Euglycemic Diabetic Ketoacidosis: A Potential Complication of Treatment With Sodium–Glucose Cotransporter 2 Inhibition

Anne L. Peters; Elizabeth O. Buschur; John B. Buse; Pejman Cohan; Jamie C. Diner; Irl B. Hirsch

Disclosures

Diabetes Care. 2015;38(9):1687-1693. 

In This Article

Conclusions

This is the first case series of euDKA associated with use of SGLT-2 inhibitors. These agents, by inhibiting glucose reabsorption, promote glycosuria, lower plasma glucose, and induce modest weight loss.[1] SGLT-2 inhibitors have been approved for use in people with type 2 diabetes, and clinical trials are on-going in individuals with type 1 diabetes. Two prior cases of euDKA with SGLT-2 inhibitors have been reported. One was in a woman who had type 2 diabetes as well as Prader-Willi syndrome treated with a low-carbohydrate diet who developed euDKA while on ipragliflozin.[14] The other was a man with type 1 diabetes who was not entirely forthcoming about the medications he had been taking. Although it seems he was taking canagliflozin, whether he was still administering insulin was not clear.[15]

The most important feature in all of these initial cases is that the patients did not recognize they had ketoacidosis, which is typically associated with severe hyperglycemia. As a result, instead of increasing insulin doses, insulin was unchanged or decreased. When patients presented for acute medical care, their providers often failed to recognize the DKA, leading to unnecessary testing and treatment. All of the patients reported here were treated with canagliflozin, likely because it was first to market and has the greatest exposure in the population. Other SGLT-2 inhibitors are similar in action, and we speculate that they are likely to pose similar risk for euDKA. The overall risk for developing euDKA on SGLT-2 inhibitors is unknown; ongoing trials should further define the risk, particularly in type 1 diabetes and postoperatively in individuals with type 2 diabetes. All of the patients presented are quite similar biochemically and all responded readily to intravenous fluids and insulin once the syndrome was recognized. Although alcohol intake was included as a potential contributor in some of the patients, most of the patients denied recent or excessive alcohol use. Most of the patients were women, but there were no consistent patterns in age or BMI. In the patients with type 1 diabetes, concomitant mild infection, increased activity, and/or reduced food intake coupled with acute insulin dose reduction or omission were potential contributors in many patients, whereas in others, no contributing factors were identified. Many of the patients reported nausea; however, it seems more likely than not that nausea was a consequence instead of a contributor to the euDKA or ketosis in most patients.

The mechanism of euDKA is not fully elucidated. The first description was in a series of 37 patients (mean age 18.6 years; range 10–28) who presented with DKA and a blood glucose level of less than 300 mg/dL (16.7 mmol/L).[11] Vomiting was seen in 32% and was the most common presenting feature. Interestingly, although the authors were not able to explain the phenomenon, a letter to the editor opined that the cause of the euDKA was due to a lower renal threshold for glucose and a loss of large amounts of glucose in the urine in the presence of an increased rate of gluconeogenesis and free fatty acid release,[16] foreshadowing the findings in this case series. A recent publication from Japan similarly suggested this potential mechanism for euDKA with SGLT-2 inhibition, without reporting the details in the one patient identified.[17]

Increased renal clearance of glucose mediated by the SGLT-2 inhibitor led to deceivingly low blood glucose levels in the setting of illness, and the reduced insulin doses at a time of heightened insulin resistance may have tipped the balance toward ketosis resulting in euDKA. In our series, illness and a reduction in food intake and/or insulin doses preceded the development of DKA in some but not all patients. Normally, fasting glucose reflects hepatic glucose production, inhibited at relatively low portal insulin concentrations. Suppression of ketogenesis requires somewhat higher insulin levels.[18] Arguably, in the setting of SGLT-2 inhibition, fasting glucose can be maintained at reasonable levels despite very low portal insulin because of urinary glucose loses. This may predispose to ketosis and, most importantly, may uncouple ketosis from the finding of severe hyperglycemia. Furthermore, SGLT-2 inhibitors are associated with an increase in plasma glucagon levels through uncertain mechanisms.[19,20] Hyperglucagonemia increases the propensity toward ketone production.[21] Through their mechanism of action, SGLT-2 inhibitors also predispose to a negative fluid and sodium balance and may thereby compound the already hypovolemic state of DKA, particularly in the setting of nausea and poor oral intake. Hypovolemia drives elevations in glucagon, cortisol, and epinephrine, which further increase insulin resistance, lipolysis, and ketogenesis.

