diabetic ketoacidosis

Can You Have DKA Without High Blood Sugars?

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Diabetic ketoacidosis (DKA) is a potentially fatal complication of diabetes typically associated with dangerously high blood glucose levels. However, this is not always the case, specifically for those who take a new class of diabetes drugs called SGLT-2 inhibitors.

People with diabetes who are on insulin treatment should be keenly aware of the dangers of diabetic ketoacidosis, or DKA. Indeed, many people with type 1 diabetes find out their diagnosis because they land in an emergency room in a state of diabetic ketoacidosis.

What is diabetic ketoacidosis (DKA)?

Diabetic ketoacidosis (DKA) occurs when someone does not have enough insulin in their body. Because there is not enough insulin to allow glucose to enter the body’s cells from the blood to be used for energy, the body responds by burning fat.

When this happens, ketones are produced, which can build up in the bloodstream. Ketones are acidic, so when ketone levels get too high, the blood can become acidic, which affects the function of the brain and other organs, and can be life-threatening.

Can you have diabetic ketoacidosis without high blood glucose levels?

Yes, it is possible to enter a state of diabetic ketoacidosis (DKA) without high blood glucose levels (also known as serum glucose levels).

Measuring blood glucose levels with glucometer

While people often associate diabetic ketoacidosis with high blood glucose levels, many don’t realize that they can become ill from ketoacidosis when their blood glucose level is under 240 mg/dl. A rare type of diabetic ketoacidosis, called euglycemic diabetic ketoacidosis (EDKA), occurs when blood glucose levels are not elevated, but there isn’t enough insulin in the body to prevent the breakdown of fats. Although cases of EDKA have occurred in people with type 1 and type 2 diabetes mellitus, type 1 patients are at higher risk for diabetic ketoacidosis than type 2 patients.

Since the introduction of sodium glucose cotransporter-2 (SGLT-2) inhibitors, emergency rooms have seen an increase in cases of euglycemic diabetic ketoacidosis. Current estimates peg EDKA cases at 2.6% to 3.2% of all DKA cases seen in emergency rooms – though this percentage might be low due to underreporting.

SGLT-2 inhibitors: A new cause of rare DKA called euglycemic DKA

SGLT-2 inhibitors, sold under the brand names of Jardiance, Invokana, Farxiga, and Steglatro, help reduce blood glucose by preventing reabsorption of glucose in the kidneys. Instead, the body gets rid of the excess glucose through the urine. It is important to note that the FDA has approved SGLT-2 use for people with type 2 diabetes only.

Euglycemic DKA can arise from prescribing SGLT-2 inhibitors off-label to people with type 1 diabetes

Some physicians, however, have prescribed SGLT-2s off-label to people with type 1 diabetes. Many people taking both insulin and an SGLT-2 benefit from lower glucose levels, fewer post-meal ups and downs, and weight loss, all without an added risk for hypoglycemia.

Once a SGLT-2 drug enters the picture, though, the risk of euglycemic DKA is 5-10% higher for people with type 1 diabetes than those not taking that medication.

Euglycemic diabetic ketoacidosis is much trickier for people with diabetes to discern, though, because the classic tip-off of sustained, elevated blood sugars is absent. Blood sugar is below – sometimes well below – 240 mg/dl.

One recent case study described a person with type 1 who was experiencing euglycemic DKA with blood sugar around 75 mg/dl.

When to check for diabetic ketoacidosis (DKA)

If high blood sugar does not alert people with type 1 to check their ketone levels, what should they look for instead?

Classic diabetic ketoacidosis symptoms:

According to Dr. Charles Alexander, a Pennsylvania-based clinician and medical advisor to diaTribe, euglycemic DKA presents with many similar symptoms of classic DKA, including:

  • Nausea and vomiting
  • Abdominal pain
  • Excessive thirst
  • Feeling of being unwell or weak, without any known reason
  • Lethargy
  • Loss of appetite

Ketone test strips

The importance of testing ketone levels

Alexander strongly suggests that people with type 1 who take an SGLT-2 check their ketone levels every morning. This suggestion is in line with the consensus standards issued by leading clinicians worldwide (including Alexander) on managing the risk of DKA in people with type 1 who take SGLT-2s.

