SGLT2 Inhibitors and Diabetic Ketoacidosis: What You Need to Know About the Risk

When you're managing type 2 diabetes, finding a medication that lowers blood sugar without causing weight gain or low blood sugar is a win. That’s why SGLT2 inhibitors became so popular. Drugs like canagliflozin, dapagliflozin, and empagliflozin help the kidneys flush out extra glucose through urine. They also reduce heart failure risk and slow kidney damage-proven benefits from big studies like EMPA-REG and DECLARE-TIMI. But there’s a hidden danger that many patients and even some doctors don’t fully understand: diabetic ketoacidosis, especially the sneaky, hard-to-detect version called euglycemic DKA.

What Is Euglycemic DKA, and Why Is It Dangerous?

Traditional diabetic ketoacidosis (DKA) looks like this: blood sugar skyrockets above 250 mg/dL, you feel sick, breath smells fruity, and you’re dehydrated. It’s a medical emergency. But with SGLT2 inhibitors, DKA can happen even when your blood sugar is normal-or just slightly high-below 200 mg/dL. This is called euglycemic DKA (euDKA). And it’s dangerous because it slips under the radar.

Instead of high glucose, you get ketones building up in your blood. Your body starts burning fat for fuel because insulin isn’t working well enough, even if your sugar levels don’t scream “emergency.” Symptoms? Nausea, vomiting, stomach pain, fatigue, trouble breathing. These can be mistaken for the flu, food poisoning, or just being tired. By the time someone realizes it’s DKA, it’s often advanced.

According to the FDA and European Medicines Agency (EMA), up to 40% of DKA cases linked to SGLT2 inhibitors are euDKA. A 2023 review of over 1,200 reported cases found nearly half had blood sugar under 250 mg/dL. That’s not rare. It’s a pattern.

How Do SGLT2 Inhibitors Cause This?

These drugs work by blocking glucose reabsorption in the kidneys. That sounds good-it lowers blood sugar. But here’s the catch: they also lower insulin levels slightly and increase glucagon, a hormone that tells the liver to make more glucose. When you’re stressed, sick, or not eating enough, your body turns to fat for energy. That’s normal. But with SGLT2 inhibitors, the fat breakdown goes into overdrive, flooding your blood with ketones.

Unlike insulin-dependent type 1 diabetes, where DKA happens fast, SGLT2-related euDKA creeps in. It’s often triggered by something else: an infection, skipping meals, cutting carbs too hard, drinking alcohol, or surgery. One study showed 33% of cases happened during illness, 24% after insulin was reduced, and 15% around surgery.

The risk isn’t the same for everyone. People with low insulin production (low C-peptide levels) are at higher risk. One analysis found that those with C-peptide below 1.0 ng/mL had a 4x higher chance of DKA than those with higher levels. It’s also more common with higher doses-canagliflozin 300 mg carries more risk than 100 mg.

Who’s Most at Risk?

Not everyone on SGLT2 inhibitors will get euDKA. But some groups need to be extra careful:

• People with type 1 diabetes using these drugs off-label (not approved in most countries)
• Those with long-standing type 2 diabetes and declining beta-cell function
• Patients who reduce insulin or carbohydrate intake suddenly
• Anyone preparing for surgery or hospitalization
• People with a history of DKA
• Those who binge on alcohol or have eating disorders

Most cases happen within the first year of starting the drug, with the median time to onset being about 28 weeks. That’s not a fluke-it’s a pattern. And the mortality rate for SGLT2-related DKA is higher than traditional DKA: 4.3% versus 2.1%. Why? Because it’s missed. By the time labs are done, the acidosis is severe.

What Do Doctors Recommend Now?

Guidelines have changed. The American Diabetes Association, the Endocrine Society, and the European Association for the Study of Diabetes all agree: you can’t rely on blood sugar alone to rule out DKA in someone on an SGLT2 inhibitor.

Here’s what they say now:

• Check ketones if you feel nauseous, have abdominal pain, or are unusually tired-even if your glucose is below 250 mg/dL.
• Stop SGLT2 inhibitors at least 3 days before any surgery or procedure requiring fasting.
• Hold the drug during acute illness (like flu, infection, or vomiting).
• Don’t start SGLT2 inhibitors in people with low insulin production or a history of DKA.

A 2022 study in Diabetes Care showed that teaching patients to check ketones at home reduced DKA episodes by 67%. Simple. Effective. Life-saving.

How to Check for Ketones at Home

You don’t need a hospital to spot early warning signs. You can test for ketones at home using:

• Urine strips (like Ketostix)-cheaper, but slower to show changes
• Blood ketone meters (like Precision Xtra)-faster, more accurate, measures beta-hydroxybutyrate

If your ketone level is:

• Trace or small: Drink water, monitor, check again in 2-4 hours
• Moderate or large: Call your doctor or go to the ER-do not wait

Don’t wait for high blood sugar. Don’t assume you’re “just sick.” If you’re on an SGLT2 inhibitor and feel off, test for ketones. It’s the only way to catch euDKA early.

Are These Drugs Still Safe?

Yes-for most people. The benefits are real. SGLT2 inhibitors cut heart failure hospitalizations by 30%, reduce kidney disease progression by 30-40%, and lower cardiovascular death in high-risk patients. The absolute risk of DKA is still low: about 0.1 to 0.5 events per 100 patients per year. That’s rare. But rare doesn’t mean impossible.

Think of it like this: wearing a seatbelt doesn’t guarantee you won’t get hurt in a crash. But it reduces the chance of death. SGLT2 inhibitors are like that. They’re powerful tools, but they need smart use.

Doctors now screen for risk before prescribing. If you have low C-peptide, recent weight loss, or a history of ketoacidosis, they’ll likely choose another class of medication-like GLP-1 agonists or metformin.

What’s Next? New Drugs and Better Tools

Pharmaceutical companies aren’t ignoring this. A new class of drugs called SGLT1/2 dual inhibitors-like licogliflozin-is being tested. Early data suggests they may cause less ketone buildup because they also slow sugar absorption in the gut, which helps stabilize insulin levels.

Machine learning models are also being developed to predict who’s most at risk. A 2024 study in Lancet Digital Health built a tool using 15 factors-age, kidney function, insulin use, BMI, C-peptide levels-and could predict DKA risk with 87% accuracy. That means in the near future, your doctor might run a quick risk score before prescribing.

The FDA and EMA now require all new SGLT2 inhibitor trials to specifically monitor for euDKA. Labels have been updated. Pharmacies now include warning inserts. But the real change has to happen at the patient level.

What You Should Do Right Now

If you’re taking an SGLT2 inhibitor:

• Know the symptoms: nausea, vomiting, stomach pain, fatigue, rapid breathing
• Ask your doctor if you’re at higher risk for euDKA
• Get a ketone testing kit and learn how to use it
• Stop the drug before surgery or during serious illness
• Don’t cut carbs drastically without talking to your care team
• Call your doctor or go to the ER if ketones are moderate or large-even if your blood sugar is normal

If you’re not on one but considering it, ask: “Do I have low insulin production? Have I ever had DKA? Am I willing to check ketones if I get sick?” If the answer is no, there are other options.

SGLT2 inhibitors are not the enemy. But they’re not risk-free. Understanding euDKA isn’t about fear-it’s about control. You’re not just managing blood sugar. You’re managing your whole body’s balance. And sometimes, that means looking beyond glucose.