What does metformin (biguanide oral hypoglycemic agent) do?

What Metformin Does

Metformin is an antihyperglycemic medication that primarily decreases hepatic glucose production, reduces intestinal glucose absorption, and improves insulin sensitivity in peripheral tissues—all without stimulating insulin secretion or causing hypoglycemia when used alone. 1, 2

Primary Mechanisms of Action

Metformin works through several distinct pathways that collectively lower blood glucose:

• Hepatic effects: Suppresses gluconeogenesis (glucose production) in the liver by potentiating insulin's effects and opposing glucagon action 2, 3
• Intestinal effects: Decreases glucose absorption from the gastrointestinal tract 2, 4
• Peripheral tissue effects: Increases insulin-mediated glucose uptake in skeletal muscle by enhancing glucose transporter movement to cell membranes and improving their function 3, 5
• Insulin levels: Does not increase insulin secretion; fasting insulin levels remain unchanged or may actually decrease during treatment 1, 6

This mechanism is fundamentally different from sulfonylureas or insulin, which work by increasing insulin levels and therefore carry hypoglycemia risk. 1

Clinical Effectiveness

Metformin typically reduces HbA1c by 1.0-1.5 percentage points when used as monotherapy, making it comparable in efficacy to sulfonylureas but with a superior safety profile. 1, 6

Cardiovascular and Mortality Benefits

Beyond glucose control, metformin provides substantial cardiovascular protection:

• Reduces all-cause mortality by 36% and myocardial infarction risk by 39% based on UKPDS data 7
• Decreases risks of microvascular complications, cardiovascular events, and death compared to other first-line agents 1
• These cardiovascular benefits, combined with its glucose-lowering efficacy, establish metformin as the preferred first-line medication for type 2 diabetes when no other specific considerations dictate therapy choice 1

Weight and Metabolic Effects

Metformin is weight-neutral or promotes modest weight loss, a critical advantage over sulfonylureas (which cause ~2 kg weight gain) and insulin. 1, 6

Additional metabolic benefits include:

• Reduces hypertriglyceridemia and suppresses fatty acid oxidation 3
• May improve hepatic steatosis in patients with metabolic dysfunction-associated liver disease 1

Safety Profile and Side Effects

Common Adverse Effects

The principal limitation of metformin is gastrointestinal intolerance (bloating, abdominal discomfort, diarrhea), which can be mitigated by:

• Starting with low doses (500 mg once or twice daily) and titrating gradually 6, 8
• Taking medication with meals 6, 8
• Using extended-release formulations 1, 8

These GI effects are the most common reason for discontinuation but rarely cause serious harm. 1, 9

Vitamin B12 Deficiency

Long-term metformin use is associated with vitamin B12 deficiency, which can worsen neuropathy symptoms in diabetic patients. 1, 6

• Periodic testing of vitamin B12 levels is recommended, especially after 4-5 years of continuous use 6
• This is a commonly overlooked complication that requires proactive monitoring 6

Lactic Acidosis Risk

The most serious but extremely rare complication is lactic acidosis (less than 1 case per 100,000 treated patients). 1, 7

Critical safety parameters for metformin use:

• Safe to use with eGFR ≥30 mL/min/1.73 m² 1, 6
• Must be discontinued if eGFR falls below 30 mL/min/1.73 m² 6
• For eGFR 30-45 mL/min/1.73 m², use lower doses and monitor eGFR every 3-6 months due to increased risk of periodic drops below 30 1, 6
• Temporarily discontinue during acute illness with nausea, vomiting, or dehydration to prevent accumulation 6

The most common prescribing error is failing to adjust or discontinue metformin in patients with declining renal function. 6

Hypoglycemia Considerations

Metformin monotherapy does not cause hypoglycemia because it does not increase insulin secretion. 1, 6

However, hypoglycemia risk increases when metformin is combined with:

• Sulfonylureas or meglitinides 1
• Insulin 1, 6

When initiating metformin in patients already on these medications, reassess the need for and/or dose of the hypoglycemia-causing agents. 1

Clinical Positioning

Metformin remains the preferred first-line medication for type 2 diabetes when the primary goal is glucose lowering without additional comorbidity considerations (such as established cardiovascular disease or chronic kidney disease requiring specific SGLT2 inhibitor or GLP-1 RA therapy). 1

This recommendation is based on:

• Proven efficacy in reducing HbA1c comparable to other oral agents 1
• Superior cardiovascular outcomes and mortality reduction 1, 7
• Weight neutrality or modest weight loss 1, 6
• Low hypoglycemia risk 1
• Extensive safety track record over six decades 4
• Low cost and wide availability 1

When HbA1c is ≥1.5% above goal, dual-combination therapy or more potent agents should be considered rather than metformin monotherapy. 1