At the first sign of any type of diabetic ketoacidosis, one should test ketone levels, even if blood sugar levels are within range. From ketone blood meters that measure BHB to urine strips that measure AcAc to meters that measure breath ketones, here is a primer on the most effective ways to test ketone levels.

It’s possible to check ketone levels with a simple, over-the-counter urine test strips or a ketone meter.

If you see elevated ketones, start hydrating aggressively as able, suggests Dr. Julie Hendrix, an endocrinologist in private practice in Franklin, Tennessee. She says it’s also important to take insulin and to consume a fast-acting carbohydrate, ideally a glucose-containing fluid such as apple juice.

SGLT-2 inhibitor drugs: The trigger, not the cause, of euglycemic diabetic ketoacidosis (EDKA)

Typically, taking an SGLT-2 by itself is not what triggers an episode of euglycemic diabetic ketoacidosis. Other factors combine with the action of SGLT-2s to act as triggers.

Factors that contribute to euglycemic diabetic ketoacidosis (EDKA)

Many factors are related to some type of so-called starvation (when the body is unable to use, or does not have enough carbs for energy), such as:

  • Fasting
  • Not able to eat due to illness
  • Acute viral or bacterial infections
  • Following a low carbohydrate or ketogenic diet
  • Insulin pump malfunctions or missed insulin doses
  • Surgery
  • Pregnancy
  • A significant increase in exercise length or intensity

What to do in the event of euglycemic ketoacidosis (EDKA)

The idea of both taking insulin with normal blood glucose levels, and consuming carbs if diabetic ketoacidosis is suspected, are highly counterintuitive to most people with type 1. But without enough insulin and glucose, ketone levels will continue to rise, even if blood sugars are in range.

Consuming carbohydrates with insulin helps switch the body back to seeking energy from glucose, rather than fat. That fuel switch stops the liver from making glucose from fat, which halts ketone overproduction.

When persistent vomiting is present, all bets are off: seek IV hydration and medical treatment immediately.

Euglycemic ketoacidosis (EDKA) at the emergency room: Case studies

IV bag in emergency room

Not long after the drug Invokana went on the market in 2013, people with both type 1 and type 2 started showing up in emergency rooms with euglycemic diabetic ketoacidosis.

Because EDKA is quite rare and health care providers had been taught that diabetic ketoacidosis only occurs when blood glucose levels are high, many emergency room professionals were deceived by blood sugar that was in a normal or slightly elevated range, and initially dismissed the possibility of diabetic ketoacidosis. Eventually euglycemic diabetic ketoacidosis was diagnosed, but many more hours passed than would have if high blood sugar had been present.

Emergency room physicians have written many case studies about euglycemic diabetic ketoacidosis since then:

  • One person, originally diagnosed as having type 2 and taking an SGLT-2, presented at the emergency room with a blood serum glucose level of 75 and had not eaten in two days. Her labs indicated a transition to LADA, as well as being in euglycemic diabetic ketoacidosis.
  • A teenager with type 1, on an insulin pump but not taking SGLT-2s, presented at the emergency room with an initial glucose of 109. She had been vomiting intermittently for the previous 24 hours. Ultimately, she was diagnosed both with appendicitis and with EDKA.
  • A man in his 60s with type 2 was initially treated for a stroke that was evident on a CT scan. On the fifth day of his hospital stay, he became quite drowsy and was suddenly breathing rapidly. Bloodwork revealed severe acidosis, ultimately attributed to the Jardiance he had taken for years.

