Metformin Side Effects: Common and Serious Adverse Reactions
Metformin commonly causes gastrointestinal side effects including diarrhea, nausea, abdominal discomfort, and flatulence, while its most serious but rare side effect is lactic acidosis, which can be life-threatening and requires immediate medical attention. 1, 2
Common Side Effects
Gastrointestinal Effects
- Diarrhea (affects approximately 53% of patients compared to 12% on placebo) 2
- Nausea and vomiting (affects approximately 26% of patients compared to 8% on placebo) 2
- Abdominal discomfort and bloating 1
- Flatulence (affects approximately 12% of patients compared to 6% on placebo) 2
- Indigestion (7% vs 4% on placebo) 2
- Metallic taste in mouth (affects about 3% of patients when starting the medication) 2
- Reduced appetite (can be problematic especially in older adults) 1
Other Common Side Effects
- Asthenia (weakness) (9% vs 6% on placebo) 2
- Headache (6% vs 5% on placebo) 2
- Vitamin B12 deficiency with long-term use 1
Serious Side Effects
Lactic Acidosis
- A rare but potentially fatal complication characterized by buildup of lactic acid in the blood 2
- Warning signs include:
- Cold hands or feet
- Dizziness or lightheadedness
- Slow or irregular heartbeat
- Extreme weakness or fatigue
- Difficulty breathing
- Unusual drowsiness
- Stomach pain, nausea, or vomiting 2
Risk Factors for Lactic Acidosis
- Severe kidney problems (eGFR <30 mL/min/1.73 m²) 1
- Liver impairment 1
- Heart failure 1
- Excessive alcohol consumption 2
- Dehydration (from fever, vomiting, diarrhea, or excessive sweating) 2
- Hypoxemic conditions 1
- Recent procedures with iodinated contrast agents 1
- Acute illness that may compromise renal or liver function 1
Timing and Management of Side Effects
Onset and Duration
- Gastrointestinal side effects typically occur during the initial phase of treatment 3
- Some patients may experience GI effects even after prolonged treatment 3
- GI side effects generally improve over time as the body adjusts to the medication 2
Strategies to Minimize Side Effects
- Start with a low dose and gradually increase (slow titration) 1, 4
- Take medication with meals to reduce gastrointestinal effects 2
- Consider extended-release formulation which has fewer GI side effects compared to immediate-release (11.71% vs 26.34% overall GI adverse events) 5, 4
- Temporary discontinuation during acute illness or procedures with contrast agents 1
- Dose reduction or elimination for persistent GI side effects 1
- Monitor vitamin B12 levels with long-term use 1
Special Populations
Older Adults
- Metformin can be used safely in older adults if prescription guidelines are followed 1
- May be used with eGFR ≥30 mL/min/1.73 m² (lower doses for eGFR 30-45) 1
- Monitor eGFR every 3-6 months in those at risk for kidney function decline 1
- GI side effects and reduced appetite may be more problematic in older adults 1
Women of Reproductive Age
- May result in ovulation in some premenopausal anovulatory women, potentially leading to unintended pregnancy 2
When to Discontinue Metformin
- Development of lactic acidosis (medical emergency) 2
- Severe or persistent gastrointestinal side effects despite dose adjustments 1
- Decline in kidney function (eGFR <30 mL/min/1.73 m²) 1
- Before procedures with iodinated contrast agents 1
- During acute illness that may compromise renal or liver function 1
- Hypoxemic conditions or impaired hepatic function 1
Common Pitfalls and Caveats
- Metformin-induced chronic diarrhea may be misdiagnosed as irritable bowel syndrome 6
- Metformin rarely causes hypoglycemia by itself but can do so when combined with insulin or sulfonylureas 2
- Gastrointestinal side effects are often underreported or wrongly diagnosed as primary gastrointestinal disorders 3
- Before extensive evaluation of GI problems in patients on metformin, consider temporary discontinuation, dose titration, or proper intake timing 3
- Metformin should be temporarily discontinued before imaging studies using iodinated contrast 1
By understanding these side effects and implementing appropriate management strategies, many patients can successfully continue metformin therapy despite initial adverse reactions, maintaining the benefits of this first-line diabetes medication.