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 side effects is the goal. SGLT2 inhibitors like canagliflozin, dapagliflozin, and empagliflozin have been praised for helping the heart and kidneys while also reducing blood glucose. But behind the benefits is a hidden danger: diabetic ketoacidosis - and not the kind you might expect.

What Makes SGLT2 Inhibitors Different?

SGLT2 inhibitors work by making your kidneys flush out extra sugar through urine. That’s it. No insulin needed. This is why they’re so popular - they don’t cause low blood sugar like some other diabetes drugs, and they often help people lose weight. But here’s the catch: when your body loses glucose through urine, it starts looking for other fuel sources. That means fat gets broken down into ketones. Normally, that’s fine. But when ketones build up too fast and your body can’t balance them, you get ketoacidosis.

The scary part? This doesn’t always happen with high blood sugar. In fact, most cases linked to SGLT2 inhibitors happen when blood glucose is below 250 mg/dL - sometimes even under 200 mg/dL. That’s called euglycemic diabetic ketoacidosis, or euDKA. And because doctors and patients are trained to look for high blood sugar as the red flag, euDKA often gets missed.

How Common Is This Risk?

It’s rare - but serious. Studies show about 0.1 to 0.5 cases of DKA happen per 100 patients using SGLT2 inhibitors each year. That’s less than 1 in 200 people. But compare that to non-users: only 0.03 to 0.1 cases per 100 patients. So while the absolute risk is low, it’s still three times higher than with other diabetes medications.

And here’s what makes it worse: nearly half of these cases are euDKA. A 2023 analysis of FDA reports found that 48.7% of DKA cases tied to SGLT2 inhibitors had blood sugar levels below 250 mg/dL. That’s not a typo. These patients aren’t in the classic diabetic crisis you see in textbooks. They feel sick, but their glucometer doesn’t scream danger.

Why Does euDKA Happen?

It’s not just the drug. It’s what happens when the drug meets real life.

Most euDKA cases happen during stress: illness, surgery, fasting, or suddenly cutting back on carbs. One study found that 32.7% of cases followed an infection or fever. Another 24.1% happened after someone reduced their insulin dose - often because they thought they didn’t need it anymore, thanks to the SGLT2 inhibitor doing the work.

Alcohol binges and prolonged fasting (like for a colonoscopy) are also triggers. People think, “I’m not eating, so I’ll skip my pill,” not realizing that without carbs, the body turns to fat - and the drug keeps pushing glucose out, making ketone production worse.

Even more concerning: people with low insulin production - those with C-peptide levels under 1.0 ng/mL - are at much higher risk. One study showed 2.4% of these patients developed DKA on SGLT2 inhibitors, compared to just 0.6% in those with normal insulin output. That’s why these drugs aren’t recommended for type 1 diabetes unless under strict supervision.

Who’s at Highest Risk?

Not everyone on SGLT2 inhibitors will get euDKA. But some people are far more vulnerable:

• People with type 1 diabetes (unless under expert care)
• Those with low C-peptide levels (sign of poor insulin production)
• Patients who recently had surgery or are fasting
• Anyone who cuts carbs drastically - like on a keto diet
• People with kidney problems or who are dehydrated
• Those taking insulin along with SGLT2 inhibitors without adjusting doses

And timing matters. Most cases happen within the first year - especially around 28 weeks after starting the drug. That’s when people feel fine, think the medication is working perfectly, and let their guard down.

What Are the Symptoms?

Because blood sugar isn’t sky-high, symptoms can be vague - and easily mistaken for the flu:

• Nausea and vomiting
• Abdominal pain (often mistaken for stomach bug)
• Deep, rapid breathing
• Extreme fatigue or confusion
• Fruity-smelling breath
• Feeling unusually thirsty or urinating more than usual

Dr. Anne Peters, a leading diabetes expert, says euDKA makes up 30-40% of all DKA cases in SGLT2 users. And because it’s not obvious, diagnosis is often delayed - which is why mortality is higher: 4.3% for euDKA versus 2.1% for classic DKA.

What Do Doctors Recommend?

Regulators like the FDA and EMA have updated labels to warn about euDKA. But the real action is in clinical practice.

The American Diabetes Association and the Endocrine Society now say: if you’re on an SGLT2 inhibitor and you feel sick - even with normal blood sugar - check your ketones. Use a urine strip or a blood ketone meter. Don’t wait for glucose to rise. If ketones are moderate or high, get help immediately.

Before any surgery or procedure that requires fasting, stop the SGLT2 inhibitor at least 3 days ahead. Same goes for serious illness - like pneumonia or a bad flu. Don’t just “hold the pill” - talk to your doctor. They may need to switch you to insulin temporarily.

A 2022 study showed that when patients were taught to check ketones when ill, DKA cases dropped by 67%. Education works.

Are SGLT2 Inhibitors Still Safe?

Yes - for most people. The cardiovascular and kidney benefits are real. In trials like EMPA-REG OUTCOME and DECLARE-TIMI 58, patients on these drugs had fewer heart attacks, strokes, and hospitalizations for heart failure. They also slowed kidney decline.

But safety isn’t about avoiding risk. It’s about managing it. The risk of euDKA is small, but the consequences are severe. That’s why patient selection matters more than ever.

For someone with strong insulin production, no history of DKA, and no plans to fast or go low-carb, SGLT2 inhibitors remain a powerful tool. But for someone with borderline insulin output, a history of eating disorders, or who’s about to have surgery - the risks may outweigh the benefits.

What’s Next?

Pharmaceutical companies are working on new versions - dual SGLT1/SGLT2 inhibitors like licogliflozin - that may reduce ketone production. Early data looks promising.

Meanwhile, AI tools are being tested to predict who’s at risk before they even start the drug. A 2024 Lancet study built a model using 15 clinical factors - age, kidney function, insulin levels, BMI, and more - and it predicted DKA risk with 87% accuracy.

The message isn’t to avoid SGLT2 inhibitors. It’s to use them wisely. Know your risk. Know the signs. And never ignore nausea or fatigue just because your blood sugar looks fine.

Final Thought: Know the Signs, Don’t Panic

SGLT2 inhibitors are not dangerous drugs. They’re powerful tools - but like any tool, they need the right conditions to be used safely. If you’re on one, don’t stop without talking to your doctor. But do learn the symptoms. Keep ketone strips on hand. Test when you’re sick. Speak up if something feels off. The goal isn’t to avoid the medication - it’s to use it with eyes wide open.