What is the best treatment option for a patient with an elevated Hemoglobin A1C (HbA1C) level and intolerance to semaglutide (GLP-1 receptor agonist)?

Treatment for A1C 14% with Semaglutide Intolerance

For a patient with A1C 14% who cannot tolerate semaglutide, initiate basal insulin immediately at 10 units per day or 0.1-0.2 units/kg per day, titrating by 2 units every 3 days to reach fasting plasma glucose goals, while continuing metformin if the patient is on it. 1

Immediate Insulin Initiation Required

• At A1C >10% (86 mmol/mol) or blood glucose ≥300 mg/dL, insulin is the first injectable therapy recommended, particularly when symptoms of hyperglycemia are present. 1
• An A1C of 14% represents severe hyperglycemia requiring the most potent glucose-lowering therapy available, which is insulin. 2
• Prolonged severe hyperglycemia (A1C >9% for months) significantly increases complication risk and should be specifically avoided. 2

Basal Insulin Initiation Protocol

Starting Dose

• Begin with 10 units per day OR 0.1-0.2 units/kg per day of basal insulin analog (glargine, detemir, degludec) or bedtime NPH insulin. 1
• Choice of basal insulin should be based on person-specific considerations, including cost. 1

Titration Strategy

• Increase dose by 2 units every 3 days to reach fasting plasma glucose goal (80-130 mg/dL) without hypoglycemia. 1
• For hypoglycemia: determine cause; if no clear reason, lower dose by 10-20%. 1
• Reassess and modify regularly every 3-6 months to avoid therapeutic inertia. 1

Adding Prandial Insulin When Needed

• If A1C remains above goal after optimizing basal insulin, add prandial insulin starting with one dose at the largest meal. 1
• Start with 4 units per day or 10% of basal insulin dose. 1
• Increase dose by 1-2 units or 10-15% twice weekly based on postprandial glucose readings. 1
• If A1C <8% when adding prandial insulin, consider lowering the basal dose by 4 units per day or 10% of basal dose. 1

Alternative GLP-1 Receptor Agonist Options

Since semaglutide intolerance is specified, consider alternative GLP-1 receptor agonists if the intolerance was specific to semaglutide rather than a class effect:

• Other GLP-1 RAs (liraglutide, dulaglutide, exenatide) may be better tolerated and could provide 2-2.5% A1C reduction with weight loss benefits. 2, 3
• At baseline A1C of 10-11%, GLP-1 RAs have demonstrated HbA1c reductions of 2.5-3.1%, which may be superior to basal insulin alone. 4
• However, at A1C 14%, a GLP-1 RA alone would likely be insufficient without concurrent insulin therapy. 2

Combination Therapy Approach

• If trying an alternative GLP-1 RA, combine it with basal insulin from the start given the severity of hyperglycemia (A1C 14%). 1, 2
• Fixed-ratio combination products (IDegLira or iGlarLixi) can be considered if appropriate. 1
• The combination of GLP-1 RA with insulin provides greater efficacy, durability of glycemic effect, and weight/hypoglycemia benefits compared to insulin intensification alone. 1

Additional Medication Considerations

SGLT2 Inhibitors

• Consider adding an SGLT2 inhibitor if the patient has cardiovascular disease, heart failure, or chronic kidney disease, as these provide cardiovascular and renal benefits independent of A1C. 1
• SGLT2 inhibitors can reduce insulin requirements and provide weight benefits. 2

Metformin

• Continue metformin if already prescribed and tolerated, as it provides complementary mechanisms to insulin. 2

Critical Pitfalls to Avoid

• Do not delay insulin intensification while trying multiple oral agents at this A1C level—this prolongs exposure to severe hyperglycemia and increases complication risk. 2
• Do not rely solely on sliding scale insulin without optimizing basal insulin first, as this is ineffective for long-term management. 2
• If the patient develops hypoglycemia on sulfonylureas when intensifying to complex insulin regimens, discontinue the sulfonylurea as it significantly increases hypoglycemia risk. 2, 4
• Prescribe glucagon for emergent hypoglycemia when initiating insulin therapy. 1

Monitoring Requirements

• Check A1C every 3 months to assess treatment effectiveness. 5
• Monitor for hypoglycemia, especially during the first 1-2 months after insulin initiation. 5
• Provide comprehensive diabetes self-management education on insulin injection technique, self-monitoring of blood glucose, and recognition/management of hypoglycemia. 2