In adults, what laboratory criteria define pre‑diabetes and what clinical indications (e.g., BMI ≥ 35 kg/m², age < 60 years, fasting glucose ≥ 110 mg/dL, HbA1c ≥ 6.0%, history of gestational diabetes, multiple metabolic‑cardiovascular risk factors) warrant starting metformin?

Prediabetes Diagnosis and Metformin Initiation

Defining Prediabetes

Prediabetes is diagnosed when any one of three laboratory thresholds is met: HbA1c 5.7–6.4%, fasting plasma glucose 100–125 mg/dL, or 2-hour oral glucose tolerance test 140–199 mg/dL. 1

Laboratory Criteria

• HbA1c 5.7–6.4% (39–47 mmol/mol) measured in an NGSP-certified laboratory standardized to the DCCT assay 1
• Impaired Fasting Glucose (IFG): 100–125 mg/dL (5.6–6.9 mmol/L) after ≥8-hour fast 1
• Impaired Glucose Tolerance (IGT): 140–199 mg/dL (7.8–11.0 mmol/L) at 2 hours during 75-g oral glucose tolerance test 1

Important nuance: The World Health Organization uses a higher IFG threshold of 110 mg/dL (6.1 mmol/L) rather than 100 mg/dL, reflecting ongoing international debate about optimal cutpoints. 1

Test Selection Considerations

• HbA1c is the most practical screening tool because it requires no fasting and has superior pre-analytical stability compared to glucose measurements 2
• Do not use HbA1c in conditions with altered red cell turnover: pregnancy (second/third trimester), hemoglobinopathies (sickle cell disease/trait), hemodialysis, recent blood loss or transfusion, or erythropoietin therapy—use plasma glucose criteria exclusively in these situations 1, 2
• Fasting glucose has 12–15% day-to-day variability, meaning a single measurement can fluctuate substantially without true metabolic change 2
• OGTT is most sensitive for detecting prediabetes but is cumbersome and less reproducible 2

Who Should Be Screened

Universal Screening Age

• Begin screening at age 45 years for all adults, particularly those with overweight or obesity 1

Earlier Screening Criteria

Screen at any age if BMI ≥25 kg/m² (≥23 kg/m² in Asian Americans) PLUS any one of the following risk factors: 1

• First-degree relative with diabetes 1
• High-risk race/ethnicity (African American, Latino, Native American, Asian American, Pacific Islander) 1
• History of cardiovascular disease 1
• Hypertension (≥140/90 mmHg or on antihypertensive therapy) 1
• HDL cholesterol <35 mg/dL and/or triglycerides >250 mg/dL 1
• Women with polycystic ovary syndrome 1
• Physical inactivity 1
• History of gestational diabetes mellitus 1
• Clinical conditions associated with insulin resistance (severe obesity, acanthosis nigricans) 1

Screening Intervals

• Annual testing for individuals with diagnosed prediabetes 1
• Every 3 years minimum if initial screening is normal 1
• Every 3 years lifelong for women with prior gestational diabetes 1

When to Prescribe Metformin

Metformin should be considered for prediabetes prevention specifically in patients with fasting glucose ≥110 mg/dL (6.1–6.9 mmol/L), HbA1c ≥6.0% (42–46 mmol/mol), history of gestational diabetes, age <60 years, and BMI ≥35 kg/m². 3

Evidence-Based Indications

The Diabetes Prevention Program Outcomes Study demonstrated that metformin significantly decreased diabetes development in specific high-risk subgroups: 3

• Fasting plasma glucose 110–125 mg/dL (6.1–6.9 mmol/L) versus 100–109 mg/dL 3
• HbA1c 6.0–6.4% (42–46 mmol/mol) versus <6.0% 3
• Women with history of gestational diabetes mellitus 3

Critical Considerations Against Universal Metformin Use

Three compelling reasons argue against routine metformin for all prediabetes: 3

1. Approximately two-thirds of people with prediabetes never develop diabetes, even after many years 3
2. Approximately one-third of people with prediabetes return to normal glucose regulation spontaneously 3
3. Prediabetes does not confer risk for microvascular complications (retinopathy, nephropathy, neuropathy), so metformin treatment will not prevent these outcomes 3

The Cardiovascular Disease Connection

The association between prediabetes and cardiovascular disease is mediated through non-glycemic risk factors (hypertension, dyslipidemia, obesity), not the mildly elevated glucose itself. 3, 4 Therefore, the primary clinical approach should target all metabolic risk factors—cholesterol, blood pressure, and weight—rather than glucose alone. 4

Practical Algorithm for Metformin Initiation

Reserve metformin for the highest-risk prediabetes patients: 3

• Fasting glucose ≥110 mg/dL (6.1–6.9 mmol/L) OR
• HbA1c ≥6.0% (42–46 mmol/mol) OR
• History of gestational diabetes mellitus

AND consider these additional high-risk features:

• BMI ≥35 kg/m² 3
• Age <60 years 3
• Multiple metabolic-cardiovascular risk factors 4

Alternative approach: Follow high-risk patients closely with annual testing and introduce metformin immediately only when they meet diagnostic criteria for diabetes (fasting glucose ≥126 mg/dL, HbA1c ≥6.5%, or 2-hour OGTT ≥200 mg/dL). 3

Common Pitfalls to Avoid

• Do not rely on fasting glucose alone in high-risk populations (especially African Americans), as it detects only 27% of prediabetes cases compared to 87% with complete OGTT 5
• Do not use point-of-care HbA1c assays for diagnosis—they lack the analytical precision required 6
• Do not prescribe metformin to all prediabetes patients—prioritize lifestyle intervention (weight reduction, physical activity) as the preferred first-line approach 4
• Do not overlook cardiovascular risk factor management—when prediabetes is identified, concurrently assess and treat hypertension, dyslipidemia, and obesity 1, 4
• Confirm borderline results with repeat testing on a separate day (typically 3–6 months later) given the substantial day-to-day glucose variability 2