In type 2 diabetes, SGLT2 inhibitors were linked to diabetic ketoacidosis vs. DPP-4 inhibitors

A cohort study's finding of increased risk of diabetic ketoacidosis with sodium-glucose cotransporter-2 (SGLT2) inhibitors is relevant to clinical decision making, but not definitive given the limitations of observational research, an ACP Journal Club commentary said.


Researchers used data from Canada and the United Kingdom to look at rates of diabetic ketoacidosis (DKA) among hundreds of thousands of patients who initiated a sodium-glucose cotransporter-2 (SGLT2) inhibitor (alone or in combination with other antidiabetic drugs) or a dipeptidyl peptidase-4 (DPP-4) inhibitor. They found increased risk of DKA with SGLT2 inhibitors as a class and individually, with no difference by age, sex, or whether a patient was a new user. However, DKA risk was lower among patients who had taken insulin.

The review was published online July 28, 2020, by Annals of Internal Medicine and summarized in the August 2020 ACP Diabetes Monthly. The following commentary by Aris Liakos, MD, MSc, PhD, Apostolos Tsapas, MD, PhD, MSc(Oxon), and Eleni Bekiari, MD, MSc, PhD, was published in the ACP Journal Club section of the Dec. 15, 2020, Annals of Internal Medicine.

Based on data from adverse event reporting systems, regulatory authorities have warned about the risk for DKA in patients with type 2 diabetes treated with SGLT2 inhibitors. Douros and colleagues attempted to clarify this safety signal by comparing the risk for DKA in patients treated with SGLT2 inhibitors vs. DPP-4 inhibitors in a large data set compiled using propensity-score matching from clinical and administrative databases. They found that SGLT2 inhibitors were associated with an almost 3-fold increase in the incidence of DKA, which is higher than reported in randomized, placebo-controlled, cardiovascular outcome trials and meta-analyses.

The conclusions of the analysis are important for clinical decision making, but caution is warranted due to limitations inherent to observational research as well as shortcomings related to the ascertainment of DKA. Although patients in the exposure and control groups were matched for a series of factors considered important for the incidence of DKA, data for baseline glycemia and renal function were not available for most patients; thus, residual confounding from these 2 important DKA confounders is possible. Similarly, ascertainment of the outcome was based only on International Classification of Diseases, 10th Revision, coding of a primary diagnosis of DKA, so patients with other primary diagnoses who are often perplexed by a secondary diagnosis of DKA could have been missed. Likewise, it is unclear whether the dataset efficiently captured cases of euglycemic ketoacidosis, which reportedly is associated with the use of SGLT2 inhibitors. On the other hand, incidence of DKA may have been inflated following dissemination of relevant safety concerns to health care professionals.

Although real-world evidence may be better suited than randomized trials to reach conclusions about sparse outcomes, such as DKA, estimating the true incidence of this relatively rare complication from routinely collected health care data is challenging.