Many of these case studies stress that all people with diabetes who take SGLT-2s should be considered as potentially in DKA if they come to the emergency room, and that appropriate laboratory tests be run to confirm or rule out that diagnosis.

What to do if you’re being denied treatment for diabetic ketoacidosis in the emergency room

Unfortunately, not every emergency room professional knows what EDKA is, or will know to order the correct lab tests to detect it.

It’s a very frightening prospect—you’re in the hospital because you know you are very ill, and have a good idea why, but your input is dismissed and you are not receiving the correct treatment.

In “Lessons Learned from A Scary Visit to the Emergency Room,” Stefany Sheehan, the parent of a child with T1D and member of the board of trustees at Joslin Diabetes Center, breaks down her daughter’s experience with EDKA after taking an SGLT-2 inhibitor.

If you’re headed to the emergency room, contact your endocrinologist beforehand

Alexander suggests notifying your endocrinologist that you are going to the emergency room, so that they will be able to call the emergency room to discuss your situation and advise the emergency room staff. You can also ask the emergency room staff to call your endocrinologist.

You can also take copies of articles with you to give to your emergency room team if necessary. In addition to letting emergency room personnel know you are well educated about your diabetes, you may also save them time doing research about EDKA and SLGT-2 inhibitors.

If you cannot get through to the medical team in the emergency room, ask them to call an endocrinologist from the hospital to consult, if there is one available.

Diabetic ketoacidosis (DKA) and euglycemic diabetic ketoacidosis (EDKA): The bottom line

The specter of any type of DKA is concerning to people with insulin-treated diabetes. Understanding how it can happen, how to detect it early, and how to advocate for yourself should help those taking SGLT-2s keep themselves healthy and far away from a DKA emergency.

Diabetic Ketoacidosis (DKA)

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Short-term high blood sugars are rarely lethal. However, for people with type 1 diabetes, and some with type 2 who are not producing enough insulin, periods of high blood sugars can lead to diabetic ketoacidosis (DKA). DKA is extremely dangerous, and if untreated it is deadly.

The absence of insulin allows your blood to slowly become acidic. The body’s cells cannot survive under acidic conditions, so the liver will try to help the cells that are starved for glucose and secrete glucose. 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.

Diabetic ketoacidosis is always ultimately caused by a lack of insulin, and usually occurs in patients with undiagnosed type 1 diabetes. It can also happen when patients miss insulin doses (or don’t realize that their insulin pumps have failed). Other health issues, such as the flu, dehydration, or physical exhaustion can also cause DKA to develop more quickly.

Who Can Develop Diabetic Ketoacidosis (DKA)?

People with type 1 diabetes and type 2 diabetes can develop DKA. Those with type 1 diabetes are at a much higher risk, because they naturally make little or no insulin. Most people with type 2 diabetes secrete enough insulin to prevent diabetic ketoacidosis, even if blood sugars are chronically elevated.

Most often, DKA develops in people who have not yet been diagnosed with diabetes. Type 1 diabetes is frequently diagnosed only after DKA has sent an unsuspecting patient to the hospital. Once diagnosed, people with diabetes can avoid DKA if they learn to recognize the beginning symptoms.

How Do I Know If I Have Diabetic Ketoacidosis (DKA)?

DKA can develop slowly or quickly. At first, it is characterized by the symptoms of very high blood sugar:

  • thirstiness
  • dry mouth
  • frequent urination
  • blurry vision
  • fruity bad breath

At this point, you will likely have high blood sugars and ketones in your urine (more on this below).

If your body still doesn’t get the insulin it needs, your blood becomes more acidic. You will likely feel tired, and your body might start to feel very achy, as if with a high fever. When any of the following symptoms occur, your condition is very serious, and may develop into DKA, if it hasn’t already:

  • nausea, vomiting, or abdominal pain
  • confusion and trouble concentrating
  • dizziness
  • deep and labored breathing

DKA is a potentially life-threatening condition and requires immediate treatment at a medical center. If you think that you may have it, call your doctor immediately or go to the emergency room.

