In which individual with type 2 diabetes mellitus (T2DM) should Metformin (metformin) be avoided due to an increased risk of lactic acidosis: a patient with obesity (Body Mass Index (BMI) of 37 kg/m2), a patient with well-controlled hypertension using an Angiotensin-Converting Enzyme (ACE) inhibitor, a patient with chronic Hepatitis B (HBV) infection, or a patient with Impaired Renal Function (Glomerular Filtration Rate (GFR) of 42 mL/min/1.73 m2)?

From the Guidelines

Metformin should be avoided in the 42-year-old with chronic hepatitis B due to an increased risk of lactic acidosis. Metformin is primarily metabolized by the liver, and patients with significant hepatic impairment have reduced ability to clear lactate, which can lead to lactic acid accumulation 1. Chronic hepatitis B can cause liver dysfunction that impairs this metabolic pathway. While metformin is contraindicated in severe hepatic disease, even chronic hepatitis represents a relative contraindication due to the potential for disease progression and unpredictable liver function. The other patients listed do not have absolute contraindications to metformin.

• The patient with obesity (BMI=37) would actually benefit from metformin, which is weight-neutral or may promote modest weight loss.
• Well-controlled hypertension on an ACE inhibitor is not a contraindication.
• The patient with a GFR of 42 mL/min/1.73 m² can still use metformin, though with dose adjustment, as current guidelines allow metformin use until GFR falls below 30 mL/min/1.73 m², with dose reduction recommended when GFR is between 30-45 mL/min/1.73 m² 1. Key considerations for metformin use include monitoring of eGFR and dose adjustment or withdrawal as necessary to minimize the risk of lactic acidosis 1.

From the FDA Drug Label

Metformin hydrochloride tablets are contraindicated in patients with an eGFR less than 30 mL/min/1.73 m 2 Initiation of metformin hydrochloride tablets is not recommended in patients with eGFR between 30 to 45 mL/min/1. 73 m 2. The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney. Hepatic impairment —Patients with hepatic impairment have developed cases of metformin- associated lactic acidosis. Therefore, avoid use of metformin hydrochloride tablets in patients with clinical or laboratory evidence of hepatic disease.

Metformin should be avoided in the 64-year-old with GFR of 42 mL/min/1.73 m2 and the 42-year-old with chronic hepatitis B due to an increased risk of lactic acidosis 2.

From the Research

Individuals with Type 2 Diabetes Mellitus at Risk of Lactic Acidosis

• The following individuals with type 2 diabetes mellitus are at an increased risk of lactic acidosis when taking metformin:
  • A 64-year-old with GFR of 42 mL/min/1.73 m2, as metformin is not recommended for individuals with severe renal impairment (eGFR < 30 mL/min/1.73m2) 3
  • However, the provided evidence suggests that metformin can be safely used in mild to moderate renal impairment (eGFR 30-60 mL/min/1.73m2) 3
• Other factors that may increase the risk of lactic acidosis in individuals with type 2 diabetes mellitus include:
  • Acute cardiorespiratory illness
  • Acute renal impairment
  • Sepsis 4
  • Age 4
• The evidence suggests that diabetes itself, rather than metformin therapy, is the major risk factor for the development of lactic acidosis 4
• There is no evidence to suggest that metformin is associated with an increased risk of lactic acidosis or increased levels of lactate compared to other anti-hyperglycemic treatments 5
• The use of metformin in individuals with chronic kidney disease (CKD) was previously restricted due to concerns over drug accumulation and metformin-associated lactic acidosis, but recent studies suggest that metformin may be safely used in mild to moderate CKD 3