Initial Pharmacological Treatment for Type 2 Diabetes
Metformin is the preferred first-line pharmacologic agent for type 2 diabetes and should be initiated at or soon after diagnosis alongside comprehensive lifestyle modifications. 1, 2, 3
Treatment Algorithm Based on Presentation Severity
For Metabolically Stable Patients (A1C <8.5%, Asymptomatic)
Start metformin monotherapy if kidney function is normal (can continue with dose reduction down to GFR 30-45 mL/min, but must discontinue if GFR falls below 30 mL/min). 1, 2, 3
Metformin is inexpensive, has long-established efficacy and safety data, and may reduce cardiovascular events and death. 1, 2, 3
Do not delay pharmacologic therapy while attempting lifestyle modifications alone—initiate metformin at or soon after diagnosis. 2
For Marked Hyperglycemia (Blood Glucose ≥250 mg/dL or A1C ≥8.5%) With Symptoms
Initiate basal insulin immediately while simultaneously starting and titrating metformin. 1, 2, 3
Symptoms warranting this approach include polyuria, polydipsia, nocturia, and/or weight loss. 1
For Severe Presentations
Ketosis/ketoacidosis: Initiate subcutaneous or intravenous insulin to rapidly correct hyperglycemia and metabolic derangement; once acidosis resolves, start metformin while continuing subcutaneous insulin. 1
Severe hyperglycemia (blood glucose ≥600 mg/dL): Assess for hyperglycemic hyperosmolar state and treat accordingly. 1
Concurrent Lifestyle Modifications (Non-Negotiable)
Physical activity: Minimum 150 minutes per week of moderate-intensity aerobic activity, spread over at least 3 days with no more than 2 consecutive days without exercise, plus resistance training at least 2 days per week. 2, 3, 4
Nutrition: Focus on healthy eating patterns emphasizing nutrient-dense foods and decreased consumption of calorie-dense, nutrient-poor foods, particularly sugar-added beverages; implement individualized medical nutrition therapy program, preferably with a registered dietitian. 2, 3, 4
Weight loss: Target 7-10% of baseline body weight for patients with overweight or obesity. 2, 4
Treatment Intensification Timeline
Reassess A1C every 3 months until target is reached, then at least twice yearly if stable. 3, 4
If metformin monotherapy at maximum tolerated dose does not achieve A1C target over 3-6 months, add a second agent (oral agent, GLP-1 receptor agonist, or insulin). 1, 3, 4
For patients with established atherosclerotic cardiovascular disease or indicators of high cardiovascular risk, a GLP-1 receptor agonist is preferred to insulin when possible. 1
Early combination therapy can be considered at treatment initiation to extend time to treatment failure. 1
Critical Pitfalls to Avoid
Do not use insulin as initial therapy in stable patients—it does not address underlying insulin resistance and increases hypoglycemia risk. 2
Do not continue metformin if GFR falls below 30 mL/min without discontinuation. 2, 3
Do not delay treatment intensification for patients not meeting treatment goals—recommendations for intensification should not be delayed. 1
Monitor for vitamin B12 deficiency with long-term metformin use, as it is associated with deficiency and worsening neuropathy symptoms; consider periodic testing. 1
Glycemic Targets
Target A1C <7% for most non-pregnant adults with type 2 diabetes. 3, 4
More stringent targets (<6.5%) may be appropriate for patients with short diabetes duration, long life expectancy, and no significant cardiovascular disease if achievable without significant hypoglycemia. 3, 4
Less stringent targets (<8%) are appropriate for patients with history of severe hypoglycemia, limited life expectancy, advanced complications, or extensive comorbidities. 3, 4