Can gliclazide be added to metformin and Jardiance (empagliflozin) for inadequate glycemic control in type 2 diabetes?

Adding Gliclazide to Metformin and Empagliflozin (Jardiance) for Type 2 Diabetes

Gliclazide can be added to metformin and empagliflozin (Jardiance) for inadequate glycemic control in type 2 diabetes, but it should be considered only after optimizing the current regimen and when other preferred second-line agents like GLP-1 receptor agonists have been considered.

Current Treatment Hierarchy and Considerations

According to the most recent guidelines, the treatment algorithm for type 2 diabetes follows this hierarchy:

1. First-line: Metformin remains the optimal first-line medication 1
2. Second-line: SGLT2 inhibitors (like empagliflozin/Jardiance) or GLP-1 receptor agonists are preferred second-line options due to their cardiorenal benefits 1, 2
3. Third-line: Additional agents based on individual patient factors

When Adding Gliclazide is Appropriate

Adding gliclazide (a sulfonylurea) to metformin and empagliflozin may be considered in the following scenarios:

• When glycemic targets are not achieved with metformin and empagliflozin
• When cost is a significant barrier to GLP-1 receptor agonists
• When rapid improvement in glycemic control is needed
• When other preferred agents are contraindicated

Evidence Supporting Triple Therapy with Gliclazide

The FDA label for empagliflozin (Jardiance) specifically mentions studies where it was used in combination with metformin and a sulfonylurea, demonstrating efficacy and safety in this triple therapy approach 3. In clinical trials:

• Adding empagliflozin to metformin and sulfonylurea provided statistically significant reductions in HbA1c compared to placebo
• The combination resulted in reductions of 0.8% in HbA1c (for both 10mg and 25mg doses of empagliflozin)
• The triple therapy also provided benefits in terms of fasting plasma glucose and body weight 3

Studies specifically examining gliclazide with metformin have shown:

• Significant reductions in HbA1c (from 9.9% to 8.4%) 4
• Improvements in both fasting and postprandial glucose levels 5

Important Precautions When Adding Gliclazide

1. Hypoglycemia risk: The combination of empagliflozin, metformin, and a sulfonylurea increases the risk of hypoglycemia. Monitor blood glucose closely and consider:

   • Starting with a lower dose of gliclazide
   • Educating patients about hypoglycemia symptoms and management
   • Providing clear instructions on timing of medication with meals

2. Weight considerations: While empagliflozin promotes weight loss, sulfonylureas like gliclazide may cause weight gain, potentially offsetting some benefits 3, 6

3. Cardiovascular effects: Empagliflozin has proven cardiovascular benefits, but the addition of sulfonylureas may not provide additional CV protection 2

Monitoring Recommendations

When initiating triple therapy with gliclazide, metformin, and empagliflozin:

• Check HbA1c after 3 months to assess efficacy 1
• Monitor for hypoglycemia, especially in the first few weeks
• Evaluate weight changes
• Assess renal function periodically
• Consider de-intensification of therapy if HbA1c falls below 6.5% 1

Alternative Options to Consider Before Adding Gliclazide

Before adding gliclazide, consider:

1. Optimizing current therapy:

   • Ensuring maximum tolerated dose of metformin
   • Optimizing the dose of empagliflozin

2. Adding a GLP-1 receptor agonist instead of gliclazide:

   • Current guidelines prioritize GLP-1 RAs over sulfonylureas 2
   • GLP-1 RAs offer cardiovascular benefits and weight reduction

3. DPP-4 inhibitors as an alternative with lower hypoglycemia risk (though not preferred over GLP-1 RAs or SGLT2 inhibitors) 1

Conclusion

While gliclazide can be effectively added to metformin and empagliflozin for improved glycemic control, current guidelines suggest considering GLP-1 receptor agonists before sulfonylureas when additional therapy is needed beyond metformin and an SGLT2 inhibitor. However, when cost, access, or other patient factors limit the use of preferred agents, gliclazide represents a reasonable option with proven efficacy in combination therapy.