When should medication be started in an adult with prediabetes who, after 3–6 months of intensive diet, ≥5–7 % weight loss and regular aerobic activity, still has fasting glucose 110–125 mg/dL or glycated hemoglobin ≥6.0 % (42 mmol/mol), or who has high‑risk features such as BMI ≥35 kg/m², age < 60 years, prior gestational diabetes, fasting glucose ≥115 mg/dL, glycated hemoglobin ≥6.2 % (44 mmol/mol) or rapid progression, assuming estimated glomerular filtration rate ≥45 mL/min/1.73 m²?

When to Start Medication in Prediabetes

Metformin should be started in adults with prediabetes who meet high-risk criteria: age 25–59 years with BMI ≥35 kg/m², prior gestational diabetes, fasting glucose ≥110 mg/dL, or A1C ≥6.0%, especially after lifestyle modification has been attempted. 1, 2

High-Risk Features That Trigger Medication Consideration

The American Diabetes Association identifies specific populations where pharmacotherapy becomes essential rather than optional:

• Age 25–59 years with BMI ≥35 kg/m²: In this subgroup from the Diabetes Prevention Program, metformin was as effective as intensive lifestyle modification, with crude diabetes incidence of 14–22 cases per 100 person-years without intervention. 1, 2

• Prior gestational diabetes: Women with GDM history achieved 50% diabetes risk reduction with metformin that was maintained over 10–15 years, equivalent to intensive lifestyle intervention. 1, 2

• Fasting glucose ≥110 mg/dL or A1C ≥6.0%: These higher baseline glycemic markers identify patients who experienced greater risk reductions with metformin in 15-year DPPOS follow-up. 1, 2

• A1C ≥6.2% or fasting glucose ≥115 mg/dL: These thresholds represent particularly high progression risk, with crude incidence reaching 14–22 cases per 100 person-years. 1

The Algorithmic Approach to Medication Initiation

Step 1: Confirm Prediabetes Diagnosis

• Fasting glucose 100–125 mg/dL, A1C 5.7–6.4%, or 2-hour OGTT glucose 140–199 mg/dL. 2

Step 2: Implement Lifestyle Modification First

• All patients should receive intensive lifestyle intervention targeting 5–7% weight loss and ≥150 minutes weekly of moderate physical activity. 1
• Reassess after 3–6 months of documented lifestyle efforts. 1

Step 3: Identify High-Risk Features

Start metformin immediately if ANY of the following are present:

• Age 25–59 years AND BMI ≥35 kg/m². 1, 2
• Prior gestational diabetes (regardless of current BMI). 1, 2
• Fasting glucose ≥110 mg/dL. 1, 2
• A1C ≥6.0% (42 mmol/mol). 1, 2

Consider metformin strongly if multiple moderate-risk features:

• Age 25–59 years with BMI 30–34.9 kg/m². 2
• Fasting glucose 105–109 mg/dL. 2
• A1C 5.8–5.9%. 2
• Rapid progression of glucose levels over 6–12 months. 1

Step 4: Verify No Contraindications

• eGFR must be ≥45 mL/min/1.73 m² (≥30 for initiation, dose-adjust if 30–44). 2
• No hepatic dysfunction, severe infection, or hypoxia. 2

Step 5: Initiate and Titrate Metformin

• Start 500 mg once or twice daily with meals. 2
• Titrate gradually to target 1500–2000 mg daily to minimize gastrointestinal effects. 2
• Monitor vitamin B12 levels periodically, especially after 4–5 years or if anemia/neuropathy develops. 1, 2

Evidence Strength and Nuances

The 2025 American Diabetes Association guidelines represent the most current recommendation, upgrading pharmacotherapy from "may be considered" to "should be considered" for high-risk groups. 1 This reflects strengthening evidence from long-term DPPOS follow-up showing sustained benefit and narrowing effectiveness gap between metformin and lifestyle modification over time. 1, 2

Critical distinction by age: In the community-based ARIC study of older adults (mean age 75 years) with prediabetes, only 9% progressed to diabetes over 6 years, with regression to normoglycemia or death more common than progression. 1, 3 This contrasts sharply with the 29% 3-year diabetes incidence in younger DPP participants. 1 Therefore, medication is most justified in adults under 60 years where progression risk substantially outweighs competing mortality risk. 1

Common Pitfalls to Avoid

• Don't wait indefinitely for lifestyle modification alone: If high-risk features are present (BMI ≥35, prior GDM, FG ≥110, A1C ≥6.0), metformin should be started concurrently with lifestyle intervention, not sequentially after failure. 1, 2

• Don't use metformin in older adults (≥75 years) without careful risk-benefit assessment: Progression rates are substantially lower and competing risks higher in this population. 1, 3

• Don't forget B12 monitoring: Long-term metformin (≥4–5 years) causes biochemical B12 deficiency; check levels periodically, especially in patients with anemia or peripheral neuropathy. 1, 2

• Don't overlook cardiovascular risk factors: Prediabetes confers heightened cardiovascular risk independent of diabetes progression; screen and treat hypertension, dyslipidemia, and tobacco use. 1

Additional Pharmacotherapy Options

Beyond metformin, other agents have demonstrated diabetes prevention efficacy but lack the same guideline support:

• GLP-1 receptor agonists (liraglutide) reduce diabetes incidence but are not routinely recommended for prediabetes prevention. 1

• Weight loss medications (orlistat, phentermine-topiramate) decrease diabetes incidence and may support person-centered care goals when weight management is prioritized. 1

• Pioglitazone may be considered specifically in patients with prior stroke, insulin resistance, and prediabetes to reduce recurrent stroke/MI risk, though weight gain, edema, and fracture risks require careful consideration. 1