What are the side effects of metformin (biguanide oral hypoglycemic)

Metformin Side Effects

Metformin commonly causes gastrointestinal side effects including diarrhea (53% of patients), nausea/vomiting (26%), flatulence (12%), and abdominal discomfort (6%), while serious complications like lactic acidosis are rare but potentially fatal with mortality rates of 30-50%. 1, 2

Common Gastrointestinal Side Effects

The most frequent adverse reactions are gastrointestinal in nature and typically occur early in treatment:

• Diarrhea is the most common side effect, affecting over half of patients (53%) compared to 12% on placebo, and led to discontinuation in 6% of patients in clinical trials 1
• Nausea and vomiting occur in approximately 26% of patients versus 8% on placebo 1
• Flatulence affects 12% of patients, with additional symptoms including indigestion (7%), abdominal discomfort (6%), and bloating 1, 2
• These gastrointestinal symptoms are usually mild, transient, and self-limiting, though they can be problematic especially in older adults where reduced appetite may occur 3, 4

Managing GI Side Effects

Start with a low dose (500 mg daily) and titrate slowly every 2 weeks while taking the medication with meals to minimize gastrointestinal intolerance. 3, 2

• Extended-release formulations significantly reduce GI side effects compared to immediate-release metformin, with one study showing GI adverse events decreased from 26.34% to 11.71% after switching 5, 2
• For persistent GI side effects despite these measures, dose reduction or complete elimination of metformin may be necessary 3, 2
• Metformin should be temporarily discontinued during acute illness, nausea, vomiting, or dehydration 3

Vitamin B12 Deficiency

Long-term metformin use interferes with vitamin B12 absorption and requires periodic monitoring, especially in patients with anemia or peripheral neuropathy. 3, 2

• Approximately 7% of patients develop subnormal vitamin B12 levels during metformin therapy 1
• The American Diabetes Association recommends periodic testing of vitamin B12 levels in all metformin-treated patients, particularly those with anemia or peripheral neuropathy, as deficiency can worsen neuropathy symptoms 3, 2

Lactic Acidosis (Rare but Serious)

Lactic acidosis is a rare but potentially fatal complication with an incidence of 2-9 cases per 100,000 patient-years and mortality rates of 30-50% if not promptly treated. 2

Risk Factors for Lactic Acidosis

Metformin is contraindicated in the following high-risk situations:

• Severe renal impairment (eGFR <30 mL/min/1.73 m²) 3, 2
• Severe heart failure with left ventricular ejection fraction <30% 2
• Impaired hepatic function due to increased risk of lactate accumulation 3
• Dehydration or hypoxemic conditions 2
• Administration of iodinated contrast agents 2

Safe Use Guidelines by Renal Function

• Metformin can be safely used with eGFR ≥30 mL/min/1.73 m² per FDA labeling 3
• For eGFR 30-45 mL/min/1.73 m², use lower doses and monitor eGFR every 3-6 months 2
• Patients should stop metformin immediately if experiencing symptoms of lactic acidosis: dyspnea, nausea, vomiting, or abdominal pain 3

Perioperative Management

Stop metformin the night before major surgery and do not restart until 48 hours postoperatively after confirming adequate renal function. 2

• For minor or ambulatory surgery, metformin can be continued except in cases of severe renal failure 2
• Temporarily discontinue before procedures involving contrast agents 3

Hypoglycemia Risk

When used as monotherapy, metformin rarely causes hypoglycemia, making it a preferred agent for older adults at increased risk of hypoglycemia. 2, 4

• Unlike insulin and sulfonylureas, metformin does not increase body weight 4
• The American Diabetes Association recommends medication classes with low hypoglycemia risk for older adults, making metformin ideal for this population 3

Less Common Side Effects

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

• Abnormal stools, myalgia, lightheadedness, dyspnea, rash, increased sweating, taste disorder, chest discomfort, chills, flushing, and palpitations 1
• Headache (6%) and asthenia/weakness (9%) 1
• Rare postmarketing reports of cholestatic, hepatocellular, and mixed hepatocellular liver injury 1

Clinical Pitfall

Chronic diarrhea in diabetic patients on metformin is frequently misdiagnosed as irritable bowel syndrome, leading to unnecessary investigations and treatments. 6

• Always consider metformin as the cause of chronic diarrhea before pursuing extensive workup in patients taking this medication 6
• Discontinuation of metformin typically results in significant improvement of gastrointestinal symptoms 6