Cardiovascular outcomes and mortality after initiation of canagliflozin: Analyses from the EASEL Study

Abstract Introduction In the EASEL study of patients with type 2 diabetes and high cardiovascular risk, initiation of sodium glucose co‐transporter 2 inhibitors (SGLT2i) was associated with lower risk of cardiovascular events and mortality and higher risk of below‐knee lower extremity (BKLE) amputation versus non‐SGLT2i therapies. This analysis further examined risk of cardiovascular events, cardiovascular and noncardiovascular death and BKLE amputation with the SGLT2i canagliflozin versus non‐SGLT2i. Methods New user cohorts were constructed from Department of Defense Military Health System patients initiating canagliflozin or non‐SGLT2i (4/1/2013‐12/31/2016). Propensity score matching (1:1) controlled for imbalances in baseline covariates. Incidence rates, hazard ratios and 95% confidence intervals for time to first composite outcome of all‐cause mortality (ACM) and hospitalization for heart failure (HHF), composite major adverse cardiovascular events (MACE) and individual components were evaluated using conditional Cox models. The National Death Index was used to differentiate cardiovascular from noncardiovascular death. The exploratory safety end‐point was BKLE amputation. Results After propensity matching, 15 394 patients with well‐balanced baseline covariates were followed for a median of 2.03 years (intent‐to‐treat). Canagliflozin showed significant benefit for ACM and HHF (P < .0001), MACE (P = .0001), cardiovascular death (P < .0001) and noncardiovascular death (P = .0018). No significant difference in risk of BKLE amputation was observed (P = .20), though few events were observed. Results were generally consistent in on‐treatment analyses. Conclusions In this high cardiovascular risk cohort studied in routine clinical practice, canagliflozin was associated with lower risk of cardiovascular events, cardiovascular death and all‐cause mortality with no significant increase in BKLE amputation risk versus non‐SGLT2i.


| INTRODUC TI ON
Sodium glucose co-transporter 2 inhibitors (SGLT2i) are a relatively new class of antihyperglycemic agents (AHAs) that increase urinary glucose excretion (ie, glycosuria) and modestly reduce circulating plasma glucose. 5,29 The EMPA-REG OUTCOME cardiovascular (CV) outcomes trial of the SGLT2i empagliflozin in patients with type 2 diabetes mellitus (T2DM) and established CV disease has shown reductions in the primary outcome of major adverse CV events (MACE, the composite of CV death, nonfatal myocardial infarction [MI] and nonfatal stroke) and hospitalization for heart failure (HHF). 8,43 The CANagliflozin cardioVascular Assessment Study (CANVAS) Program CV outcomes trial of the SGLT2i canagliflozin in patients with T2DM and established CV disease or high CV risk also showed reductions in the primary outcome of MACE as well as HHF. 23,26 The Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58 (DECLARE-TIMI 58) CV outcomes trial of the SGLT2i dapagliflozin in patients with T2DM and established CV disease or high CV risk showed noninferiority in the co-primary end-point of MACE and a reduction in the second co-primary endpoint of the composite outcome of HHF and CV death. 40 Confirming these results, real-world studies of SGLT2i have consistently shown CV benefits with SGLT2i in a broad range of patients with T2DM, including those with high CV risk. 14,15,25,28,38 However, there have been concerns raised about the design of many of these pharmacoepidemiologic cohort studies, with suggestions made to improve their rigor and reduce the risk of immortal time bias, misclassification exposure bias and lead-in time bias. 31,32 Regarding safety, below-knee lower extremity (BKLE) amputation is a potentially serious complication of T2DM. 41 The CANagliflozin cardioVascular Assessment Study (CANVAS) Program showed an excess risk of 3 events per 1000 patient-years of BKLE amputation with canagliflozin in a large CV outcome trial consisting of 10 142 T2DM patients with (66%) and without (34%) established atherosclerotic CV disease followed for a mean of 3.6 years. 18,24 In contrast, an increased risk of BKLE amputation was not observed in a pooled analysis of 12 randomized controlled Phase 3 and Phase 4 clinical studies of canagliflozin in 8114 patients with T2DM with a low incidence (6.6%) of established CV disease 42 followed for a mean of 0.9 years (data on file). Results from observational studies in T2DM patients with and without established CV disease have been mixed on the risk of BKLE amputation in patients newly initiating an SGLT2i compared with other oral diabetes therapies, glucagon-like peptide-1 (GLP-1) receptor agonists and insulin. 1,28,38,39,42 In the prior analysis of the EASEL (Evidence for Cardiovascular Outcomes With Sodium Glucose Cotransporter 2 Inhibitors in the Real World) population-based cohort study in patients with T2DM and high CV risk, SGLT2i treatment was associated with a lower risk of all-cause mortality (ACM), HHF, and the composite of ACM, nonfatal MI and nonfatal stroke, and a higher risk of BKLE amputation compared to treatment with a non-SGLT2i. 38 Patients in the prior analysis of EASEL were categorized as new users of SGLT2i, even if they were eligible new users of SGLT2i and non-SGLT2i at different times during the study, potentially introducing a lead-in time bias. 31 Therefore, we reanalysed the EASEL study to consider the potential for time-varying exposure and allowed eligible patients to enter either respective arm of the study that corresponded to their active drug exposure (particularly for the on-treatment period), decreasing the risk of time bias. We elected to focus on the specific SGLT2i canagliflozin and further differentiate CV from non-CV causes of mortality.

