What are the common side effects of Metformin (biguanide) and how can they be managed?

Metformin Side Effects and Management

Metformin commonly causes gastrointestinal side effects including diarrhea (53% of patients), nausea/vomiting (26%), flatulence (12%), and abdominal discomfort (6%), which are typically transient and can be effectively managed through dose titration, taking medication with meals, or switching to extended-release formulations. 1

Common Gastrointestinal Side Effects

The most frequent adverse effects of metformin are gastrointestinal in nature and include:

• Diarrhea is the most common side effect, occurring in approximately 53% of patients in clinical trials, compared to 12% with placebo 1
• Nausea and vomiting affect approximately 26% of patients versus 8% with placebo 1
• Flatulence occurs in 12% of patients 1
• Abdominal discomfort and indigestion affect 6-7% of patients 1
• Metallic taste occurs in approximately 3% of patients when starting therapy, though this typically resolves quickly 1
• Reduced appetite can be particularly problematic in older adults 2

These gastrointestinal symptoms are generally self-limiting and improve after taking the medication for several weeks 1, 3

Serious Side Effects

Lactic Acidosis

• Lactic acidosis is a rare but potentially fatal complication with mortality rates of 30-50% if not promptly treated, occurring in approximately 2-9 cases per 100,000 patient-years 4
• Risk factors include: severe kidney problems (eGFR <30 mL/min/1.73 m²), liver impairment, congestive heart failure (especially with left ventricular ejection fraction <30%), dehydration, hypoxemic conditions, and administration of iodinated contrast agents 4, 1
• Symptoms requiring immediate medical attention include: unusual weakness/fatigue, unusual muscle pain, trouble breathing, unusual sleepiness, unexplained stomach problems with nausea/vomiting/diarrhea, feeling cold (especially in extremities), dizziness/lightheadedness, and slow or irregular heartbeat 1

Vitamin B12 Deficiency

• Long-term metformin use can interfere with vitamin B12 absorption, leading to deficiency that may worsen peripheral neuropathy symptoms 4, 1
• Approximately 7% of patients develop subnormal vitamin B12 levels during treatment 1
• Periodic monitoring of vitamin B12 levels is recommended for patients on long-term therapy 4, 1

Hypoglycemia

• Metformin rarely causes hypoglycemia when used as monotherapy 4, 1
• Risk increases when combined with sulfonylureas or insulin, or in patients who don't eat enough or consume excessive alcohol 1

Management Strategies for GI Side Effects

Initial Dosing and Titration

• Start with a low dose and gradually increase (slow titration) to minimize gastrointestinal side effects 4, 3
• Take medication with meals to help reduce GI symptoms 4, 1, 3
• Most GI side effects are transient and resolve after several weeks of continued therapy 1, 3

Extended-Release Formulation

• Consider switching to extended-release metformin for patients experiencing persistent GI side effects 4
• In patients switched from immediate-release to extended-release formulations, GI adverse events decreased from 26.34% to 11.71%, and diarrhea decreased from 18.05% to 8.29% 5

Dose Adjustment or Discontinuation

• Temporary discontinuation may be necessary during acute illness, procedures with contrast agents, or when acute conditions may compromise renal or liver function 2, 4
• Dose reduction or elimination may be required for patients with persistent gastrointestinal side effects that don't resolve with conservative measures 2
• For older adults with eGFR 30-45 mL/min/1.73 m², use lower doses 4

Special Considerations for Older Adults

• Metformin remains the first-line agent for older adults with type 2 diabetes when used appropriately 2
• GI side effects and reduced appetite can be particularly problematic in older adults, potentially requiring dose reduction or discontinuation 2
• Metformin is contraindicated in advanced renal insufficiency and should be used cautiously in those with impaired hepatic function or heart failure due to increased lactic acidosis risk 2
• Monitor eGFR every 3-6 months in older adults at risk for kidney function decline 4

Perioperative Management

• Stop metformin the night before major surgery and do not restart until 48 hours post-operatively, only after confirming adequate renal function 4
• For minor or ambulatory surgery, metformin can be continued except in cases of severe renal failure 4

Important Caveats

• Avoid excessive alcohol intake, as this increases the risk of lactic acidosis 1
• Chronic diarrhea attributed to metformin can persist for years and may be misdiagnosed as other GI conditions like irritable bowel syndrome 6
• GI side effects can occur even after prolonged treatment with metformin, not just during the initial phase 7
• Despite potential side effects, metformin remains first-line therapy due to its proven efficacy in glycemic control and reduction of mortality and complications when used appropriately 4