|Year : 2018 | Volume
| Issue : 2 | Page : 24-26
Euglycemic diabetic ketoacidosis caused by canagliflozin: A rare case report
Rupali Lahoria, Sachin Pandove, Deepak Bhasin, Harpal Singh, Surinder Pal Singh, Rajit Jhingan
Department of Pulmonary and Critical Care, Max Super Speciality Hospital, Mohali, Punjab, India
|Date of Web Publication||21-Nov-2018|
Surinder Pal Singh
Department of Pulmonary and Critical Care, Max Super Speciality Hospital, Mohali, Punjab
Source of Support: None, Conflict of Interest: None
Drugs are one of the rare precipitating factors for diabetic ketoacidosis (DKA) in diabetes mellitus. Medications causing DKA are corticosteroids, pentamidine, clozapine, etc. Even rare is for an oral hypoglycemic agent to cause DKA, but since the approval of the first-in-class drug in 2013, data have emerged suggesting that sodium glucose transporter-2 inhibitors, including canagliflozin, may lead to DKA. This is a case of a 46-year-old male patient who was admitted to the intensive care unit with signs and symptoms suggestive of DKA. He was recently started on canagliflozin. He had a blood glucose level of 243 mg/dl, urine was positive for ketones, and his arterial blood gas was suggestive of high anion gap metabolic acidosis. All the precipitating causes of DKA were ruled out. Based on the above findings and laboratory results, the possibility of canagliflozin-induced ketoacidosis was kept and managed on the lines of DKA.
Keywords: Canagliflozin, diabetic ketoacidosis, euglycemic diabetic ketoacidosis, sodium glucose transporter-2 inhibitors
|How to cite this article:|
Lahoria R, Pandove S, Bhasin D, Singh H, Singh SP, Jhingan R. Euglycemic diabetic ketoacidosis caused by canagliflozin: A rare case report. Saudi Crit Care J 2018;2:24-6
|How to cite this URL:|
Lahoria R, Pandove S, Bhasin D, Singh H, Singh SP, Jhingan R. Euglycemic diabetic ketoacidosis caused by canagliflozin: A rare case report. Saudi Crit Care J [serial online] 2018 [cited 2019 Mar 22];2:24-6. Available from: http://www.sccj-sa.org/text.asp?2018/2/2/24/245944
| Introduction|| |
The prevalence of type 2 diabetes mellitus (T2DM) is increasing globally, particularly in developing countries., In India, it is estimated that over 65 million people have T2DM, making it the country with the second highest number of cases, behind only China., DM is associated with many microvascular, macrovascular, and other complications. Among these, diabetic ketoacidosis (DKA) is the most serious hyperglycemic emergency in patients with type 1 DM (T1DM) and T2DM and is associated with significant morbidity and mortality.
The most common scenarios for DKA are underlying or concomitant infection (40%), missed or disrupted insulin treatments (25%), and newly diagnosed, previously unknown diabetes (15%). Other associated causes make up roughly 20% in the various scenarios. Drugs are one of the rare precipitating factors for DKA in DM. Medications causing DKA are corticosteroids, pentamidine, clozapine, etc., Even rare is for an oral hypoglycemic agent (OHA) to cause DKA, but since the approval of the first-in-class drug in 2013, data have emerged suggesting that sodium glucose transporter-2 (SGLT-2) inhibitors, including canagliflozin, may lead to DKA.
We present the case of a 46-year-old male patient who was admitted to the intensive care unit (ICU) with severe anion gap metabolic acidosis and ketoacidosis with relatively normal glucose levels. All the findings were consistent with canagliflozin-induced ketoacidosis.
| Case Report|| |
A 46-year-old male patient was admitted to the ICU of a tertiary care hospital with chief complaints of generalized body weakness, vomiting, vague uneasiness in chest, and epigastric discomfort since 4 days prior to the admission and drowsiness since few hours prior. He was diagnosed as T2DM 3 years back and was on OHA and insulin, but his insulin was suddenly stopped and he was recently started on canagliflozin 1 day prior to the onset of symptoms. He was taking canagliflozin 300 mg per day and was also on levothyroxine for hypothyroidism.
There was no history of fever, diarrhea, burning micturition, increased urinary frequency, or poor appetite. On presentation, he was drowsy but arousable and hemodynamically stable, but was having acidotic breathing. His arterial blood gas was suggestive of high anion gap metabolic acidosis (pH – 6.9, bicarbonate – 3.1, anion gap – 25). Laboratory investigation revealed urinary ketones positive; normal renal function test, liver function test, and complete blood count; and HbA1c of 13.8. Based on his clinical profile, he was expected to have high sugars, but he had blood glucose level of 243 mg/dl which was probably because of the glycosuric effect of SGLT-2 inhibitors. His urine routine examination showed no evidence of urinary tract infection (UTI) and his blood and urine cultures were also sterile. Electrolyte disturbances in the form of hypokalemia (3.1) and severe hypophosphatemia (0.9) were also present. He was resuscitated with fluids and, after correction of hypokalemia, he was started on insulin infusion along with the ongoing replacement of potassium and phosphorus. However, despite fluid resuscitation, insulin, and electrolyte correction, his bicarbonates and pH did not improve and had worsening encephalopathy, drowsiness, and acidotic breathing. He was initiated on noninvasive ventilation and, in view of worsening metabolic acidosis despite fluid resuscitation, he was initiated on hemodialysis (HD). Postdialysis, he again developed metabolic acidosis which gradually recovered in the next 24 h not requiring another session of HD. Based on the above findings and laboratory results, the possibility of canagliflozin-induced ketoacidosis was kept and managed on the lines of DKA with intensified insulin regimen along with fluids and electrolyte correction. Insulin infusion along with dextrose to prevent hypoglycemia was continued for 48 h till anion gap was normalized and ketones were cleared. Subsequently, his condition improved in the next 2–3 days, shifted to subcutaneous insulin, and subsequently discharged home in satisfactory condition.
