How Does Glipizide Work? All About This Sulfonylurea’s Mechanism of Action

If you have Type 2 diabetes, you may know about a group of medications called sulfonylureas. They’re the oldest and one of the most commonly prescribed diabetes medications worldwide.

Sulfonylureas aren't considered first-choice medications for Type 2 diabetes in most people. But they’re effective at decreasing blood glucose (sugar), so they may be considered if metformin isn’t an option or doesn’t work well enough for you.

Here we’ll cover how glipizide, a common sulfonylurea, works. Learning about glipizide’s mechanism of action can help you understand why it’s effective at treating diabetes.

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What is glipizide?

Glipizide is an oral medication that treats Type 2 diabetes. It’s part of a group of medications called sulfonylureas.

Glipizide is available as an immediate-release (IR) and extended-release (ER) tablet (Glucotrol XL). Sulfonylureas like glipizide are often combined with other diabetes medications like metformin (Glumetza, Fortamet) as part of a treatment regimen for Type 2 diabetes.

Glipizide is typically taken once or twice daily by mouth. It’s important to take glipizide IR 30 minutes before a meal. This is because it’s designed to decrease blood glucose that spikes after you eat a meal. If you take it on an empty stomach, your blood glucose could become too low (hypoglycemia). And taking glipizide IR with food can delay when it starts working. Glipizide ER should be taken with breakfast or your first main meal of the day.

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How does glipizide work?

Sulfonylureas like glipizide mainly work by stimulating your pancreas to release more insulin. Your pancreas is an organ below your stomach. One of its major functions is to regulate blood glucose by producing insulin. Insulin is a hormone that’s typically released when you consume food, because eating causes your blood glucose to increase.

However, this process is disrupted in people with Type 2 diabetes. Your pancreas still makes insulin, but your body doesn’t respond to it as expected. And your pancreas may struggle to make enough insulin the longer you have diabetes.

This is where sulfonylureas come in. They attach to a specific receptor (binding site) on certain cells in your pancreas that produce insulin. These cells are called pancreatic beta cells (β-cells). When glipizide binds to β-cells, calcium flows in and causes them to tighten (contract). This contraction causes insulin to be pushed out of the β-cells and into the blood.

There’s also evidence that glipizide lowers blood glucose in other ways. This includes limiting glucose production in the liver and preventing insulin from being cleared from the blood.

It’s important to note that sulfonylureas rely on β-cells to work. So if your pancreas doesn’t have functioning β-cells, as is the case in Type 1 diabetes, sulfonylureas won’t work. 

Additionally, Type 2 diabetes can decrease β-cell function. And long-term use of sulfonylureas may also cause β-cells to deteriorate. Both these things can make sulfonylureas less effective after several years of use.

Good to know: Glipizide stimulates insulin release from the pancreas whether there’s glucose in your blood or not. This is why sulfonylureas have a high risk for hypoglycemia. Taking glipizide with meals minimizes the risk of hypoglycemia.

Does glipizide begin to work immediately?

Glipizide works fairly quickly. But how quickly depends on which product you’re taking.

Your pancreas may start releasing insulin within 30 minutes of taking glipizide IR tablets. Maximum effects happen after about 1 to 3 hours. It can take 2 to 3 hours for your pancreas to start releasing insulin after taking ER tablets, and 6 to 12 hours for maximum glucose-lowering effects.

How do you know if glipizide is working?

You may not notice glipizide working. One way to tell if it's working is to check your blood glucose regularly. With sulfonylureas, checking your blood glucose 1 to 2 hours after a meal is usually a good idea. If your blood glucose level is too high after a meal, it’s possible that you may need a higher glipizide dosage. If it’s too low, you may need a lower dosage.

To track your blood glucose, your diabetes care team may recommend a glucose meter (glucometer) or a continuous glucose monitor. Checking periodically helps ensure that your glucose remains within a safe range. Your care team will let you know how often to check your blood glucose, and what your target blood glucose goals are.

Your healthcare team will also check your hemoglobin A1C (HbA1c or A1C) periodically. A1C is a measure of your average blood glucose over the previous 3 months. It’s a good indicator of how well your diabetes is being managed. In general, sulfonylureas lower A1C by about 1.5%.

How is glipizide different from other sulfonylureas?

Glipizide is different from other sulfonylureas like glimepiride (Amaryl) and glyburide (Glynase) in many ways. We’ll cover a few differences below:

• How quickly it works: Glipizide starts working to lower blood glucose within 30 minutes of taking it. Glipizide IR blood levels are highest about 1 to 3 hours after you take it. Glimepiride blood levels are highest 2 to 3 hours after a dose, and peak levels of glyburide occur about 4 hours after a dose. For glipizide ER, blood levels are highest 6 to 12 hours after a dose.

• How long it lasts: Glipizide IR can last up to 24 hours in your body. But blood levels of the medication decrease just a few hours after you take your dose. So like other sulfonylureas, it needs to be taken daily to work. Some people may get better results taking it twice a day. Other sulfonylureas can also last for 24 hours, but blood levels of glimepiride, glyburide, and glipizide ER tend to fluctuate less than glipizide IR.

• Risks for certain groups: Compared to glimepiride, glyburide, and glipizide ER, glipizide IR may be preferred in people at greater risk of hypoglycemia, including adults 65 years and older. Additionally, glipizide IR may be preferred in people with kidney problems.

• Overall safety: It’s not completely clear if one sulfonylurea is safer than another. But some research indicates that glimepiride may be the safest.

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Written by:

Austin Ulrich, PharmD, BCACP

Austin Ulrich, PharmD, BCACP, is a board-certified ambulatory care clinical pharmacist. In his early career, he provided direct patient care in a variety of settings, including hospital and community pharmacies, and in a primary care clinic as a clinical pharmacist.

Edited by:

Amy B. Gragnolati, PharmD, BCPS

Amy Gragnolati, PharmD, BCPS, is a pharmacy editor for GoodRx. Amy currently holds her pharmacist license in Georgia and California.

Reviewed by:

Alyssa Billingsley, PharmD

Alyssa Billingsley, PharmD, is the director of pharmacy content for GoodRx. She has over a decade of experience as a pharmacist and has worked in clinical, academic, and administrative roles.

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