What are sulfonylureas?

October 7, 2025 •

3 min read

Although their use has declined, sulfonylureas have been a mainstay in treating Type 2 Diabetes (T2D) for over 60 years and can decrease glycated hemoglobin A1C (HbA1c) by 1% to 1.25%. So, what are sulfonylureas and how do they work?

Quick Summary

Sulfonylureas are a class of oral medications used to manage type 2 diabetes by stimulating the pancreas to release more insulin, thereby lowering blood glucose levels. They are often used as a second-line therapy.

Key Points

Mechanism of Action: Sulfonylureas work by stimulating the pancreatic β-cells to release more insulin, which helps lower blood glucose levels.
Primary Use: They are used to treat type 2 diabetes, often as a second-line therapy after metformin, especially when cost is a factor.
Generations: Second-generation sulfonylureas (glipizide, glyburide, glimepiride) are more potent and more commonly used than first-generation agents.
Main Side Effects: The most significant side effects are a high risk of hypoglycemia (low blood sugar) and weight gain.
Cardiovascular Safety: The cardiovascular safety is debated; newer agents like glimepiride are considered neutral, while older agents have been associated with increased risk.
Contraindications: They are contraindicated in patients with type 1 diabetes, diabetic ketoacidosis, or known hypersensitivity to sulfa drugs.
Efficacy: Sulfonylureas are effective at lowering A1C, with an average reduction of 1% to 1.5%, comparable to metformin.

Understanding Sulfonylureas and Their Role in Diabetes Management

Sulfonylureas are a class of oral antidiabetic drugs primarily used to treat type 2 diabetes mellitus (T2D). They function as insulin secretagogues, stimulating the pancreatic β-cells to produce and release more insulin, which helps lower blood glucose levels. These medications are effective in individuals who still have some capacity to produce insulin.

Historically, sulfonylureas were a primary treatment for T2D and remain a cost-effective option for glycemic control. Despite the availability of newer drugs, about 25% of U.S. adults with diabetes were using sulfonylureas between 2015 and 2018. They are often recommended as a second-line treatment after metformin, particularly when cost is a concern.

How Do Sulfonylureas Work?

Sulfonylureas act on pancreatic β-cells. Their mechanism involves:

Binding to SUR1: Sulfonylureas bind to the sulfonylurea receptor (SUR1) on β-cells.
Closing Potassium Channels: This binding closes ATP-sensitive potassium channels.
Depolarization: The resulting buildup of potassium ions depolarizes the cell membrane.
Calcium Influx: Depolarization opens voltage-dependent calcium channels, allowing calcium to enter the cell.
Insulin Release: Increased intracellular calcium triggers the release of insulin.

This glucose-independent mechanism contributes to the risk of hypoglycemia.

Generations of Sulfonylureas

Sulfonylureas are categorized by generation based on potency and side effects.

First-Generation: Less potent drugs like chlorpropamide and tolbutamide; rarely used due to higher side effect risk.
Second-Generation: More potent and commonly used drugs, including glipizide, glyburide, and glimepiride. Gliclazide is also in this group but not available in the U.S..
Third-Generation: Some sources consider glimepiride in this category due to its structure and selectivity for pancreatic β-cells.

Major Side Effects and Risks

The main drawbacks of sulfonylureas are hypoglycemia and weight gain.

Hypoglycemia: The most common and serious side effect due to non-glucose-dependent insulin release. Risk factors include longer-acting agents, elderly patients, or those with kidney/liver issues. Symptoms include sweating, shakiness, and confusion.
Weight Gain: Patients may gain around 2 kg (4.4 lbs).
Cardiovascular Risk: An early study linked tolbutamide to increased CV mortality, though more recent studies like CAROLINA found glimepiride did not increase CV risk. Some analyses suggest potential CV risk with certain sulfonylureas (like glyburide), while others find neutrality for newer agents.

Other potential side effects include dizziness, headache, and nausea.

Comparison with Other Diabetes Medications

Here's a comparison of sulfonylureas with other common diabetes drug classes:


Feature	Sulfonylureas (e.g., Glimepiride, Glipizide)	Metformin	DPP-4 Inhibitors (e.g., Sitagliptin)	SGLT2 Inhibitors (e.g., Empagliflozin)
Primary Mechanism	Increases insulin secretion	Decreases liver glucose production, increases insulin sensitivity	Increases insulin release in a glucose-dependent way	Increases glucose excretion in urine
A1C Lowering	High (1-1.5%)	High (1-1.5%)	Intermediate (0.4-0.9%)	Intermediate (0.5-1.0%)
Hypoglycemia Risk	High	Very Low	Low	Very Low
Weight Effect	Weight Gain	Weight Loss or Neutral	Neutral	Weight Loss
Cost	Low	Low	High	High
CV/Renal Benefits	Neutral (newer agents) to potentially increased risk (older agents)	Potential benefit	Neutral	Proven benefits

Conclusion

Sulfonylureas are an effective and affordable class of medications for lowering blood sugar in type 2 diabetes. Their ability to significantly reduce A1C makes them valuable, often as an addition to metformin. However, the substantial risks of hypoglycemia and weight gain necessitate careful patient selection and monitoring. Newer-generation drugs are generally preferred due to a better safety profile. The decision to use a sulfonylurea should be tailored to the individual, considering their health status, potential side effects, and the cost and benefits of alternative therapies.

For more information, you can consult authoritative sources like the American Diabetes Association: https://diabetesjournals.org/books/book/47/chapter/5111054/Sulfonylureas

Frequently Asked Questions

The main function of sulfonylureas is to treat type 2 diabetes by stimulating the pancreas to release more insulin into the bloodstream, which in turn lowers blood glucose levels.

Common examples of second-generation sulfonylureas, which are most frequently prescribed, include glipizide (Glucotrol), glyburide (Glynase, Diabeta), and glimepiride (Amaryl).

Yes, sulfonylureas are very commonly prescribed as an add-on therapy to metformin. This combination targets two different mechanisms to improve glucose control: metformin increases insulin sensitivity while sulfonylureas increase insulin secretion.

The most serious and common side effect of sulfonylurea therapy is hypoglycemia, or low blood sugar. This occurs because the medication stimulates insulin release regardless of your current blood glucose level.

Yes, weight gain is a common side effect associated with sulfonylureas. On average, patients may gain around 2 kg (4.4 pounds).

Sulfonylureas should be used with caution in elderly patients because they have a higher risk of experiencing severe hypoglycemia. Shorter-acting agents like glipizide or glimepiride are generally recommended over longer-acting ones like glyburide for this population.

Sulfonylureas are contraindicated for patients with type 1 diabetes, diabetic ketoacidosis (DKA), and those with a known allergy or hypersensitivity to sulfonylureas or other sulfa drugs.