What is the reduction in Hemoglobin A1c (HbA1c) with metformin (biguanide) therapy?

From the Guidelines

Metformin typically reduces HbA1c by approximately 1-2 percentage points when used as monotherapy in patients with type 2 diabetes. The exact reduction varies based on several factors including baseline A1c levels, with those having higher initial levels often experiencing greater reductions. Standard dosing of metformin ranges from 500-2550 mg daily, usually divided into two or three doses, with the maximum effect generally seen at doses of 2000 mg daily.

Key Points

• The full glycemic benefit of metformin usually develops over 2-3 months of consistent use 1.
• Metformin works primarily by decreasing hepatic glucose production, improving insulin sensitivity in peripheral tissues, and reducing intestinal glucose absorption.
• For optimal results, metformin should be taken with meals to minimize gastrointestinal side effects, and patients should combine medication with lifestyle modifications including diet and exercise.
• The medication's effectiveness may diminish over time as diabetes progresses, potentially requiring additional medications to maintain glycemic control.

Evidence

• A study published in 2025 found that metformin is effective and safe, and reduces risks of microvascular complications, cardiovascular events, and death 1.
• Another study found that metformin reduces HbA1c levels to a greater extent than DPP-4 inhibitors (mean between-group difference, −0.43% [CI, −0.55% to −0.31%]) 1.

Considerations

• Metformin is contraindicated in patients with renal insufficiency, liver dysfunction, severe infection, or hypoxia, or in patients undergoing major surgery 1.
• The dose of metformin should be reduced if eGFR is 45 to 59 mL/min/(1.73 m2) 1.
• Metformin may be safely used in people with estimated glomerular filtration rate ≥30 mL/min/1.73 m² 1.

From the FDA Drug Label

The results are presented in Table 7 *Not statistically significant Metformin Hydrochloride Tablets (n=141) Placebo (n=145) p-Value FPG (mg/dL) Baseline 241.5 237.7 NS * Change at FINAL VISIT –53.0 6.3 0.001 Hemoglobin A1c (%) Baseline 8.4 8.2 NS * Change at FINAL VISIT –1. 4 0.4 0.001

• Metformin reduces HbA1c by -1.4% compared to placebo in patients with type 2 diabetes mellitus.
• Another study showed that metformin reduces HbA1c by -1.7% compared to baseline in patients with inadequate glycemic control on glyburide 2.

From the Research

Reduction in HbA1c Levels with Metformin

• Metformin monotherapy has been shown to lower HbA1c levels by 1.12% (95% CI 0.92-1.32) compared to placebo 3.
• The addition of metformin to oral therapy has been found to lower HbA1c levels by 0.95% (0.77-1.13) compared to placebo added to oral therapy 3.
• The addition of metformin to insulin therapy has been found to lower HbA1c levels by 0.60% (0.30-0.91) compared to insulin only 3.
• Higher doses of metformin have been associated with a significantly greater reduction in HbA1c levels compared to lower doses, with no significant increase in side effects 3.

Combination Therapy with Metformin

• Combination therapy with metformin and a sulfonylurea has been found to result in a significant reduction in fasting plasma glucose, with a decrease from 154 mg/dL to 132 mg/dL 4.
• Combination therapy with metformin and a dipeptidyl peptidase-4 inhibitor has been found to result in a reduction in HbA1c levels, with 22.2% of patients achieving an HbA1c level of <7% without hypoglycemic events 4.
• Combination therapy with metformin, a sulfonylurea, and a dipeptidyl peptidase-4 inhibitor has been found to result in marked improvements in HbA1c levels, with decreases from 11.1% to 6.1%, 7.9% to 6.0%, and 8.6% to 7.1% in three Japanese patients with type 2 diabetes mellitus 5.

Comparison of Metformin Combination Therapies

• Metformin and sulfonylurea combination therapy has been compared to metformin plus a glucagon-like peptide 1 analogue, with results showing no significant difference in all-cause mortality, cardiovascular mortality, or serious adverse events, but a higher risk of hypoglycemic episodes with the sulfonylurea combination 6.
• Metformin and sulfonylurea combination therapy has been compared to metformin plus a dipeptidyl-peptidase 4 inhibitor, with results showing no significant difference in all-cause mortality, cardiovascular mortality, or serious adverse events, but a higher risk of hypoglycemic episodes with the sulfonylurea combination 6.
• Metformin and sulfonylurea combination therapy has been compared to metformin plus a thiazolidinedione, with results showing no significant difference in all-cause mortality, cardiovascular mortality, or serious adverse events, but a higher risk of hypoglycemic episodes with the sulfonylurea combination 6.