What medication to add for uncontrolled diabetes in a patient already taking Trulicity (dulaglutide) and metformin?

Adding a Third Medication for Uncontrolled Diabetes with Trulicity and Metformin

For patients with uncontrolled diabetes already on Trulicity (dulaglutide) and metformin, an SGLT2 inhibitor is the most appropriate medication to add as third-line therapy due to its complementary mechanism of action, cardiovascular benefits, and weight reduction effects.

Rationale for SGLT2 Inhibitor Addition

The American Diabetes Association (ADA) guidelines recommend a patient-centered approach when selecting additional glucose-lowering medications, considering factors such as:

• Efficacy in lowering HbA1c
• Cardiovascular and renal benefits
• Impact on weight
• Risk of hypoglycemia
• Side effect profile
• Cost and patient preferences 1

When a patient is already on metformin and a GLP-1 receptor agonist (like Trulicity) but still has uncontrolled diabetes, adding an SGLT2 inhibitor provides several advantages:

1. Complementary mechanism of action: SGLT2 inhibitors work independently of insulin by increasing urinary glucose excretion, which complements the incretin-based action of GLP-1 RAs 2

2. Cardiovascular benefits: SGLT2 inhibitors have demonstrated significant cardiovascular risk reduction, with empagliflozin reducing major adverse cardiovascular events by 14% and cardiovascular death by 38% in patients with established cardiovascular disease 2

3. Weight reduction: SGLT2 inhibitors provide additional weight loss benefits beyond those already achieved with GLP-1 RAs 3

4. Low hypoglycemia risk: The combination has a low risk of hypoglycemia when added to metformin and GLP-1 RA therapy 4

Evidence Supporting This Approach

A 2022 study demonstrated that adding empagliflozin to patients inadequately controlled on dual therapy provided significant improvements in glycemic control, with a 16.1% decrease in HbA1c compared to only 8.2% decrease without the addition 3. The study also showed a 23.8% decrease in fasting blood sugar and modest weight reduction.

Another study showed that empagliflozin as add-on therapy resulted in HbA1c reductions of 0.09-0.56% compared to placebo, along with significant reductions in fasting plasma glucose and body weight 4.

The 2025 ADA Standards of Care specifically recommends SGLT2 inhibitors for patients with uncontrolled diabetes, particularly those with cardiovascular disease, heart failure, or chronic kidney disease 1.

Specific SGLT2 Inhibitor Options

Among SGLT2 inhibitors, options include:

• Empagliflozin: Strong cardiovascular outcome data, reduces cardiovascular death and hospitalization for heart failure 2
• Canagliflozin: Effective for glycemic control but has warnings about bone fracture risk 5
• Dapagliflozin: Beneficial effects for heart failure patients, including those with preserved ejection fraction 2

Important Considerations and Monitoring

When adding an SGLT2 inhibitor:

• Start at the lowest dose and titrate as needed to minimize side effects
• Monitor for genital mycotic infections, which are more common with SGLT2 inhibitors 4
• Assess renal function before initiation and periodically during treatment
• Educate patients about potential side effects including polyuria and risk of volume depletion
• Monitor HbA1c every 3-6 months to assess efficacy 2

Alternative Options (If SGLT2 Inhibitors Are Contraindicated)

If SGLT2 inhibitors are contraindicated or not tolerated:

1. Basal insulin: Consider if HbA1c remains significantly elevated (≥10%) or if the patient has symptoms of hyperglycemia 1

2. Thiazolidinediones (TZDs): May be considered but carry risks of weight gain, edema, and heart failure 1

3. Sulfonylureas: Lower cost option but higher risk of hypoglycemia and weight gain without cardiovascular benefits 2

Caution

• Avoid DPP-4 inhibitors when already on a GLP-1 RA as they work through similar pathways and should not be prescribed in combination 1
• Monitor for hypoglycemia if adding other agents, particularly if considering insulin or sulfonylureas
• Assess renal function before initiating SGLT2 inhibitors, as their glucose-lowering efficacy decreases when eGFR falls below 45 mL/min/1.73 m² 1

By adding an SGLT2 inhibitor to the combination of metformin and Trulicity, you can achieve better glycemic control while providing additional cardiovascular and renal benefits with minimal risk of hypoglycemia.