From the Guidelines
Metformin, Ozempic (semaglutide), and Jardiance (empagliflozin) have a low risk of causing hypoglycemia when used alone, but the risk increases when combined with insulin or insulin secretagogues like sulfonylureas. When considering the risk of hypoglycemia associated with these medications, it's essential to understand their mechanisms of action. Metformin reduces glucose production by the liver and improves insulin sensitivity, while Ozempic stimulates insulin release only when blood glucose is elevated, and Jardiance works by increasing glucose excretion through the urine 1. The most recent and highest quality study, published in 2025, supports the use of metformin as a first-line treatment for type 2 diabetes, citing its effectiveness in reducing HbA1c levels, body weight, and plasma lipid levels, with a low risk of hypoglycemia 1. Key points to consider when prescribing these medications include:
- Monitoring for hypoglycemia symptoms, especially when starting treatment or adjusting doses
- Being aware of the increased risk of hypoglycemia when combining these medications with insulin or insulin secretagogues
- Keeping fast-acting carbohydrates available to treat low blood sugar if it occurs
- Considering the individual patient's factors, such as comorbidities, hypoglycemia risk, and patient preferences, when choosing a pharmacologic treatment 2. Overall, the evidence suggests that metformin, Ozempic, and Jardiance are effective treatments for type 2 diabetes with a low risk of hypoglycemia when used alone, but it's crucial to carefully consider the individual patient's needs and monitor for potential side effects 1, 2.
From the FDA Drug Label
Metformin hydrochloride tablets may increase the risk of hypoglycemia when combined with insulin and/or an insulin secretagogue. Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues Insulin and insulin secretagogues (e.g., sulfonylurea) are known to cause hypoglycemia. JARDIANCE may increase the risk of hypotension in patients at risk for volume contraction Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues [see Warnings and Precautions (5.5)]
- Metformin: may increase the risk of hypoglycemia when combined with insulin and/or an insulin secretagogue 3.
- Empagliflozin (Jardiance): may increase the risk of hypoglycemia when used with insulin and/or an insulin secretagogue 4.
- Semaglutide (Ozempic): The FDA drug label does not answer the question.
From the Research
Metformin and Hypoglycemia
- Metformin is known for having a low risk of inducing hypoglycemia compared to other oral hypoglycemics or insulin 5, 6, 7.
- However, there have been case reports of symptomatic hypoglycemia with therapeutic doses of metformin, suggesting that there is a risk, although rare 5.
- The risk of hypoglycemia with metformin can be reduced by taking it with meals 5.
Ozempic (Semaglutide) and Hypoglycemia
- There is no direct evidence provided in the given studies regarding the risk of hypoglycemia with Ozempic (Semaglutide).
- However, as a glucagon-like peptide-1 (GLP-1) receptor agonist, it is known that these types of medications have a low risk of hypoglycemia when used alone, but the risk may increase when combined with other diabetes medications 6, 8.
Jardiance (Empagliflozin) and Hypoglycemia
- Jardiance (Empagliflozin), a sodium-glucose cotransporter-2 (SGLT-2) inhibitor, is generally well tolerated and associated with a low risk of hypoglycemia 9.
- When used in combination with metformin, empagliflozin has an additive effect on glycemic control with a low risk of hypoglycemia 9.
- The fixed-dose combination of empagliflozin and metformin can improve glycemic control, body weight, and blood pressure while maintaining a low risk of hypoglycemia 9.