Cardiovascular Outcomes and Risks After Initiation of a Sodium Glucose Co-Transporter 2 Inhibitor: Results From the EASEL Population-Based Cohort Study
Background: Clinical trials have shown cardiovascular benefits and potential risks from sodium glucose co-transporter 2 inhibitors (SGLT2i). Trials may have limited ability to address individual endpoints or safety concerns.
Methods: We performed a population-based cohort study among type 2 diabetes patients with established cardiovascular disease newly initiated on antihyperglycemic agents (AHAs) within the US Department of Defense Military Health System between 4/1/2013 and 12/31/2016. Incidence rates, hazard ratios (HRs), and 95% confidence intervals (CIs) for time to first composite endpoint of all-cause mortality (ACM) and hospitalization for heart failure (HHF) event, major adverse cardiovascular events (MACE; defined as ACM, nonfatal myocardial infarction, and nonfatal stroke), and individual endpoints were evaluated using conditional Cox models comparing new SGLT2i users with other AHAs. Exploratory safety endpoint was below-knee lower extremity amputation (BKA). Intent-to-treat and on-treatment analyses were performed.
Results: After propensity matching, 25,258 patients were followed for a median of 1.6 years. Compared with non-SGLT2i, initiation of SGLT2i was associated with a lower rate of ACM and HHF (1.73 vs. 3.01 events per 100 person-years; HR 0.57; 95% CI: 0.50-0.65) and MACE (2.31 vs. 3.45 events per 100 person-years; HR 0.67, 95% CI: 0.60-0.75). SGLT2i initiation was also associated with a ≈two-fold higher risk of BKA (0.17 vs. 0.09 events per 100 person-years; HR 1.99, 95% CI: 1.12-3.51). Due to the disproportionate canagliflozin exposure in the database, the majority of amputations were observed on canagliflozin. Results were consistent in the on-treatment analysis.
Conclusions: In this high-risk cohort, initiation of SGLT2i was associated with lower ACM, HHF, and MACE and higher BKA risk. Findings underscore the potential benefit and risks to be aware of when initiating SGLT2i. It remains unclear whether the BKA risk extends across the class of medication as the study was not powered to make comparisons among individual treatments.
- Received August 21, 2017.
- Accepted November 12, 2017.