What Are Ketones?

Diabetic ketoacidosis involves the dangerous overproduction of ketones.

Ketones are a byproduct of your body burning fat for fuel. Most of the time, there’s nothing unsafe about ketones — the body safely produces ketones when fasting or when you’ve eaten few carbohydrates. Your body may even create ketones overnight, between breakfast and dinner. Many people enjoying low-carbohydrate diets, both with and without diabetes, have consistent low levels of ketones circulating. But in excessive concentrations, ketones become very dangerous.

If you do not have enough insulin and are experiencing prolonged high blood sugars, your body will begin to harvest fat for energy. Eventually, it will consume your muscles and organs. This will cause ketones to build up in your blood, making it more acidic. Your kidneys will eventually try to help filter out the extra glucose in the blood by secreting the glucose along with your urine. You can detect DKA by checking for ketones.

How to Check for Ketones

Many experts recommend checking for ketones if you have had prolonged high blood sugars. The American Diabetes Association suggests testing for ketones every four to six hours when blood sugar remains elevated above 240 mg/dL.

It is also wise to check for ketones during illness, especially any dehydrating illness — one that causes vomiting or diarrhea, or makes it difficult to eat or drink. These conditions can greatly accelerate the development of DKA.

There are test kits for ketones that use blood or urine. Those that use urine are less expensive and more common, though blood meters may be more accurate and easier to interpret.

Checking Urine for Ketones

A ketone urine test works by dipping a ketone test strip into a sample or fresh stream of urine. You wait for a little while (see instructions on the test kit) and the strip will change color. You then match the color with the color strip on the side of the bottle to determine your level of ketones. Typically, the darker the strip, the more ketones you have.

Checking Blood for Ketones

There are now a few devices on the market that can check your blood for ketones. These devices work the same way as a typical blood glucose meter. You apply a drop of blood to the strip and the meter will tell you your level of ketones.

How to Treat Diabetic Ketoacidosis (DKA)

You always should treat DKA by trusting to the supervision of a qualified medical professional. This is not a health condition to handle at home! Typically, the treatment will include:

  • Intravenous (IV) fluids to restore proper levels of hydration
  • Insulin to lower the high blood sugars
  • Electrolytes to restore the imbalance caused by dehydration
  • Treatment of any illness or infection that may be contributing to DKA

If you suspect you have DKA, seek emergency medical care. In the meantime, be sure to drink plenty of water and treat the high blood sugars as your doctor has advised you.

If you need to go to the ER, let the paramedics know that you think you have diabetic ketoacidosis. If you can remember, let them know how much insulin you used recently and when.

How to Treat Slightly Elevated Ketones

If you only have mild symptoms of high blood sugar and a ketone test does not indicate that you’re in immediate danger of DKA, then you need to know what to do so your situation doesn’t worsen. Don’t hesitate to contact your healthcare provider so they can help you monitor your situation closely.

The most important thing to do is to bring your blood sugar back down to healthy levels. If you’re an insulin user, the usual prescription is to administer a correction dose of insulin.

Gary Scheiner, a CDE, author, and person living with type 1 diabetes, shares his insight on the quantity of insulin that should be given: “When elevated ketones are present, it is generally safe to administer the usual ‘correction dose’ based on one’s target blood glucose and insulin sensitivity.  Often, there is an insulin deficit since the body is either insulin-resistant or has received very little working insulin for the past several hours, so a bit more than the standard amount may be warranted.  However, the standard dose will at least start the process toward recovery.”

Be sure to drink plenty of water and if you are alone, try to find someone who can be with you while you continue to monitor your blood sugar and ketone levels, to make sure the situation does not get worse.

