What are the initial medications for type 2 diabetes (T2D)?

Initial Medications for Type 2 Diabetes (T2D)

Metformin is the preferred initial pharmacological agent for the treatment of type 2 diabetes, unless contraindicated or not tolerated. 1

First-Line Therapy

• Most patients should begin with lifestyle modifications (weight loss education, exercise, dietary changes) alongside pharmacological treatment 1
• Metformin should be started at the time of T2D diagnosis in most patients 1
• Metformin offers several advantages as first-line therapy:
  • Long-established evidence base for efficacy and safety 1
  • Inexpensive compared to newer agents 1
  • May reduce risk of cardiovascular events and mortality 1
  • Weight-neutral or may promote modest weight loss 1, 2
  • Low risk of hypoglycemia when used as monotherapy 2, 3

Metformin Initiation and Dosing

• Start at a low dose and gradually titrate upward to minimize gastrointestinal side effects 2
• Take with meals to improve tolerability 2
• Extended-release formulation may be better tolerated in patients experiencing GI side effects with immediate-release formulation 4
• Can be used safely in patients with eGFR ≥30 mL/min/1.73 m², though dose should be reduced with declining renal function 1
• Monitor vitamin B12 levels periodically, as long-term use may be associated with deficiency 1

Special Circumstances for Initial Therapy

• For patients with markedly symptomatic hyperglycemia, elevated blood glucose (≥300 mg/dL) or HbA1c >10%, consider insulin therapy with or without metformin from the outset 1
• Initial combination therapy (rather than stepwise addition) may be considered when HbA1c is ≥1.5% above target or ≥9% 1

When Metformin Alone Is Insufficient

• If monotherapy with metformin at maximum tolerated dose does not achieve or maintain HbA1c target over 3 months, add a second agent 1
• Options for second-line therapy include:
  • Sulfonylureas (low cost, but risk of hypoglycemia and weight gain) 1
  • Thiazolidinediones (risk of edema, heart failure, fractures) 1
  • DPP-4 inhibitors (weight neutral, low hypoglycemia risk, but higher cost) 1
  • GLP-1 receptor agonists (promote weight loss, but GI side effects and higher cost) 1
  • SGLT2 inhibitors (benefit in cardiovascular disease, promote weight loss) 1
  • Basal insulin (highest efficacy but risk of hypoglycemia and weight gain) 1

Cardiovascular Considerations

• For patients with established atherosclerotic cardiovascular disease, heart failure, or chronic kidney disease, consider SGLT2 inhibitors or GLP-1 receptor agonists with demonstrated cardiovascular benefit as part of the glucose-lowering regimen 1
• These agents may be considered independent of HbA1c levels in patients with these conditions 1

Common Pitfalls and Caveats

• Delaying intensification of therapy when glycemic targets are not met can lead to prolonged hyperglycemia and increased risk of complications 1
• Metformin is contraindicated in patients with severe renal impairment (eGFR <30 mL/min/1.73 m²) due to risk of lactic acidosis, though this complication is rare 1, 2
• Gastrointestinal side effects are common with metformin but can often be managed with dose titration and taking with meals 2, 4
• The progressive nature of T2D means that many patients will eventually require combination therapy or insulin 1
• Regular reassessment of medication regimen (every 3-6 months) is necessary to ensure glycemic targets are being met 1