| Discussion|| |
Canagliflozin belongs to SGLT-2 inhibitors, a newer class of anti-diabetic medications that are approved by the US Food and Drug Administration (FDA) for lowering blood sugar in adults with T2DM. Canagliflozin lowers plasma glucose via an insulin-independent mechanism by lowering the renal threshold for glucose and promoting urinary glucose excretion (~80–120 g/day), which leads to a mild osmotic diuresis and net caloric loss. Canagliflozin has a half-life of 10.6 h (100 mg dose); 13.1 h (300 mg dose) and protein bound: 99% (predominantly to albumin). Canagliflozin was shown to reduce HbA1c, body weight, and blood pressure (BP) in patients with T2DM from India using pooled data from six placebo-controlled studies. Also, there is lesser incidence of hypoglycemia associated with canagliflozin compared to other hypoglycemic drugs. Because of these additional properties of reduction in weight and BP, canagliflozin is being used more and more these days.
Canagliflozin was generally well tolerated. The most common adverse reactions associated with canagliflozin were genital mycotic infections, UTIs, osmotic diuresis, and reduced intravascular volume. However, rare case reports of DKA and related events associated with canagliflozin started to occur during the course of treatment. DKA is a rare but serious adverse event seen increasingly with canagliflozin and other SGLT-2 inhibitors.
The FDA Adverse Event Reporting System database identified 73 cases of DKA from March 2013 to May 2015 for patients using this class of medications.
The European Medicines Agency had also reported a total of 101 cases of DKA in patients treated with SGLT-2 inhibitors for T2DM worldwide as of May 19, 2015. According to several studies, the overall frequency of reported events suggestive of DKA is <0.1%. The incidence of DKA and related events (ketoacidosis, metabolic acidosis, and acidosis) with canagliflozin was 0.07%, corresponding to 12 events out of the 17,596 patients in a study done by Erondu et al. SGLT-2 inhibitors cause ketoacidosis.
The median time to onset of symptoms following initiation of drug therapy was 2 weeks (range 1–175 days). Even single dose of canagliflozin can cause life-threatening ketoacidosis as was also seen in our case. This alerts clinicians to monitor their patients while being on SGLT-2 inhibitors.
Typically DKA is associated with hyperglycemia above 250 mg/dL, euglycemic DKA (euDKA) was originally defined as DKA with plasma glucose levels <300 mg/dL occurring in young T1DM patients, two-thirds of whom were female; however, for many patients in the reported cases and in ours, the blood glucose levels were lower, with a mean of 243 mg/dL. On the whole, euDKA is pathophysiologically similar to DKA except for the circumstance–SGLT-2-induced glycosuria–that “artificially” lowers plasma glucose levels and predisposes to increased ketogenesis. This euDKA may be underrecognized and result in delayed treatment with the necessary aggressive intravenous hydration and insulin.
It is always important to rule out other potential causes of DKA including major illness, dehydration, and inadequate insulin intake as was done in our case Our patient was evaluated in detail to identify any precipitating cause for DKA. All the tests for infection or other medical disorder that could precipitate the event were negative. His blood and urine cultures, chest X-ray, ultrasonography abdomen, electrocardiography, troponins, and lipase were all unremarkable. He did not skip any of his medications and had no history of any off-label medication intake. He developed symptoms after one dose of canagliflozin and his condition did not improve even after dialysis, till the drug was metabolized. The drug has half-life of 10.6 h (100 mg dose); 13.1 h (300 mg dose), and is nondialyzable as it is 99% protein bound (predominantly to albumin).
There have been no case reports of ketoacidosis caused by SGLT-2 inhibitors from India other than a case of pseudoketoacidosis caused by them, where authors warned about the potential of these drugs to cause biochemical changes similar to ketoacidosis but without any symptom.
Stopping insulin and starting SGLT-2 inhibitors alone can cause fatal ketoacidosis as happened in our case. The potential complications related to SGLT-2 inhibition are predictable, detectable, and preventable, and clinicians must also be aware of relatively rare complications such as ketoacidosis which if identified and treated early can certainly save a life.
| Conclusion|| |
Canagliflozin is a newer OHA and is being prescribed more and more these days because of the additional effect on the reduction of BP and weight. Our case clearly illustrates the rare association of ketoacidosis with SGLT-2 inhibitors. Therefore, physicians must be aware of potential, relatively uncommon, and life-threatening side effect of new OHA in patients with T2DM. Early identification of the cause and initiation of appropriate therapy should be instituted. Further research and monitoring of adverse events is clearly needed to determine the frequency and severity of these reactions.
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Conflicts of interest
There are no conflicts of interest.
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