After Diabetic Ketoacidosis (DKA)

It is normal to feel tired for a few days after a DKA episode. Check your blood sugars and call your doctor if you are uncomfortable with your numbers. If you don’t already own a blood ketone meter or urine ketone strips, consider the small investment and remember to use it anytime blood sugars go over 240mg/dL or 13mmol. The key to avoiding DKA is to manage ketones at their earliest onset.

DKA Hospitalization Is on the Rise, Mortality Declining

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Hospitalization rates for diabetic ketoacidosis (DKA) are on the rise, according to new data from the Centers for Disease Control and Prevention (CDC).

After a nearly 10-year period of slight decline, age-adjusted rates of hospitalization for the life-threating, preventable diabetes complication increased nearly 55% between 2009 and 2014, Stephen R. Benoit, MD, from the CDC’s National Center for Chronic Disease Prevention and Health Promotion, Division of Diabetes Translation, and colleagues report in an article published in the March 30 issue of the Morbidity and Mortality Weekly Report.

However, the increasing hospitalization rate has not led to higher in-hospital mortality, which decreased consistently during the period of study, the authors stress.

Data from the CDC’s US Diabetes Surveillance System indicated a rise in DKA hospitalizations from 2009 through 2014. To further investigate that trend, the authors sought to estimate rates of DKA hospitalization and in-hospital case fatality using 2000 to 2014 data from the Agency for Healthcare Research and Quality’s National Inpatient Sample.

“Overall, age-adjusted DKA hospitalization rates decreased slightly from 2000 to 2009, then reversed direction, steadily increasing from 2009 to 2014 at an average annual rate of 6.3%,” they report.

Overall, the rate increased 54.9%, climbing from 19.5 per 1000 persons in 2009 to 30.2 in 2014. The increase was seen across all age groups, but was highest in adults younger than 45 years (44.3 per 1000 persons in 2014) and lowest in those 65 years and older (less than 2.0 per 1000 persons in 2014).

Meanwhile, in-hospital case-fatality rates declined 63.6% overall, at an annual average rate of 6.8% (from 1.1% to 0.4%, and the decline was observed across all age groups and both sexes, the authors report. “Although the highest case-fatality rates were observed among persons aged ≥75 years, this group experienced the largest absolute decrease across the entire period,” they note.

Although the causes of the increase in DKA-related hospitalizations are not clear, the authors hypothesize that the jump might reflect changes in case definition, lower thresholds for hospitalization, and the introduction of new medications such as sodium-glucose cotransporter 2 (SGLT2) inhibitors for type 2 diabetes that potentially increase DKA risk, as reported previously by Medscape Medical News.

 Similarly, the causes of the declining in-hospital mortality rates have not been established but may be the result of better management and treatment thanks to an improved understanding of DKA pathophysiology and the adoption of treatment guidelines, the authors say. “Another possibility is that hospital admission of less severe cases has resulted in higher admission rates and contributed to the lower in-hospital case-fatality rates over time,” they write.

The fact that, in 2014, DKA hospitalization rates among persons with diabetes younger than 45 years was approximately 27 times higher than in adults 65 or older points to the importance of considering demographic and clinical characteristics of younger diabetes patients when looking to understand the increase in DKA hospitalizations. “Information from studies among these groups might help determine whether factors such as symptom recognition, adherence to therapy, self-management skills, access to care, or cost of treatment should be a focus of DKA prevention strategies.”

Further research might also identify populations at increased risk for DKA hospitalization. “Evidence-based, targeted prevention measures, such as diabetes self-management education and support might help reverse the trend in this potentially life-threatening but avoidable complication of diabetes,” the authors conclude.

Recurrent DKA tied to fragmented care

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Among patients with diabetes, increased number of episodes of diabetic ketoacidosis is correlated with increased fragmentation of care and mortality, according to recent findings.

Amisha Wallia, MD, assistant professor in the division of endocrinology, metabolism and molecular medicine at Northwestern University Feinberg School of Medicine, and colleagues evaluated 3,615 patients with diabetic ketoacidosis (DKA) enrolled in the Chicago HealthLNK Data Repository (CHDR) between 2006 and 2012. The CDHR is an electronic health recordlinkage tool encompassing records from five large academic health centers within the Chicago area.

