What is the next step in managing a patient with type 2 diabetes on Jardiance (Empagliflozin) and metformin, with an elevated Hemoglobin A1c (HbA1c) level?

Management of Inadequate Glycemic Control on Jardiance and Metformin

Add a GLP-1 receptor agonist to the current regimen of metformin and Jardiance (empagliflozin) 10 mg daily. 1, 2

Rationale for Treatment Intensification

Your patient has an HbA1c of 8.4% on dual therapy with metformin and empagliflozin 10 mg, indicating inadequate glycemic control. The 2018 ADA/EASD consensus guidelines recommend treatment intensification when HbA1c remains ≥1.5% above the individualized target (typically 7.0%) 1. With an HbA1c of 8.4%, this patient clearly meets criteria for adding a third agent 2.

Why GLP-1 Receptor Agonist is the Optimal Choice

The combination of metformin, SGLT2 inhibitor, and GLP-1 receptor agonist addresses multiple pathophysiological defects in type 2 diabetes and provides superior glycemic control compared to other third-line options. 2

• GLP-1 receptor agonists provide significant HbA1c reduction of 1-2% when added to existing therapy 2
• They offer cardiovascular risk reduction in patients with established atherosclerotic cardiovascular disease 1, 2
• GLP-1 receptor agonists promote weight loss rather than weight gain, complementing the weight-neutral to weight-reducing effects of metformin and empagliflozin 1, 2
• The risk of hypoglycemia remains low with this triple combination 1, 2

Alternative Considerations Before GLP-1 RA

Before adding a third agent, consider maximizing the empagliflozin dose from 10 mg to 25 mg daily. 3

• Clinical trials demonstrate that empagliflozin 25 mg provides superior HbA1c reduction compared to 10 mg 3, 4
• In the EMPA-REG OUTCOME trial, both doses showed cardiovascular benefits, but dose-response data support using the higher dose when glycemic control is inadequate 3
• Empagliflozin 25 mg is well-tolerated with a similar adverse event profile to the 10 mg dose 4, 5

Why Not Other Options

Insulin should be reserved for patients who fail triple therapy or present with severe hyperglycemia (HbA1c >10%), significant symptoms, or evidence of catabolism. 1

• At HbA1c 8.4%, this patient does not meet criteria for immediate insulin initiation 1, 6
• GLP-1 receptor agonists achieve equivalent or superior HbA1c reduction compared to basal insulin without the weight gain and hypoglycemia risk 6
• Studies comparing GLP-1 RAs to insulin glargine in patients with HbA1c >9% showed equal or superior efficacy with the GLP-1 RA 6

Sulfonylureas are not recommended due to increased hypoglycemia risk and weight gain. 1

DPP-4 inhibitors provide less robust HbA1c reduction (typically 0.5-0.7%) compared to GLP-1 receptor agonists. 1

Implementation Strategy

1. Uptitrate empagliflozin to 25 mg daily first 3, 4

   • This simple dose adjustment may provide an additional 0.1-0.3% HbA1c reduction 3
   • Reassess HbA1c after 3 months 1, 2

2. If HbA1c remains >7.5% after 3 months, add a GLP-1 receptor agonist 1, 2

   • Select an agent with proven cardiovascular benefits if the patient has established cardiovascular disease 1
   • Start with a low dose and titrate gradually to minimize gastrointestinal side effects 2

3. Monitor HbA1c every 3 months until target is achieved, then every 6 months 1, 2

Common Pitfalls to Avoid

• Therapeutic inertia: Delaying treatment intensification when HbA1c remains above target for >3-6 months leads to prolonged hyperglycemia and increased risk of complications 1, 2
• Premature insulin initiation: Starting insulin before optimizing oral/injectable non-insulin therapies exposes patients to unnecessary hypoglycemia and weight gain 1, 6
• Ignoring cardiovascular benefits: The combination of SGLT2 inhibitor and GLP-1 RA provides additive cardiovascular and renal protection beyond glycemic control 1, 2
• Inadequate dose optimization: Failing to maximize empagliflozin to 25 mg before adding additional agents 3, 4

Monitoring Parameters

• Renal function: Both metformin and empagliflozin require dose adjustment with declining kidney function 2
• Vitamin B12 levels: Check periodically in patients on long-term metformin therapy 2
• Genital mycotic infections and urinary tract infections: More common with SGLT2 inhibitors 3
• Volume status: SGLT2 inhibitors can cause volume depletion, particularly in elderly patients or those on diuretics 3