What are suitable adjunctive therapies for metformin (biguanide)?

Adjunctive Therapies to Metformin for Type 2 Diabetes

For patients with type 2 diabetes not achieving glycemic targets on metformin alone, a GLP-1 receptor agonist or SGLT2 inhibitor with demonstrated cardiovascular risk reduction should be added as the preferred second agent, especially in patients with established ASCVD, heart failure, or chronic kidney disease. 1

Selection of Adjunctive Therapy Based on Patient Characteristics

First-Line Considerations:

• Metformin remains the preferred initial pharmacologic agent for type 2 diabetes 1
• When metformin alone fails to achieve or maintain glycemic targets after approximately 3 months, add a second agent based on the following patient-specific factors:

For Patients with Established Cardiovascular or Renal Disease:

1. GLP-1 receptor agonists with proven cardiovascular benefit 1

   • Reduces cardiovascular events, promotes weight loss
   • Associated with fewer hypoglycemic events than insulin
   • May cause gastrointestinal side effects

2. SGLT2 inhibitors 1

   • Beneficial in patients with heart failure or chronic kidney disease
   • Promotes weight loss and lowers blood pressure
   • Risk of genitourinary infections and diabetic ketoacidosis

For Patients Without Established Cardiovascular Disease:

Consider the following options based on specific patient needs:

1. Sulfonylureas 1

   • High efficacy, low cost
   • Risk of hypoglycemia and weight gain

2. Thiazolidinediones 1

   • Durable effect on glycemic control
   • Risk of weight gain, edema, heart failure, bone fractures

3. DPP-4 inhibitors 1

   • Weight neutral, well tolerated
   • Lower efficacy for A1C reduction compared to other options

4. Basal insulin 1

   • High efficacy when other agents inadequate
   • Risk of hypoglycemia and weight gain

Special Considerations

For Patients with Markedly Elevated A1C:

• If A1C ≥9% (75 mmol/mol), consider initial dual therapy with metformin plus a second agent 1
• If A1C ≥10% (86 mmol/mol) or blood glucose ≥300 mg/dL (16.7 mmol/L), consider insulin-based therapy, especially if patient shows catabolic features (weight loss, ketosis) 1

For Patients Needing Injectable Therapy:

• GLP-1 receptor agonists are generally preferred over insulin as the first injectable therapy due to:
  • Similar efficacy to insulin
  • Lower risk of hypoglycemia
  • Beneficial effects on weight 1
  • Potential cardiovascular benefits

For Combination Injectable Therapy:

When basal insulin has been titrated to an acceptable fasting blood glucose but A1C remains above target, options include:

• Adding a GLP-1 receptor agonist
• Adding a single injection of rapid-acting insulin before the largest meal
• Switching to twice-daily premixed insulin 1

Practical Implementation

• Start with low doses and titrate gradually to minimize side effects
• Reassess medication regimen every 3-6 months 1
• Consider cost and patient preferences when selecting therapy
• Continue metformin when adding other agents unless contraindicated 1

Common Pitfalls to Avoid

1. Clinical inertia: Don't delay treatment intensification when glycemic targets aren't met 1
2. Overlooking cardiovascular and renal benefits: Prioritize agents with proven cardiovascular or renal benefits in appropriate patients 1
3. Ignoring weight effects: Consider impact on weight when selecting therapy, especially in overweight/obese patients
4. Hypoglycemia risk: Be cautious with sulfonylureas and insulin in patients at high risk for hypoglycemia
5. Neglecting cost considerations: Newer agents (GLP-1 RAs, SGLT2 inhibitors) may be more expensive but offer additional benefits beyond glycemic control

By following this evidence-based approach to selecting adjunctive therapy to metformin, clinicians can optimize glycemic control while addressing individual patient needs and comorbidities.