Risk of sudden cardiac arrest and ventricular arrhythmia with sulfonylureas: An experience with conceptual replication in two independent populations

Abstract

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

Sulfonylureas and the Risk of Ventricular Arrhythmias Among People with Type 2 Diabetes: A Systematic Review of Observational Studies

“…No studies reported sudden cardiac death as an individual endpoint. One study at a moderate risk of bias using US Medicaid claims data conducted an intraclass comparison, reporting an increased risk for a composite end point of sudden cardiac death and fatal VA among glimepiride users (aHR: 1.33, 95% CI: 1.02–1.75) and no association among glyburide users (aHR: 0.91, 95% CI: 0.72–1.20), both relative to glipizide 16 …”

“…After applying the ROBINS-I tool, 2 studies were assigned a moderate risk of bias, 16,17 4 studies were assigned a serious risk of bias, [18][19][20][21] and 11 studies were assigned a critical risk of bias 19,[22][23][24][25][26][27][28][29][30][31] (Table 3, Figure 2). The domain "'risk of bias due to confounding"' was one of the ROBINS-I domains most responsible for the overall risk of bias.…”

“…The analysis of Medicaid claims data suggested an increased risk of cardiac arrest/VA with glimepiride (aHR: 1.17, 95% CI: 0.96-1.42) and a lower risk with glyburide (aHR: 0.87, 95% CI: 0.74-1.03); these trends were not observed in the analysis of Optum claims data (glimepiride = aHR: 0.84, 95% CI: 0.65-1.08; glyburide = aHR: 1.11, 95% CI: 0.86-1.42). 16…”

Validation of ICD-9-CM and ICD-10-CM Diagnostic Codes for Identifying Patients with Out-of-Hospital Cardiac Arrest in a National Health Insurance Claims Database

“…Several population-based OHCA studies have been conducted using administrative databases in the US 20–24 and outside the US 7 , 25 , 26 based on the above-mentioned validated OHCA-related diagnostic codes. However, because coding practices and reimbursement policies may differ across healthcare systems, it should not be taken for granted that the validity of case definitions established in one database can be extrapolated to another database.…”

Sulfonylurea is associated with higher risks of ventricular arrhythmia or sudden cardiac death compared to metformin: a population-based cohort study

“…Recent studies have shown that the risk of VA/SCD differed by choice of sulfonylurea (55)(56)(57)(58). Further research comparing risk of VA/SCD between different drugs of the sulfonylurea class is warranted, such that clinicians can avoid choosing sulfonylurea with high arrhythmogenic risk.…”