Omeprazole and cardiovascular risk via induction of statin dysmetabolism

BackgroundStatins are a first line treatment for reducing cardiovascular risk. While drug-drug interactions which cause symptomatic side effects are well known, drug- drug interactions which decrease statin effectiveness are poorly understood. MethodsA multicentre prospective observational study of 1362 participants on chronic statin medication underwent quantitative mass spectrometry (LC-MS/MS) of statin metabolites up to 13 hours post-dose. Participants were followed up to 5 years for major adverse cardiovascular events (MACE) as a composite of stroke, acute myocardial infarction and all-cause mortality. Linear modelling of statin lactone with co-prescribed medications, and multivariable cox proportional hazards modelling of statin metabolites, co-prescriptions and 5-year MACE were performed. An interventional mouse model of atheroma progression was used to validate the results. ResultsThere were 1139 (83.6%) male and 223 (16.4%) female participants, mean age was 59{+/-}9.4. Of all 51 co-prescribed drugs, omeprazole was the second most common (57.4%), and was the strongest determinant of increased plasma statin lactone, demonstrating a [~]1.41 fold increase in lactone concentration and a 1.46-fold increase in 5-year rates of major adverse cardiovascular events (MACE). Independent of statin drug dose and achieved LDL cholesterol levels, plasma atorvastatin lactone (ATVLAC) levels [≥]3.9ng/mL strongly predicted MACE (HR=2.45) and all-cause mortality (HR=3.18). In a mouse model of atheroma formation, omeprazole co- administration with atorvastatin resulted in increased lactonization (1.87-fold) and significantly higher lesion area (2.97-fold). ConclusionOmeprazole co-prescription with atorvastatin represents a novel drug- drug interaction mediated by increased statin lactonization and is strongly associated with increased 5-year MACE. RegistrationURL: https://clinicaltrials.gov/; ID: NCT03042286 Clinical PerspectiveO_ST_ABSWhat is New?C_ST_ABSDiscovery of novel drug-drug interactions are difficult because drug metabolism is not directly measured in clinical care. In this study, we used a well powered prospective study to quantitatively phenotype statin metabolism and discover medical and clinical determinants of dysmetabolism. Co-prescription of omeprazole was strongly associated with statin lactone production (a statin metabolite that does not affect HMG-CoA reductase and is postulated to cause off target side effects). These patients had higher rates of MACE, independent of classical predictors such as LDL cholesterol and other Framingham risk factors. In mice co-administered either omeprazole or lansoprazole with statin, both statin lactonization and neointimal plaque formation were increased. What are the clinical implications?This study provides insights into a novel drug-drug interaction between statins and proton pump inhibitors, two of the most prescribed medication classes in the world, suggesting that this class of drugs should not be prescribed with statins. We also demonstrate a novel methodology for discovering DDIs through the direct quantification of drug metabolism in real-world clinical cohorts. The findings may be of use in precision medicine initiatives regarding cardiovascular management and statin use.