SGLT2 inhibitors are popular diabetes medications thanks to their ability to lower blood glucose levels, with a very low risk of hypoglycemia. These drugs don’t just help remove excess glucose from your bloodstream — they also improve and protect kidney function, decrease the risk of heart failure, and help with weight loss.
While these benefits can have a big impact on your diabetes management and long-term health, SGLT2s also have a dangerous side effect that many people are unaware of. These drugs can carry an unacceptably high risk of diabetic ketoacidosis (DKA) for people who follow a strict low-carb or ketogenic diet.
How SGLT2 Inhibitors Work
In a nutshell, SGLT2 inhibitors prevent your kidneys from absorbing as much glucose from your food, preventing that sugar from entering your bloodstream. Instead, that sugar is excreted through your urine. For many, this results in an immediate decrease in blood sugar levels and often some weight loss.
SGLT2s include empagliflozin (Jardiance), dapagliflozin (Farxiga), canagliflozin (Invokana), bexagliflozin (Brenzavvy), and ertugliflozin (Steglatro). All brands are pills taken orally once a day.
The most widely known side effect is dehydration. This effect is relatively straightforward: As a result of increased urination, you may be very thirsty and need to drink a lot of water daily. In rare cases, dehydration can be severe and dangerous. Drinking enough water every single day is a critical part of taking these medications.
Other side effects of SGLT2s include an increased risk of yeast infections for women (because glucose in your urine feeds the growth of bacteria) and men (balanitis). There have also been rare reports of necrotizing genital infections.
Risky Business: Low-Carb Diets and SGLT2s
Low-carb diets naturally increase your body’s production of ketones — and that can be a good thing if you’re trying to lose weight. When you’re consuming very few carbohydrates, your body burns fat more quickly for fuel, using the resulting ketones for energy.
In small amounts, ketones are safe and normal. Most people, with or without diabetes, produce small amounts of ketones in the fasting state (like before eating breakfast). But very large amounts of ketones can lead to DKA, a dangerous and potentially even deadly condition.
Diabetic ketoacidosis (DKA) occurs when an absence of insulin causes your blood to become acidic. The body’s cells cannot survive under acidic conditions. When combined with dehydration, this process accelerates into a poisonous cocktail that undermines the heart, impairs the brain, and can lead to death in days.
In people with diabetes, an ultra-low-carb diet (fewer than 50 grams per day) is usually safe — until you add another component that can cause the production of ketones to spiral out of control. That’s exactly what SGLT2 inhibitors can do.
On their own, SGLT2s do not cause DKA. Instead, they create an ideal environment for the production of ketones when combined with another ketone-inducing factor, like a low-carb diet, dehydration, acute illness, pump failures, fasting, or skipping insulin doses.
Just one of these additional factors can drive your ketone production into overdrive, sending you into DKA. And unlike the DKA that most people with diabetes are probably familiar with, this can even occur when blood sugar levels remain at a healthy level.
“A low-carb diet increases the risk of DKA because when a patient consumes a low-carb diet, their total daily dose (TDD) of insulin is decreased,” explains Kelsey Hutter MS, RD, CDCES, LD/N, who’s also lived with type 1 diabetes (T1D) for 15 years. Though it’s usually considered healthy to reduce your insulin requirements, when people are using a low-carb diet and SGLT2s at the same time, they can end up using less insulin than they really need, even at healthy blood sugar levels.
SGLT2s significantly reduce how much glucose your body absorbs from your food by passing the glucose out through your urine. On top of it all, you’re peeing significantly more, which means you’re constantly on the edge of dehydration. Dehydration also contributes to the production of ketones. Hutter adds that SGLT2s increase your body’s use of body fat for fuel. This further contributes to ketone production.
SGLT2s and DKA in Type 2 Diabetes
While DKA isn’t often associated with type 2 diabetes (T2D), it’s becoming more common — especially in people taking SGLT2s.
One particular study shares the details of a 58-year-old man with type 2 diabetes (T2D) and high blood pressure. This man was prescribed an SGLT2 inhibitor as part of his treatment plan. He was not taking insulin.
“[He] was brought in by ambulance and admitted to the intensive care unit for weakness, lethargy, and altered mental status,” explains the study.
They determined his blood pressure was very high, and he was in severe DKA.
The man’s blood work showed an A1C of 6.7 percent but a blood glucose level of 373 mg/dL at the time of admission. While he’d been taking an SGLT2 medication for some time, the only change he’d made in the past month before this episode of DKA was starting a ketogenic diet.
“Our case demonstrates an example in which the use of SGLT2 inhibitors with adherence to a ketogenic diet and intermittent fasting can lead to DKA,” explains the study.
The doctors also concluded that his blood glucose levels and his pH levels indicate that his blood glucose levels were generally tightly managed. This unlucky man must have thought that he was doing everything right.
“The unique presentation of DKA induced by SGLT2 inhibitors makes its diagnosis challenging, especially when all other precipitating factors are ruled out. Furthermore, upon review of his other [diabetes] medications, none are associated with DKA making them as less likely the cause of his presentation. In this case, investigating the patient’s history including his recent change in diet revealed a significant culprit for his presentation.”
SGLT2s and Type 1 Diabetes
SGLT2 inhibitors are only approved by the U.S. Food and Drug Administration (FDA) for the treatment of type 2 diabetes, but there has always been great interest in using them for type 1, too. Studies suggest that patients with T1D can enjoy the same benefits, such as improved glucose levels, modest weight loss, and improved long-term kidney health:
“Clinical trials of SGLT2 inhibitors added to intensified insulin therapy in adults with T1D have shown moderate reductions in A1C, glycemic variability, TDD of insulin, blood pressure, body weight, and increased time in range without increase in hypoglycemia,” explains Hutter.
However, being insulin-dependent, people with T1D face an especially high risk of DKA when taking these medications. As a result, SGLT2s are only rarely prescribed off-label to people with T1D.
“I currently work with two endocrinologists and one advanced practice provider,” explains Hutter. “One of our endocrinologists will prescribe SGLT2s on a rare occasion to patients with T1D. She will prescribe to patients that are obese and have a high TDD of insulin. Our endo does advise against consuming a low-carb diet and warns them of the DKA risks.”
Hutter adds that many endocrinologists will prescribe SGLT2s in T1D only if a patient has been diagnosed with heart disease or kidney disease.
The growing consensus for T1D is simply that the risk of DKA with SGLT2s is too risky.
“In my professional opinion, I feel there is not enough research to conclude that type 1s can safely take SGLT2s,” says Hutter. “It is still too soon to make an evidence-based conclusion on the safety of SGLTs and T1D. There are other options, including GLP-1s, that may offer more benefit and less risk.”
This risk has also caused health authorities to proceed cautiously. The FDA and the European Medicines Agency (EMA) both considered approving SGLT2s for T1D, and both concluded the risk of DKA was too significant. While both also acknowledged there are multiple benefits of these medications for T1Ds, they felt that more studies were necessary to better understand the safety risks.
Carbohydrate consumption was listed as one of many factors that can contribute to DKA while taking an SGLT2. Other factors include excessive alcohol use, illicit drugs, viral or bacterial infection, vomiting, and insulin pump or infusion site failure.
“Any patient with type 1 diabetes that takes an SGLT2 is at risk for DKA,” explains Hutter.
Use With Caution
SGLT2 inhibitors offer wonderful benefits for people with type 2 diabetes. But these powerful medications should be approached with knowledge and caution. If you have type 1 diabetes, or if you eat a low-carb or ketogenic diet, the research suggests taking an SGLT2 medication can be dangerous.
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