(C32) The Interaction Between Gliclazide and Omeprazole via CYP2C19 and the Risk of Hypoglycaemia: A Case-Crossover Study using Primary Care Data from the UK

Publication Number: 976

Background: Most type-2 diabetes mellitus (T2DM) patients are comorbid and thus treated with multiple different medications, which increases the risk for potentially harmful drug-drug interactions (DDIs). Within T2DM management, several non-insulin antidiabetic drugs (NIADs) are metabolized by cytochrome P450 (CYP) enzymes, such as the sulfonylurea gliclazide via CYP2C19. When co-administered with CYP2C19 inhibitors, patients might be at an elevated risk of experiencing hypoglycaemia, the most common serious side effect of gliclazide. However, there is limited evidence on an interaction between gliclazide and omeprazole, a frequently co-prescribed proton-pump inhibitor that reduces the activity of CYP2C19.

Objectives: To assess if there is a signal of an increased risk of hypoglycaemia associated with concomitant use of gliclazide and omeprazole due to a CYP2C19-mediated DDI.

Methods: We conducted a case-crossover designed analysis with a 1-day induction period, a 30-day referent, a 90-day washout, and a 30-day hazard window using the IQVIA Medical Research Database (IMRD), incorporating data from THIN, a Cegedim database. We included patients (>= 18 years) who had a first hypoglycaemic event recorded after their first-ever NIAD prescription between January 1st 2000 and May 31st 2021. Patients with a diagnosis of gestational diabetes and polycystic ovarian syndrome, as well as the use of insulin prior NIAD usage, were excluded. Conditional logistic regression estimated odds ratios (ORs) with 95% confidence intervals (CIs) in order to evaluate whether the risk of hypoglycaemia is elevated after adding omeprazole, the potentially interacting (precipitant) drug to gliclazide, the object drug of interest. We adjusted for potential confounders, such as drugs that may elicit the outcome (e.g., atenolol) considering the respective time window. We conducted several sensitivity analyses to address potential exposure misclassification by shortening and combining different lengths of the hazard (e.g., 14-days), referent (e.g., 14-days), and washout windows (e.g., 60-days).

Results: Among the study population consisting of 9,682 T2DM patients, we identified 3,263 individuals who were exposed to gliclazide for at least 151-days prior to and including the date of the outcome. The adjusted OR comparing the exposure to omeprazole during the hazard (56 patients) and the referent window (15 patients), was 15.7 (95% CI, 6.5-37.9). The results of the sensitivity analyses were consistent with the findings from the main analysis.

Conclusions: This study identified an elevated risk associated with initiating omeprazole when already exposed to gliclazide. However, further studies with larger databases are needed to evaluate the safety of this DDI.