What is the first line treatment for Type 2 Diabetes Mellitus (T2DM)?

First-Line Treatment for Type 2 Diabetes Mellitus

Metformin should be initiated as first-line pharmacologic therapy for newly diagnosed Type 2 Diabetes Mellitus, combined with lifestyle modification (medical nutrition therapy and exercise), unless the patient presents with severe hyperglycemia (HbA1c >9% or fasting glucose ≥11.1 mmol/L) or metabolic decompensation requiring insulin. 1

When to Start Metformin

• Initiate metformin when lifestyle interventions alone fail to achieve glycemic targets (HbA1c <7.0%) 1
• Metformin should be considered specifically in overweight patients with T2DM without established cardiovascular disease and at moderate cardiovascular risk 1
• For patients with established atherosclerotic cardiovascular disease (ASCVD), heart failure, or chronic kidney disease, consider adding an SGLT2 inhibitor or GLP-1 receptor agonist with proven cardiovascular benefit to metformin from the outset 2

Metformin Dosing Strategy

Start low and titrate gradually to minimize gastrointestinal side effects:

• Initial dose: 500 mg once daily with meals 2
• Titration: Increase by 500 mg weekly as tolerated 2
• Target dose: 1000 mg twice daily (2000 mg total daily) 2
• Maximum dose: 2000-2550 mg daily in divided doses 2

Extended-release formulation advantages:

• Once-daily dosing (typically with evening meal) improves adherence 2
• Better gastrointestinal tolerability compared to immediate-release formulation 3
• Provides equivalent glycemic control at comparable total daily doses 3

Renal Function Considerations

Metformin dosing must be adjusted based on estimated glomerular filtration rate (eGFR):

• eGFR ≥60 mL/min/1.73 m²: Continue standard dosing (up to 2000 mg daily) 2
• eGFR 45-59 mL/min/1.73 m²: Consider dose reduction in high-risk patients; monitor eGFR every 3-6 months 1, 2
• eGFR 30-44 mL/min/1.73 m²: Reduce dose to 1000 mg daily (half standard dose) 1, 2
• eGFR <30 mL/min/1.73 m²: Discontinue metformin (contraindicated) 1, 2

The 2016 FDA guidance expanded metformin use in mild-to-moderate kidney disease by using eGFR instead of serum creatinine, but strict monitoring remains essential 1

When Metformin is NOT First-Line

Immediate insulin therapy is required in these scenarios:

• Severe hyperglycemia: HbA1c >9% or fasting plasma glucose ≥11.1 mmol/L with symptomatic hyperglycemia 1
• Metabolic decompensation: Diabetic ketoacidosis or hyperosmolar hyperglycemic state 1
• Inability to distinguish Type 1 from Type 2 diabetes at presentation 1

For these patients, short-term intensive insulin therapy (2 weeks to 3 months) allows β-cell recovery, after which many can transition to metformin-based regimens 1

Contraindications and Precautions

Absolute contraindications:

• eGFR <30 mL/min/1.73 m² 1
• Severe liver dysfunction 1
• Acute conditions: severe infection, sepsis, hypoxia, major surgery 1
• Active heart failure requiring hospitalization 1

Temporary discontinuation required:

• Before iodinated contrast procedures (in patients with eGFR 30-60 mL/min/1.73 m²) 1, 2
• During acute illness compromising renal or hepatic function 2

Monitoring Requirements

• Monitor eGFR at least annually in patients with normal renal function 2
• Increase monitoring to every 3-6 months when eGFR <60 mL/min/1.73 m² 1, 2
• Check vitamin B12 levels periodically, especially after 4+ years of therapy or in patients with anemia/peripheral neuropathy 2

Long-term metformin use can cause vitamin B12 deficiency, which may contribute to neuropathy 1, 2

Why Metformin Remains First-Line

Despite newer agents showing cardiovascular benefits in recent trials, metformin maintains its first-line status due to:

• Proven cardiovascular mortality reduction (36% reduction in all-cause mortality, 39% reduction in myocardial infarction in UKPDS) 4
• Weight-neutral or modest weight loss effect 1, 4
• Minimal hypoglycemia risk when used as monotherapy 1, 4
• Decades of safety data and low cost 5
• Efficacy: reduces HbA1c by 1.0-1.5% 1

Common Pitfalls to Avoid

• Don't delay metformin initiation: Start pharmacotherapy promptly when lifestyle modifications fail to achieve targets within 3 months 1
• Don't ignore gastrointestinal side effects: These are usually transient; starting with low doses and gradual titration minimizes this issue 1, 2
• Don't forget renal monitoring: Failure to adjust doses or discontinue metformin in declining renal function risks lactic acidosis, though this complication is rare (<1 per 100,000 patients) 4
• Don't use metformin alone in high-risk cardiovascular patients: For patients with established ASCVD, heart failure, or advanced CKD, add SGLT2 inhibitors or GLP-1 receptor agonists with proven cardiovascular benefits from the start 1, 2

When to Intensify Beyond Metformin

Add a second agent if glycemic targets are not achieved after 3 months at maximum tolerated metformin dose 2

Choice of second agent depends on patient characteristics:

• Established ASCVD or high cardiovascular risk: Add SGLT2 inhibitor or GLP-1 receptor agonist with proven cardiovascular benefit 1, 2
• Chronic kidney disease: Add SGLT2 inhibitor (reduces CKD progression) or GLP-1 receptor agonist 1
• No cardiovascular disease or CKD: Options include DPP-4 inhibitors, sulfonylureas, α-glucosidase inhibitors, TZDs, or insulin 1

Continue metformin when adding other agents, including insulin, as long as it remains tolerated and not contraindicated 2