What is the risk of hypoglycemia when combining glipizide (sulfonylurea) with metformin (biguanide)?

From the Guidelines

Combining glipizide with metformin significantly increases the risk of hypoglycemia, posing a moderate to high risk of low blood sugar episodes, particularly in vulnerable populations such as the elderly, those with renal impairment, or during periods of fasting or increased physical activity. This combination therapy works synergistically to lower blood glucose levels, with glipizide stimulating insulin secretion from pancreatic beta cells regardless of glucose levels, and metformin improving insulin sensitivity and reducing hepatic glucose production 1. The risk of hypoglycemia is higher with sulfonylureas, such as glipizide, compared to metformin or thiazolidinediones, and the combination of metformin plus sulfonylureas is associated with a 6 times higher risk of hypoglycemia than the combination of metformin plus thiazolidinediones 1.

Key considerations to minimize the risk of hypoglycemia when combining glipizide with metformin include:

• Starting with lower doses of glipizide (2.5-5mg daily) when adding to metformin therapy
• Taking glipizide with meals to reduce the peak insulin secretion
• Maintaining consistent carbohydrate intake to avoid sudden drops in blood glucose levels
• Avoiding alcohol consumption, which can potentiate hypoglycemic effects
• Educating patients to recognize hypoglycemic symptoms, such as shakiness, sweating, confusion, and dizziness, and instructing them to carry fast-acting carbohydrates like glucose tablets
• Ensuring regular blood glucose monitoring, especially when initiating therapy or adjusting doses, to promptly identify and manage hypoglycemic episodes 1.

It is also essential to consider the patient's kidney function, as decreased kidney function can increase the risk of hypoglycemia due to decreased clearance of insulin and oral agents, and impaired kidney gluconeogenesis 1. Metformin should not be given to patients with serum creatinine concentrations of 1.5 mg/dL or greater in men and 1.4 mg/dL or greater in women, as it may build up with even modest impairment of kidney function, putting patients at risk of lactic acidosis 1.

From the FDA Drug Label

Insulin and insulin secretagogues (e.g., sulfonylurea) are known to cause hypoglycemia. Metformin hydrochloride tablets may increase the risk of hypoglycemia when combined with insulin and/or an insulin secretagogue. Inform patients that hypoglycemia may occur when metformin hydrochloride tablets is coadministered with oral sulfonylureas and insulin.

The risk of hypoglycemia is increased when glipizide (a sulfonylurea) is combined with metformin. To minimize this risk, a lower dose of glipizide may be required when used in combination with metformin 2. Key points to consider:

• Hypoglycemia can occur when metformin is coadministered with oral sulfonylureas like glipizide.
• Patients should be informed about the risks of hypoglycemia, its symptoms, and treatment 2.

From the Research

Risk of Hypoglycemia with Glipizide and Metformin

• The combination of glipizide and metformin can increase the risk of hypoglycemia due to their synergistic effects on glucose control 3.
• A study found that the incidence of symptoms of hypoglycemia was 12.6% in patients treated with glipizide/metformin combination tablets, with no patients requiring medical assistance for hypoglycemia 3.
• Another study compared the risk of hypoglycemia between sitagliptin and glipizide when added to metformin therapy, and found that the risk of confirmed hypoglycemic events was lower with sitagliptin (adjusted hazard ratio = 0.05) 4.
• However, a case report suggested that metformin alone can cause symptomatic hypoglycemia in some patients, highlighting the need for careful monitoring and patient education 5.
• The addition of glipizide to metformin has been shown to improve glycemic control, but the risk of hypoglycemia should be considered when making treatment decisions 6.
• A review of glucose-lowering treatments noted that sulphonylureas, including glipizide, can cause dose-related hypoglycemia, and that the combination of metformin and sulphonylurea may increase overall mortality 7.

Factors Influencing Hypoglycemia Risk

• The risk of hypoglycemia with glipizide and metformin may be influenced by factors such as patient characteristics, glycemic control, and concomitant medications 4.
• The timing and dose of glipizide and metformin administration may also impact the risk of hypoglycemia, with patients experiencing hypoglycemic events primarily between midnight and 7 A.M. or between 7 A.M. and noon 5.
• Patient education on the risks and symptoms of hypoglycemia, as well as the importance of monitoring blood glucose levels, is crucial for minimizing the risk of hypoglycemia 5.