SGLT2i therapy associated with lower risk of MACE at the cost of more lower leg amputations
Cardiovascular Outcomes and Risks After Initiation of a Sodium Glucose Cotransporter 2 Inhibitor: Results From the EASEL Population-Based Cohort Study (Evidence for Cardiovascular Outcomes With Sodium Glucose Cotransporter 2 Inhibitors in the Real World)
Introduction and Methods
Sodium glucose co-transporter 2 inhibitors (SGLT2i) inhibit the reabsorption of glucose and sodium in the renal proximal convoluting tubule. This results, among other effects, in a reduction in circulating glycated hemoglobin A1c, as well as in reductions in major adverse cardiovascular events (MACE), including cardiovascular (CV) mortality, nonfatal myocardial infarction (MI), nonfatal stroke, hospitalization for heart failure (HHF), and all-cause mortality (ACM) [1,2]. However, SGLT2i are also associated with increased risk for genitourinary tract infections, diabetic ketoacidosis, acute kidney injury, fractures, and atraumatic below-knee lower extremity amputation (BKA), although reliable data on BKA are scarce [3,4].
This retrospective analysis evaluated whether new initiation of an SGLT2i is associated with lower risk of CV events and increased risk of BKA compared with other anti-hyperglycemic agents (AHAs) in patients with type 2 diabetes mellitus (T2DM) and established CV disease. Eligible patients with T2DM were required to be ≥18 years of age and have ≥1 year of observation prior to the index date, with established CV disease.
Data from the Department of Defense (DoD) Military Health System (MHS)  were used, and 2 population-based cohorts were included:
- new users of SGLT2i, including canagliflozin, empagliflozin, and dapagliflozin
- new users of non-SGLT2i AHAs, including dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, thiazolidinediones (TZD), sulfonylureas (SU), insulin, and other AHAs (acarbose, bromocriptine, miglitol, nateglinide, and repaglinide).
The primary outcome was the composite of ACM and HHF. BKA was assessed as a safety endpoint and encompasses minor (digits, partial foot, and ankle disarticulation) and major amputations (below-knee). The median follow-up was 1.6 years.
- The incidence rate of the primary outcome was 1.73 vs. 3.01 per 100 person-years (PY) among new users of SGLT2i and non-SGLT2i AHAs, respectively (HR: 0.57; 95%CI: 0.50-0.65; P <0.0001).
- Compared with non-SGLT2i AHAs, initiation of an SGLT2i was associated with a lower rate of ACM (1.29 vs. 2.26 events per 100 PY; HR: 0.57; 95% CI: 0.49-0.66; P <0.0001) and HHF (0.51 vs. 0.90 events per 100 PY; HR: 0.57; 95%CI: 0.45-0.73; P <0.0001).
- The treatment benefit associated with SGLT2i started early and persisted over the study period.
- The rate of BKA was approximately two-fold higher in the ITT cohort, with 35 vs. 18 events in patients following initiation of SGLT2i versus non-SGLT2i AHAs, respectively (0.17 vs. 0.09 per 100 PY; HR: 1.99; 95%CI: 1.12-3.51; P=0.018).
- The risk was qualitatively similar in the on-treatment cohort, with 17 vs. 9 events among new users of SGLT2i and non-SGLT2i AHAs, respectively (0.14 vs. 0.07 per 100 PY; HR: 2.01; 95%CI: 0.89-4.53; P=0.09).
In a population-based cohort with T2DM and established CV disease the initiation of SGLT2i was associated with a lower risk of mortality, HHF, and MACE. However, the use of SGLT2i was also associated with an approximately two-fold higher risk of BKA.
In their editorial article, Bonaca and Beckman  comment on the limitations of the study of Udel et al, which include that the study was underpowered for below knee amputation, follow-up was too short for long-term effect, diabetic patients without CV disease were not included, and only all-cause, but not CV death was reported. The authors emphasize the following: ‘In contrast to the more consistent cardiovascular benefits described across these studies, however, is a finding isolated to the CANVAS trial (Canagliflozin Cardiovascular Assessment Study) showing an excess risk of amputation with canagliflozin. These divergent signals of harm in the limb coupled with general cardiovascular benefit have raised questions, including whether the observation is a result of chance alone as well as the potential mechanisms of harm. They also stand in contrast to other recent studies that demonstrate consistency in cardiovascular and limb benefits for antithrombotic and lipid-lowering therapies.’