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

Most people taking SGLT2 inhibitors for type 2 diabetes focus on the benefits: better blood sugar control, weight loss, and lower risk of heart failure. 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 isn’t sky-high. You might feel fine - until you collapse.

What Are SGLT2 Inhibitors?

SGLT2 inhibitors are a class of diabetes drugs that make your kidneys flush out extra sugar through urine. That’s it. No insulin needed. The first one, canagliflozin (Invokana), hit the market in 2013. Since then, dapagliflozin (Farxiga), empagliflozin (Jardiance), and ertugliflozin (Steglatro) have joined the list. They’re popular because they work well, help with weight, and protect the heart and kidneys.

But here’s the catch: by lowering blood sugar so effectively, they also change how your body handles fat. When glucose isn’t available, your body turns to fat for energy - producing ketones. Normally, insulin keeps ketone levels in check. But in some people, especially when they’re sick, fasting, or cutting carbs, SGLT2 inhibitors can push ketone production into dangerous territory - even when blood sugar stays normal.

What Is Euglycemic DKA?

Traditional diabetic ketoacidosis (DKA) shows up with blood sugar over 250 mg/dL, fruity breath, nausea, and confusion. It’s obvious. euDKA? Not so much. Blood sugar is often below 200 mg/dL - sometimes even normal. That’s why it’s missed. Patients think they’re fine. Doctors assume it’s not DKA. By the time they check ketones, it’s too late.

The European Medicines Agency (EMA) confirmed this in 2023: cases of euDKA in SGLT2 inhibitor users are real, serious, and often atypical. In fact, 30-40% of DKA cases in people on these drugs happen with normal or only slightly elevated glucose. A 2023 FDA analysis of over 1,200 cases found nearly half were euDKA. The median time to onset? Just 28 weeks after starting the drug.

Why Does This Happen?

SGLT2 inhibitors don’t cause DKA on their own. Something else has to trigger it. Common triggers include:

• Illness (infections, flu, COVID-19)
• Reduced food intake or fasting
• Insulin dose reduction or omission
• Surgery or major stress
• Excessive alcohol use

People with low insulin production - like those with long-standing type 2 diabetes and low C-peptide levels - are at highest risk. One study showed 2.4% of users with C-peptide under 1.0 ng/mL developed DKA, compared to just 0.6% in those with higher levels. That’s a four-fold difference.

Even more concerning: the risk doesn’t go away after the first few months. While 63% of cases happen within the first year, they can still occur years later if you get sick or stop eating.

The Numbers Don’t Lie

Is this risk rare? Yes - but not rare enough to ignore.

Studies estimate 0.1 to 0.5 cases of DKA per 100 patient-years with SGLT2 inhibitors. That means about 1 in 200 to 1 in 1,000 people on these drugs will have an episode. Compare that to 0.03-0.1 cases per 100 patient-years in non-users - so roughly 3 to 5 times higher risk.

And here’s the kicker: mortality is higher. One study found a 4.3% death rate in SGLT2-related DKA cases, compared to 2.1% in classic DKA. Why? Because it’s harder to diagnose. Patients delay care. Doctors delay testing. By the time ketones are checked, acidosis is severe.

Who Should Avoid These Drugs?

Not everyone should take SGLT2 inhibitors. The American Diabetes Association (ADA) and other guidelines now clearly say: avoid them if you have:

• A history of DKA
• Type 1 diabetes (unless under strict supervision with insulin)
• Severely reduced insulin production (low C-peptide)
• Conditions that cause dehydration or low blood volume

Also, don’t start them if you’re planning surgery, fasting for a test, or about to go on a very low-carb diet. These are red flags.

What Should You Do If You’re on One?

If you’re taking dapagliflozin, empagliflozin, or canagliflozin, here’s what you need to know:

1. Know the symptoms: Nausea, vomiting, stomach pain, unusual tiredness, trouble breathing, confusion. These aren’t just "flu symptoms." They could be DKA.
2. Check ketones when you’re sick: Even if your blood sugar is 150 mg/dL. Use urine strips or a blood ketone meter. If ketones are moderate or high, go to the ER - don’t wait.
3. Stop the drug if you’re ill: Don’t push through. If you have an infection, are vomiting, or can’t eat, pause your SGLT2 inhibitor. Talk to your doctor before restarting.
4. Don’t skip insulin: If you’re on insulin too, never reduce or stop it without medical advice. SGLT2 inhibitors don’t replace insulin.
5. Discontinue before surgery: Most guidelines say stop at least 3 days before any procedure requiring fasting.

A 2022 study in Diabetes Care showed that when patients were taught to check ketones and recognize symptoms, DKA cases dropped by 67%. Education saves lives.

What About the Benefits?

Yes, SGLT2 inhibitors reduce heart failure hospitalizations by 30% and slow kidney disease progression. The EMPA-REG OUTCOME trial showed empagliflozin cut cardiovascular death by 38%. These are huge wins.

But benefits don’t erase risks. The question isn’t whether these drugs are good - it’s whether they’re right for you. For someone with heart disease and strong insulin production? Likely yes. For someone with a history of eating disorders, frequent infections, or low insulin? Probably not.

What’s Being Done?

Regulators are acting. The FDA and EMA now require clear warnings about euDKA in prescribing information. The EMA specifically told doctors: "Don’t rule out DKA just because glucose is normal." New research is underway. A 2024 Lancet Digital Health study built a machine learning model that predicts DKA risk using 15 factors - including age, kidney function, insulin use, and recent illness. It’s 87% accurate. This could soon help doctors decide who should avoid SGLT2 inhibitors before they even start.

Drugmakers are also exploring dual SGLT1/2 inhibitors like licogliflozin, which may carry less DKA risk. Early trials look promising.

Bottom Line

SGLT2 inhibitors are powerful tools - but they’re not risk-free. euDKA is rare, but deadly. And it’s silent. You won’t feel it coming unless you know what to look for.

If you’re on one of these drugs, talk to your doctor about your personal risk. Get a ketone test kit. Know your symptoms. Don’t wait for blood sugar to spike before acting. Your life might depend on catching it early - before it’s too late.