The researchers stratified patients with DKA hospitalizations into groups of one, two, three or four or more DKA inpatient encounters during the study interval. Patients with more than one hospitalization for DKA during the study period were classified as recurrent. Care fragmentation was defined as DKA hospitalization at more than one hospital during the study interval.

The researchers found that of the participants with DKA, most had only one DKA hospitalization (78.4%), followed by two to three hospitalizations (15.7%) and four or more DKA hospitalizations (5.8%).

Although participants with four or more hospitalizations accounted for only 5.8% of the participant population, these participants encompassed 26.3% of inpatients encounters. Black race, Medicare or Medicaid insurance or uninsured states were more common in participants with recurrent DKA.

Recurrent DKA was documented in 780 of all participants and fragmented care was noted in 16% of all participants. Fragmented care participants were more likely to have had four or more DKA hospitalizations (28%) compared with two to three hospitalizations (11.6%; P = .0001), and participants in the four or more hospitalizations group had greater odds of having fragmented care (OR = 2.96; 95% CI, 1.99-4.3). Thirty-five percent of fragmented encounters were determined to occur outside of the participants’ “primary site” of health care. Ninety-nine percent of participants with recurrent DKA had inpatient encounters at two hospitals, and 11 were hospitalized at more than two hospitals.

Fragmented care was associated with a 1.88-fold increase in DKA visit count after adjustment for age, sex, race and insurance status (P < .0001). Fourteen percent of participants died during the study. In the fully adjusted model, which included fragmentation, DKA visit count, age, sex, race and insurance status, the number of DKA encounters (OR = 1.28; 95% CI, 1.04-1.58) and age (OR = 1.06; 95% CI, 1.05-1.07) were associated with death.

“Patients with fragmented care may utilize health care differently from patients who limit their care to one center,” the researchers wrote. “Therefore, unique approaches requiring collaboration between institutions may also be necessary to improve the health of this particular group of patients. This study, in addition to identifying the scope and toll of recurrent DKA on patients in Chicago, identifies just such a population of patients for whom efforts at prevention and follow-up may require a more tailored approach.” – by Jennifer Byrne

Three Diabetes Drugs Linked to Ketoacidosis, FDA Warns

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Three type 2 diabetes drugs — canagliflozin (Invokana), dapagliflozin (Farxiga), and empagliflozin (Jardiance) — may lead to ketoacidosis, the FDA warned today.

The sodium-glucose co-transporter-2 (SGLT2) inhibitors are designed to lower blood sugar in patients with diabetes, but the FDA is investigating a connection between the drugs and dangerously high acid levels in the blood. They are also looking at whether changes will need to be made to the prescribing information, they said in the warning, which is posted online.

At least two studies presented here at the annual meeting of the American Association of Clinical Endocrinologists have found a connection between the SGLT2 inhibitors and diabetic ketoacidosis (DKA).

“Healthcare professionals should evaluate for the presence of acidosis, including ketoacidosis, in patients experiencing these signs or symptoms,” the FDA said. “Discontinue SGLT2 inhibitors if acidosis is confirmed, and take appropriate measures to correct the acidosis and monitor sugar levels.” The signs and symptoms listed included difficulty breathing, nausea, vomiting, abdominal pain, confusion, and unusual fatigue or sleepiness.

The FDA is issuing the warning after they searched their database of adverse event complaints, they said in an announcement. From March 2013 to June 2014 there were 20 cases of DKA reported, most of them with type 2 diabetes as the indication. Hospitalization was required in all of the cases, and the median time to onset was 2 weeks after starting the drug.

“I would encourage that these cases be studied so we can learn the scenarios behind them so they can be broadcast,” said Farhad Zangeneh, MD, medical director of Endocrine, Diabetes and Osteoporosis Clinic, in an interview with MedPage Today. “The important thing here it is good to know as much info as available.”

