What are the side effects of metformin in a 29‑year‑old obese man with newly diagnosed type 2 diabetes mellitus (T2DM) (fasting plasma glucose 126 mg/dL, hemoglobin A1c 6.4‑6.5%)?

Side Effects of Metformin

Metformin's most common side effects are gastrointestinal—including diarrhea (53%), nausea/vomiting (26%), flatulence (12%), and abdominal discomfort—which are typically transient and can be minimized by starting at 500 mg daily with meals and titrating slowly over 1–2 weeks. 1

Common Gastrointestinal Side Effects

The FDA label reports the following adverse reaction rates from clinical trials in adults with type 2 diabetes 1:

• Diarrhea: 53% (vs 12% placebo)
• Nausea/vomiting: 26% (vs 8% placebo)
• Flatulence: 12% (vs 6% placebo)
• Abdominal discomfort: 6% (vs 5% placebo)
• Indigestion: 7% (vs 4% placebo)

Diarrhea led to discontinuation in 6% of patients. 1 These gastrointestinal symptoms are dose-dependent and usually resolve within 2–4 weeks of continued therapy. 2, 3

Management Strategy for GI Side Effects

Start with 500 mg once or twice daily with meals, then increase by 500 mg every 1–2 weeks up to a maximum of 2000–2550 mg daily in divided doses. 4, 2 If GI symptoms persist despite slow titration:

• Switch to extended-release metformin at the same total daily dose, which significantly reduces GI side effects 2, 3
• Allow 2–4 weeks to assess tolerance on the new formulation 2
• If symptoms remain intolerable, discontinue metformin and substitute with a GLP-1 receptor agonist or SGLT2 inhibitor 2

Less Common Side Effects (1–5% incidence)

The FDA label documents additional adverse reactions occurring in 1–5% of patients 1:

• Abnormal stools
• Lightheadedness/dizziness
• Dyspnea (shortness of breath)
• Metallic taste (affects ~3% of patients, typically transient) 1
• Myalgia
• Nail disorder
• Rash and increased sweating

Vitamin B12 Deficiency

Long-term metformin use interferes with vitamin B12 absorption, and periodic testing of B12 levels is recommended, especially after 4–5 years of continuous therapy or in patients with anemia or peripheral neuropathy. 2, 3, 1

• Approximately 7% of patients develop subnormal B12 levels during treatment 1
• B12 deficiency can worsen peripheral neuropathy symptoms 2, 5
• Supplementation should be initiated if deficiency is detected 3

Lactic Acidosis (Rare but Serious)

Lactic acidosis is a rare but potentially fatal complication with mortality rates of 30–50% if untreated, occurring at an incidence of approximately 2–9 cases per 100,000 patient-years. 2, 1

Risk Factors for Lactic Acidosis 2, 1:

• Severe renal impairment (eGFR <30 mL/min/1.73 m²)
• Liver impairment
• Severe heart failure (LVEF <30%)
• Acute illness with dehydration, vomiting, or diarrhea
• Hypoxemic conditions
• Excessive alcohol consumption (binge or chronic)
• Administration of iodinated contrast agents

Warning Signs of Lactic Acidosis 1:

Patients should seek immediate medical attention if they experience:

• Feeling cold in hands or feet
• Dizziness or lightheadedness
• Slow or irregular heartbeat
• Severe weakness or fatigue
• Difficulty breathing
• Unusual sleepiness or drowsiness
• Stomach pains, nausea, or vomiting

Hypoglycemia Risk

Metformin monotherapy rarely causes hypoglycemia because it does not stimulate insulin secretion. 5, 1 However, hypoglycemia risk increases when metformin is combined with:

• Sulfonylureas
• Insulin
• Inadequate food intake
• Excessive alcohol consumption 1

Patients on combination therapy require education about hypoglycemia symptoms and management. 2

Renal Function Considerations

For this 29-year-old patient with normal renal function, no dose adjustment is needed, but metformin must be discontinued if eGFR falls below 30 mL/min/1.73 m² and dose-reduced to 1000 mg daily maximum if eGFR is 30–44 mL/min/1.73 m². 2, 3

• Monitor eGFR every 3–6 months in patients at risk for declining kidney function 2, 5
• Temporarily discontinue metformin during acute illness with nausea, vomiting, or dehydration 2
• Stop metformin the night before major surgery; restart only after 48 hours and confirmation of adequate renal function 2

Postmarketing Adverse Events

Rare cases of hepatic injury have been reported, including cholestatic, hepatocellular, and mixed hepatocellular liver injury. 1

Common Clinical Pitfalls to Avoid

The most common prescribing error is failing to adjust or discontinue metformin in patients with declining renal function. 2 Additional pitfalls include:

• Not counseling patients about temporary discontinuation during acute illness 2
• Failing to monitor B12 levels in long-term users 2, 3
• Starting at too high a dose, leading to intolerable GI symptoms and discontinuation 4, 2
• Not educating patients about alcohol avoidance 1

Special Considerations for This Patient

For a 29-year-old obese man with newly diagnosed T2DM (FPG 126 mg/dL, HbA1c 6.4–6.5%), metformin is the appropriate first-line agent with an expected HbA1c reduction of 1.0–1.5 percentage points and weight neutrality or modest weight loss (1–3%). 2, 5 The patient should be counseled that:

• GI side effects are common initially but usually resolve within 2–4 weeks 2, 3
• Taking medication with meals reduces side effects 2, 3
• Lactic acidosis is extremely rare in patients without risk factors 2
• B12 monitoring will be needed after several years of therapy 2, 3