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

Common Side Effects of Metformin

Gastrointestinal disturbances are the most common side effects of metformin, including diarrhea (occurring in up to 53% of patients), nausea/vomiting (26%), flatulence (12%), abdominal discomfort (6%), and indigestion (7%). 1

Gastrointestinal Side Effects

• Diarrhea is the most prevalent side effect, leading to discontinuation in approximately 6% of patients 1
• Nausea, vomiting, and flatulence are also commonly reported and can significantly impact quality of life 1
• These side effects are typically mild and transient, often resolving with continued use 2
• GI side effects can occur both during initial therapy and after prolonged treatment periods 3
• About 3% of patients may experience an unpleasant metallic taste (dysgeusia) when starting metformin 1

Management of Gastrointestinal Side Effects

• Starting with a low dose and gradually titrating upward can minimize GI side effects 4
• Taking metformin with meals can help reduce gastrointestinal disturbances 1, 2
• Extended-release formulations may improve GI tolerability compared to immediate-release forms 5
• In a retrospective study, patients switched from immediate-release to extended-release metformin experienced significantly fewer GI side effects (26.34% vs. 11.71%) 5

Serious but Rare Side Effects

Lactic Acidosis

• Lactic acidosis is a rare but potentially fatal complication with mortality rates of 30-50% if not promptly treated 4
• Incidence is very low at less than 1 case per 100,000 treated patients 6
• Risk factors include:
  • Severe kidney problems (eGFR <30 mL/min/1.73 m²) 4
  • Liver impairment 1
  • Heart failure, particularly with left ventricular ejection fraction <30% 4
  • Dehydration, especially during acute illness with fever, vomiting, or diarrhea 1
  • Excessive alcohol consumption 1
  • Administration of iodinated contrast agents 4

Vitamin B12 Deficiency

• Long-term metformin use can lead to vitamin B12 deficiency, occurring in approximately 7% of patients 1
• The American Diabetes Association recommends periodic monitoring of vitamin B12 levels in patients on long-term therapy 6
• B12 deficiency can potentially worsen peripheral neuropathy symptoms 4

Special Considerations

• Metformin rarely causes hypoglycemia when used as monotherapy 1, 4
• Temporary discontinuation is recommended during:
  • Acute illness 6
  • Major surgery (stop the night before and restart 48 hours after confirming adequate renal function) 4
  • Procedures involving iodinated contrast agents 4
• Metformin may be safely used in patients with eGFR as low as 30 mL/min/1.73 m², with dose adjustments recommended for eGFR 30-45 mL/min/1.73 m² 6, 4

Pitfalls and Caveats

• Metformin-induced chronic diarrhea may be misdiagnosed as irritable bowel syndrome or other primary gastrointestinal disorders 7
• Before extensive evaluation of GI problems in patients on metformin, consider temporary discontinuation, dose adjustment, or changing administration timing 3
• Liver injury (cholestatic, hepatocellular, and mixed hepatocellular) has been reported in post-marketing surveillance, though causal relationships are difficult to establish 1