But he added that we should look at the background before issuing a general warning against the class. He manages hundreds of patients with the three SGLT2 inhibitors, he said, and has never had any problems. He suggested starting with low doses and making sure that patients are always well hydrated, have no renal problems, and get their lab work done.

Many doctors prescribe SGLT2 inhibitors off-label to type 1 diabetes patients, said Zangeneh, but in that case, the patients should at least be “super-patients” — they should be well controlled, hand-picked, excellent carb-counters.

“Certainly this report warrants a closer look at these cases to find out the exact details of the individual scenarios,” he added.

In one of the studies presented here, researchers led by Foiqa Chaudhry, MD, an endocrinology fellow at the University of Florida, described two cases of DKA that developed after the patients were taking SGLT2 inhibitors. An 18-year-old female presented with persistent vomiting and abdominal pain for the last 24 hours. She’d had type 2 diabetes since she was 8, but had never had ketoacidosis.

She had started taking metformin and canagliflozin 3 weeks earlier, and her primary care physician increased the dosage from 100 mg to 300 mg one week earlier. She was treated for diabetic ketoacidosis with an insulin drip and an IVF, and was eventually discharged.

In the other case, a 55-year-old man presented with dizziness. It was found that he had recently started taking glipizide and dapagliflozin. He was treated for mild DKA and sent home. The authors of the paper said that the safety of SGLT2 therapy warrants further study.

“In the cases presented, given the degree of poor baseline glycemic control, it is concerning if these agents propagated the state of dehydration thus accelerating the development of DKA,” they wrote. “As such, it is suggested that more specific counseling be given to patients regarding hydration status when being started on this class of medications.”

In an email to MedPage Today, Chaudhry said, “Though causality cannot be established with case reports alone, in our care of two patients with type 2 DM [diabetes mellitus] who developed hyperglycemic DKA — which happened to be temporally related to the use of SGLT2 inhibitor therapy — one must at least be vigilant about monitoring the volume status in these patients to avoid the potential complication of DKA.”

And in a late-breaking trial of 10 type 1 diabetes patients on insulin, liraglutide, and dapagliflozin, one of the patients developed DKA, according to the researchers, who were led by Nitesh Kuhadiya, MD, at the University of Buffalo.

“This is the first study demonstrating that the addition of dapagliflozin to insulin and liraglutide in patients with T1D results in a significant improvement in glycemia,” they wrote. “However, care would have to be exercised in terms of the reduction in insulin dose and thus the occurrence of euglycemic DKA.”

The FDA said that the cases they analyzed were atypical because glucose levels were only mildly elevated at less than 200 mg/dL in some reports. With type 1 diabetes patients who have DKA, these levels are usually greater than 250 mg/dL, they noted.

They added that, in most of the cases, a high anion gap metabolic acidosis was accompanied by higher blood or urine ketones. “Potential DKA-triggering factors that were identified in some cases included acute illness or recent significant changes such as infection, urosepsis, trauma, reduced caloric or fluid intake, and reduced insulin dose,” they wrote. “Potential factors, other than hypoinsulinemia, contributing to the development of a high anion gap metabolic acidosis identified in the cases included hypovolemia, acute renal impairment, hypoxemia, reduced oral intake, and a history of alcohol use.”

But they noted that for half of the cases, there was no triggering factor that was listed.

One other late-breaking study found that dapagliflozin improved beta-cell function and insulin sensitivity in 24 patients with type 2 diabetes. Lead author Carolina Solis-Herrera, MD, a resident at the University of Texas Health Science Center at San Antonio, said that there was no evidence of DKA in their trial.

“We did not find that in our study, but it’s definitely something that should be looked into,” she told MedPage Today.

The FDA asked healthcare professionals to report adverse events and side effects from these products to their MedWatch program.