  • Patient education on recognizing and managing hypoglycemia symptoms 2

• For patients taking Rybelsus during fasting periods (like Ramadan):

  • Titrate the dose to at least 7 mg approximately 2-3 weeks before fasting periods 3
  • Individualize dosing at meal times, considering that absorption is affected by food and drinks 3

Practical Considerations

• Oral semaglutide represents an additional treatment option for patients not achieving glycemic goals despite treatment with metformin, either alone or with other hypoglycemic agents 4
• The low intrinsic risk of hypoglycemia makes Rybelsus a favorable option for patients concerned about hypoglycemic episodes 5
• Rybelsus may be particularly beneficial for patients with type 2 diabetes who need effective glycemic control without the increased risk of hypoglycemia associated with other agents 6

Special Situations

• In rare cases, semaglutide has been used to treat reactive hypoglycemia related to dumping syndrome after bariatric surgery, actually reducing hypoglycemic episodes in this specific condition 7
• For patients with cardiovascular disease, the cardiovascular safety profile of oral semaglutide appears to be similar to that of injectable semaglutide, with no increased risk of cardiovascular events 6

Remember that while Rybelsus itself has minimal hypoglycemia risk, patient education about proper administration (taking on an empty stomach with a small sip of water and waiting 30 minutes before eating) is essential for both efficacy and safety 4.