What diabetic medicine can be taken with metformin (biguanide)?

Best Diabetic Medications to Take with Metformin

For patients with type 2 diabetes who need additional medication beyond metformin, a GLP-1 receptor agonist or SGLT2 inhibitor should be added as the preferred second-line agent, especially for those with established cardiovascular disease, heart failure, or chronic kidney disease. 1

Preferred Second-Line Agents

For Patients with Cardiovascular Disease, Heart Failure, or CKD:

• First choice: SGLT2 inhibitors (empagliflozin, canagliflozin, dapagliflozin) 1, 2

  • Reduce cardiovascular events and mortality
  • Particularly beneficial for patients with heart failure
  • Provide moderate A1C reduction (0.7-1.0%)
  • Associated with weight loss
  • Low risk of hypoglycemia

• Alternative first choice: GLP-1 receptor agonists (semaglutide, dulaglutide, liraglutide) 1

  • Demonstrated cardiovascular benefit
  • Provide significant A1C reduction (0.8-1.7%)
  • Associated with weight loss
  • Low risk of hypoglycemia

For Patients Without Established CVD:

• Consider patient-specific factors: 1
  • Need for weight loss: GLP-1 RA or SGLT2 inhibitor
  • Cost concerns: Sulfonylureas (but higher hypoglycemia risk)
  • Elderly or frail patients: DPP-4 inhibitors (weight neutral, low hypoglycemia risk)

Medication Options by Class

SGLT2 Inhibitors

• Examples: Empagliflozin, dapagliflozin, canagliflozin, ertugliflozin 1
• Benefits:
  • Cardiovascular protection
  • Weight loss (2-3 kg)
  • Blood pressure reduction
  • Low hypoglycemia risk
• Cautions:
  • Not recommended for eGFR <30 mL/min/1.73m² 1
  • Risk of genital mycotic infections
  • Risk of euglycemic diabetic ketoacidosis 2

GLP-1 Receptor Agonists

• Examples: Semaglutide, dulaglutide, liraglutide, exenatide 1
• Benefits:
  • Potent A1C reduction
  • Significant weight loss
  • Cardiovascular benefits
  • Low hypoglycemia risk
• Cautions:
  • Injectable (except oral semaglutide)
  • Gastrointestinal side effects
  • Higher cost 1

DPP-4 Inhibitors

• Examples: Sitagliptin, saxagliptin, linagliptin, alogliptin 1
• Benefits:
  • Well tolerated
  • Weight neutral
  • Low hypoglycemia risk
  • Oral administration
• Limitations:
  • Modest A1C reduction (0.5-0.8%) 3, 4
  • No proven cardiovascular benefit 2

Sulfonylureas

• Examples: Glimepiride, glipizide, glyburide 1
• Benefits:
  • Low cost
  • Effective A1C reduction (1.0-1.5%)
• Cautions:
  • Risk of hypoglycemia
  • Weight gain
  • Possible cardiovascular concerns 1

Combination Considerations

• Metformin + SGLT2 inhibitor: 5

  • Complementary mechanisms
  • Additive effects on weight loss
  • Low hypoglycemia risk
  • Empagliflozin 10-25mg with metformin reduces A1C by 0.6-0.7% more than metformin alone

• Metformin + DPP-4 inhibitor: 3, 4

  • Well-tolerated combination
  • Weight neutral
  • Low hypoglycemia risk
  • Reduces A1C by 0.65-1.1% more than metformin alone

• Metformin + GLP-1 RA: 1, 6

  • Potent combination for A1C reduction and weight loss
  • Low hypoglycemia risk
  • Injectable therapy (except oral semaglutide)

Special Considerations

• Monitoring needs:

  • Check vitamin B12 levels periodically in patients on long-term metformin 1, 2
  • Monitor renal function when combining metformin with SGLT2 inhibitors 2
  • Evaluate treatment response after 3 months 2

• Common pitfalls to avoid:

  • Failing to consider cardiovascular and renal benefits beyond A1C reduction
  • Not adjusting doses of sulfonylureas when adding a second agent (increased hypoglycemia risk)
  • Overlooking the need for temporary metformin discontinuation during procedures with iodinated contrast 2
  • Continuing ineffective combinations beyond 3-6 months without reassessment 1

Algorithm for Selection

1. Assess patient for established ASCVD, heart failure, or CKD

   • If present → SGLT2 inhibitor or GLP-1 RA
   • If absent → proceed to step 2

2. Consider key patient factors:

   • Need for weight loss → GLP-1 RA or SGLT2 inhibitor
   • Elderly/frail → DPP-4 inhibitor
   • Cost concerns → Sulfonylurea (with hypoglycemia precautions)
   • Injection aversion → Oral agents (SGLT2i, DPP-4i)
   • Severe hyperglycemia (A1C ≥10%) → Consider insulin 1

3. Evaluate response after 3 months

   • If target not achieved → Consider triple therapy or insulin