| MATERIAL S AND ME THODS
This was a retrospective new user cohort study using the Department of Defense (DoD) Military Health System (MHS) data, which integrates all medical, clinical, pharmacy and administrative data for every eligible MHS beneficiary across the United States. The DoD is composed of active or retired service members and their dependents, with approximately 10 million patients actively receiving care.
In accordance with transparency and openness promotion guidelines, the analytic methods and study materials are stored at Health ResearchTx and could be made available to other researchers for purposes of reproducing the results or replicating the procedure. 10

| New users cohort creation
The study included 2 comparator cohorts: new users of canagliflozin or new users of non-SGLT2i on top of standard-of-care therapy.
The non-SGLT2i cohort included dipeptidyl peptidase-4 (DPP-4) inhibitors, GLP-1 receptor agonists, thiazolidinediones, sulfonylureas, insulin, and other AHAs (acarbose, bromocriptine, miglitol, nateglinide and repaglinide) and excluded metformin. Patients with any exposure to any other SGLT2i (ie, empagliflozin or dapagliflozin) were excluded. New users were defined as patients whose first exposure to a non-metformin AHA during the study period from 4/1/2013 to 12/31/2016 occurred ≥365 days after the start of observation in the database, with no prior exposure to any medication within the same AHA medication class in the prior 365 days, and the date of the first dispensing of the therapy of interest was considered the index date.
Eligible patients with T2DM were required to have ≥1 year of observation before the index date, with established CV disease (including coronary artery disease, heart failure, cerebrovascular disease and peripheral artery disease), and be ≥18 years of age. Patients with type 1 diabetes mellitus or secondary diabetes mellitus were excluded from this study. Patients were followed from the index date until the first occurrence of any of the following: (a) outcome of interest, (b) death, (c) disenrollment from the DoD or (d) last observation in the database.
The above analytical design was prespecified in the study protocol, noting that patients who met the new user criteria for both treatment arms were eligible for inclusion in both cohorts, as of the date of earliest initiation of each treatment, specifically addressing the study design issues raised by others. 31,32 For these patients, baseline characteristics were independently assessed as of each index date, and patients were available for potential matching in both instances to an eligible subject from the other treatment arm.
Patients who initiated canagliflozin and a non-SGLT2i on the same day were excluded from the analysis.
Exposure propensity score (EPS) matching was used to reduce confounding due to imbalance in baseline covariates.

