What first‑line medication should be started for an adult with type 2 diabetes who has a blood glucose of 145 mg/dL (fasting or random)?

First-Line Medication for Type 2 Diabetes with Blood Glucose 145 mg/dL

Start metformin immediately at 500–850 mg once or twice daily with meals, titrating up to 2,000 mg/day over 1–2 weeks as tolerated, while simultaneously implementing lifestyle modifications including 150 minutes of weekly moderate-intensity exercise and a 5–7% weight loss goal. 1, 2

Why Metformin Is the Clear First Choice

• Metformin is the foundation of type 2 diabetes therapy and should be started at diagnosis unless contraindicated, regardless of baseline glucose level. 1, 2
• Metformin decreases hepatic glucose production and sensitizes peripheral tissues to insulin, directly targeting the core pathophysiologic defects of type 2 diabetes. 1, 3
• Metformin has been shown to decrease mortality rates in patients with type 2 diabetes, making it superior to other oral agents as first-line therapy. 3
• The medication is effective, safe, and inexpensive compared to other glucose-lowering agents. 1

Interpreting the Blood Glucose of 145 mg/dL

• A blood glucose of 145 mg/dL (whether fasting or random) indicates mild hyperglycemia that does not require insulin at this stage. 1, 2
• This glucose level is below the threshold for immediate insulin therapy (≥300–350 mg/dL or HbA1c ≥9%), so oral medication is appropriate. 1, 4
• Confirm the diagnosis with either a fasting plasma glucose ≥126 mg/dL, HbA1c ≥6.5%, or 2-hour glucose ≥200 mg/dL on oral glucose tolerance testing if not already established. 2, 5

Metformin Dosing and Titration

• Start with 500–850 mg once or twice daily with meals to minimize gastrointestinal side effects. 1, 3
• Titrate up to 2,000 mg/day (1,000 mg twice daily) over 1–2 weeks as tolerated, which is the maximum effective dose for most patients. 1, 4
• Some patients may benefit from doses up to 2,550 mg/day, though incremental benefit beyond 2,000 mg is modest. 4

Essential Lifestyle Modifications (Not Optional)

• At least 150 minutes per week of moderate-intensity physical activity (e.g., brisk walking) can reduce HbA1c by 0.4–1.0% and improve cardiovascular risk factors. 2, 5
• Target 5–7% weight loss from baseline through a low-fat, reduced-calorie diet with 40–50% complex carbohydrates, 10–20% protein, and monounsaturated fats. 6, 3, 5
• Physical activity increases insulin sensitivity and can reduce insulin requirements by 20–30%. 4

When to Reassess and Intensify Therapy

• Recheck HbA1c after 3 months of metformin plus lifestyle modifications. 1, 4
• If HbA1c remains >7% despite maximum-dose metformin, add a second agent—preferably a GLP-1 receptor agonist or SGLT2 inhibitor if the patient has cardiovascular disease, kidney disease, or high cardiovascular risk. 1, 2
• Do not delay treatment intensification if glycemic targets are not met after 3 months, as prolonged hyperglycemia increases complication risk. 1, 4

Contraindications and Special Situations

• Hold metformin if eGFR <30 mL/min/1.73 m² or in the setting of acute kidney injury, severe infection, or contrast administration. 1, 4
• Metformin can cause vitamin B12 deficiency with long-term use; consider periodic testing, especially if neuropathy symptoms develop. 1
• If metformin is contraindicated or not tolerated, consider a GLP-1 receptor agonist, SGLT2 inhibitor, or DPP-4 inhibitor as alternative first-line therapy. 1, 2

Common Pitfalls to Avoid

• Do not start with a sulfonylurea as first-line therapy, as these agents increase hypoglycemia risk and do not reduce mortality like metformin. 1, 3
• Do not delay metformin initiation while attempting lifestyle modifications alone for more than 3 months, as this prolongs hyperglycemia exposure. 1, 4
• Do not start insulin at this glucose level unless there are signs of severe hyperglycemia (glucose ≥300 mg/dL, HbA1c ≥9%, or catabolic features like weight loss). 1, 4
• Do not use sliding-scale insulin as monotherapy if insulin is eventually needed; this approach is condemned by all major diabetes guidelines. 4

Expected Outcomes with Metformin

• Metformin typically reduces HbA1c by 1.0–1.5% when combined with lifestyle modifications. 3, 2
• Absolute reductions in microvascular disease (3.5%), myocardial infarction (3.3–6.2%), and mortality (2.7–4.9%) have been demonstrated with intensive glucose-lowering strategies over 2 decades. 2
• Most patients achieve fasting glucose <130 mg/dL and HbA1c <7% with metformin monotherapy if started early in the disease course. 1, 3