What medication can be added to metformin (biguanide) and Jardiance (empagliflozin) for a patient with diabetes?

Adding a Third Medication to Metformin and Jardiance (Empagliflozin) for Type 2 Diabetes

For patients already on metformin and empagliflozin (Jardiance) who need additional glycemic control, a GLP-1 receptor agonist is the preferred medication to add as a third agent, particularly for patients with established cardiovascular disease.

Rationale for Adding a Third Agent

• Type 2 diabetes is a progressive disease, often requiring combination therapy as maintenance of glycemic targets with dual therapy becomes insufficient over time 1
• Each additional medication class typically provides an additional 0.7-1.0% reduction in HbA1c 1
• Triple therapy becomes necessary when dual therapy fails to maintain glycemic control, particularly in patients with higher baseline HbA1c levels 1

Preferred Third Agent Options

First Choice: GLP-1 Receptor Agonist

• GLP-1 receptor agonists are preferred injectable agents over insulin when a third agent is needed, offering similar efficacy with lower risk of hypoglycemia and beneficial effects on body weight 2
• For patients with established atherosclerotic cardiovascular disease (ASCVD), heart failure, or chronic kidney disease, a GLP-1 receptor agonist with demonstrated cardiovascular benefit should be considered regardless of A1C level 1
• GLP-1 receptor agonists provide potent glucose-lowering effects with the additional benefits of weight reduction and minimal hypoglycemia risk 2

Alternative Options:

• DPP-4 inhibitors (e.g., sitagliptin) - well-tolerated with neutral effects on weight and low hypoglycemia risk 3
• Thiazolidinediones (e.g., pioglitazone) - effective for insulin resistance but may cause weight gain and fluid retention 4
• Sulfonylureas - effective but associated with higher risk of hypoglycemia and weight gain 2
• Basal insulin - highly effective when HbA1c levels are significantly elevated (≥10% or ≥86 mmol/mol) or when catabolic features are present 2

Clinical Decision-Making Algorithm

1. Assess cardiovascular risk status:

   • If patient has established ASCVD, heart failure, or CKD: Prioritize a GLP-1 receptor agonist with proven cardiovascular benefits 1
   • If no established cardiovascular disease: Consider patient-specific factors below

2. Consider patient-specific factors:

   • Risk of hypoglycemia: Avoid sulfonylureas if high risk 2
   • Weight concerns: Favor GLP-1 receptor agonists (promote weight loss) over sulfonylureas or insulin (promote weight gain) 2
   • Cost/insurance coverage: May influence medication selection 2
   • Injection preference: If patient prefers oral medications, consider DPP-4 inhibitors 3

3. Evaluate HbA1c level:

   • If HbA1c is ≥10% or patient has catabolic symptoms: Consider insulin 2
   • If HbA1c is moderately elevated: GLP-1 receptor agonists or other oral agents may be sufficient 2

Monitoring and Follow-up

• Regular monitoring of HbA1c every 3-6 months to assess efficacy 1
• Evaluate for medication-specific side effects (e.g., gastrointestinal symptoms with GLP-1 receptor agonists) 2
• Assess for vitamin B12 deficiency in patients on long-term metformin therapy 2
• Treatment regimens should be continuously reviewed for efficacy, side effects, and patient burden 2

Important Considerations

• The combination of metformin and empagliflozin has already demonstrated improved glycemic control with low hypoglycemia risk, reduced body weight, and decreased blood pressure 5, 6
• Adding a GLP-1 receptor agonist to this combination can provide complementary mechanisms of action for more robust glycemic control 2
• Fixed-dose combination formulations, when available, may improve medication adherence 7