| Study outcomes
The primary outcome of the study was the composite of ACM and HHF. In addition, a composite of MACE (CV death, nonfatal MI and nonfatal stroke), an expanded MACE outcome that included HHF, a modified MACE that included non-CV death (ACM, nonfatal MI and nonfatal stroke), and a composite of modified MACE + HHF, as well as the individual components of the composite end-points, were evaluated. MI and stroke events were considered nonfatal if patients did not die during hospitalization for the index event. BKLE amputation was assessed as a safety end-point and includes both minor (digits, partial foot and ankle disarticulation) and major (below-knee) amputations.
ACM was defined as any record of death regardless of cause.
To differentiate the cause of death, patients who died were linked with the National Death Index (NDI), which utilizes coroner records and other available sources to determine cause of death. 22  ICD-10 diagnosis codes, and BKLE amputation was ascertained based on ICD-9 and ICD-10 procedure codes, consistent with our prior work (Table S1). 38 Patients with a history of BKLE amputation events before the index exposure were excluded from comparative analyses of BKLE amputation to avoid confounding due to inherent intrasubject risk, potential for reverse causation and potential for immortal time bias in the situation in which such patients may no longer be at risk for future BKLE amputation events at the location of a prior amputation.

| Statistical analysis
The statistical methods employed in this study were consistent with those described previously. 38 Specifically, conditional Cox proportional hazards regression based on time to first event was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs), comparing the treatment effect of canagliflozin against non-SGLT2i Due to the potential heterogeneity of non-SGLT2i new users (eg, insulin use may represent an advanced stage of T2DM and sulfonylureas may be associated with heart failure-related outcomes), sensitivity analyses were conducted to assess whether the study findings were driven by any particular subset of patients. As part of sensitivity analyses, patients receiving insulin, sulfonylureas and thiazolidinediones were removed (individually and collectively) from the non-SGLT2i cohort along with their canagliflozin matching pairs to further evaluate treatment effect, as done previously. 7,14 Several subgroup analyses were prespecified, including sex, age, insulin use, GLP-1 receptor agonist use, history of heart failure, recent HHF (past 12 months), number of CV risk factors (ie, CV disease, coronary artery disease, peripheral vascular disease), renal disease by CCI score and chronic renal disease.
The study protocol was reviewed and approved by the DoD Institutional Review Board, and all analyses were performed by a research organization 10 using SAS V9.4 (SAS Institute Inc).

| Study population
Overall, 7713 new users of canagliflozin and 102 516 new users of a non-SGLT2i with T2DM and established CV disease were identified during the study period ( Figure S1). There were 99 (1.3%) patients who started canagliflozin and a non-SGLT2i on the same day and Among the 555 patients with an ACM outcome in this analysis, the cause of death for 552 (99.5%) patients was ascertained based on the NDI file. The remaining 3 patients, for whom a cause of death could not be determined, were excluded, along with their respective match, from comparative analyses that included CV and non-CV death.

| CV and mortality outcomes
The primary composite outcome of ACM and HHF and secondary  Figure S4). Results of sensitivity analyses that removed patients treated with insulin, sulfonylureas and thiazolidinediones at baseline, individually and in combination, were generally quantitatively consistent with the overall study results, suggesting that none of these medications were disproportionally impacting the final results ( Figure S5).

| Safety outcome
Excluding patients with previous BKLE amputation events (n = 6) and their respective matches, a total of 50 new BKLE amputation events TA B L E 1 Baseline characteristics by treatment cohort before and after propensity matching a   Figure S3). Because the number of events was relatively limited, the CI for the HR is quite wide and contains the point estimate that was observed in the CANVAS Program. 23 Generally consistent results were observed among all prespecified subgroups ( Figure S6).

DATA AVA I L A B I L I T Y S TAT E M E N T
In accordance with transparency and openness promotion guidelines, the analytic methods and study materials are stored at Health ResearchTx and could be made available to other researchers for purposes of reproducing the results or replicating the procedure.

E TH I C S S TATEM ENT
The study protocol was reviewed and approved by the DoD