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

Most people taking SGLT2 inhibitors for type 2 diabetes don’t think about diabetic ketoacidosis. They’re told these drugs help with weight loss, lower blood pressure, and protect the heart and kidneys. And they do. But there’s a quiet danger hiding in plain sight: euglycemic diabetic ketoacidosis, or euDKA. It doesn’t look like the DKA you learned about in medical school. Blood sugar? Often normal. Symptoms? Nausea, fatigue, deep breathing. And because it doesn’t scream "high glucose," it gets missed-sometimes for days.

What Are SGLT2 Inhibitors, Really?

SGLT2 inhibitors are a class of diabetes drugs that work by making your kidneys dump sugar into your urine. Canagliflozin (Invokana), dapagliflozin (Farxiga), empagliflozin (Jardiance), and ertugliflozin (Steglatro) all do this. They’re not insulin. They don’t force your body to use glucose. Instead, they let your body get rid of it naturally. That’s why they help with weight loss and lower blood pressure. They’ve been shown in big trials like EMPA-REG OUTCOME and DECLARE-TIMI 58 to cut heart failure hospitalizations and slow kidney disease progression.

But here’s the trade-off: when you pull glucose out through the kidneys, your body starts looking for other fuel. That means fat breakdown. And fat breakdown produces ketones. Normally, that’s fine. But in some people-especially under stress-it goes too far.

The Silent Killer: Euglycemic DKA

Traditional diabetic ketoacidosis (DKA) looks like this: blood sugar over 250 mg/dL, fruity breath, vomiting, confusion, rapid breathing. Easy to spot. But euDKA? Blood sugar can be 150, 120, even 90 mg/dL. You might feel terrible, but your glucometer says "not bad." That’s why it’s so dangerous.

The European Medicines Agency (EMA) confirmed in June 2023 that this isn’t rare. Over 48% of DKA cases linked to SGLT2 inhibitors in FDA reports between 2013 and 2022 had blood glucose under 250 mg/dL. Patients weren’t hyperglycemic. They were ketoacidotic. And because doctors didn’t suspect DKA, treatment was delayed. The mortality rate for these cases? 4.3%, nearly double that of classic DKA.

Who’s at Risk?

Not everyone on an SGLT2 inhibitor gets euDKA. But certain situations make it far more likely:

• Illness: Infections, flu, COVID-19-any illness that reduces food intake increases ketone production.
• Insulin reduction: Especially in people with type 2 diabetes who still have some insulin production. Cutting insulin too much can trigger ketosis.
• Surgery or fasting: Even a 12-hour fast before a colonoscopy can be enough if you’re on an SGLT2 inhibitor.
• Alcohol binges: Alcohol blocks liver glucose production and promotes fat breakdown.
• Low beta-cell function: People with very low C-peptide levels (under 1.0 ng/mL) are at higher risk. This means their pancreas barely makes insulin anymore.
• High-dose drugs: Canagliflozin 300 mg carries more risk than 100 mg.

When Does It Happen?

The timing matters. Most euDKA cases happen within the first year of starting the drug. The median time to onset? Just 28 weeks. That’s less than seven months. Many patients are still adjusting to the medication, thinking it’s working perfectly. They’re not monitoring ketones. They don’t know what to look for.

One study found that 63% of cases occurred in the first year. That’s not a fluke. It’s a pattern. And it’s why guidelines now say: if you’re starting an SGLT2 inhibitor, talk about DKA risk before you even take the first pill.

What Do the Guidelines Say?

The American Diabetes Association (ADA), the Endocrine Society, and the American Association of Clinical Endocrinologists (AACE) all agree on the same basics:

• Stop the drug before surgery. At least 3 days before any procedure that requires fasting.
• Hold the drug during illness. If you’re sick, vomiting, or not eating, pause the medication.
• Check ketones if you feel off. Even if your blood sugar is normal. Use urine strips or a blood ketone meter.
• Don’t ignore symptoms. Nausea, abdominal pain, fatigue, trouble breathing-these aren’t "just a bug." They could be euDKA.

A 2022 study in Diabetes Care showed that when patients were taught to check ketones during illness, DKA cases dropped by 67%. Education works.

Why Is This Risk Underestimated?

Some studies say the risk is low. A 2023 meta-analysis of 71,553 patients found no significant increase in DKA compared to placebo. Others show a threefold increase. Why the contradiction?

Because many trials exclude high-risk patients. They don’t include people with low insulin production, those on low-dose insulin, or those with recent illness. Real-world data tells a different story. The CVD-REAL 2 study found 0.1 to 0.5 DKA events per 100 patient-years with SGLT2 inhibitors. That sounds small. But for an individual patient? It’s life-threatening.

The truth? The benefit-risk balance is good for most people with type 2 diabetes. But for some, the risk is real-and preventable.

What Should You Do?

If you’re on an SGLT2 inhibitor:

• Know the symptoms: Nausea, vomiting, belly pain, unusual tiredness, rapid breathing, confusion.
• Keep ketone strips at home. Buy them at any pharmacy. They’re cheap. Test them if you’re sick, stressed, or not eating.
• Call your doctor if ketones are moderate or high. Even if your blood sugar is fine.
• Don’t restart the drug after a DKA episode without a clear plan. Many people get re-prescribed the same drug after recovery. That’s dangerous.

If you’re a provider:

• Screen for risk factors before prescribing. Check C-peptide if possible. Avoid in insulin-deficient patients.
• Don’t assume normal glucose means no DKA. Always consider euDKA in sick patients on SGLT2 inhibitors.
• Document the conversation. Write down that you warned the patient about ketone risk. It matters.

The Future: Better Tools, Safer Drugs

New research is coming. A 2024 study in Lancet Digital Health built a machine learning model that predicts DKA risk with 87% accuracy using 15 clinical factors-things like age, kidney function, insulin dose, and recent infections. This could help doctors decide who should avoid SGLT2 inhibitors altogether.

Pharmaceutical companies are also working on dual SGLT1/SGLT2 inhibitors like licogliflozin, which may have a lower DKA risk because they slow sugar absorption in the gut, reducing the need for fat breakdown. Phase 3 trials are underway.

The FDA now requires all new SGLT2 inhibitor trials to monitor specifically for euDKA. That’s progress.

Bottom Line

SGLT2 inhibitors are powerful tools. They save hearts and kidneys. But they come with a hidden danger: euDKA. It doesn’t announce itself with high blood sugar. It sneaks in with nausea and fatigue. And if you don’t check ketones, you might not know it’s happening until it’s too late.

The good news? You can prevent it. Know the signs. Test ketones when you’re sick. Talk to your doctor. Don’t let the benefits blind you to the risk. Because in diabetes care, the safest drug is the one you use with your eyes wide open.