In conclusion, euDKA appears to be a worrisome adverse event associated with SGLT-2 inhibitor use in patients with type 1 and type 2 diabetes. During the preparation and review of this article, a similar number of additional cases of euDKA in patients with type 1 and type 2 diabetes treated with SGLT-2 inhibitors were reported to us by reviewers and collaborators; thus, we suspect that this is not a rare occurrence, particularly in type 1 diabetes. Further, during review the U.S. Food and Drug Administration posted a warning based on 20 cases of acidosis with ketosis in the setting of SGLT-2 inhibitor therapy, largely in patients with in type 2 diabetes.[22] While the frequency and mechanism of this complication require more study, clinicians and patients need to appreciate the potential risk when prescribing these agents.

At this time, SGLT-2 inhibitors are not approved by regulatory authorities in the setting of type 1 diabetes. If a clinician and patient with type 1 diabetes decide that the benefits of off-label use of SGLT-2 inhibitors outweigh the risks, the patient should be carefully and extensively counseled regarding the observations reported and, at a minimum, instructed to check urine or blood ketones if he or she feels unwell, even if plasma glucose is normal. Arguably, even greater vigilance for symptoms and ketonuria should be exercised in the setting of more than minimal alcohol consumption or if insulin doses are reduced for any reason, including for prolonged exercise or reduced carbohydrate intake. Early detection of ketosis could likely prevent patients from deteriorating; however, patients are generally asymptomatic until they have developed euDKA. The only way to ensure timely recognition would be to use daily urine or blood ketone testing. If moderate or large urine ketones are present, patients should be instructed by their providers to automatically withhold SGLT-2 inhibitor use at least temporarily, to contact their provider, to maintain vigorous hydration, and to consume carbohydrates to allow at least full-dose insulin therapy until ketones resolve. If for any reason the patient is not able to take liquids and carbohydrates liberally or self-monitor carefully, it would be prudent for the patient to seek medical attention promptly in a setting where intravenous fluids can be administered.

Although the U.S. Food and Drug Administration guidance[22] to the general public suggests "do not stop or change your diabetes medicines without first talking to your prescriber," we believe this refers to patients with type 2 diabetes who are currently taking SGLT-2 inhibitors on-label and doing well on the therapy without DKA. Individuals with type 2 diabetes do not need to monitor their urine ketones, but it is important that providers recognize that euDKA can occur in any individual with type 1 or type 2 diabetes taking an SGLT-2 inhibitor. Our advice to providers treating patients with type 1 diabetes off-label would be to withhold SGLT-2 inhibitor therapy if patients experience minimally symptomatic moderate to large ketonuria or ketonemia. Obviously, this is an issue that needs to be worked out between patients and providers individually. More importantly, if a patient develops DKA in the setting of SGLT-2 inhibitor therapy, the SGLT-2 inhibitor should be not be restarted immediately because two of the patients reported here who continued SGLT-2 inhibitor therapy had recurrences of DKA or symptomatic ketosis.

Both of the cases of euDKA in patients with type 2 diabetes occurred in the postoperative period. The potential for postoperative euDKA in the setting of SGLT-2 inhibitor therapy deserves special attention because the exact duration of the metabolic effects of the SGLT-2 inhibitors are not known. Although they have a half-life of ~12 h, the pharmacodynamic effects could last longer and simply stopping the drug 24–48 h before surgery may have little effect. We hope that future research will provide guidance for specific recommendations in the perioperative setting. Given the occurrence of euDKA in two individuals with type 2 diabetes, it would be prudent to be aware of this complication for patients with type 2 diabetes, particularly those with a history of DKA[23] or who are in the postoperative period.

Finally, awareness that DKA can occur in the setting of relative euglycemia is critical to recognize this life-threatening complication of diabetes. All patients with type 1 or type 2 diabetes who experience nausea, vomiting, shortness of breath, or malaise in the setting of SGLT-2 inhibitor therapy should be promptly evaluated for urine and/or plasma ketones at home or in a medical setting, even if glucose levels are nearly normal.

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