Diabetic Ketoacidosis and Related Events in the Canagliflozin Type 2 Diabetes Clinical Program

On 15 May 2015, the U.S. Food and Drug Administration (FDA) issued a Drug Safety Communication based upon a search of the FDA Adverse Event Reporting System database that indicated that medicines for type 2 diabetes in the sodium–glucose cotransporter 2 (SGLT2) inhibitor class (which includes canagliflozin, empagliflozin, and dapagliflozin) may lead to ketoacidosis. The FDA also noted that patients may present atypically, with only slightly increased levels of blood glucose (1). In addition, several case reports and series have described diabetic ketoacidosis (DKA) in patients with type 1 diabetes or type 2 diabetes treated with SGLT2 inhibitors (2–4).

An analysis of all serious adverse events of DKA and related terms of ketoacidosis, metabolic acidosis, and acidosis was performed using a database that contained data from 17,596 patients, with nearly 24,000 patient-years of exposure, compiled from completed and ongoing randomized, controlled clinical studies of canagliflozin. The overall mean exposure in this analysis was 1.4 years. Table 1 includes details regarding the studies included in this analysis, which was conducted by Janssen Research & Development, LLC (the sponsor of canagliflozin). A history of type 1 diabetes or DKA was an exclusion criterion in all studies. Ascertainment of potential events for inclusion in this analysis was done using investigator-reported adverse events. Four adverse event terms (i.e., diabetic ketoacidosis, ketoacidosis, metabolic acidosis, and acidosis) from the Medical Dictionary for Regulatory Activities (MedDRA) were searched. Cases meeting standard criteria for a regulatory definition of a serious adverse event (e.g., resulting in hospitalization or a medically important event) were included in this analysis. All unblinded cases in this analysis came from completed studies or unblinded data sets previously used to support canagliflozin global marketing dossiers or required for responses to health authorities. Through 11 May 2015, there were 12 patients with 13 unblinded serious adverse events of DKA, ketoacidosis, metabolic acidosis, and acidosis, and 3 additional serious adverse events that remain blinded and were not included in the current analysis. These 3 additional events come from the ongoing CANagliflozin cardioVascular Assessment Study (CANVAS), which is blinded and is being monitored by an independent data monitoring committee. Data from the 12 unblinded patients with serious adverse events are discussed below.

The incidence of serious adverse events of DKA and related events in the canagliflozin randomized clinical trial database was 0.07% (12 of 17,596). The incidence of serious adverse events of DKA and related events by treatment group was 0.07% (4 of 5,337), 0.11% (6 of 5,350), and 0.03% (2 of 6,909) with canagliflozin 100 and 300 mg and comparator, respectively; corresponding incidence rates were 0.522, 0.763, and 0.238 per 1,000 patient-years, respectively. After being diagnosed with a DKA-related event, 6 patients on canagliflozin (3 on canagliflozin 100 mg, 3 on canagliflozin 300 mg, and none on comparator) were reported to have autoimmune diabetes (latent autoimmune diabetes of adulthood [LADA] or type 1 diabetes) or to have tested positive for GAD65 antibodies. Excluding these 6 patients, the incidences of serious adverse events of DKA and related events by treatment group in patients with type 2 diabetes were 0.02% (1 of 5,334), 0.06% (3 of 5,347), and 0.03% (2 of 6,909) with canagliflozin 100 and 300 mg and comparator, respectively, with corresponding incidence rates of 0.130, 0.381, and 0.238 per 1,000 patient-years, respectively. The race and ethnicity of the patients with severe adverse events of DKA and related events were as follows: 1 Hispanic or Latino American Indian or Alaska native patient; 1 Hispanic or Latino white patient; and 10 non-Hispanic or Latino white patients. Compared with other patients in the canagliflozin program, these 12 patients were predominantly male, white, and older and had a longer duration of diabetes, lower BMI, higher HbA_1c, and lower estimated glomerular filtration rate at baseline (Table 2). Specific details of the 12 patients with serious adverse events of DKA and related events are reported in Table 3. Eight of the 12 patients in this analysis were enrolled in the CANVAS trial, which included patients with significant comorbid conditions; of these 8 patients, all 7 in the canagliflozin treatment groups were on insulin. The 10 patients with blood glucose values reported at presentation had levels that were >300 mg/dL (16.7 mmol/L) and ranged from 347 to 571 mg/dL (19.3 to 31.7 mmol/L). One other patient on canagliflozin 300 mg had several blood glucose levels ranging from 148 to 320 mg/dL (8.2 to 17.8 mmol/L), but dates and times of these measurements were not provided. Of the 10 patients on canagliflozin with a DKA-related event, 8 were receiving insulin therapy (note that ∼31% of patients [n = 5,407] in the canagliflozin type 2 diabetes program were on background insulin therapy), with 4 having questionable compliance with insulin therapy at the time of the event. One of these 4 patients also had a second event postoperatively after a cholecystectomy. The other 4 patients on insulin therapy with a DKA-related event had concomitant diagnoses of pancreatic cancer, myocardial infarction, gastroenteritis, and viral infection. Among the 2 canagliflozin patients not on insulin therapy with an event, 1 had type 1 diabetes and 1 had a subcutaneous abscess and chronic pancreatitis.

