(247) Post-authorisation safety study (PASS) assessing the risk of liver, renal, genitourinary, and diabetic ketoacidosis outcomes among users of empagliflozin versus DPP-4 inhibitors in patients with type 2 diabetes mellitus (T2D)

Publication Number: 1238

Background: Jardiance (empagliflozin), a sodium-glucose cotransporter 2 (SGLT2) inhibitor, is used to improve glycaemic control among patients with T2D by reducing renal glucose reabsorption. Given its mechanism of action, the risks of liver, renal, genitourinary, and diabetic ketoacidosis are of interest.

Objectives: To estimate the risks of acute liver injury in patients without predisposing conditions (ALI1) and in all patients (ALI2), acute kidney injury (AKI), chronic kidney disease (CKD), severe complications of urinary tract infections (UTI), genital infections (GI), severe GI (GIH), and diabetic ketoacidosis (DKA) among empagliflozin users compared with dipeptidyl peptidase-4 inhibitors (DPP-4i) users in patients with T2D.

Methods: A non-interventional cohort study was conducted in the United Kingdom’s Clinical Practice Research Datalink, the Danish Population Registries, and the HealthCore Integrated Research Database (HIRD) (United States). Patients with T2D initiating empagliflozin or a DPP-4i between August 2014 and August 2019 (index date), aged ≥ 18 years, with a minimum of 12 months of continuous health plan registration immediately preceding their index date comprised the overall study population. Incidence rates by exposure and corresponding incidence rate ratios (IRR) were generated, adjusted for deciles of propensity scores calculated within outcome-specific analysis groups. IRRs from all data sources were pooled via meta-analysis.

Results: Across all data sources, the overall study population comprised 64,599 empagliflozin initiators with a mean age of 57.2 years and 203,315 DPP-4i initiators with a mean age of 62.1 years. Approximately 60% of all initiators were male.
Comparing empagliflozin initiators with DPP-4i initiators, there was an increased risk (pooled adjusted IRR [95% confidence interval]) of DKA: 2.19 [1.74-2.76]; GI in males: 4.04 [3.46-4.71]; GIH in males: 4.04 [3.44-4.75]; GI in females: 3.24 [2.81-3.74]; and GIH in females: 3.34 [2.83-3.95]. On the other hand, there was a decreased risk (pooled adjusted IRR [95% confidence interval]) of ALI1: 0.77 [0.50-1.19]; ALI2: 0.70 [0.56-0.88]; AKI: 0.54 [0.41-0.73]; CKD: 0.53 [0.43-0.65]; and UTI: 0.51 [0.37-0.72].
Results were generally consistent across data sources and in subgroup and sensitivity analyses.

Conclusions: Empagliflozin use was associated with notable increased risks of DKA and GI and notable decreased risks of ALI, AKI, CKD, and UTI, compared with DPP-4i use.
The increased risks of DKA and GI observed in these populations are consistent with information in empagliflozin’s risk management plan and are known class effects for SGLT2 inhibitors. The decreased risks observed for other outcomes may reflect beneficial metabolic effects of empagliflozin.