Three Side Effects of Metformin
The three most clinically significant side effects of metformin in an adult patient with type 2 diabetes are: (1) gastrointestinal disturbances including diarrhea and nausea, (2) vitamin B12 deficiency with long-term use, and (3) lactic acidosis (rare but potentially fatal).
1. Gastrointestinal Side Effects
Diarrhea, nausea, vomiting, flatulence, and abdominal discomfort are the most common adverse reactions, occurring in up to 53% of patients for diarrhea and 26% for nausea/vomiting in clinical trials 1.
These gastrointestinal symptoms are dose-dependent and typically mild and transient, though they led to discontinuation in 6% of patients in clinical trials 1, 2.
Starting with a low dose and gradually titrating upward, taking medication with meals, or switching to extended-release formulation can minimize these effects 3.
The American Diabetes Association recommends switching to extended-release metformin if chronic diarrhea persists with immediate-release formulation 3.
2. Vitamin B12 Deficiency
Long-term metformin use definitively causes biochemical vitamin B12 deficiency, with approximately 7% of patients developing subnormal levels in clinical trials of 29-week duration 1.
Vitamin B12 deficiency can worsen peripheral neuropathy symptoms and cause macrocytic anemia 3, 4.
The American Diabetes Association recommends periodic measurement of vitamin B12 levels in all metformin-treated patients, especially those with anemia or peripheral neuropathy 3.
This occurs because metformin interferes with vitamin B12 absorption in the gastrointestinal tract 3.
3. Lactic Acidosis
Lactic acidosis is a rare but potentially fatal complication with mortality rates of 30-50% if not promptly treated, occurring at an incidence of approximately 2-9 cases per 100,000 patient-years 3.
The American College of Clinical Endocrinologists warns that lactic acidosis is characterized by buildup of lactic acid in the blood and can be precipitated by severe kidney problems, liver impairment, or heart failure 3.
Risk factors include severe renal impairment (eGFR <30 mL/min/1.73 m²), liver dysfunction, severe heart failure, dehydration, hypoxemic conditions, and administration of iodinated contrast agents 3, 1.
Metformin is contraindicated when eGFR falls below 30 mL/min/1.73 m², and dose reduction to maximum 1,000 mg daily is required when eGFR is 30-44 mL/min/1.73 m² 3.
Important Clinical Considerations
Despite these potential side effects, metformin remains first-line therapy for type 2 diabetes due to its proven efficacy in glycemic control, neutral effect on body weight, minimal hypoglycemia risk, and reduction in mortality and complications when used appropriately 5, 3.
The risk of lactic acidosis is minimal provided that contraindications (particularly renal impairment) and prescribing guidelines are respected 6, 2.
When used as monotherapy, metformin rarely causes hypoglycemia, distinguishing it from sulfonylureas 3, 6.