What is the best next step for a patient with type 2 diabetes mellitus not achieving adequate glycemic control on metformin: adding Gliclazide, Sitagliptin, or Empagliflozin?

Empagliflozin is the Best Add-On Therapy for Type 2 Diabetes Not Controlled on Metformin

For a 45-year-old newly diagnosed patient with type 2 diabetes who has inadequate glycemic control after 2 months on metformin, empagliflozin is the recommended add-on therapy over gliclazide or sitagliptin due to its proven benefits in reducing mortality, cardiovascular events, and kidney disease progression. 1

Rationale for Choosing Empagliflozin

• SGLT-2 inhibitors like empagliflozin are strongly recommended as the preferred second-line therapy after metformin by the American College of Physicians and other major guidelines 1, 2
• Empagliflozin specifically is recommended in patients with type 2 diabetes to reduce cardiovascular events and the risk of death 1
• Empagliflozin provides significant benefits beyond glycemic control, including:
  • Reduction in all-cause mortality 1, 2
  • Reduction in major adverse cardiovascular events (MACE) 1, 2
  • Reduction in progression of chronic kidney disease 1, 2
  • Reduction in hospitalization due to heart failure 1, 2
  • Beneficial effects on body weight and blood pressure 3, 4

Comparison with Alternative Options

Empagliflozin vs. Gliclazide (Sulfonylurea)

• Empagliflozin demonstrated superior durability of glycemic control compared to sulfonylureas in long-term studies 4
• Sulfonylureas like gliclazide are associated with significant hypoglycemia risk (24% of patients) compared to empagliflozin (only 2%) 4
• Empagliflozin leads to weight loss (approximately 3-4% from baseline), while sulfonylureas typically cause weight gain 3, 4
• Empagliflozin reduces systolic blood pressure by approximately 3-4 mmHg, while sulfonylureas may increase it 3

Empagliflozin vs. Sitagliptin (DPP-4 inhibitor)

• The American College of Physicians specifically recommends against adding DPP-4 inhibitors like sitagliptin to metformin for reducing morbidity and mortality (strong recommendation; high-certainty evidence) 1
• DPP-4 inhibitors have neutral effects on cardiovascular outcomes, while empagliflozin has proven cardiovascular benefits 1, 2
• Some DPP-4 inhibitors (saxagliptin) are not recommended in patients with high risk of heart failure 1

Dosing and Administration

• Empagliflozin is available in 10 mg and 25 mg tablets for once-daily oral administration 3
• Start with 10 mg once daily, which can be increased to 25 mg once daily if needed for additional glycemic control 3
• Continue metformin at the current effective dose 3
• The combination of empagliflozin with metformin has shown significant reductions in HbA1c (approximately 0.7-0.8% more than metformin alone) 3, 5

Monitoring and Safety Considerations

• Monitor renal function (eGFR) at least annually, with increased frequency to every 3-6 months if eGFR falls below 60 ml/min/1.73 m² 1
• Empagliflozin can be initiated in patients with eGFR ≥20 ml/min/1.73 m² 1
• Common side effects include genital mycotic infections (more common in females) and urinary tract infections 6
• Implement sick day management protocols to prevent dehydration and diabetic ketoacidosis during acute illness 1
• Self-monitoring of blood glucose might be unnecessary in patients receiving metformin combined with empagliflozin unless there are specific concerns about hypoglycemia 1, 2

Target Goals and Follow-up

• Target HbA1c levels between 7% and 8% for most adults with type 2 diabetes 1, 2
• Evaluate response after approximately 3 months of therapy 1
• If glycemic targets are not achieved after 3 months, consider increasing the dose of empagliflozin or adding a third agent (preferably a GLP-1 receptor agonist) 1

By choosing empagliflozin as the add-on therapy to metformin for this patient, you are providing evidence-based care that addresses not only glycemic control but also reduces the risk of cardiovascular events, kidney disease progression, and mortality.