How do you interpret diabetes test results for a patient with diabetes, including A1C (hemoglobin A1C) tests, to guide treatment decisions and adjust medication regimens, such as metformin (metformin hydrochloride), sulfonylurea, or pioglitazone (thiazolidinedione)?

Interpreting Diabetes Test Results to Guide Treatment Decisions

A1C testing should be performed routinely in all patients with diabetes—at least twice yearly in those meeting treatment goals with stable control, and quarterly in those whose therapy has changed or who are not meeting glycemic goals, with the treatment goal being an A1C <7% and significant treatment regimen changes warranted when A1C is consistently >8%. 1

A1C Testing Frequency and Interpretation

Testing Schedule

• Perform A1C testing every 3 months to determine whether metabolic control has reached and been maintained within the target range, as A1C reflects mean glycemia over the preceding 2-3 months 1
• Test at least twice yearly in patients meeting treatment goals with stable glycemic control 1
• Test quarterly in patients whose therapy has changed or who are not meeting glycemic goals 1

Understanding A1C Values

The correlation between A1C and mean plasma glucose is critical for interpretation 1, 2:

A1C (%)	Mean Plasma Glucose (mg/dL)	Mean Plasma Glucose (mmol/L)
6%	126-135	7.0-7.5
7%	154-170	8.6-9.5
8%	183-205	10.2-11.5
9%	212-240	11.8-13.5
10%	240-275	13.4-15.5

Note: These values apply only to assay methods certified as traceable to the DCCT reference method 1

Treatment Goals and Decision Points

Target A1C

• The goal of therapy should be an A1C <7% based on the direct relationship between A1C values and risk of chronic complications demonstrated in the DCCT 1
• Physicians should reevaluate and significantly change the treatment regimen in patients with A1C results consistently >8% 1

Medication Adjustment Based on A1C

When A1C is consistently >8%, intensify therapy immediately:

Adding Metformin

• Metformin monotherapy reduces A1C by approximately 1.4% from baseline values around 8.4% 3
• In combination with sulfonylurea (glyburide), metformin produces A1C reductions of 1.7% when added to failing sulfonylurea therapy 3
• Metformin reduces fasting plasma glucose by approximately 53-63.5 mg/dL 3

Adding or Adjusting Sulfonylurea

• When added to metformin, sulfonylurea (gliclazide) produces A1C reductions of approximately 0.77% over 2 years 4
• Combination metformin/sulfonylurea therapy is effective but may require addition of third agent if A1C remains >8% 3

Adding Pioglitazone (Thiazolidinedione)

• Pioglitazone should be considered when A1C remains >7% despite maximal/highest tolerated doses of metformin and sulfonylurea 5
• Pioglitazone addition to metformin/sulfonylurea combination reduces A1C by 0.67-0.78% at 3-6 months 5
• Starting dose of pioglitazone 30 mg daily can be considered (rather than 15 mg) if contraindications do not exist 5
• Pioglitazone produces A1C reductions of 0.89-1.03% when added to either metformin or sulfonylurea over 2 years 4
• Pioglitazone is particularly effective in improving insulin sensitivity, reducing fasting insulin and improving HOMA-S significantly more than metformin 6

Critical Pitfalls and Caveats

When A1C May Be Unreliable

A1C should NOT be used as the sole monitoring tool in the following conditions 7:

• Hemolytic anemias or conditions with shortened erythrocyte lifespan 1, 7
• Recent blood loss or transfusion 7
• Pregnancy (second and third trimesters) 7
• Hemoglobin variants 1, 7
• Hereditary macrocytosis 7

In these situations:

• Use only plasma glucose criteria (fasting plasma glucose, 2-hour post-prandial glucose) for diagnosis and monitoring 7
• Consider fructosamine or glycated serum protein (GSP) testing, which reflects 1-2 weeks of glycemic control 1
• Implement self-monitoring of blood glucose (SMBG) or continuous glucose monitoring (CGM) 7

Assay Quality Requirements

• Use only A1C assay methods certified as traceable to the DCCT reference method through the National Glycohemoglobin Standardization Program (NGSP) 1, 2
• All results should be reported as "% HbA1c" or "% HbA1c equivalents" 1
• Laboratories should participate in College of American Pathologists proficiency testing 1

Recognizing Discordant Results

When A1C does not correlate with clinical situation or SMBG results:

• Consider conditions affecting erythrocyte turnover 1, 7
• Obtain complete blood count to assess mean corpuscular volume and evaluate for hemolysis 7
• Compare A1C with fasting plasma glucose and/or 2-hour oral glucose tolerance test 7
• Marked discrepancies should prompt consideration that the A1C assay may not be reliable for that individual 7

Practical Treatment Algorithm

Step 1: Initial Assessment

• Obtain baseline A1C using NGSP-certified assay 1, 2
• Document baseline fasting plasma glucose 3
• Assess for conditions that may affect A1C reliability 7

Step 2: Treatment Initiation Based on A1C

• A1C 7-8%: Initiate or optimize metformin monotherapy (up to 2550 mg/day) 3
• A1C 8-9%: Consider combination metformin + sulfonylurea 3
• A1C >9%: Consider triple therapy (metformin + sulfonylurea + pioglitazone) or insulin 5, 8

Step 3: Reassessment at 3 Months

• If A1C <7%: Continue current regimen, recheck A1C in 3 months 1
• If A1C 7-8%: Add second agent or optimize doses 3
• If A1C >8%: Significantly change treatment regimen—add third agent or consider insulin 1

Step 4: Long-term Monitoring

• Stable patients (A1C <7%): Test A1C every 6 months 1
• Unstable patients or therapy changes: Test A1C every 3 months 1
• Use point-of-care A1C testing when available for timely treatment decisions 1

Special Considerations for Combination Therapy

Metformin + Sulfonylurea Failure

When A1C remains >7% on maximal doses of metformin and sulfonylurea:

• Add pioglitazone 30 mg daily (can start at 30 mg rather than 15 mg if no contraindications) 5
• Expect A1C reduction of 0.67-0.78% within 3-6 months 5
• Note: Patients with baseline A1C ≥9% are less likely to achieve A1C <7% with pioglitazone addition alone 5

Triple Therapy Considerations

• Triple therapy with metformin + sulfonylurea + pioglitazone can reduce insulin requirements by up to 71.81% in insulin-treated patients 8
• Monitor for hypoglycemia, particularly in patients not adhering to follow-up schedules 8
• Average weight gain with pioglitazone is approximately 2.23 kg 8