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 no contraindications, started immediately at diagnosis alongside lifestyle modifications. 1, 2, 3
Metformin Initiation Protocol
Start metformin 500 mg once or twice daily with meals at the time of diagnosis, titrating gradually over several weeks to a target dose of 2,000 mg daily (1,000 mg twice daily or extended-release formulation once daily) to minimize gastrointestinal side effects. 1, 3
Continue metformin indefinitely as the foundation of therapy even when additional agents are added, unless contraindications develop. 1, 3
Metformin reduces all-cause mortality by approximately 36% and cardiovascular mortality by 39% compared with conventional therapy, while being inexpensive and carrying minimal hypoglycemia risk when used alone. 1, 4
Renal-Based Dosing Requirements
eGFR ≥ 45 mL/min/1.73 m²: Use standard dosing up to 2,000 mg daily. 1
eGFR 30–44 mL/min/1.73 m²: Reduce dose by 50% (approximately 1,000 mg daily) and provide sick-day guidance to hold during vomiting, dehydration, or acute illness. 1
eGFR < 30 mL/min/1.73 m²: Discontinue metformin due to lactic acidosis risk. 1, 3
Concurrent Lifestyle Modifications
Target at least 150 minutes per week of moderate-intensity aerobic activity combined with resistance training at least 2 days per week. 2
Aim for 5–10% weight loss from baseline through dietary improvement, restricting calorie intake to approximately 1,500 kcal/day with fat limited to 30–35% of total energy intake. 1, 2
Lifestyle interventions alone can decrease HbA1c by approximately 2% and produce weight loss of 5 kg, making them as effective as many glucose-lowering drugs. 1
When to Add a Second Agent
Re-evaluate glycemic control after 3 months of metformin plus lifestyle modifications. 1, 3
Add an SGLT-2 inhibitor or GLP-1 receptor agonist if HbA1c remains above target (7–8%) after 3 months, as both classes uniquely reduce all-cause mortality and major adverse cardiovascular events with high-certainty evidence. 1, 3
Choosing Between SGLT-2 Inhibitors and GLP-1 Agonists
Prioritize SGLT-2 inhibitors when the patient has congestive heart failure, chronic kidney disease (eGFR 30–90 mL/min/1.73 m²), or needs cardiovascular mortality reduction, as these agents reduce heart failure hospitalization by 18–25% and slow CKD progression by 24–39%. 1, 2, 5
Prioritize GLP-1 receptor agonists (preferably semaglutide or tirzepatide) when the patient has increased stroke risk, needs substantial weight loss (>10% body weight reduction goal), or has established atherosclerotic cardiovascular disease, as this class specifically reduces stroke incidence and achieves greater weight reduction. 1, 2, 5
Exception: High-Risk Patients at Diagnosis
In patients with established cardiovascular disease, heart failure, or chronic kidney disease at diagnosis, add an SGLT-2 inhibitor or GLP-1 receptor agonist to metformin immediately, independent of baseline HbA1c, because both agents provide mortality and morbidity benefits beyond glycemic control. 1, 2, 3
This dual-therapy approach at diagnosis is advised because most high-risk patients rapidly progress to needing combination therapy, and delaying organ-protective agents increases morbidity. 1
Exception: Severe Hyperglycemia at Diagnosis
- Start basal insulin instead of metformin when HbA1c is > 10% (or fasting plasma glucose ≥ 300 mg/dL) with symptomatic hyperglycemia (polyuria, polydipsia, weight loss) or evidence of catabolism, to prevent metabolic decompensation and preserve β-cell function. 2, 3
Glycemic Targets
Target HbA1c between 7% and 8% for most adults with type 2 diabetes, balancing microvascular protection against hypoglycemia and treatment burden. 1, 2, 3
De-intensify therapy when HbA1c falls below 6.5% to avoid hypoglycemia and overtreatment. 1, 2
Critical Safety Monitoring
Perform annual vitamin B12 testing in patients on long-term metformin, especially those with anemia or peripheral neuropathy, because metformin can cause biochemical B12 deficiency. 1, 2
Measure eGFR at baseline, 2 weeks after starting an SGLT-2 inhibitor, then every 3–6 months to monitor renal safety. 1
What NOT to Use
Do not add DPP-4 inhibitors to metformin as second-line therapy because they do not reduce morbidity or all-cause mortality despite lowering HbA1c (strong recommendation, high-certainty evidence). 1, 3
Avoid sulfonylureas as second-line agents in most patients because they are inferior to SGLT-2 inhibitors and GLP-1 agonists for reducing mortality and morbidity, and they increase hypoglycemia risk and cause weight gain. 1, 3
Common Pitfalls to Avoid
Do not discontinue metformin when adding a second agent unless a contraindication develops; combination therapy is supported by evidence. 1, 3
Do not delay treatment intensification beyond 3 months of inadequate control, as treatment inertia increases microvascular complication risk. 2, 3
When SGLT-2 inhibitors or GLP-1 agonists achieve adequate glycemic control, immediately reduce or discontinue sulfonylureas or long-acting insulins due to severe hypoglycemia risk. 1, 2
Self-monitoring of blood glucose is unnecessary when metformin is combined with either an SGLT-2 inhibitor or GLP-1 agonist alone, as these combinations carry minimal hypoglycemia risk. 1, 3