What is the recommended pharmacologic management for impaired fasting glucose in adults, including first‑line therapy, dosing, indications, and alternatives if metformin is contraindicated?

Pharmacotherapy of Impaired Fasting Glucose

Metformin is the recommended first-line pharmacologic therapy for adults with impaired fasting glucose (IFG) who require drug intervention, initiated at 500 mg twice daily with meals and titrated to 2000 mg daily over 3–4 weeks. 1, 2

When to Initiate Pharmacotherapy

• Metformin should be started in adults with IFG when lifestyle modifications (diet and exercise) have failed to achieve glycemic targets after 3–6 months. 1
• For patients with IFG and additional cardiovascular risk factors (hypertension, dyslipidemia, obesity), earlier pharmacologic intervention with metformin is reasonable to reduce progression to type 2 diabetes and cardiovascular events. 1, 3
• IFG is defined as fasting plasma glucose 100–125 mg/dL (5.6–6.9 mmol/L), and both IFG and IGT (impaired glucose tolerance) carry substantially increased risk of progressing to diabetes—approximately 60% of future diabetes cases have either IFG or IGT 5 years prior. 3

First-Line Therapy: Metformin

Dosing and Titration

• Start metformin 500 mg orally twice daily with meals, then increase by 500 mg weekly based on tolerability until reaching 2000 mg daily (the optimal therapeutic dose for most patients). 1, 4, 2
• The maximum FDA-approved dose is 2550 mg daily, but doses above 2000 mg provide minimal additional glycemic benefit and increase gastrointestinal side effects. 4, 2
• For patients with gastrointestinal intolerance, start with 500 mg once daily and titrate more gradually, or consider extended-release formulations. 4, 2

Renal Function Requirements

• Assess estimated glomerular filtration rate (eGFR) before initiating metformin and at least annually thereafter. 1, 2
• Metformin is contraindicated when eGFR <30 mL/min/1.73 m²; initiation is not recommended when eGFR is 30–45 mL/min/1.73 m². 1, 2
• For eGFR 45–59 mL/min/1.73 m², no dose adjustment is needed initially, but monitor renal function every 3–6 months and reduce dose if eGFR declines further. 1, 4

Efficacy and Safety

• Metformin reduces progression from IFG to type 2 diabetes by approximately 31% in randomized controlled trials, though lifestyle intervention (diet and exercise) is more effective with a 58% risk reduction. 3
• Metformin provides cardiovascular mortality benefit, causes weight loss or weight neutrality (not weight gain), and carries minimal hypoglycemia risk when used as monotherapy. 1, 5
• The risk of lactic acidosis with metformin is extremely low (approximately 3 cases per 100,000 patient-years) when prescribing guidelines are followed. 1

Alternatives When Metformin Is Contraindicated

GLP-1 Receptor Agonists

• If metformin is contraindicated (eGFR <30 mL/min/1.73 m² or gastrointestinal intolerance despite extended-release formulation), a GLP-1 receptor agonist is the preferred alternative for patients with IFG and high cardiovascular risk. 1, 6, 7
• GLP-1 receptor agonists (liraglutide, semaglutide, dulaglutide) reduce HbA1c by 0.6–1.5%, promote weight loss of 2–5 kg, and have proven cardiovascular benefits in high-risk populations. 1, 6, 7
• Start semaglutide 0.25 mg subcutaneously weekly, increase to 0.5 mg after 4 weeks, then to 1.0 mg if needed; or start liraglutide 0.6 mg daily, increase to 1.2 mg after 1 week, then to 1.8 mg if needed. 1

SGLT2 Inhibitors

• For patients with IFG and established cardiovascular disease, heart failure, or chronic kidney disease (eGFR ≥20 mL/min/1.73 m²), an SGLT2 inhibitor (empagliflozin, dapagliflozin, canagliflozin) is a reasonable alternative when metformin is contraindicated. 1
• SGLT2 inhibitors reduce HbA1c by 0.5–0.8%, promote weight loss, and provide cardiovascular and renal protection independent of glycemic effects. 1
• Initiate dapagliflozin 10 mg daily or empagliflozin 10 mg daily (can increase to 25 mg if needed); ensure eGFR >20 mL/min/1.73 m² before starting. 1

Agents to Avoid

• Sulfonylureas (glyburide, glipizide, glimepiride) should be avoided in patients with IFG because they cause weight gain, carry high hypoglycemia risk (especially in older adults), and lack cardiovascular benefit. 1
• Thiazolidinediones (pioglitazone) cause weight gain, fluid retention, and increased fracture risk, making them less suitable for IFG management. 1

Monitoring and Follow-Up

• Reassess fasting glucose and HbA1c every 3 months after initiating metformin to determine if glycemic targets are achieved. 1, 4
• If fasting glucose remains ≥126 mg/dL (7.0 mmol/L) or HbA1c ≥6.5% after 3 months on maximum-tolerated metformin dose, the patient has progressed to type 2 diabetes and requires treatment intensification. 1, 4
• Monitor for vitamin B12 deficiency in patients on long-term metformin (>4 years), especially if anemia or peripheral neuropathy develops. 1, 4

Common Pitfalls to Avoid

• Do not delay metformin initiation in patients with IFG and multiple cardiovascular risk factors—early intervention reduces progression to diabetes and cardiovascular events. 1, 3
• Do not prescribe sulfonylureas as first-line therapy for IFG; they increase hypoglycemia risk without proven cardiovascular benefit. 1
• Do not continue metformin if eGFR falls below 30 mL/min/1.73 m²; switch to a GLP-1 receptor agonist or SGLT2 inhibitor (if eGFR ≥20 mL/min/1.73 m²). 1, 2
• Temporarily discontinue metformin before procedures using iodinated contrast in patients with eGFR 30–60 mL/min/1.73 m², history of liver disease, alcoholism, or heart failure; restart 48 hours after the procedure if renal function is stable. 2