What are the treatment options for prediabetes with an A1c (hemoglobin A1c) level between 5.7% and 6.4%?

Prediabetes A1C: Definition and Treatment

For prediabetes defined as A1C 5.7-6.4%, intensive lifestyle modification targeting 7% weight loss and 150 minutes weekly of moderate-intensity physical activity is the first-line treatment, with metformin reserved only for high-risk individuals (BMI >35 kg/m², age <60 years, A1C ≥6.0%, or prior gestational diabetes). 1, 2, 3

Diagnostic Criteria

• Prediabetes is diagnosed when A1C is 5.7-6.4% (39-47 mmol/mol), fasting plasma glucose is 100-125 mg/dL, or 2-hour glucose during oral glucose tolerance test is 140-199 mg/dL. 1
• The A1C test must be performed using an NGSP-certified method in an accredited laboratory. 1
• Confirmation with repeat testing is recommended in the absence of unequivocal hyperglycemia. 1

Risk Stratification by A1C Level

• Individuals with A1C 5.7-6.0% have a 5-year diabetes risk of 9-25%, while those with A1C 6.0-6.4% face a 25-50% risk. 1, 2
• Risk increases disproportionately at the higher end of the prediabetes range. 1
• Approximately 10% of people with prediabetes progress to diabetes annually in the US. 3
• Prediabetes is associated with increased cardiovascular disease risk (excess absolute risk of 8.75 per 10,000 person-years) and mortality (7.36 per 10,000 person-years). 3

First-Line Treatment: Intensive Lifestyle Modification

The cornerstone of prediabetes management is referral to an intensive behavioral lifestyle program with specific, measurable goals. 1, 2

Specific Lifestyle Targets

• Achieve and maintain at least 7% loss of initial body weight. 1, 2
• Perform at least 150 minutes per week of moderate-intensity physical activity (such as brisk walking). 1, 2
• A variety of eating patterns featuring individualized reduced-calorie meal plans can be effective. 1

Evidence for Lifestyle Intervention

• Lifestyle modification reduces diabetes incidence by 58% over 3 years (6.2 cases prevented per 100 person-years). 1, 3
• Long-term benefits persist: 43% reduction at 7 years (Finnish DPS), 34% reduction at 10 years, and 27% reduction at 15 years (Diabetes Prevention Program). 1
• The Da Qing study demonstrated 39% reduction in diabetes risk at 30 years. 1
• Lifestyle modification produces larger benefits than metformin. 3

Technology-Assisted Programs

• Certified technology-assisted diabetes prevention programs may be effective and should be considered based on patient preference. 1
• These programs should be covered by third-party payers given their cost-effectiveness. 1

Metformin Therapy: Selective Use Only

Metformin should be reserved for specific high-risk subgroups, not used routinely for all individuals with prediabetes. 2, 3

Specific Criteria for Metformin Consideration

Metformin may be considered when patients meet multiple high-risk criteria:

• BMI >35 kg/m² (metformin was as effective as lifestyle modification in this group) 2
• Age <60 years (metformin was not significantly better than placebo in those ≥60 years) 2
• A1C ≥6.0% or fasting plasma glucose ≥110 mg/dL 2, 3, 4
• History of gestational diabetes (metformin showed equivalent 50% risk reduction to lifestyle) 2

Metformin Efficacy

• Metformin decreases diabetes risk by 3.2 cases per 100 person-years over 3 years. 3
• This represents approximately half the benefit of intensive lifestyle modification. 3

Rationale Against Routine Metformin Use

• Approximately two-thirds of people with prediabetes do not develop diabetes, even after many years. 4
• Approximately one-third of people with prediabetes return to normal glucose regulation. 4
• People with prediabetes are not at risk for microvascular complications of diabetes. 4
• The association between prediabetes and cardiovascular disease is primarily due to associated nonglycemic risk factors (obesity, hypertension, dyslipidemia), not the slightly elevated glucose. 4

Monitoring and Follow-Up

• Annual monitoring for progression to type 2 diabetes is recommended for all individuals with prediabetes. 1, 2
• Recheck A1C in 3 months to assess response to lifestyle changes. 2
• Monitor cardiovascular risk factors including blood pressure, lipids, and smoking status. 2
• Testing should be performed using laboratory-based methods, not point-of-care devices, for diagnosis. 1

Important Caveats

• A1C may be problematic in the presence of hemoglobinopathies or conditions affecting red blood cell turnover. 1
• A1C 5.7-6.4% is less sensitive for detecting at-risk individuals than impaired fasting glucose or impaired glucose tolerance, particularly among non-Hispanic whites (detecting only 9.9% versus 31.4% of African Americans and 35.2% of Hispanics). 5
• Glucose-based testing (fasting or 2-hour post-load) correlates more strongly with insulin resistance and secretion than A1C. 5, 6
• Waist circumference and abdominal obesity significantly modify diabetes risk in prediabetic individuals, particularly in women and men with lower A1C ranges. 7