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

When you’re managing type 2 diabetes, finding a medication that helps control blood sugar, protects your heart, and reduces kidney damage feels like a win. SGLT2 inhibitors-drugs like canagliflozin, dapagliflozin, and empagliflozin-deliver on all three. But behind the benefits lies a quiet, dangerous risk: diabetic ketoacidosis (DKA) that doesn’t look like DKA at all.

What Makes This DKA Different?

Most people think of DKA as a crisis with blood sugar soaring above 250 mg/dL, fruity breath, vomiting, and confusion. That’s classic DKA, usually seen in type 1 diabetes. But with SGLT2 inhibitors, things get tricky. A lot of cases now show up with blood sugar levels below 200 mg/dL-sometimes even normal. This is called euglycemic DKA, or euDKA.

It’s not rare. Studies show euDKA makes up 30-40% of all DKA cases in people taking these drugs. And here’s the problem: if your doctor checks your blood sugar and sees it’s "not that high," they might not think to test for ketones. That’s when things go wrong. Patients end up in the ER with severe acidosis, dehydration, and abdominal pain-sometimes after days of feeling just "off."

Why Do SGLT2 Inhibitors Cause This?

These drugs work by making your kidneys dump glucose into your urine. That lowers blood sugar. But here’s the side effect no one talks about: they also reduce insulin levels slightly and increase glucagon. That pushes your body into fat-burning mode-producing ketones-even when glucose is low.

Add in a trigger-like skipping meals, getting sick, cutting back on carbs, or having surgery-and your body starts flooding with ketones. No high sugar? No warning. Just fatigue, nausea, rapid breathing. It’s easy to mistake for the flu.

The Numbers Don’t Lie

A 2024 review in Metabolites analyzed over 350,000 people with type 2 diabetes. Those on SGLT2 inhibitors had nearly three times the risk of DKA compared to those on DPP-4 inhibitors. The incidence? About 0.1 to 0.5 cases per 100 patient-years. That sounds small. But when you consider millions are on these drugs, that’s thousands of preventable hospitalizations.

And the death rate? One 2021 study found it was 4.3% for SGLT2-related DKA-more than double the rate of traditional DKA. Why? Because diagnosis is delayed. People don’t get tested for ketones because their sugar looks fine.

Who’s at Highest Risk?

Not everyone on SGLT2 inhibitors gets euDKA. But certain people are far more vulnerable:

• Those with low insulin production (C-peptide <1.0 ng/mL)
• People who recently cut insulin doses or stopped insulin entirely
• Patients with type 1 diabetes using SGLT2 inhibitors off-label
• Anyone fasting, sick, or preparing for surgery
• Those drinking heavily or on very low-carb diets

One study found 2.4% of people with low C-peptide levels developed DKA on SGLT2 inhibitors-compared to just 0.6% in those with normal insulin production. That’s a 4-fold difference.

When It Happens-And How to Spot It Early

Most cases occur within the first year. The median time from starting the drug to DKA? Just 28 weeks. That’s less than 7 months.

Symptoms to watch for:

• Nausea or vomiting
• Abdominal pain (often mistaken for stomach flu)
• Unexplained fatigue or weakness
• Rapid, deep breathing
• Fruity-smelling breath
• Confusion or difficulty concentrating

None of these require high blood sugar. If you’re on an SGLT2 inhibitor and feel this way-even if your sugar is 150 or 180-test for ketones.

What Doctors Should Do

Guidelines from the American Diabetes Association, the European Association for the Study of Diabetes, and the Endocrine Society all agree: check ketones when sick.

If you’re feeling unwell, stop your SGLT2 inhibitor. Drink water. Test your urine or blood ketones. If ketones are moderate or large, go to the ER. Don’t wait. Don’t assume it’s just a virus.

Before any surgery-even a dental procedure-stop the drug at least 3 days ahead. Same for severe illness: pneumonia, heart attack, stroke. These drugs aren’t safe when your body is under stress.

What You Can Do

If you’re on one of these drugs, here’s your action plan:

1. Ask your doctor for a ketone test kit (urine strips or a blood meter).
2. Keep it in your medicine cabinet. Don’t wait until you’re sick to buy it.
3. Test ketones if you’re vomiting, nauseous, or feeling unusually tired-even if your sugar is normal.
4. Never stop insulin without talking to your doctor-even if you’re on an SGLT2 inhibitor.
5. Inform all healthcare providers you’re taking an SGLT2 inhibitor before any procedure or hospital admission.

A 2022 study showed patient education cut DKA cases by 67%. Knowledge saves lives.

The Bigger Picture: Benefits vs. Risk

Yes, these drugs carry risk. But they also reduce heart failure hospitalizations, slow kidney disease, and lower death rates in people with heart disease. The EMPA-REG OUTCOME and DECLARE-TIMI 58 trials proved that.

The key isn’t avoiding these drugs. It’s using them wisely. For someone with strong insulin production, no history of DKA, and good access to ketone testing? The benefits far outweigh the risk.

For someone with borderline insulin output, a history of ketoacidosis, or no way to monitor ketones? This drug might not be right.

What’s Next?

Pharmaceutical companies are working on next-gen drugs-like licogliflozin, a dual SGLT1/2 inhibitor-that may carry less DKA risk. The FDA now requires all new SGLT2 trials to monitor for euDKA specifically.

Machine learning models are being trained to predict who’s most at risk. One 2024 study built an algorithm using 15 factors-like age, kidney function, insulin use, and BMI-that predicted DKA with 87% accuracy. Soon, doctors might screen patients before prescribing.

Final Thought

SGLT2 inhibitors aren’t dangerous. But they’re not harmless, either. They’re powerful tools-and like any powerful tool, they need respect. The biggest mistake isn’t taking them. It’s assuming they’re safe because your sugar looks fine.

If you’re on one, know the signs. Test your ketones. Talk to your doctor. Your life might depend on it.