Sulfonylureas and Hypoglycemia: How to Lower Your Risk of Low Blood Sugar

When you're managing type 2 diabetes, keeping blood sugar stable is the goal. But for many people taking sulfonylureas, that stability comes with a dangerous catch: low blood sugar, or hypoglycemia. It’s not rare. About 1 in 10 people on these drugs will have at least one episode where their blood sugar drops so low they feel shaky, sweaty, confused, or worse. And for some, it happens often-multiple times a week. This isn’t just inconvenient. It’s dangerous. Severe hypoglycemia can lead to falls, seizures, hospital visits, and even heart problems. The good news? You don’t have to accept this as normal. There are clear, proven ways to reduce your risk-and some people have cut their low blood sugar episodes by more than half just by switching medications or changing how they take their pills.

Why Sulfonylureas Cause Low Blood Sugar

Sulfonylureas work by forcing your pancreas to release insulin, no matter what your blood sugar level is. That’s different from newer drugs that only boost insulin when your blood sugar is high. This forced insulin release is why hypoglycemia is so common. Even if you skip a meal, exercise more than usual, or drink alcohol, your body keeps pumping out insulin. And when insulin runs wild without glucose to use, your blood sugar plummets.

Not all sulfonylureas are the same. The biggest offender is glyburide (also called glibenclamide). It sticks around in your body for up to 10 hours, and its metabolites keep working even after the original drug is gone. That’s why so many people on glyburide report nighttime lows-sometimes waking up drenched in sweat, heart racing, or too confused to get out of bed. In contrast, glipizide and glimepiride clear out much faster. Glipizide’s half-life is only 2 to 4 hours. That means less time for your blood sugar to drop unexpectedly.

Studies show glyburide causes about 36% more severe hypoglycemia than glipizide. In one study, people on glyburide had 1.8 hospitalizations for low blood sugar per 100 people each year. Those on glipizide? Only 1.2. That difference isn’t small. It’s life-changing.

Who’s Most at Risk

Age is a big factor. If you’re over 65, your body doesn’t bounce back from low blood sugar as well. Your liver doesn’t release glucose as quickly, and your brain doesn’t trigger warning signs like hunger or shakiness as strongly. That’s why the American Geriatrics Society says glyburide should be avoided in older adults. Even if your doctor says it’s fine, ask if glipizide or glimepiride might be safer.

Genetics also play a role. Some people have a gene variation called CYP2C9*2 or CYP2C9*3. These versions of the gene slow down how fast your body breaks down sulfonylureas. If you have one of these variants, even a normal dose can build up to dangerous levels. Research shows these people have more than double the risk of severe hypoglycemia. Testing for this isn’t routine yet-but if you’ve had multiple low blood sugar episodes without clear cause, it’s worth asking your doctor about it.

Other risk factors? Skipping meals, drinking alcohol without food, taking too high a dose, or mixing sulfonylureas with other drugs. Medications like gemfibrozil (for cholesterol) and sulfonamide antibiotics can push sulfonylureas out of protein binding sites in your blood, making more of the drug free and active. That can spike your risk by over 200%.

How to Spot a Low Blood Sugar Episode

Early signs are often subtle-and easy to ignore. You might feel:

• Sweaty, even in a cool room
• Shaky or jittery
• Irritable or confused
• Heart racing
• Unusually hungry

These symptoms hit fast. In one study, 85% of people felt sweating before their blood sugar dropped below 60 mg/dL. If you wait until you’re dizzy or slurring your words, it’s already serious. The key is catching it early.

Some people, especially those with long-term diabetes, lose their warning signs. This is called hypoglycemia unawareness. If you’ve had several lows without feeling them coming, you’re at much higher risk of a dangerous episode. That’s when continuous glucose monitoring (CGM) becomes essential.

How to Prevent Low Blood Sugar

Prevention starts with your medication choice. If you’re on glyburide and you’ve had even one low blood sugar episode, talk to your doctor about switching. Glipizide, glimepiride, or gliclazide (used in Europe and Australia) are safer options. Gliclazide is especially interesting-it targets only the pancreas and doesn’t affect other tissues, which may explain why it causes fewer lows.

Dosing matters too. Starting low and going slow cuts risk dramatically. The American Diabetes Association recommends beginning with just 1.25 mg of glyburide or 2.5 mg of glipizide. Many people are started on 5 mg or more-way too high. A 2022 survey found that 78% of endocrinologists now follow this low-start approach. If your doctor didn’t, ask why.

