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

Metformin Side Effects

The most common side effects of metformin are gastrointestinal symptoms—particularly diarrhea (53%), nausea/vomiting (26%), flatulence (12%), and abdominal discomfort—which typically resolve with continued use and can be minimized by gradual dose titration and taking the medication with meals. 1

Gastrointestinal Side Effects (Most Common)

The gastrointestinal adverse effects are by far the most frequent concern with metformin therapy:

• Diarrhea occurs in approximately 53% of patients, leading to discontinuation in 6% of cases 1
• Nausea and vomiting affect 26% of patients 1
• Flatulence occurs in 12% of patients 1
• Abdominal discomfort affects 6% of patients 1
• Indigestion occurs in 7% of patients 1

These gastrointestinal symptoms are generally self-limiting and improve after several weeks of therapy 2. The key clinical strategy is to start with a low dose (500 mg once or twice daily) and titrate gradually while taking metformin with meals to minimize these effects 3, 4.

If standard metformin is not tolerated due to GI upset, switching to extended-release formulation should be attempted first before considering alternative agents 5.

Vitamin B12 Deficiency (Important Long-Term Risk)

Long-term metformin use is associated with vitamin B12 deficiency, requiring periodic monitoring, especially in patients with anemia or peripheral neuropathy 3:

• Approximately 7% of patients develop subnormal vitamin B12 levels during 29-week clinical trials 1
• The American Diabetes Association recommends periodic testing of vitamin B12 levels in all metformin-treated patients 3
• Monitoring should be considered especially after 4-5 years of continuous use 6
• Deficiency risk is higher in patients with previous gastric/small bowel surgery, vegans, or those with existing anemia or neuropathy 6

This is a clinically significant concern because vitamin B12 deficiency can worsen symptoms of diabetic neuropathy, potentially confounding the clinical picture 4.

Lactic Acidosis (Rare but Serious)

Lactic acidosis is the most serious potential complication, though extremely rare (0.03 cases per 1000 patient-years), with mortality risk of 0.015 per 1000 patient-years 7:

• This complication is predictable and preventable rather than spontaneous 7
• Most cases occur in patients who should not have been prescribed metformin due to contraindications 7
• Metformin must be discontinued if eGFR falls below 30 mL/min/1.73 m² 3
• Patients should stop metformin during acute illness with nausea, vomiting, or dehydration 3

Warning signs include unexplained hyperventilation, myalgias, malaise, unusual somnolence, feeling cold in extremities, dizziness, or slow/irregular heartbeat 1.

Less Common Side Effects

Additional adverse reactions reported in 1-5% of patients include 1:

• Abnormal stools
• Myalgia
• Lightheadedness
• Dyspnea
• Rash and sweating
• Metallic taste (affects about 3% of patients, typically transient) 1
• Asthenia (weakness) in 9% 1
• Headache in 6% 1

Hypoglycemia Risk

Metformin monotherapy rarely causes hypoglycemia because it does not increase insulin secretion 4, 2:

• Insulin levels remain unchanged or may decrease during metformin treatment 4
• Hypoglycemia risk increases when metformin is combined with sulfonylureas or insulin 3, 1
• Patients on combination therapy require education about hypoglycemia symptoms and management 1

Postmarketing Adverse Events

Rare hepatic injury has been reported with postmarketing surveillance 1:

• Cholestatic, hepatocellular, and mixed hepatocellular liver injury have been documented 1
• These reactions are reported voluntarily, making frequency estimation difficult 1

Clinical Pitfalls to Avoid

The most common prescribing error is failing to adjust or discontinue metformin in patients with declining renal function 3:

• Monitor eGFR every 3-6 months in patients at risk for kidney function decline 4
• Dose reduction should be considered when eGFR is 30-45 mL/min/1.73 m² 6
• Temporary discontinuation is required before procedures involving iodinated contrast agents 1

In older adults, persistent GI side effects can lead to inadequate nutrition, necessitating dose reduction or discontinuation 4. The daily dose should be increased slowly in this population to minimize gastrointestinal intolerance 4.

Special Consideration: Reproductive Effects

Treatment with metformin may result in ovulation in some premenopausal anovulatory women, potentially leading to unintended pregnancy 1. This is particularly relevant in women with polycystic ovary syndrome.