Initial Treatment for Type 2 Diabetes
Metformin is the preferred initial pharmacological agent for type 2 diabetes and should be started at or soon after diagnosis, combined with lifestyle modifications including nutrition counseling, weight loss education, and exercise. 1
Treatment Algorithm
Step 1: Assess Disease Severity at Presentation
Mild to Moderate Presentation (A1C <8.5%, no ketosis/acidosis):
- Start metformin immediately at diagnosis 1
- Begin at 500 mg daily, increase by 500 mg every 1-2 weeks up to 2000 mg daily in divided doses 1
- Extended-release formulation can be used once daily for improved GI tolerability 2
- Concurrent lifestyle modifications are essential 1
Severe Presentation (A1C ≥8.5% or blood glucose ≥250 mg/dL with symptoms):
- Initiate insulin therapy immediately (with or without metformin) 1
- Start basal insulin at 0.5 units/kg/day 1
- Add metformin once metabolic stability is achieved 1
Critical Presentation (blood glucose ≥300 mg/dL, A1C ≥10%, or ketoacidosis):
- Insulin is mandatory - basal plus mealtime insulin preferred 1
- Manage ketoacidosis with IV insulin until resolution 1
- Transition to subcutaneous insulin and add metformin after stabilization 1
Why Metformin First?
The evidence supporting metformin as first-line therapy is robust across multiple high-quality guidelines 1:
- Efficacy: Lowers A1C by approximately 1.0-1.5% 3, 4
- Cardiovascular benefit: 36% reduction in all-cause mortality and 39% reduction in myocardial infarction in UKPDS 3
- Weight: Neutral or promotes modest weight loss, unlike sulfonylureas or insulin 1
- Hypoglycemia risk: Minimal when used as monotherapy 1
- Cost: Inexpensive and widely available 1
- Safety: Long-standing evidence base with favorable safety profile 1, 5
Special Considerations for Cardiovascular/Renal Disease
If the patient has established atherosclerotic cardiovascular disease, heart failure, or chronic kidney disease (eGFR ≥30 mL/min/1.73 m²):
- Add SGLT2 inhibitor or GLP-1 receptor agonist with demonstrated cardiovascular benefit to metformin at diagnosis 1
- This recommendation is independent of A1C level 1
- These agents reduce cardiovascular events by 12-26%, heart failure by 18-25%, and kidney disease progression by 24-39% 5
Renal Function Considerations
Metformin can be safely used with reduced kidney function 1:
- eGFR ≥30 mL/min/1.73 m²: Metformin is safe 1
- eGFR 30-45 mL/min/1.73 m²: Reduce dose 1
- eGFR <30 mL/min/1.73 m²: Contraindicated 1
The previous concerns about lactic acidosis have been largely disproven, with incidence less than 1 per 100,000 treated patients 3.
Common Pitfalls to Avoid
Do not delay treatment intensification - if metformin monotherapy at maximum tolerated dose (2000 mg/day) does not achieve A1C target within 3 months, add a second agent immediately 1. The progressive nature of type 2 diabetes means most patients will eventually require combination therapy 1.
Do not overlook GI side effects - metformin causes bloating, abdominal discomfort, and diarrhea in many patients 1. Mitigate this by gradual dose titration or switching to extended-release formulation 1, 2.
Monitor vitamin B12 - metformin use is associated with vitamin B12 deficiency and potential worsening of neuropathy symptoms 1. Consider periodic testing 1.
Do not use metformin alone in severely hyperglycemic patients - when blood glucose is ≥250 mg/dL or A1C ≥8.5% with symptoms, insulin must be initiated first 1.
Pediatric Considerations
For children and adolescents with type 2 diabetes 1:
- A1C <8.5% without ketosis: Start metformin, titrate to 2000 mg/day 1
- A1C ≥8.5% or symptomatic: Start long-acting insulin (0.5 units/kg/day) plus metformin 1
- Ketoacidosis: IV insulin until resolution, then subcutaneous insulin plus metformin 1
- GLP-1 receptor agonists approved for youth ≥10 years can be added if metformin fails 1