Can Metformin (biguanide) cause hypoglycemia?

From the Guidelines

Metformin typically does not cause hypoglycemia when used alone. Unlike insulin or sulfonylureas, metformin works primarily by reducing glucose production in the liver and improving insulin sensitivity in peripheral tissues, rather than directly increasing insulin secretion. This mechanism allows blood glucose to be lowered toward normal levels but generally not below normal. However, hypoglycemia can occur in specific circumstances: when metformin is combined with other diabetes medications (especially insulin or sulfonylureas), during periods of fasting or reduced caloric intake, with excessive alcohol consumption, or with intense exercise without adequate carbohydrate intake. Patients with severe kidney or liver disease may also be at higher risk for hypoglycemia on metformin due to impaired drug clearance. The risk of hypoglycemia increases when multiple glucose-lowering agents are used together, as their effects can be additive. Patients taking metformin should be aware of hypoglycemia symptoms such as shakiness, sweating, confusion, and weakness, particularly if they have risk factors or are taking multiple diabetes medications 1.

Some key points to consider:

• Metformin is effective and safe, and reduces risks of microvascular complications, cardiovascular events, and death 1.
• Metformin is available in an immediate-release form for twice-daily dosing or as an extended-release form that can be given once daily 1.
• The principal side effects of metformin are gastrointestinal intolerance due to bloating, abdominal discomfort, and diarrhea; these can be mitigated by gradual dose titration and/or using extended-release formulation 1.
• Metformin may be safely used in people with estimated glomerular filtration rate ≥30 mL/min/1.73 m² 1.
• Very high circulating levels (e.g., as a result of overdose or acute kidney injury) have been associated with lactic acidosis, although this complication is very rare 1.

It's essential to note that while metformin itself does not typically cause hypoglycemia, the combination of metformin with other diabetes medications or certain lifestyle factors can increase this risk. Therefore, patients should be educated on the signs and symptoms of hypoglycemia and how to manage it appropriately.

From the FDA Drug Label

Metformin hydrochloride tablets rarely cause hypoglycemia (low blood sugar) by themselves. However, hypoglycemia can happen if you do not eat enough, if you drink alcohol, or if you take other medicines to lower blood sugar.

1. 3 Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues 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.

Metformin can cause hypoglycemia in certain situations, such as:

• When taken with other medicines that lower blood sugar, like insulin or insulin secretagogues 2
• If you do not eat enough
• If you drink alcohol However, metformin rarely causes hypoglycemia by itself 2.

From the Research

Metformin and Hypoglycemia

• Metformin is a biguanide used in the treatment of non-insulin-dependent diabetes mellitus (NIDDM) that alleviates hyperglycemia by inhibiting hepatic glucose production and improving peripheral insulin sensitivity 3.
• Unlike sulfonylureas, metformin does not stimulate insulin secretion, which reduces the risk of hypoglycemia 3, 4, 5.
• Studies have shown that metformin monotherapy does not cause hypoglycemia, making it a suitable option for patients with NIDDM, especially those who are obese or have hyperlipidemia 3, 4, 5.
• However, when metformin is used in combination with sulfonylureas or insulin, the risk of hypoglycemia may increase 6.
• A study found that the addition of insulin to metformin was associated with a higher risk of hypoglycemia compared to the addition of sulfonylurea 6.

Mechanism of Action

• Metformin acts on the liver to suppress gluconeogenesis, reducing hepatic extraction of certain substrates and opposing the effects of glucagon 7.
• It also enhances insulin-stimulated glucose uptake into skeletal muscle, increasing the movement of insulin-sensitive glucose transporters into the cell membrane 7.
• Metformin improves insulin sensitivity by increasing insulin-mediated insulin receptor tyrosine kinase activity, activating post-receptor insulin signaling pathways 7.

Clinical Implications

• Metformin is considered a first-line agent for the treatment of NIDDM, particularly in obese and/or hyperlipidemic patients 3, 4, 5.
• The risk of lactic acidosis associated with metformin can be minimized by adhering to prescribing guidelines and avoiding accumulation of metformin or lactate in the body 3, 4, 5.
• Patients and clinicians should consider the risks and benefits of adding insulin versus sulfonylurea to metformin therapy, taking into account the increased risk of hypoglycemia associated with insulin 6.