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

When you hear about SGLT2 inhibitors, you might think of weight loss, lower blood pressure, or better kidney outcomes. These drugs-like empagliflozin, a sodium-glucose cotransporter-2 inhibitor used to treat type 2 diabetes by making the kidneys flush out excess sugar, dapagliflozin, and canagliflozin-have changed how doctors treat diabetes. But there’s a dangerous side effect hiding in plain sight: diabetic ketoacidosis, and not the kind you’d expect.

What’s So Different About This DKA?

Most people know diabetic ketoacidosis (DKA) as a crisis with blood sugar over 250 mg/dL, vomiting, confusion, and fruity-smelling breath. That’s classic DKA, usually seen in type 1 diabetes when insulin is missing. But with SGLT2 inhibitors, something stranger happens. Patients develop DKA even when their blood sugar is barely above normal-sometimes under 200 mg/dL. This is called euglycemic DKA, or euDKA.

Why does this matter? Because if your doctor checks your blood sugar and sees 180 mg/dL, they might not suspect DKA. You could be in serious danger and not know it. The European Medicines Agency confirmed this in 2023: many life-threatening cases happened because doctors didn’t recognize the warning signs. A 2023 FDA analysis found that nearly half of all DKA cases linked to SGLT2 inhibitors had blood sugar below 250 mg/dL. That’s not rare. That’s the norm.

How Do These Drugs Trigger Ketoacidosis?

SGLT2 inhibitors work by blocking sugar reabsorption in the kidneys. That sounds good-more sugar leaves in urine, lower blood glucose. But here’s the catch: they also reduce insulin demand. Your pancreas doesn’t have to work as hard. That’s fine for most people. But in some, it tips the balance.

When insulin drops-even slightly-and your body is under stress (like an infection, surgery, or not eating enough), your fat cells start breaking down. This releases fatty acids, which your liver turns into ketones. Normally, insulin keeps this in check. But with SGLT2 inhibitors, insulin levels are already low, and the body keeps making ketones. No sugar spike? No problem. Ketones still build up. That’s euDKA.

Studies show the risk is real. One study of over 350,000 people found that SGLT2 inhibitors tripled the chance of DKA compared to other diabetes drugs like DPP-4 inhibitors. The DAPA-KETO trial showed dapagliflozin users had more ketoacidosis events than those on insulin or other medications. Even the EMPA-REG OUTCOME trial, which proved these drugs save hearts and kidneys, had to report DKA as a side effect.

Who’s Most at Risk?

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

• Type 2 diabetes with low insulin production-If your pancreas is already worn out, even a small drop in insulin can trigger ketones. One study found that 2.4% of users with C-peptide under 1.0 ng/mL developed DKA, compared to 0.6% in those with higher levels.
• People cutting carbs or fasting-Going on a keto diet? Skipping meals? These drugs work better when you eat less sugar. But that’s exactly when your body starts burning fat. Dangerous combo.
• Those with infections or illness-A cold, flu, or UTI can spike stress hormones. That pushes your body into fat-burning mode. If you’re on an SGLT2 inhibitor, your body can’t respond with enough insulin to stop ketone production.
• People reducing insulin-If you’re on insulin and your doctor cuts your dose because your sugars are “under control,” you might be setting yourself up for euDKA.
• Those with alcohol use-Alcohol lowers blood sugar and increases ketone production. Add an SGLT2 inhibitor? Risk jumps.

The average time to euDKA after starting the drug? Around 28 weeks. Most cases happen within the first year. That means if you’ve been on it for six months and feel off, don’t ignore it.

What Are the Symptoms? (And Why You’ll Miss Them)

You might think, “If my sugar’s normal, I’m fine.” That’s the trap.

euDKA symptoms look like a bad flu:

• Nausea and vomiting
• Abdominal pain (often mistaken for food poisoning)
• Deep, fast breathing
• Extreme fatigue or confusion
• Unexplained weight loss

No fruity breath? No high sugar? That doesn’t mean it’s not DKA. In fact, the American Diabetes Association says euDKA makes up 30-40% of all DKA cases in SGLT2 inhibitor users. Doctors who only check glucose will miss it. You need to check ketones.

What Should You Do? (Practical Steps)

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

1. Know the symptoms. Nausea, vomiting, fatigue? Don’t brush it off. Call your doctor.
2. Test for ketones when you’re sick. Use urine strips or a blood ketone meter. If ketones are moderate or high-even if your sugar is 150 mg/dL-go to the ER.
3. Stop the drug before surgery. The American Association of Clinical Endocrinologists says stop at least 3 days before any procedure that requires fasting.
4. Don’t skip meals or go on extreme diets. Low-carb diets increase ketone production. If you’re on an SGLT2 inhibitor, talk to your doctor before changing your diet.
5. Don’t reduce insulin without supervision. If you’re on insulin and your doctor wants to lower it, ask about ketone risk.
6. Limit alcohol. Especially binge drinking. It’s a known trigger.

One 2022 study in Diabetes Care found that teaching patients how to check ketones cut DKA cases by 67%. Knowledge saves lives.

Are These Drugs Still Safe?

Yes-but only if you use them right. The EMPA-REG OUTCOME trial showed empagliflozin reduced heart failure hospitalizations and kidney failure. The DECLARE-TIMI 58 trial confirmed similar benefits for dapagliflozin. These drugs aren’t just pills-they’re life-extenders.

But the risk of euDKA is real. The FDA and EMA agree: the benefits outweigh the risks for most people with type 2 diabetes… if they’re monitored. The absolute risk? About 0.1 to 0.5 cases per 100 patients per year. That’s low. But when it happens, it can be fatal. The death rate for euDKA is 4.3%, higher than traditional DKA.

That’s why guidelines now say: avoid SGLT2 inhibitors in people with type 1 diabetes (unless closely monitored), those with a past DKA episode, or those with very low insulin production.

What’s Next?

Researchers are working on solutions. One new drug, licogliflozin, blocks both SGLT1 and SGLT2. Early data suggests it may cause fewer ketones because it slows sugar absorption in the gut, reducing the insulin drop. Phase 3 trials are ongoing.

The FDA now requires all new SGLT2 inhibitor trials to include specific monitoring for euDKA. Machine learning models are being built to predict who’s at highest risk-using 15 factors like age, C-peptide, kidney function, and diet. One model in Lancet Digital Health predicted risk with 87% accuracy.

The message is clear: SGLT2 inhibitors are powerful tools. But they’re not risk-free. You need to know the signs. You need to test ketones. You need to speak up if you feel off.

Final Thought

SGLT2 inhibitors are not the enemy. They’ve helped millions live longer, healthier lives. But they’re not simple pills. They change how your body handles fuel. That’s powerful-and that’s why you need to be smarter about how you use them. Know the signs. Test ketones. Speak up. Your life might depend on it.