Side Effects of Metformin
The most common side effects of metformin are gastrointestinal disturbances, including diarrhea (occurring in up to 53% of patients), nausea/vomiting (26%), flatulence (12%), abdominal discomfort (6%), and indigestion (7%). 1
Common Side Effects
Gastrointestinal Effects
- Diarrhea: Most frequent side effect, affecting over half of patients taking metformin 1
- Nausea and vomiting: Second most common side effect 1
- Abdominal discomfort and bloating: Frequently reported 1
- Flatulence: Occurs in approximately 12% of patients 1
- Metallic taste (dysgeusia): Affects about 3% of patients when starting the medication 1
These GI side effects are typically transient and can be mitigated by:
- Starting with a low dose and gradually titrating upward
- Taking metformin with meals
- Using extended-release formulations instead of immediate-release 2, 3
Other Common Side Effects
- Vitamin B12 deficiency: Long-term metformin use is associated with decreased vitamin B12 levels, which may worsen symptoms of neuropathy 2
- Asthenia (weakness): Reported in about 9% of patients 1
- Headache: Occurs in approximately 6% of patients 1
Serious but Rare Side Effects
Lactic Acidosis
This is a rare but potentially fatal complication with the following symptoms:
- Feeling cold in hands or feet
- Dizziness or lightheadedness
- Slow or irregular heartbeat
- Extreme weakness or fatigue
- Trouble breathing
- Drowsiness
- Stomach pains, nausea, or vomiting 1
Risk factors for lactic acidosis include:
- Severe kidney problems (eGFR <30 mL/min/1.73 m²)
- Liver disease
- Excessive alcohol consumption
- Dehydration
- Hypoxemic conditions
- Severe infections 2, 1
Hypoglycemia
Metformin rarely causes hypoglycemia when used alone but may increase the risk when combined with:
- Sulfonylureas
- Insulin
- Excessive alcohol consumption 1
Special Considerations
Renal Function
- Metformin is safe in patients with eGFR ≥30 mL/min/1.73 m² 2
- Lower doses should be used in patients with eGFR 30-45 mL/min/1.73 m² 2
- Contraindicated in advanced renal insufficiency (eGFR <30 mL/min/1.73 m²) 2
- eGFR should be monitored every 3-6 months in at-risk patients 2
Temporary Discontinuation
Metformin should be temporarily discontinued:
- Before procedures using iodinated contrast
- During hospitalizations
- During acute illness that may compromise renal or liver function 2
Monitoring Recommendations
- Regular monitoring of vitamin B12 levels, especially in patients reporting fatigue, peripheral neuropathy, or anemia 2
- Periodic assessment of renal function 2
Mitigating Side Effects
- Extended-release formulations have been shown to reduce GI side effects compared to immediate-release metformin 3
- Gradual dose titration can significantly reduce the incidence of GI side effects 4
- Taking metformin with meals can improve tolerability 4
Long-term Considerations
- Some patients may develop chronic diarrhea that can be misdiagnosed as irritable bowel syndrome 5
- GI side effects may lead to discontinuation of therapy in some patients 6
- GI side effects can occur even after prolonged treatment with metformin 6
For patients who cannot tolerate metformin despite mitigation strategies, alternative glucose-lowering medications should be considered based on patient-specific factors, comorbidities, and treatment goals 2.