What are the side effects of metformin (biguanide oral hypoglycemic)

Metformin Side Effects

Metformin's most common side effects are gastrointestinal—including diarrhea, nausea, vomiting, abdominal discomfort, and flatulence—while long-term use is definitively associated with vitamin B12 deficiency, and rarely, it can cause life-threatening lactic acidosis. 1

Common Gastrointestinal Side Effects

The gastrointestinal adverse effects are the predominant concern with metformin therapy:

• Diarrhea occurs in approximately 30-53% of patients and is the most frequent side effect, sometimes severe enough to require discontinuation in 3.85-6% of cases 1, 2, 3
• Nausea and vomiting affect 8-26% of patients, typically occurring early in treatment 1, 2, 4
• Abdominal discomfort, bloating, and flatulence occur in 6-12% of patients 1, 2
• Metallic taste develops in approximately 3% of patients but is typically transient 2, 3
• Loss of appetite can be problematic, particularly in older adults 5, 6

These gastrointestinal effects generally diminish after several weeks of therapy, but some patients experience persistent symptoms even after prolonged use 1, 4

Vitamin B12 Deficiency

Long-term metformin use is definitively associated with biochemical vitamin B12 deficiency, and the American Diabetes Association recommends periodic measurement of vitamin B12 levels in all metformin-treated patients, especially those with anemia or peripheral neuropathy. 1

• Approximately 7% of patients develop subnormal vitamin B12 levels during treatment 2
• This deficiency can worsen symptoms of peripheral neuropathy in diabetic patients 5, 6
• The mechanism involves interference with vitamin B12 absorption in the intestine 6

Lactic Acidosis: Rare but Life-Threatening

Lactic acidosis is a rare but potentially fatal complication with mortality rates of 30-50% if not promptly treated, occurring in approximately 2-9 cases per 100,000 patient-years. 6, 2

Warning Signs of Lactic Acidosis (Require Immediate Medical Attention):

• Feeling cold in hands or feet 2
• Dizziness or lightheadedness 2
• Slow or irregular heartbeat 2
• Severe weakness or fatigue 2
• Unusual sleepiness or drowsiness 2
• Trouble breathing or hyperventilation 2
• Unexplained stomach pain, nausea, or vomiting 2

High-Risk Conditions for Lactic Acidosis:

• Severe renal impairment (eGFR <30 mL/min/1.73 m²) is an absolute contraindication 1, 6
• Severe heart failure (left ventricular ejection fraction <30%) 6
• Liver dysfunction or impairment 6, 2
• Dehydration from illness, vomiting, or diarrhea 6, 2
• Excessive alcohol consumption (binge drinking or chronic use) 2
• Administration of iodinated contrast agents 6
• Acute conditions: heart attack, severe infection, sepsis, or stroke 6, 2

Less Common Side Effects

• Hypoglycemia is rare with metformin monotherapy but can occur when combined with insulin or sulfonylureas, or in the setting of inadequate food intake or alcohol consumption 2
• Asthenia (weakness) occurs in approximately 9% of patients 2
• Headache affects about 6% of patients 2
• Hepatic injury (cholestatic, hepatocellular, or mixed) has been reported in postmarketing surveillance 2

Clinical Management Strategies to Minimize Side Effects

Start metformin at 500 mg once or twice daily with meals and titrate gradually to the maximum effective dose of 2000-2550 mg/day to minimize gastrointestinal side effects. 1

Specific Strategies:

• Use extended-release formulations, which have significantly fewer GI side effects compared to immediate-release (11.71% vs 26.34% in patients switched from immediate-release) 5, 7
• Take medication with meals to reduce GI symptoms 1
• Consider temporary dose reduction or discontinuation for persistent GI side effects 5, 6
• Instruct patients to stop metformin during acute illness with nausea, vomiting, or dehydration 1, 2

Perioperative and Procedural Considerations

• Stop metformin the night before major surgery and do not restart until 48 hours post-operatively after confirming adequate renal function 6
• Temporarily discontinue before procedures involving iodinated contrast agents 2
• For minor or ambulatory surgery, metformin can be continued except in severe renal failure 6

Common Pitfalls to Avoid

• Do not dismiss chronic diarrhea as irritable bowel syndrome without considering metformin as the cause, as this can lead to unnecessary investigations and misdiagnosis 8
• Do not use metformin when eGFR falls below 30 mL/min/1.73 m², and reduce dose when eGFR is 30-45 mL/min/1.73 m² 1, 6
• Monitor renal function every 3-6 months in patients at risk for kidney function decline 6
• Do not exceed the maximum dose of 2550 mg/day, as higher doses increase risk of lactic acidosis and worsen GI side effects without additional glycemic benefit 6