In summary, DKA and related events occurred at a low frequency in patients participating in the randomized, controlled canagliflozin type 2 diabetes clinical trial program. Although there are limited epidemiological data on the incidence of DKA in patients with type 2 diabetes, the overall incidence rates of these events in the current analysis are consistent with the broad range reported in existing observational data. Specifically, a study in Northern Sweden reported an estimated DKA incidence rate of 0.5 per 1,000 patient-years (5), and an analysis of four large U.S. commercial claims databases (i.e., the Truven MarketScan Commercial Claims and Encounters, MarketScan Medicare Supplemental Beneficiaries, the MarketScan Multistate Medicaid Database, and the Optum Clinformatics database) found a DKA incidence rate in the range of 0.32 to 2.0 per 1,000 patient-years (data on file). However, given the potential for incomplete reporting or underreporting of DKA, the incidence of DKA in patients with type 2 diabetes, including patients treated with canagliflozin and other SGLT2 inhibitors, may be underestimated.

Although there were some differences in baseline characteristics between all patients and the subset of patients who developed DKA and related events, there was no clear baseline clinical phenotype that allowed the identification of specific individual patients at risk for developing DKA. Nevertheless, most patients had a known precipitating factor for DKA at the time of these events. Some reports note that patients who presented with DKA had atypically low blood glucose values; however, of the 10 patients treated with canagliflozin who presented with DKA and related events and had available blood glucose values at presentation, 9 patients had blood glucose values >250 mg/dL (13.9 mmol/L). We postulate that patients diagnosed as having type 2 diabetes or misdiagnosed as having type 2 diabetes (e.g., LADA, type 1 diabetes) and who have a low β-cell reserve coupled with a potential SGLT2 inhibitor–associated increase in glucagon (6–8) are unable to produce sufficient insulin to suppress hepatic ketogenesis and peripheral lipolysis, which in the setting of an acute illness (and associated increase in insulin resistance) can develop DKA. Further prospective research is needed to better understand the incidence and underlying mechanism(s) of DKA associated with SGLT2 inhibitors.

Funding. This article was supported by Janssen Research & Development, LLC. Technical editorial assistance was provided by Alaina DeToma, PhD, of MedErgy HealthGroup, and was funded by Janssen Global Services, LLC. Canagliflozin has been developed by Janssen Research & Development, LLC, in collaboration with Mitsubishi Tanabe Pharma Corporation.

Duality of Interest. N.E., M.D., K.W., and G.M. are full-time employees of Janssen Research & Development, LLC. No other potential conflicts of interest relevant to this article were reported.

Author Contributions. N.E., M.D., K.W., and G.M. contributed to the design; acquisition, analysis, and interpretation of the data; and development of the manuscript. All authors approved the final version of the manuscript submitted. G.M. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.