What are alternative medications for type 2 diabetes (T2D) patients who cannot take metformin (biguanide)?

Alternative Medications for Type 2 Diabetes When Metformin Cannot Be Used

For patients who cannot take metformin, SGLT2 inhibitors are the preferred alternative for most patients with type 2 diabetes, particularly those with chronic kidney disease (eGFR ≥20 mL/min/1.73 m²), as they provide cardiovascular and renal protection independent of glucose lowering. 1

First-Line Alternatives to Metformin

SGLT2 Inhibitors (Preferred Option)

• SGLT2 inhibitors should be initiated in most patients with type 2 diabetes and CKD with eGFR ≥20 mL/min/1.73 m², independent of HbA1c or need for additional glucose lowering. 1
• These agents reduce CKD progression, heart failure, and cardiovascular disease risk independent of their glucose-lowering effects. 1
• The cardiovascular and kidney benefits are consistent regardless of baseline albuminuria, including patients with normal albumin excretion. 1
• Available agents include canagliflozin, dapagliflozin, and empagliflozin, with specific eGFR thresholds varying by agent. 1
• Common pitfall: Glucose-lowering efficacy decreases as eGFR declines, but cardiovascular and kidney benefits persist. 1

GLP-1 Receptor Agonists (Strong Second Choice)

• Long-acting GLP-1 receptor agonists (dulaglutide, liraglutide, semaglutide) are the preferred add-on therapy for patients not achieving glycemic targets or unable to use metformin/SGLT2 inhibitors. 1
• These agents reduce major adverse cardiovascular events (MACE) in patients with type 2 diabetes, with benefits extending to those without established cardiovascular disease. 1
• GLP-1 receptor agonists reduce albuminuria and slow eGFR decline. 1
• Liraglutide showed significantly greater MACE risk reduction in patients with eGFR <60 mL/min/1.73 m² compared to those with eGFR ≥60 mL/min/1.73 m². 1
• Most formulations require no dose adjustment for renal impairment, except exenatide (avoid once-weekly formulation with eGFR <30 mL/min/1.73 m²). 1
• Weight loss benefit without increased hypoglycemia risk when used alone. 1

Traditional Second-Line Options

Sulfonylureas

• Sulfonylureas reduce HbA1c by 1.0-1.5% and are appropriate for patients who cannot tolerate metformin, but carry significant hypoglycemia risk. 1, 2
• Available agents in most markets include glimepiride, gliclazide, glipizide, and gliquidone. 1
• Glimepiride has a dosage range of 0.5-8 mg/day, with little efficacy difference between 4 and 8 mg/day. 2
• Major caveat: High risk of hypoglycemia (10-20% with monotherapy, >50% when combined with insulin), particularly in elderly patients and those with renal/hepatic dysfunction. 1, 2
• Cause moderate weight gain. 1
• Gliquidone is preferred for patients with mild renal insufficiency. 1
• Comparative data suggest metformin + sulfonylurea combination may increase overall mortality. 3
• Cost advantage: Low cost compared to newer agents. 1

Thiazolidinediones (TZDs)

• TZDs (rosiglitazone, pioglitazone) reduce HbA1c by 0.7-1.0% in Chinese patients. 1
• Do not cause hypoglycemia when used alone. 1
• Significant safety concerns: edema, heart failure, bone fractures, and potential bladder cancer risk with pioglitazone. 1, 3
• Cause weight gain and fluid retention, more pronounced when combined with insulin. 1
• Should be avoided in patients with heart failure or at risk for fractures. 1

DPP-4 Inhibitors

• Reduce HbA1c by approximately 0.7% on average. 1, 3
• Low hypoglycemia risk and weight neutral. 1
• Require dose adjustment for renal impairment (except linagliptin). 1
• Saxagliptin may increase risk of heart failure and fractures. 3
• Potential safety signals for pancreatitis and pancreatic cancer remain unresolved. 3
• High cost relative to efficacy. 1

Insulin Therapy

When to Consider Insulin

• Insulin should be initiated without delay in patients with markedly symptomatic diabetes, HbA1c ≥10%, or blood glucose ≥300 mg/dL (16.7 mmol/L). 1
• Basal insulin added to oral therapy lowers HbA1c by 0.7-2.5% on average. 3
• Major drawbacks: highest risk of hypoglycemia and weight gain among all glucose-lowering agents. 1
• Variable cost depending on formulation. 1

Clinical Decision Algorithm

Step 1: Assess for cardiovascular disease, heart failure, or chronic kidney disease

• If present: Prioritize SGLT2 inhibitor (if eGFR ≥20 mL/min/1.73 m²) 1
• Consider adding GLP-1 receptor agonist if additional glucose lowering needed 1

Step 2: If no cardiovascular/kidney disease and patient needs moderate glucose lowering

• GLP-1 receptor agonist preferred if weight loss desired 1
• Sulfonylurea if cost is primary concern and hypoglycemia risk acceptable 1

Step 3: If severe hyperglycemia (HbA1c ≥10% or glucose ≥300 mg/dL)

• Initiate insulin therapy with or without additional agents 1

Step 4: Avoid in specific populations

• TZDs: avoid in heart failure, fracture risk 1, 3
• Sulfonylureas: use cautiously in elderly, renal/hepatic impairment 1, 2
• DPP-4 inhibitors: limited role given modest efficacy and cost 3

Key Monitoring Considerations

• SGLT2 inhibitors: Monitor for genital mycotic infections, volume depletion, and diabetic ketoacidosis (rare). 1
• GLP-1 receptor agonists: Gastrointestinal side effects common initially; monitor for pancreatitis symptoms. 1, 3
• Sulfonylureas: Frequent glucose monitoring essential due to hypoglycemia risk. 1, 2
• All agents: Adjust dosing based on renal function per specific agent requirements. 1