What to do when Rybelsus (semaglutide) is not enough to lower glucose levels?

When Rybelsus (Oral Semaglutide) Is Insufficient for Glucose Control

Add another glucose-lowering medication to Rybelsus rather than switching away from it, with the specific choice determined by the presence of cardiovascular disease, heart failure, or chronic kidney disease. 1

Prioritize Based on Comorbidities First

If Patient Has ASCVD, Heart Failure, or CKD

Add an SGLT2 inhibitor immediately, regardless of current A1C level. 1 This recommendation takes precedence over glycemic control alone because SGLT2 inhibitors reduce cardiovascular death and heart failure hospitalizations independent of glucose-lowering effects. 1

• For patients with heart failure (either reduced or preserved ejection fraction), SGLT2 inhibitors are specifically recommended to prevent HF hospitalizations. 1
• For patients with CKD (eGFR 20-60 mL/min/1.73 m²), SGLT2 inhibitors reduce progression of kidney disease. 1
• No dose adjustment is required for Rybelsus in any degree of renal impairment. 1

If Patient Has None of These High-Risk Conditions

Your medication choice depends on A1C gap and weight management goals:

Algorithm Based on A1C Gap

A1C is 1.5% or More Above Goal

You need high-potency therapy. Add basal insulin or switch to injectable semaglutide/tirzepatide. 1

• Injectable semaglutide and tirzepatide provide the greatest A1C reductions among all glucose-lowering agents (comparable to or exceeding insulin). 1
• Injectable GLP-1 RAs and tirzepatide have lower hypoglycemia risk and promote weight loss compared to insulin. 1
• If severe hyperglycemia is present (glucose ≥300 mg/dL or A1C >10%) with catabolic features (weight loss, ketosis), initiate insulin immediately. 1

A1C is Less Than 1.5% Above Goal

Add metformin if not already prescribed, or add an SGLT2 inhibitor for additional modest glucose lowering plus weight benefits. 1

• Metformin remains foundational therapy and can be safely combined with Rybelsus. 1
• SGLT2 inhibitors provide moderate A1C reduction (0.5-0.8%) with weight loss and blood pressure benefits even in patients without cardiovascular disease. 1
• Avoid sulfonylureas due to hypoglycemia risk and weight gain without cardiovascular benefits. 1

Practical Considerations

Before Adding Medications

• Verify Rybelsus dosing is optimized: Ensure patient has been titrated to 14 mg (the maximum dose) before declaring inadequate response. 2, 3
• Confirm adherence: Rybelsus must be taken on an empty stomach with no more than 120 mL of plain water, with no food/drink/medications for 30 minutes after. 1 Poor absorption from incorrect administration is a common cause of apparent treatment failure.

If Cost Is Prohibitive for Combination Therapy

Switch from oral semaglutide (Rybelsus) to injectable semaglutide, which provides substantially greater glucose-lowering efficacy at similar cost. 1 Injectable semaglutide achieves greater A1C reductions than the oral formulation due to higher bioavailability. 2

Managing Hypoglycemia Risk

If adding insulin or sulfonylureas to Rybelsus, reduce the dose of insulin or sulfonylurea by 20-30% at initiation to prevent hypoglycemia. 4 GLP-1 receptor agonists like semaglutide enhance insulin secretion, creating additive hypoglycemia risk with these agents. 4

Common Pitfalls to Avoid

• Don't discontinue Rybelsus when adding therapy. The combination provides additive glucose-lowering effects and Rybelsus offers cardiovascular benefits beyond glycemic control. 1
• Don't add another GLP-1 receptor agonist or DPP-4 inhibitor. These work through the same pathway and should never be combined. 5
• Don't delay intensification. Waiting months to add therapy when A1C remains elevated leads to prolonged hyperglycemia exposure and increased complication risk. 1
• Don't assume maximum dose is required for everyone. Some patients achieve adequate response at submaximal Rybelsus doses (7 mg) and don't require escalation. 5