First-Line Medication for Type 2 Diabetes
Metformin is the preferred first-line pharmacologic agent for type 2 diabetes if not contraindicated and if tolerated. 1
Initial Treatment Approach
Starting Metformin
- Begin metformin at or soon after diagnosis unless contraindications exist, alongside lifestyle modifications (diet and exercise) 1
- Start with 500 mg once or twice daily with food to minimize gastrointestinal side effects 1, 2
- Titrate gradually by 500 mg weekly until reaching the maximum effective dose of 2000 mg daily (typically 1000 mg twice daily) 1, 2
- Extended-release formulations can be dosed once daily with the evening meal, which may improve adherence and tolerability 2, 3
Why Metformin First
- Reduces cardiovascular events and all-cause mortality by 36% and myocardial infarction by 39% based on UKPDS data 1, 4
- Does not cause hypoglycemia when used as monotherapy 1
- Weight-neutral or promotes modest weight loss, unlike sulfonylureas or insulin 1, 5
- Cost-effective compared to other antidiabetic agents 1
- Lowers HbA1c by 1.0-1.5% versus placebo 1, 5
When to Start Insulin Instead
Bypass metformin and initiate insulin therapy immediately in the following situations 1:
- HbA1c ≥10% at diagnosis 1
- Blood glucose ≥300 mg/dL (16.7 mmol/L) 1
- Symptomatic hyperglycemia with catabolic features (weight loss, polyuria, polydipsia) 1
- Ketonuria present (indicating profound insulin deficiency) 1
Once symptoms resolve with insulin, you can often transition back to metformin-based therapy unless type 1 diabetes is confirmed 1.
Contraindications and Dose Adjustments
Renal Function Considerations
- eGFR ≥60 mL/min/1.73 m²: Continue standard dosing up to 2000 mg daily 2
- eGFR 45-59 mL/min/1.73 m²: Consider dose reduction in high-risk patients 2
- eGFR 30-44 mL/min/1.73 m²: Reduce dose to 1000 mg daily (half the standard dose) 2
- eGFR <30 mL/min/1.73 m²: Discontinue metformin 2
- Monitor eGFR annually if normal, but every 3-6 months if <60 mL/min/1.73 m² 2
Other Contraindications
- Severe liver dysfunction 1
- Acute conditions causing hypoxia: severe infection, sepsis, respiratory failure 1, 6
- Temporarily discontinue before major surgery or iodinated contrast procedures 2
- Hypovolemia or dehydration 6
Common Pitfalls and How to Avoid Them
Gastrointestinal Side Effects
- Start low (500 mg) and go slow with weekly titration to minimize nausea, diarrhea, and abdominal discomfort 1, 2
- If GI intolerance occurs, switch to extended-release formulation which is better tolerated 3
- Take with meals to reduce GI symptoms 1
Vitamin B12 Deficiency
- Monitor vitamin B12 levels periodically, especially after 4+ years of use 1, 2
- Check B12 in patients with anemia or peripheral neuropathy 1, 2
Lactic Acidosis Risk
- While historically feared, lactic acidosis occurs in less than 1 per 100,000 treated patients 4
- Risk is minimized by avoiding use in contraindicated conditions (renal failure, hypoxia, severe infection) 1, 6
When Metformin Monotherapy Is Insufficient
If HbA1c remains above target after 3 months at maximum tolerated metformin dose, add a second agent 1:
- For patients with established cardiovascular disease, heart failure, or chronic kidney disease: Add an SGLT2 inhibitor or GLP-1 receptor agonist with proven cardiovascular benefit 2, 7
- For patients with HbA1c ≥9% at diagnosis: Consider starting dual therapy immediately rather than sequential monotherapy 1
- Continue metformin when adding other agents, including insulin, as long as tolerated and not contraindicated 2
Alternative First-Line Options
If metformin is contraindicated or not tolerated, choose an alternative based on patient-specific factors (cardiovascular disease, heart failure, chronic kidney disease, hypoglycemia risk, weight concerns, and cost) 1. However, recent evidence suggests that in patients requiring cardio-renal protection, SGLT2 inhibitors or GLP-1 receptor agonists may be preferred as first-line therapy even over metformin 7.