Adverse Effects of Metformin
Gastrointestinal Adverse Effects
Gastrointestinal symptoms are the most common adverse effects of metformin, occurring in approximately 20% of patients and representing the primary reason for treatment discontinuation. 1
Most Common GI Side Effects (by frequency):
- Diarrhea – occurs in 53% of patients on metformin versus 12% on placebo 1
- Nausea/vomiting – occurs in 26% versus 8% on placebo 1
- Flatulence – occurs in 12% versus 6% on placebo 1
- Abdominal discomfort – occurs in 6% versus 5% on placebo 1
- Indigestion – occurs in 7% versus 4% on placebo 1
Key Clinical Considerations:
- Diarrhea leads to discontinuation in 6% of patients, making it the most clinically significant GI adverse effect 1
- GI symptoms can occur even after years of stable dosing, not just during initiation 2
- Doses exceeding 1,500 mg daily are associated with a marked increase in diarrhea, nausea, vomiting, and abdominal discomfort 3
Mitigation Strategies:
- Switching from immediate-release to extended-release metformin reduces overall GI events from 26% to 12% and diarrhea from 18% to 8% 3
- Taking metformin with meals or within 15 minutes after eating significantly reduces GI symptoms 4, 3
- Adding probiotics to metformin therapy decreases the risk of diarrhea, bloating, and constipation 3, 5
- Starting at low doses (500 mg once daily) and gradual titration by 500 mg weekly minimizes GI intolerance 6, 7
Vitamin B12 Deficiency
Metformin definitively causes vitamin B12 deficiency through impaired absorption, occurring in approximately 7% of patients during 29-week trials. 1
Clinical Impact:
- Long-term metformin use (>4 years) interferes with vitamin B12 absorption 3, 8
- Vitamin B12 deficiency can worsen peripheral neuropathy and contribute to fatigue 8
- Megaloblastic anemia is rare but reported 7
Monitoring Recommendations:
- Assess vitamin B12 levels in all patients on metformin for >4 years, especially those with anemia or peripheral neuropathy 3, 8
- Check B12 levels in patients presenting with fatigue, as this is the most common etiology of metformin-associated fatigue 8
- Supplement if deficient; metformin can be continued with B12 replacement 8
Lactic Acidosis
Metformin-associated lactic acidosis (MALA) is rare (2-9 cases per 100,000 patient-years) but carries a 30-50% mortality rate if not promptly treated. 8, 9
Risk Factors:
- eGFR <30 mL/min/1.73 m² (absolute contraindication) 3, 8
- Severe heart failure (left ventricular ejection fraction <30%) 8
- Advanced liver disease 9
- Acute conditions: severe dehydration, sepsis, acute heart failure, hypoxic states 3, 8
- Recent myocardial infarction 3
Prevention:
- Discontinue metformin immediately when eGFR falls below 30 mL/min/1.73 m² 3, 8
- Reduce dose to maximum 1,000 mg daily when eGFR is 30-44 mL/min/1.73 m² 3
- Hold metformin during acute illnesses causing volume depletion 3
- Temporarily discontinue before procedures with iodinated contrast in patients with liver disease, alcoholism, or heart failure 3
Renal Function-Related Adverse Effects
Metformin accumulates when eGFR falls below 45 mL/min/1.73 m², increasing the risk of both GI intolerance and lactic acidosis even at previously tolerated doses. 3
eGFR-Based Management:
| eGFR (mL/min/1.73 m²) | Action | Maximum Daily Dose | Monitoring Frequency |
|---|---|---|---|
| ≥60 | Continue standard dosing | 2,550 mg | Annually |
| 45-59 | Continue current dose | 2,550 mg | Every 3-6 months |
| 30-44 | Reduce dose by 50% | 1,000 mg | Every 3-6 months |
| <30 | Discontinue immediately | Contraindicated | — |
Less Common Adverse Effects (1-5% incidence)
The following were reported more commonly with metformin than placebo 1:
- Asthenia (weakness) – 9% versus 6%
- Headache – 6% versus 5%
- Abnormal stools
- Myalgia
- Lightheadedness
- Dyspnea
- Nail disorder
- Rash
- Increased sweating
- Taste disorder (metallic taste) 7
- Chest discomfort
- Chills
- Flu syndrome
- Flushing
- Palpitations
Hypoglycemia
When used as monotherapy, metformin rarely causes hypoglycemia because it does not increase insulin secretion. 8, 9
- Hypoglycemia risk increases when metformin is combined with insulin or sulfonylureas 4
- Monitor glucose more closely in patients on these combinations 4
Hepatotoxicity (Postmarketing)
Cholestatic, hepatocellular, and mixed hepatocellular liver injury have been reported with postmarketing use of metformin. 1
- These are rare, spontaneous adverse events reported voluntarily 1
- Metformin is contraindicated in advanced liver disease 9
Other Metabolic Effects
- Metformin decreases absorption of folic acid, though megaloblastic anemia is rare 7
- Unlike insulin and sulfonylureas, metformin does not increase body weight 6, 9
- Metformin may actually prevent weight gain and reduce hyperinsulinemia 9
Critical Safety Considerations
Absolute Contraindications:
- eGFR <30 mL/min/1.73 m² 3, 8
- Severe renal insufficiency 8
- Advanced liver disease 9
- Congestive heart failure requiring pharmacologic treatment 9
- Hypoxic states or respiratory insufficiency 8
- Acute or chronic metabolic acidosis 1
Temporary Discontinuation Required:
- Before major surgery (stop the night before; restart only after 48 hours and confirming adequate renal function) 8
- During acute illness, severe infection, or sepsis 8
- During conditions predisposing to lactic acidosis 3
Common Pitfalls to Avoid
Failing to check eGFR before initiating metformin or when GI symptoms recur – renal accumulation is a common cause of new-onset GI symptoms in established users 3
Starting at high doses – initiating at ≥1,000 mg daily markedly increases GI side effects and treatment abandonment 3
Not switching to extended-release formulation – this simple intervention reduces GI events by approximately 50% 3
Ignoring vitamin B12 deficiency – failure to monitor B12 in long-term users can lead to worsening neuropathy and fatigue 3, 8
Continuing metformin during acute illness – this increases lactic acidosis risk and should prompt immediate discontinuation 3, 8
Exceeding 2,550 mg daily – the maximum FDA-approved dose should not be exceeded; add a second agent instead 8