What is the role of metformin (biguanide) in managing insulin resistance?

Role of Metformin in Insulin Resistance

Metformin is the preferred first-line pharmacologic agent for managing insulin resistance in type 2 diabetes, primarily working by reducing hepatic glucose production and improving peripheral insulin sensitivity without increasing insulin secretion. 1, 2

Primary Mechanism of Action

Metformin addresses insulin resistance through multiple complementary pathways:

• Reduces hepatic glucose output by suppressing gluconeogenesis and decreasing the activity of hepatic glucose-6-phosphatase, which is the primary mechanism for lowering blood glucose 1, 2
• Improves peripheral insulin sensitivity by increasing insulin-mediated glucose uptake in skeletal muscle through enhanced glucose transporter function and increased glycogen synthase activity 1, 3
• Does not stimulate insulin secretion - insulin levels remain unchanged or may decrease during treatment, distinguishing it from insulin secretagogues 4, 2
• Enhances insulin receptor signaling by increasing insulin receptor tyrosine kinase activity, which activates post-receptor insulin signaling pathways 3

Clinical Efficacy in Insulin Resistance

Metformin reduces HbA1c by 1.0-1.5% in patients with type 2 diabetes, demonstrating robust glycemic control 1

Key clinical benefits include:

• Weight-neutral or promotes modest weight loss, unlike sulfonylureas and thiazolidinediones which cause weight gain 1, 4
• Reduces cardiovascular events and mortality in obese patients with type 2 diabetes, with a 33% reduction in diabetes-related deaths and myocardial infarction compared to conventional therapy 1
• Does not cause hypoglycemia when used alone, though combination with insulin or insulin secretagogues increases hypoglycemia risk 1

Practical Implementation

Start metformin at diagnosis in patients with HbA1c ≥7.5% or when lifestyle modifications are anticipated to be insufficient 1

Dosing strategy to minimize side effects:

• Begin with low dose (500 mg once or twice daily) and gradually titrate upward to reduce gastrointestinal adverse effects 1
• Continue metformin when combining with other agents, including insulin, unless contraindicated 1
• Extended-release formulations may improve tolerability with once-daily dosing 1

Safety Considerations and Contraindications

Metformin is contraindicated when eGFR <30 mL/min/1.73 m² and requires dose reduction when eGFR is 30-45 mL/min/1.73 m² 1, 4

Additional contraindications include:

• Severe liver dysfunction, severe infection, or hypoxia due to increased lactic acidosis risk 1
• Temporarily discontinue before iodinated contrast procedures and major surgery 1
• Avoid in patients with heart failure requiring treatment (though this has been liberalized in recent years) 1

Common pitfalls to avoid:

• Monitor vitamin B12 levels periodically, especially in patients with anemia or peripheral neuropathy, as long-term use causes biochemical B12 deficiency 1, 4, 5
• Gastrointestinal side effects (nausea, diarrhea, abdominal discomfort) occur commonly but can be mitigated by slow dose titration and using extended-release formulations 1, 4
• Lactic acidosis risk is rare but serious - highest risk occurs with renal insufficiency, liver disease, or acute illness with dehydration 1, 4

Special Populations

In obese adolescents and children with insulin resistance, metformin produces modest BMI reductions of approximately 1.1 kg/m² (3% BMI reduction) and may improve markers of insulin resistance 1

In non-diabetic obese patients with normal glucose tolerance, metformin does not improve insulin sensitivity or secretion, suggesting its benefits are primarily in established hyperglycemic states 6

Limitations in Current Practice

While metformin remains guideline-recommended as first-line therapy, patients requiring cardio-renal protection may benefit from initiating SGLT2 inhibitors or GLP-1 receptor agonists as first-line agents instead of or alongside metformin 7