What are the alternative agents to metformin (biguanide) for glycemic control if it is contraindicated?

Alternative Agents When Metformin is Contraindicated

When metformin is contraindicated, DPP-4 inhibitors, SGLT-2 inhibitors, or GLP-1 receptor agonists should be considered as first-line alternatives, with selection based on patient comorbidities and contraindications. 1

First-Line Alternatives to Metformin

DPP-4 Inhibitors

• Preferred in patients with renal impairment as some can be used without dose adjustment (particularly linagliptin) 1
• Well-tolerated with low risk of hypoglycemia and weight-neutral effects 1
• Dosing considerations:
  • Sitagliptin: 100 mg daily if eGFR >50 mL/min/1.73 m²; 50 mg daily if eGFR 30-50 mL/min/1.73 m²; 25 mg daily if eGFR <30 mL/min/1.73 m² 1
  • Linagliptin: 5 mg daily with no dose adjustment needed for renal impairment 1

SGLT-2 Inhibitors

• Particularly beneficial in patients with:
  • Established atherosclerotic cardiovascular disease 1
  • Heart failure or high risk of heart failure 1
  • Chronic kidney disease (with appropriate eGFR) 1
• Contraindicated in severe renal impairment (eGFR <30 mL/min/1.73 m²) 1
• Provide additional benefits of weight loss and blood pressure reduction 1

GLP-1 Receptor Agonists

• Excellent option for patients with established cardiovascular disease 1
• Provide significant A1C reduction with added benefit of weight loss 1
• Should be avoided in patients with recent heart failure decompensation 1
• Available in once-daily or once-weekly injectable formulations 1

Second-Line Alternatives

Sulfonylureas

• Effective and inexpensive option 1
• Consider glipizide (preferred) or glimepiride at conservative initial doses in renal impairment 1
• Avoid glyburide in renal impairment (contraindicated) 1
• Caution due to hypoglycemia risk, especially in elderly patients 1

Meglitinides (Repaglinide, Nateglinide)

• Short-acting insulin secretagogues that can be used in renal impairment 1
• Initiate conservatively at 0.5 mg (repaglinide) or 60 mg (nateglinide) with meals if eGFR <30 mL/min/1.73 m² 1
• Lower risk of prolonged hypoglycemia compared to sulfonylureas 1

Agents to Avoid or Use with Caution

Thiazolidinediones (TZDs)

• Contraindicated in patients with heart failure due to increased risk of fluid retention and heart failure events 1
• Associated with weight gain, bone fractures, and potential cardiovascular concerns 1

Insulin

• Consider as initial therapy in patients with:
  • Markedly elevated blood glucose (>300 mg/dL) or A1C (>10%) 1
  • Evidence of ongoing catabolism (weight loss) 1
  • Significant hyperglycemic symptoms 1
• May be necessary in severe renal impairment (eGFR <25 mL/min/1.73 m²) 1
• Requires dose reduction in renal impairment (25-50% reduction in total daily dose) 1

Selection Algorithm Based on Patient Characteristics

1. For patients with cardiovascular disease:

   • First choice: SGLT-2 inhibitor or GLP-1 receptor agonist with proven CV benefit 1
   • Second choice: DPP-4 inhibitor (except saxagliptin in heart failure) 1

2. For patients with heart failure:

   • First choice: SGLT-2 inhibitor 1
   • Avoid: TZDs (contraindicated) and certain DPP-4 inhibitors 1

3. For patients with chronic kidney disease:

   • eGFR 30-45 mL/min/1.73 m²: SGLT-2 inhibitor, DPP-4 inhibitor, or GLP-1 receptor agonist 1
   • eGFR <30 mL/min/1.73 m²: DPP-4 inhibitor (dose-adjusted) or insulin 1

4. For elderly patients or those at high risk of hypoglycemia:

   • First choice: DPP-4 inhibitor 1
   • Avoid: Sulfonylureas and insulin if possible 1

Common Pitfalls and Caveats

• Always assess renal function before initiating alternative agents, as many require dose adjustments or are contraindicated in advanced kidney disease 1
• Monitor for specific side effects: hypoglycemia with insulin secretagogues, genital infections with SGLT-2 inhibitors, and gastrointestinal effects with GLP-1 receptor agonists 1
• Consider combination therapy with agents that have complementary mechanisms of action when monotherapy fails to achieve glycemic targets 1
• Reassess therapy regularly and adjust based on A1C, tolerability, and development of new comorbidities 1