Christian Hampp, PhD, on SGLT2 Inhibitors and Diabetic Ketoacidosis Risk in Type 1 Diabetes
The use of sodium glucose cotransporter 2 (SGLT2) inhibitors is likely associated with high rates of diabetic ketoacidosis (DKA) among patients with type 1 diabetes, especially young women, according to new findings published in Diabetes Care.
Researchers arrived at their conclusion after examining data from the Sentinel system on individuals who had initiated SGLT2 inhibitors between March 2013 and June 2018. Prevalence of type 1 diabetes was determined using a narrow definition and a broad definition, and DKA rates were measured using administrative claims data. Age- and sex-specific follow-up time in Sentinel and age- and sex-specific DKA rates from sotagliflozin trials 309, 310, and 312 were used to calculate standardized incidence ratios (SIRs).
Ultimately, 0.50% and 0.92% of SGLT2 initiators had met narrow and broad criteria for type 1 diabetes, respectively. Results of the study indicated that DKA rates were 7.3 per 100 person-years in the narrow group and 4.5 per 100 person-years in the broad group. Furthermore, among those who met narrow criteria for type 1 diabetes, DKA rates were highest for patients aged 25 to 44 years, especially women in this age group (19.7 per 100 person-years).
The researchers noted that more DKA events occurred during off-label use of SGLT2 inhibitors than would be expected based on sotagliflozin clinical trials (SIR 1.83).
Endocrinology Consultant discussed these findings and their implications further with lead author Christian Hampp, PhD, from the Center for Drug Evaluation and Research’s Office of Surveillance and Epidemiology at the US Food and Drug Administration (FDA) in Silver Spring, Maryland.
Endocrinology Consultant: What prompted you to conduct this study?
Dr Hampp: In early 2019, the FDA reviewed an application for sotagliflozin, a dual SGLT1/SGLT2 inhibitor, for the treatment of type 1 diabetes. Currently, SGLT2 inhibitors are only approved by the FDA for the treatment of type 2 diabetes. Because clinical trials for sotagliflozin in patients with type 1 diabetes showed an increased risk of diabetic ketoacidosis (DKA) compared with placebo, the FDA was interested in the prevalence of real-world, off-label use of SGLT2 inhibitors in patients with type 1 diabetes. In addition, because patients and providers who participated in the clinical trials were trained to recognize early symptoms, which may have helped prevent DKA events, the FDA considered that real-world DKA rates may be higher than rates observed in the clinical trials.
Endocrinology Consultant: Did you anticipate these findings, or were you surprised by any of them?
Dr Hampp: High rates of DKA among young patients with type 1 diabetes, and especially young women with type 1 diabetes, have been described in the literature. Our study confirms that these groups are at particularly high risk for DKA when they use SGLT2 inhibitors off-label for the treatment of type 1 diabetes. In addition, we hypothesized that DKA rates during real-world use of SGLT2 inhibitors may be higher than in clinical trials because of intensive monitoring in clinical trials. Indeed, our study demonstrated that DKA rates in the real world were 83% higher than expected based on clinical trial data, and that this discrepancy was even more pronounced among young patients.
Endocrinology Consultant: How should endocrinologists and related clinicians interpret these findings when it comes to clinical practice?
Dr Hampp: SGLT2 inhibitors are currently not approved by the FDA for the treatment of type 1 diabetes. Clinicians who intend to prescribe them ‘off-label’ should be aware of the risk for DKA and discuss the risk for DKA with their patients.
Endocrinology Consultant: What is the next step for further research?
Dr Hampp: Our study estimated the proportion of patients with type 1 diabetes among all SGLT2 inhibitor users. However, our finding of a higher prevalence of type 1 diabetes among young SGLT2 inhibitor users likely reflects that type 1 diabetes, as a proportion of any diabetes type, is relatively more common among younger patients. Conversely, future studies could describe the proportion of SGLT2 inhibitor users among patients with type 1 diabetes, which would account for the underlying disease epidemiology.
In addition, several SGLT2 inhibitors were approved for the treatment of type 1 diabetes by the European Medicines Agency. This provides additional opportunity to monitor safety in that patient population.
Hampp C, Swain RS, Horgan C, et al. Use of sodium–glucose cotransporter 2 inhibitors in patients with type 1 diabetes and rates of diabetic ketoacidosis. Diabetes Care. 2019;42(11). https://doi.org/10.2337/dc19-1481