IMPORTANCE Little is known to date about national trends in the prescribing of skeletal muscle relaxants (SMRs), the use of which is associated with important safety concerns, especially in older adults and in those who use concomitant opioids.
Background: The low cost of thiazolidinediones makes them a potentially valuable therapeutic option for the > 300 million economically disadvantaged persons worldwide with type 2 diabetes mellitus. Differential selectivity of thiazolidinediones for peroxisome proliferator-activated receptors in the myocardium may lead to disparate arrhythmogenic effects. We examined real-world effects of thiazolidinediones on outpatient-originating sudden cardiac arrest (SCA) and ventricular arrhythmia (VA). Methods: We conducted population-based high-dimensional propensity score-matched cohort studies in five Medicaid programs (California, Florida, New York, Ohio, Pennsylvania | 1999-2012) and a commercial health insurance plan (Optum Clinformatics | 2000-2016). We defined exposure based on incident rosiglitazone or pioglitazone dispensings; the latter served as an active comparator. We controlled for confounding by matching exposure groups on propensity score, informed by baseline covariates identified via a data adaptive approach. We ascertained SCA/VA outcomes precipitating hospital presentation using a validated, diagnosis-based algorithm. We generated marginal hazard ratios (HRs) via Cox proportional hazards regression that accounted for clustering within matched pairs. We prespecified Medicaid and Optum findings as primary and secondary, respectively; the latter served as a conceptual replication dataset. Results: The adjusted HR for SCA/VA among rosiglitazone (vs. pioglitazone) users was 0.91 (0.75-1.10) in Medicaid and 0.88 (0.61-1.28) in Optum. Among Medicaid but not Optum enrollees, we found treatment effect heterogeneity by sex (adjusted HRs = 0.71 [0.54-0.93] and 1.16 [0.89-1.52] in men and women respectively, interaction term p-value = 0.01).
Sulfonylureas are commonly used to treat type 2 diabetes mellitus. Despite awareness of their effects on cardiac physiology, a knowledge gap exists regarding their effects on cardiovascular events in real-world populations. Prior studies reported sulfonylurea-associated cardiovascular death but not serious arrhythmogenic endpoints like sudden cardiac arrest (ScA) or ventricular arrhythmia (VA). We assessed the comparative real-world risk of ScA/VA among users of second-generation sulfonylureas: glimepiride, glyburide, and glipizide. We conducted two incident user cohort studies using five-state Medicaid claims (1999-2012) and Optum Clinformatics commercial claims (2000-2016). Outcomes were SCA/VA events precipitating hospital presentation. We used Cox proportional hazards models, adjusted for high-dimensional propensity scores, to generate adjusted hazard ratios (aHR). We identified 624,406 and 491,940 sulfonylurea users, and 714 and 385 SCA/VA events, in Medicaid and Optum, respectively. Dataset-specific associations with SCA/VA for both glimepiride and glyburide (vs. glipizide) were on opposite sides of and could not exclude the null (glimepiride: aHR Medicaid 1.17, 95% CI 0.96-1.42; aHR optum 0.84, 0.65-1.08; glyburide: aHR Medicaid 0.87, 0.74-1.03; aHR optum 1.11, 0.86-1.42). Database differences in data availability, populations, and documentation completeness may have contributed to the incongruous results. Emphasis should be placed on assessing potential causes of discrepancies between conflicting studies evaluating the same research question. Second-generation sulfonylureas are a mainstay of type 2 diabetes mellitus (T2DM) management. Although their use is slowly declining 1 , this pharmacologic class remains the most common add-on to metformin 2,3. Cardiovascular effects of sulfonylureas continue to be debated. Findings from the recently completed Cardiovascular Outcome Trial of Linagliptin Versus Glimepiride in Type 2 Diabetes (CAROLINA) trial 4 may eventually assuage concerns of glimepiride-associated all-cause and cardiovascular death 5 reported in prior clinical trials and meta-analyses 6-10 , but little is known of cardiovascular safety among users of other sulfonylureas. Further, despite pre-existing data on sulfonylureas' effects on cardiac physiology 11-14 , neither CAROLINA nor Thiazolidinediones or Sulfonylureas Cardiovascular Accidents Intervention Trial (TOSCA.IT) provided, and Glycemia Reduction Approaches in Diabetes (GRADE) will not provide data on serious arrhythmogenic endpoints like sudden cardiac arrest (SCA) and ventricular arrhythmia (VA). Thus, there exists a major knowledge
Few population‐based studies have examined bleeding associated with clopidogrel drug–drug interactions (DDIs). We sought to identify precipitant drugs taken concomitantly with clopidogrel (an object drug) that increased serious bleeding rates. We screened 2000–2015 Optum commercial health insurance claims to identify DDI signals. We performed self‐controlled case series studies for clopidogrel plus precipitant pairs, examining associations with gastrointestinal bleeding or intracranial hemorrhage. To distinguish native bleeding effects of a precipitant, we reexamined associations using pravastatin as a negative control object drug. Among 431 analyses, 28 clopidogrel plus precipitant pairs were statistically significantly positively associated with serious bleeding. Ratios of rate ratios ranged from 1.13–3.94. Among these pairs, 13 were expected given precipitant drugs alone increased and/or were harbingers of serious bleeding. The remaining 15 pairs constituted new DDI signals, none of which are currently listed in two major DDI knowledge bases.
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