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Canagliflozin Conveys Lower Risk of Adverse CV Events in Patients With High CV Risk, T2D


Updated results from the EASEL study show that lower risks of cardiovascular (CV) events, CV death, and CV mortality accompany initiation of canagliflozin, a sodium glucose cotransporter 2 inhibitor, in patients with type 2 diabetes (T2D) and high CV risk compared with use of other drugs.

Updated results from the EASEL (Evidence for Cardiovascular Outcomes With Sodium Glucose Cotransporter 2 Inhibitors in the Real World) study show that lower risks of cardiovascular (CV) events, CV death, and CV mortality accompany initiation of canagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, in patients with type 2 diabetes (T2D) and high CV risk compared with non—SGLT2 inhibitor use.

These findings appeared in a recent issue of Endocrinology, Diabetes & Metabolism. The authors were looking to remedy possible lead-in time bias from a previous analysis of EASEL data on patients with T2D and high CV risk.

“Patients in the prior analysis of EASEL were categorized as new users of SGLT2 [inhibitors], even if they were eligible new users of SGLT2 [inhibitors] and non—SGLT2 [inhibitors] at different times during the study,” they noted. “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.”

The primary study outcome was a composite of all-cause mortality (ACM) and hospitalization for heart failure (HHF), with below-knee lower extremity (BKLE) being the safety end point. Using patient data from the Department of Defense Military Health System and the National Death Index for their new user study cohorts, propensity score matching produced 15,394 patients: 7697 each in the canagliflozin and non—SGLT2 inhibitor (dipeptidyl peptidase-4 inhibitors, GLP-1 receptor agonists, thiazolidinediones, sulfonylureas, insulin, and other antihyperglycemic agents [acarbose, bromocriptine, miglitol, nateglinide, and repaglinide]) arms.

The study period ran from April 1, 2013, through December 31, 2016; the index date was the first date patients received their therapy; and the patients were followed for a median of 2.03 (interquartile range, 1.29-2.82) years, from their index date to whichever happened first: outcome of interest, death, disenrollment from the DoD, or last observation in the database. In addition, the mean (SD) patient age was 65.6 (9.3) years and they had T2D for a mean 5.4 (1.8) years and CV disease, 4.2 (2.1) years. Hypertension, chronic obstructive pulmonary disease, and peripheral vascular disease were the most common CV comorbidities in both groups.

Specifically, initiating canagliflozin resulted in just 1.79 incidences of ACM and HHF per 100 person-years compared with 2.88 (hazard ratio [HR], 0.61; 95% CI, 0.53-0.71; P <.0001) among users who started a non—SGLT2 inhibitor during the study period. In addition, there were lower rates of ACM (1.38 vs 2.15 per 100 person-years; HR, 0.63; 95% Cl , 0.53-0.75; P <.0001) and HHF (0.51 vs 0.90 per 100 person-years; HR, 0.57; 95% Cl, 0.43-0.74; P <.0001) after starting canagliflozin.

An intent-to-treat analysis did not produce a significant difference in BKLE amputations. There were 29 and 21 events, respectively, in the canagliflozin and non—SGLT2 inhibitor cohorts (0.18 vs 0.13 per 100 person-years; HR, 1.44; 95% Cl, 0.82-2.52; P = .20).

“This subsequent analysis of the EASEL study showed that in patients with T2DM and high CV risk treated in routine clinical practice in a large US DoD healthcare system, initiation of canagliflozin treatment was associated with a lower risk of CV events, CV death and ACM, with no significant increase in the risk of BKLE amputation compared with non—SGLT2 [inhibitor] treatment, though statistical power was limited because of the limited number of events for this safety end-point,” the authors concluded.

They also noted the ongoing population-based studies in this space and that these results “are crucial to further understanding the benefits and safety of SGLT2 [inhibitors], including canagliflozin, in broad populations being recommended for treatment that may differ from the strict selection of trial participants.”


Udell JA, Yuan Z, Ryan P, et al. Cardiovascular outcomes and mortality after initiation of canagliflozin: analyses from the EASEL study. Endocrinol Diabetes Metab. 2019;3(1):e00096. doi: 10.1002/edm2.96.

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