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 (DKA). They know it’s a risk with insulin, maybe with GLP-1 drugs, but not with a pill they take daily. That’s the problem. SGLT2 inhibitors - drugs like Invokana, Farxiga, and Jardiance - are linked to a dangerous form of DKA that doesn’t look like the classic version. Blood sugar might be normal. Symptoms feel like the flu. And by the time it’s caught, it’s already serious.

What Are SGLT2 Inhibitors, Really?

SGLT2 inhibitors are oral diabetes medications that work by making your kidneys dump sugar into your urine. Instead of reabsorbing glucose like they normally do, they let it escape. That lowers blood sugar without triggering insulin spikes. It’s clever. And it works. Studies show these drugs cut heart failure hospitalizations, slow kidney decline, and even reduce death risk in people with type 2 diabetes and heart disease.

The first one, canagliflozin, got FDA approval in 2013. Since then, dapagliflozin, empagliflozin, and ertugliflozin joined the list. They’re now used by millions worldwide. But behind the benefits is a quiet danger: a spike in cases of diabetic ketoacidosis - and not the kind you’d expect.

The Silent Killer: Euglycemic DKA

Traditional DKA happens when insulin drops too low. The body burns fat for fuel, spitting out ketones. Blood sugar soars - usually above 250 mg/dL. It’s obvious. You feel awful, you’re thirsty, you’re peeing constantly, your breath smells fruity. You go to the ER. Done.

SGLT2 inhibitor-related DKA is different. It’s called euglycemic DKA, or euDKA. Blood sugar? Often below 200 mg/dL. Sometimes even normal. That’s why it’s missed. Patients think, “My sugar’s fine, I’m not in DKA.” They wait. They get sicker. Nausea, vomiting, stomach pain, fatigue, trouble breathing - classic signs of ketoacidosis - but dismissed because glucose isn’t sky-high.

Research from Canada and the UK tracked over 350,000 people. Those on SGLT2 inhibitors had nearly three times the risk of DKA compared to those on other diabetes drugs. A 2023 FDA analysis of adverse events found that almost half of the DKA cases linked to these drugs were euDKA. The median time to onset? Just 28 weeks after starting the drug. Most happen in the first year.

Why Does This Happen?

It’s not magic. It’s physiology. SGLT2 inhibitors lower blood sugar by forcing glucose out through urine. But that also lowers insulin demand. The pancreas doesn’t need to work as hard. In people with already weakened beta cells - common in long-standing type 2 diabetes - this can tip the balance. Insulin levels drop just enough to trigger fat breakdown and ketone production, but not enough to send blood sugar soaring.

It’s like a car running on fumes. The gas gauge says “full” because the fuel pump is leaking (glucose in urine), but the tank is nearly empty (low insulin). The engine sputters (ketones build up), but the dashboard doesn’t warn you.

Triggers make it worse. Skipping meals, fasting before surgery, getting sick with an infection, cutting insulin doses too much, or drinking heavily can all push someone into euDKA. A 2022 review found that 32.7% of cases followed an illness, 24.1% happened after insulin was reduced, and 15.3% occurred around surgery.

Who’s at Highest Risk?

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

• People with low C-peptide levels - this means their pancreas makes very little insulin to begin with
• Those with type 1 diabetes, even if they’re misdiagnosed as type 2
• Patients who’ve had DKA before
• Anyone cutting carbs drastically - like on a keto diet
• People with kidney problems or who are dehydrated
• Those taking higher doses (like 300 mg of canagliflozin instead of 100 mg)

One study found that people with C-peptide under 1.0 ng/mL had a 2.4% chance of developing DKA on SGLT2 inhibitors. Those with higher levels? Just 0.6%. That’s a four-fold difference.

What Doctors Are Doing About It

Regulators have taken notice. The FDA warned about DKA risk back in 2015. The European Medicines Agency updated its safety guidelines in June 2023, telling doctors: “Check for ketones even if blood sugar is normal.” The UK’s MHRA and Canada’s Health Canada have issued similar alerts.

Guidelines now say:

• Stop SGLT2 inhibitors at least 3 days before any surgery or procedure requiring fasting
• Hold the drug during acute illness - like flu, pneumonia, or a severe infection
• Test for ketones if you feel nauseous, have abdominal pain, or are unusually tired - even if your glucose is under 250 mg/dL

Dr. Anne Peters, a leading diabetes expert, says euDKA makes up 30-40% of all DKA cases in SGLT2 users. That’s not rare. It’s common enough that every doctor prescribing these drugs should assume it could happen.

What Patients Should Do

If you’re on an SGLT2 inhibitor, here’s what you need to know:

• Know the symptoms: nausea, vomiting, stomach pain, unusual fatigue, trouble breathing, fruity breath
• Keep ketone strips or a blood ketone meter at home - your pharmacy can get them for you
• Check ketones if you’re sick, skipping meals, or stressed - even if your sugar is “fine”
• If ketones are moderate or high (≥1.5 mmol/L), go to the ER. Don’t wait. Don’t try to “wait it out.”
• Tell every doctor you see that you’re on an SGLT2 inhibitor - especially before surgery or if you’re admitted to hospital

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.

Is the Risk Worth It?

Yes - for most people. The benefits of SGLT2 inhibitors are real: fewer heart attacks, less hospitalization for heart failure, slower kidney disease progression. In large trials like EMPA-REG OUTCOME and DECLARE-TIMI 58, these drugs cut cardiovascular death by up to 38% in high-risk patients.

But absolute risk matters. The DKA rate is about 0.1 to 0.5 cases per 100 patient-years. That’s low. But it’s not zero. And when it happens, it’s serious. Mortality is higher than traditional DKA - 4.3% vs. 2.1% - because it’s missed.

The new consensus? Don’t avoid these drugs. But don’t use them blindly. Screen carefully. Educate patients. Monitor during stress. Stop them when needed.

What’s Next?

Researchers are building tools to predict who’s at risk. A 2024 study in Lancet Digital Health created a machine learning model that uses 15 factors - age, kidney function, insulin use, C-peptide, BMI - to flag high-risk patients before they even start the drug. Accuracy? 87%. That’s promising.

Drugmakers are also testing dual SGLT1/SGLT2 inhibitors like licogliflozin. Early data suggests they might cause less ketosis because they slow glucose absorption in the gut, keeping insulin levels more stable.

Meanwhile, the FDA now requires all new SGLT2 inhibitor trials to include specific monitoring for euDKA. That’s a big step.

These drugs aren’t going away. But the way we use them is changing. It’s no longer just about lowering sugar. It’s about understanding the hidden dangers - and knowing how to stop them before they start.