Food timing is critical. Never take a sulfonylurea on an empty stomach. Always eat within 30 minutes. If you’re going to exercise, eat a small snack with carbs beforehand. Alcohol? Don’t drink it without food. And never drink more than one drink if you’re on these drugs.

Drug interactions are sneaky. If you’re on gemfibrozil, clarithromycin, or certain NSAIDs, your risk goes up. Tell your pharmacist you’re on a sulfonylurea when they fill any new prescription. Many don’t ask.

What to Do When Blood Sugar Drops

If you feel a low coming on, act fast. The rule is 15 grams of fast-acting carbs:

• 4 glucose tablets
• 1/2 cup of juice
• 1 tablespoon of honey
• 6 hard candies

Wait 15 minutes. Check your blood sugar again. If it’s still below 70 mg/dL, repeat. Once it’s back up, eat a small snack with protein and complex carbs-like peanut butter on toast-to keep it stable.

If you’re too confused to treat yourself, or you pass out, you need glucagon. Keep a glucagon kit at home-and make sure someone in your household knows how to use it. Many people don’t. In one survey, only 38% of people on sulfonylureas had glucagon on hand. That’s terrifying.

Technology That Helps

Continuous glucose monitors (CGMs) like Dexcom or Freestyle Libre are game-changers for sulfonylurea users. The DIAMOND trial showed that people wearing CGMs had a 48% reduction in time spent in hypoglycemia. Why? Because CGMs alert you before your blood sugar drops too low-even at night. No more waking up in a cold sweat wondering why you feel awful.

Some newer CGMs even predict lows 20 minutes in advance. That’s enough time to eat a snack and prevent a full episode. If your insurance covers CGMs, ask for one. If not, talk to your doctor about a trial. The cost of one hospital visit for severe hypoglycemia can be 10 times more than a year’s worth of CGM supplies.

How Sulfonylureas Compare to Newer Drugs

Newer diabetes drugs like GLP-1 agonists (semaglutide, liraglutide) and SGLT-2 inhibitors (empagliflozin, dapagliflozin) have much lower hypoglycemia risk-under 0.3 events per 100 people per year. That’s 5 to 6 times lower than sulfonylureas. They also help with weight loss and heart protection.

But they’re expensive. Generic glipizide costs about $4 a month. Semaglutide can cost $1,000 or more. That’s why sulfonylureas are still prescribed-especially in people without good insurance. But cost shouldn’t be the only factor. A 2021 study found that for every $1,200 saved by using sulfonylureas, you might spend $3,000 more on ER visits and lost workdays from hypoglycemia.

The future? Combination therapy. The DUAL VII trial showed that pairing a low-dose sulfonylurea with a GLP-1 agonist cut hypoglycemia risk by 58%. That’s a powerful option for people who need the cost savings of sulfonylureas but want to avoid the lows.

The Bottom Line

Sulfonylureas aren’t going away. They’re cheap, effective, and have been used for nearly 70 years. But their biggest flaw-low blood sugar-is avoidable. You don’t have to live with weekly lows. If you’re on glyburide and you’ve had even one hypoglycemic episode, ask your doctor about switching to glipizide or glimepiride. If you’re over 65, ask why you’re still on glyburide. If you’ve had multiple lows without knowing why, ask about CYP2C9 testing. And if you’re not using a CGM, ask why not.

Hypoglycemia isn’t just a side effect. It’s a signal. A signal that your treatment plan might need a rethink. Don’t ignore it. Your body is trying to tell you something. Listen.

What to Do Next

If you’re on a sulfonylurea:

1. Check which one you’re taking. If it’s glyburide, ask about switching to glipizide or glimepiride.
2. Ask if you’ve ever had a hypoglycemic episode. If yes, request a CGM trial.
3. Review all your medications with your pharmacist. Watch for interactions with gemfibrozil, sulfonamides, or NSAIDs.
4. Make sure someone in your home knows how to use glucagon.
5. Ask about CYP2C9 genetic testing if you’ve had unexplained lows.

You don’t have to accept hypoglycemia as part of managing diabetes. With the right choices, you can take a sulfonylurea safely-and live without fear of your blood sugar crashing.