Options for Additional Medication for Diabetes After Metformin
After metformin, the preferred additional medications for type 2 diabetes should be selected based on patient-specific factors, with SGLT2 inhibitors or GLP-1 receptor agonists recommended first for patients with cardiovascular disease, heart failure, or chronic kidney disease, while sulfonylureas, thiazolidinediones, DPP-4 inhibitors, or basal insulin are appropriate alternatives depending on individual patient characteristics. 1
First-Line Considerations
- Metformin should be continued as the foundation of therapy when adding second agents, as long as it's tolerated and not contraindicated 1
- For patients with established atherosclerotic cardiovascular disease (ASCVD), heart failure, or chronic kidney disease, an SGLT2 inhibitor or GLP-1 receptor agonist with demonstrated cardiovascular benefit should be added regardless of A1C level 1
- GLP-1 receptor agonists are preferred over insulin when possible due to their lower risk of hypoglycemia, favorable weight effects, and cardiovascular benefits 1
Second-Line Medication Options
SGLT2 Inhibitors (e.g., Empagliflozin)
- Lower A1C by approximately 0.7-1.0% when added to metformin 1, 2
- Provide cardiovascular and renal protection in high-risk patients 1
- Associated with weight loss and low hypoglycemia risk 2
- Particularly beneficial in patients with heart failure 1
GLP-1 Receptor Agonists
- Reduce A1C by approximately 0.7-1.0% when added to metformin 1
- Offer cardiovascular benefits, weight reduction, and low hypoglycemia risk 1
- Preferred over insulin when possible for most patients with type 2 diabetes 1
- Available in injectable forms with varying dosing schedules 1
DPP-4 Inhibitors
- Lower A1C by approximately 0.6-1.1% when added to metformin 3, 4
- Weight-neutral with low risk of hypoglycemia 3
- Well-tolerated with minimal drug-drug interactions 5
- The VERIFY trial demonstrated benefits of early combination of metformin with DPP-4 inhibitor (vildagliptin) 1
Thiazolidinediones (e.g., Pioglitazone)
- Reduce A1C by approximately 0.7-1.0% when added to metformin 6
- Effective in improving insulin sensitivity 1
- Can be used in combination with metformin, sulfonylureas, or insulin 6
- May cause weight gain and fluid retention 1
Sulfonylureas
- Lower A1C by approximately 0.7-1.0% when added to metformin 1
- Inexpensive and widely available 1
- Higher risk of hypoglycemia compared to other options 1
- May cause weight gain 1
Basal Insulin
- Highly effective when hyperglycemia is severe (A1C >10% or blood glucose >300 mg/dL) 1
- Particularly useful when catabolic features are present (weight loss, ketosis) 1
- Can be simplified or changed to oral agents as glucose toxicity resolves 1
- Higher risk of hypoglycemia compared to other options 1
Selection Algorithm Based on Patient Factors
For patients with established ASCVD, heart failure, or CKD:
- First choice: SGLT2 inhibitor or GLP-1 receptor agonist with proven cardiovascular benefit 1
For patients with obesity or where weight gain is a concern:
For patients with high hypoglycemia risk:
For patients with severe hyperglycemia (A1C >10%):
For patients with cost concerns:
Important Considerations
- Treatment intensification should not be delayed if glycemic targets are not met within approximately 3 months 1
- Medication regimens should be reevaluated every 3-6 months and adjusted as needed 1
- Initial combination therapy may be considered for patients with A1C levels 1.5-2.0% above target 1
- Extended-release metformin formulations can improve GI tolerability if that is limiting adherence to metformin 8
- Monitor for vitamin B12 deficiency with long-term metformin use, especially in patients with anemia or peripheral neuropathy 1