What is the recommended first‑line medication for an adult with type 2 diabetes, assuming no contraindications such as severe renal impairment, chronic liver disease, or prior lactic acidosis?

First-Line Medication for Type 2 Diabetes

Metformin is the mandatory first-line pharmacologic therapy for all adults with newly diagnosed type 2 diabetes who have an eGFR ≥30 mL/min/1.73 m² and no contraindications, started immediately at diagnosis alongside lifestyle modifications. 1, 2

Why Metformin Remains First-Line

Metformin's position as first-line therapy is based on compelling mortality data, not just glucose lowering. The UKPDS trial demonstrated that metformin reduces all-cause mortality by 36% and myocardial infarction by 39% compared to conventional therapy—outcomes that matter far more than HbA1c reduction alone. 2, 3

Key Advantages of Metformin

• High efficacy: Lowers HbA1c by approximately 1.5% when used as monotherapy 1
• Minimal hypoglycemia risk: Does not cause hypoglycemia when used alone 1
• Weight neutral or modest weight loss: Achieves 2-3 kg weight reduction, unlike sulfonylureas or insulin 1, 2
• Low cost: Pennies per day, making it accessible to all patients 1, 2
• Cardiovascular benefit: May lower cardiovascular mortality compared to sulfonylurea therapy 1

Practical Initiation and Dosing

Start metformin at 500 mg once or twice daily with meals and titrate gradually to minimize gastrointestinal side effects. 1

• Target dose: 1,000 mg twice daily (2,000 mg/day total) 1, 2
• Maximum dose: 2,550 mg in the U.S., though doses above 2,000 mg provide minimal additional benefit and worse tolerability 1
• Titration schedule: Increase every 1-2 weeks as tolerated 1, 2

Renal Dosing Requirements

eGFR (mL/min/1.73 m²)	Metformin Recommendation
≥45	Standard dosing up to 2,000 mg daily [1,2]
30-44	Reduce dose by 50% (≈1,000 mg daily); provide sick-day guidance [1,2]
<30	Discontinue metformin due to lactic acidosis risk [1,2]

Metformin can be safely used down to eGFR 30 mL/min/1.73 m² based on revised FDA labeling and recent evidence. 1, 2, 4, 5

Critical Safety Considerations

When to Hold Metformin Temporarily

Discontinue metformin during severe illness, vomiting, dehydration, or acute kidney injury to prevent lactic acidosis. 1

• Hold before procedures that may compromise renal function 1
• Hold during hospitalizations with acute illness 1
• Resume only after renal function stabilizes 1

Monitoring Requirements

• Vitamin B12 levels: Check annually in patients on long-term metformin, especially those with anemia or peripheral neuropathy, as metformin causes B12 deficiency 1, 2, 6
• Renal function: Monitor eGFR every 3-6 months, more frequently if borderline 1, 2

Lactic Acidosis Risk

The actual risk of lactic acidosis with metformin is extremely low—approximately 3-10 cases per 100,000 person-years, similar to the background rate in the general diabetes population. 4, 5, 3 Cases occur almost exclusively in the setting of severe acute illness or acute kidney injury, not from chronic use in stable patients with mild-moderate CKD. 1, 4, 5

When NOT to Start with Metformin

Immediate Insulin Indication

If HbA1c ≥10% or blood glucose ≥300-350 mg/dL with hyperglycemic symptoms (polyuria, polydipsia, weight loss), start insulin therapy immediately—either alone or with metformin—to prevent metabolic decompensation. 1, 2, 7

High-Risk Patients at Diagnosis

The European Society of Cardiology recommends that patients with established cardiovascular disease or very high cardiovascular risk may receive an SGLT-2 inhibitor or GLP-1 receptor agonist as first-line therapy at diagnosis, with metformin added later if needed for glycemic control. 1, 7 However, the American Diabetes Association/EASD consensus maintains that metformin should still be started in all newly diagnosed patients, with SGLT-2 inhibitors or GLP-1 receptor agonists added immediately and independent of HbA1c in high-risk individuals. 7

In practice, high-risk patients (established CVD, heart failure, or CKD) should receive both metformin AND an SGLT-2 inhibitor or GLP-1 agonist at diagnosis, as dual therapy is supported by the strongest evidence. 2, 7

What Comes After Metformin

Re-evaluate glycemic control after 3 months of metformin plus lifestyle modifications. 2, 7, 6

If HbA1c remains >7-8% after 3 months, add either an SGLT-2 inhibitor or GLP-1 receptor agonist—these are the ONLY second-line agents that reduce all-cause mortality and major cardiovascular events. 2, 7, 6

Choosing Between SGLT-2 Inhibitors and GLP-1 Agonists

• Prefer SGLT-2 inhibitor: Heart failure (especially reduced ejection fraction), chronic kidney disease (eGFR 30-90), or need for heart-failure hospitalization reduction 2, 7, 6
• Prefer GLP-1 agonist: Elevated stroke risk, need for significant weight loss (>10% body weight), or preference to avoid genital mycotic infections 2, 7, 6
• Either is appropriate: Established atherosclerotic cardiovascular disease, as both reduce MACE and all-cause mortality equally 2, 7, 6

Common Pitfalls to Avoid

• Do not wait indefinitely on failing metformin monotherapy: Add a second agent after 3 months if HbA1c is not at goal 2, 6
• Do not add DPP-4 inhibitors: They do not reduce mortality or morbidity despite lowering HbA1c 2, 7, 6
• Do not continue full-dose sulfonylureas or insulin when adding SGLT-2 inhibitors or GLP-1 agonists: Reduce or discontinue to prevent severe hypoglycemia 2, 7, 6
• Do not stop metformin when adding a second agent: Continue metformin unless eGFR falls below 30 or contraindications develop 2, 7, 6

Target HbA1c

Aim for HbA1c between 7-8% for most adults with type 2 diabetes. 1, 2, 7, 6 This range balances microvascular protection against hypoglycemia risk and treatment burden.

Deintensify treatment if HbA1c falls below 6.5% to avoid hypoglycemia and overtreatment. 1, 2, 7, 6