In a 47‑year‑old woman with type 2 diabetes, hemoglobin A1c 10.2 % despite metformin 1000 mg twice daily and Victoza (liraglutide) 1.8 mg daily who declines insulin, what is the recommended next therapeutic step?

Add a GLP-1 Receptor Agonist to the Current Regimen

For this 47-year-old woman with type 2 diabetes, HbA1c 10.2% despite metformin 1000 mg twice daily and liraglutide (Victoza) 1.8 mg daily who refuses insulin, the recommended next step is to add an SGLT2 inhibitor (empagliflozin, dapagliflozin, or canagliflozin) to the existing regimen.

Current Regimen Assessment

• The patient's HbA1c of 10.2% is markedly above the target of <7% for most adults, indicating that the current dual therapy with metformin and liraglutide is insufficient. 1
• Liraglutide 1.8 mg daily is already at the maximum approved dose, so further dose escalation of the GLP-1 receptor agonist is not possible. 2
• Metformin 1000 mg twice daily (2000 mg total) represents the optimal therapeutic dose and should be continued as foundational therapy. 2

Recommended Treatment Intensification

Add an SGLT2 inhibitor (empagliflozin 25 mg, dapagliflozin 10 mg, or canagliflozin 300 mg daily) to the current metformin + liraglutide regimen. 1, 2

Rationale for SGLT2 Inhibitor Addition

• SGLT2 inhibitors provide an additional HbA1c reduction of approximately 0.5–0.8% when added to existing therapy, which combined with optimization of the current regimen may bring HbA1c closer to target. 1, 2
• These agents offer cardiovascular and renal protection that is independent of glucose lowering, providing organ-protective benefits beyond glycemic control. 1
• SGLT2 inhibitors promote weight loss (typically 2–3 kg) rather than weight gain, which is particularly advantageous in this clinical context. 2
• They carry minimal hypoglycemia risk when used without sulfonylureas or insulin, making them safe for combination with metformin and GLP-1 receptor agonists. 1, 2

Practical Implementation

• Initiate empagliflozin 10 mg daily (can increase to 25 mg after 4 weeks), dapagliflozin 10 mg daily, or canagliflozin 100 mg daily (can increase to 300 mg). 2
• Continue metformin 1000 mg twice daily and liraglutide 1.8 mg daily without interruption. 1, 2
• Verify that estimated glomerular filtration rate (eGFR) is >45 mL/min/1.73 m² before initiating an SGLT2 inhibitor, as this is required per current regulatory guidance. 2
• Educate the patient to stop the SGLT2 inhibitor and seek urgent care if signs of euglycemic diabetic ketoacidosis develop (nausea, vomiting, abdominal pain, dyspnea). 2
• Counsel on genital hygiene to reduce the risk of mycotic infections, which occur in approximately 10% of women taking SGLT2 inhibitors. 3

Monitoring and Follow-Up

• Reassess HbA1c at 3 months after adding the SGLT2 inhibitor; this is the longest acceptable interval before evaluating treatment effectiveness and avoiding therapeutic inertia. 1, 2
• Check renal function (eGFR) at baseline and every 3–6 months, as SGLT2 inhibitors require adequate kidney function for glucose-lowering efficacy. 2, 3
• Monitor for volume depletion, especially in patients taking diuretics or with reduced oral intake. 3

If HbA1c Remains >7% After 3 Months

Despite the patient's refusal of insulin, if HbA1c remains >7% after 3 months of optimized triple therapy (metformin + liraglutide + SGLT2 inhibitor), basal insulin initiation becomes medically necessary. 1, 2

• At that point, engage in shared decision-making to revisit the insulin discussion, emphasizing that:
  • Basal insulin can be started at a low dose (10 units at bedtime) and titrated gradually. 2, 4
  • When combined with metformin and a GLP-1 receptor agonist, insulin requirements are lower (typically 20–30% less) and weight gain is minimized. 2, 5
  • The risk of hypoglycemia is very low when basal insulin is used without sulfonylureas. 1, 2
  • Prolonged exposure to HbA1c >9% significantly increases the risk of microvascular and macrovascular complications. 1, 6

Alternative Consideration: Switch to a More Potent GLP-1 Receptor Agonist

• If cost and insurance coverage permit, consider switching from liraglutide 1.8 mg daily to semaglutide 1.0–2.0 mg weekly or tirzepatide 10–15 mg weekly, as these agents provide superior HbA1c reduction (up to 1.5–2.5%) compared to liraglutide. 2, 6
• This switch, combined with the addition of an SGLT2 inhibitor, may achieve target HbA1c without insulin in some patients. 2, 6
• However, this approach is more expensive and may not be covered by all insurance plans. 2

Critical Pitfalls to Avoid

• Do not discontinue metformin when adding an SGLT2 inhibitor; metformin remains the cornerstone of therapy and provides complementary glucose-lowering through a different mechanism. 1, 2
• Do not add a DPP-4 inhibitor (sitagliptin, linagliptin) to a GLP-1 receptor agonist, as both work through the incretin pathway and no additional benefit is seen with combination therapy. 1, 2
• Do not add a sulfonylurea at this stage, as it would increase hypoglycemia risk and cause weight gain without the cardiovascular benefits of SGLT2 inhibitors. 1, 2
• Do not delay treatment intensification beyond 3 months if HbA1c remains above target, as therapeutic inertia directly increases complication risk. 1, 2
• Do not accept HbA1c 10.2% as adequate control; this level of hyperglycemia requires aggressive intervention to prevent long-term complications. 1, 6

Expected Outcomes with Triple Therapy

• The combination of metformin + liraglutide + SGLT2 inhibitor is expected to reduce HbA1c by an additional 0.5–0.8% from the current level, potentially achieving HbA1c in the range of 9.4–9.7%. 2
• While this represents improvement, it is still above the target of <7%, and the patient should be counseled that insulin may ultimately be necessary to achieve optimal glycemic control. 1, 2
• Weight loss of 2–3 kg is anticipated with SGLT2 inhibitor therapy, which may improve insulin sensitivity and contribute to better glucose control. 2
• Cardiovascular and renal protection from the SGLT2 inhibitor will reduce long-term risk of heart failure, cardiovascular death, and progression of kidney disease. 1