What is the recommended first-line therapy for a typical adult patient with type 2 diabetes (T2D)?

First-Line Therapy for Type 2 Diabetes

Metformin is the mandatory first-line pharmacologic therapy for adults with type 2 diabetes, combined with lifestyle modifications (diet and exercise), unless contraindicated or not tolerated. 1, 2

Why Metformin First

• Metformin is the optimal first-line drug based on its proven efficacy, safety profile, low cost, and cardiovascular benefits, including a 36% reduction in all-cause mortality and 39% reduction in myocardial infarction demonstrated in the UKPDS trial 1, 3
• The FDA approves metformin as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients 10 years of age and older with type 2 diabetes 2
• Metformin lowers HbA1c by approximately 1.5% without causing hypoglycemia or weight gain, and works by reducing hepatic glucose production and improving insulin sensitivity 3, 4

How to Start Metformin

• Initiate metformin at a low dose with gradual titration to minimize gastrointestinal side effects (bloating, abdominal discomfort, diarrhea) 1
• Metformin can be safely used in patients with eGFR ≥30 mL/min/1.73 m² per revised FDA labeling 1
• Monitor for vitamin B12 deficiency with long-term use, particularly in patients with anemia or peripheral neuropathy 1, 5

When to Skip Metformin and Start Insulin Instead

• If HbA1c ≥10% or blood glucose ≥300-350 mg/dL with hyperglycemic symptoms (polyuria, polydipsia, weight loss), start insulin therapy immediately 1
• Insulin is mandatory when catabolic features or ketonuria are present, reflecting profound insulin deficiency 1
• Once symptoms resolve, you can often taper insulin and transition to metformin-based therapy 1

When to Add a Second Agent to Metformin

• Add a second agent after 3 months if HbA1c remains above target (7-8% for most adults) on metformin plus lifestyle modifications 5, 6
• The American College of Physicians strongly recommends adding either an SGLT-2 inhibitor or GLP-1 agonist as second-line therapy, as these are the only drug classes that reduce all-cause mortality and major cardiovascular events 5, 6

Choosing Between SGLT-2 Inhibitors and GLP-1 Agonists

Prioritize SGLT-2 inhibitors when:

• The patient has heart failure or is at risk for heart failure (SGLT-2 inhibitors uniquely reduce heart failure hospitalization) 5, 6
• The patient has chronic kidney disease with eGFR ≥30 mL/min/1.73 m² (SGLT-2 inhibitors slow CKD progression) 5, 7
• The patient has established cardiovascular disease (SGLT-2 inhibitors reduce MACE and all-cause mortality) 5, 7

Prioritize GLP-1 agonists when:

• The patient has elevated stroke risk (GLP-1 agonists specifically reduce stroke beyond other CV benefits) 5, 6
• Weight loss is a treatment priority (GLP-1 agonists produce greater weight reduction than SGLT-2 inhibitors, often >10% body weight) 5, 8
• The patient wants to avoid genital mycotic infections (a common SGLT-2 inhibitor side effect) 5

What NOT to Add

• Do not add DPP-4 inhibitors as second-line therapy—they do not reduce death, cardiovascular events, or hospitalizations despite lowering HbA1c 5, 6
• Sulfonylureas and long-acting insulins are inferior to SGLT-2 inhibitors and GLP-1 agonists for mortality and morbidity outcomes 5, 6

Critical Safety Measure When Adding SGLT-2i or GLP-1 agonist

• Reduce or discontinue sulfonylureas or insulin when adding an SGLT-2 inhibitor or GLP-1 agonist to prevent severe hypoglycemia 5, 6
• Self-monitoring of blood glucose is typically unnecessary with metformin plus SGLT-2 inhibitor or GLP-1 agonist, as these combinations carry minimal hypoglycemia risk 5, 6

Target HbA1c

• Aim for HbA1c between 7-8% for most adults with type 2 diabetes 1, 5, 6
• Deintensify treatment if HbA1c falls below 6.5% to avoid overtreatment and hypoglycemia 5, 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 5
• Do not choose medications based solely on HbA1c reduction; prioritize agents that reduce mortality and cardiovascular events 5, 6
• Do not stop metformin when adding a second agent unless eGFR falls below 30 mL/min/1.73 m² or other contraindications emerge 5
• Do not delay treatment intensification—reassess every 3-6 months and adjust accordingly 1, 6