What to add to metformin 1000mg bid and Jardiance (Empagliflozin) 25mg for HbA1c of 8.4%?

Management of Type 2 Diabetes with HbA1c of 8.4%

For a patient with HbA1c of 8.4% already on metformin 1000mg twice daily and Jardiance (empagliflozin) 25mg, the most appropriate next step is to add a GLP-1 receptor agonist to the current regimen.

Assessment of Current Therapy

The patient's current regimen includes:

• Metformin 1000mg twice daily (maximum effective dose)
• Empagliflozin (Jardiance) 25mg daily (maximum dose)

With an HbA1c of 8.4%, the patient is not meeting the recommended target of <7% despite being on maximum doses of two effective medications.

Treatment Algorithm

Step 1: Evaluate Current Regimen

• Current therapy includes metformin (first-line agent) and an SGLT2 inhibitor (empagliflozin)
• Both medications are at maximum effective doses
• HbA1c remains elevated at 8.4%, indicating inadequate glycemic control

Step 2: Add Third Agent

Based on current guidelines, when dual therapy with metformin and an SGLT2 inhibitor does not achieve glycemic targets, the next step is to add a third agent 1, 2:

1. GLP-1 receptor agonist (Preferred option)

   • Provides significant A1c reduction (0.7-1.0%)
   • Offers additional benefits: weight loss, low hypoglycemia risk
   • Complementary mechanism to existing medications
   • For patients with HbA1c between 8-9%, adding a GLP-1 receptor agonist to metformin and SGLT2 inhibitor is particularly effective 2

2. Alternative options (if GLP-1 RA not suitable):

   • DPP-4 inhibitor (less effective than GLP-1 RA)
   • Basal insulin (consider if symptoms of hyperglycemia are present)
   • Sulfonylurea (higher hypoglycemia risk)
   • Thiazolidinedione (fluid retention concerns)

Evidence Supporting This Recommendation

The American Diabetes Association guidelines recommend that when A1c targets are not met with dual therapy, adding a third agent is appropriate 1. For patients with A1c between 8-9%, the addition of a GLP-1 receptor agonist to the current regimen is particularly effective 2.

Research evidence shows that the combination of metformin, SGLT2 inhibitor, and GLP-1 receptor agonist provides complementary mechanisms of action that can effectively lower A1c by an additional 0.7-1.0% beyond dual therapy 1.

Studies specifically examining empagliflozin add-on therapy show that while empagliflozin itself can reduce HbA1c by 0.6-0.8% when added to metformin 3, 4, patients with higher baseline A1c values often require additional therapy beyond dual treatment 5.

Important Considerations

• Monitoring: After adding the third agent, reassess HbA1c in 3 months 1
• Adherence: Confirm patient is taking current medications as prescribed
• Cost: Consider medication cost and insurance coverage, as GLP-1 receptor agonists can be expensive
• Administration: GLP-1 receptor agonists require subcutaneous injection, which may affect patient acceptance
• Contraindications: Screen for personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia type 2 before starting GLP-1 receptor agonist 1

Alternative Approach

If the patient has significant hyperglycemic symptoms or if A1c was >9%, consider initiating basal insulin therapy 1, 2. However, at an A1c of 8.4%, adding a GLP-1 receptor agonist is generally preferred over insulin as it provides similar glycemic efficacy with lower hypoglycemia risk and without weight gain 6.

Common Pitfalls to Avoid

• Therapeutic inertia: Delaying intensification of therapy when targets aren't met can lead to prolonged hyperglycemia and increased risk of complications 1
• Overlooking complementary mechanisms: The combination of metformin (decreases hepatic glucose production), SGLT2 inhibitor (increases urinary glucose excretion), and GLP-1 receptor agonist (enhances insulin secretion, reduces glucagon, delays gastric emptying) provides synergistic effects
• Ignoring patient factors: Consider renal function, cardiovascular risk, and hypoglycemia risk when selecting additional agents

By adding a GLP-1 receptor agonist to the current regimen of metformin and empagliflozin, the patient has the best chance of achieving the target A1c of <7% while minimizing risks of hypoglycemia and weight gain.