What medication should I add to a diabetic patient's regimen who has a hemoglobin A1c (HbA1c) level of 9% and is already on metformin (biguanide)?

Adding a Second Medication for a Diabetic Patient with HbA1c of 9% on Metformin

For a diabetic patient with an HbA1c of 9% who is already on metformin, you should add an SGLT2 inhibitor (specifically empagliflozin) or a GLP-1 receptor agonist as the second-line agent, with preference given to empagliflozin due to its cardiovascular benefits and efficacy in lowering HbA1c. 1

Treatment Algorithm

Step 1: Assess Patient Risk Factors

• Determine if the patient has established atherosclerotic cardiovascular disease (ASCVD), high ASCVD risk, heart failure, or chronic kidney disease (CKD) 1
• If any of these conditions are present, strongly favor an SGLT2 inhibitor or GLP-1 receptor agonist with demonstrated cardiovascular benefit 1

Step 2: Select the Appropriate Second-Line Agent

• For patients with established ASCVD or high ASCVD risk:

  • SGLT2 inhibitor (empagliflozin, canagliflozin, dapagliflozin) or GLP-1 receptor agonist (liraglutide, semaglutide, dulaglutide) is recommended 1
  • These agents have demonstrated significant reductions in cardiovascular events in large randomized controlled trials 1

• For patients without established cardiovascular disease:

  • Any of the six preferred treatment options can be considered: sulfonylurea, thiazolidinedione, DPP-4 inhibitor, SGLT2 inhibitor, GLP-1 receptor agonist, or basal insulin 1
  • Each new class of non-insulin agents added to metformin generally lowers A1C by approximately 0.7–1.0% 1

Evidence Supporting SGLT2 Inhibitors (Particularly Empagliflozin)

• Empagliflozin has demonstrated significant cardiovascular risk reduction in patients with type 2 diabetes 1

• In a 104-week trial comparing empagliflozin to glimepiride as add-on to metformin, empagliflozin showed:

  • Non-inferior glycemic control with a slight superiority at week 104 (difference -0.11%) 2
  • Significantly lower risk of hypoglycemia (2% vs 24% with glimepiride) 2
  • Weight reduction of approximately 3.9% compared to 2% weight gain with glimepiride 2

• When added to metformin, empagliflozin 25mg reduced HbA1c by 0.77% compared to placebo after 24 weeks 3

• Empagliflozin 25mg appears to be most effective among SGLT2 inhibitors for HbA1c reduction when combined with metformin 4

Important Considerations and Precautions

• Cost may be a significant factor - SGLT2 inhibitors and GLP-1 receptor agonists are generally more expensive than sulfonylureas 1

• SGLT2 inhibitors should be used with caution in patients with impaired renal function:

  • For empagliflozin: No dose adjustment required for eGFR ≥45 mL/min/1.73m² 1
  • Do not initiate if eGFR <45 mL/min/1.73m² 1

• Potential side effects of SGLT2 inhibitors include:

  • Genital mycotic infections (3.7-4.7% with empagliflozin vs 0% with placebo) 3
  • Urinary tract infections (5.1-5.6% with empagliflozin vs 4.9% with placebo) 3
  • Risk of euglycemic diabetic ketoacidosis, especially when combined with metformin 5

• If an SGLT2 inhibitor is contraindicated or not tolerated, a GLP-1 receptor agonist is preferred over insulin when possible 1

Follow-up and Monitoring

• Evaluate treatment response after approximately 3 months 1
• If HbA1c target is still not achieved, consider triple therapy or intensification to injectable therapies 1
• Regularly reassess the medication regimen every 3-6 months and adjust as needed 1

Remember that treatment intensification should not be delayed for patients not meeting glycemic goals 1. The high HbA1c of 9% indicates a need for prompt and effective intervention to reduce the risk of diabetes-related complications.