Rationale and design of the expanded combination of evolocumab plus empagliflozin in diabetes: EXCEED-BHS3 trial

Abstract

Background: Patients with type 2 diabetes mellitus (T2DM) remain at increased cardiovascular residual risk and endothelial dysfunction, even after optimizing metabolic control and treatment by sodium-glucose-2 transporter inhibitors (SGLT2-is). The present study was based on the hypothesis that proprotein convertase subtilisin/kexin 9 inhibitor (PCSK9i) therapy may mitigate endothelial dysfunction in T2DM patients who are on regular treatment by SGLT2-i. Methods: The EXCEED-BHS3 is a prospective, single-center, investigator-blinded, open-label, randomized clinical trial. Participants ( n = 110) will be randomized (1:1) to either empagliflozin 25 mg/day alone or empagliflozin 25 mg/day plus evolocumab 140 mg every 2 weeks in addition to optimal medical care. The primary endpoint was defined as the change in the 1-min flow-mediated dilation (FMD) after 16 weeks of treatment. The secondary endpoint is the FMD change after ischemia/reperfusion injury protocol (reserve FMD) after 16 weeks of treatment. Exploratory outcomes comprise the change in FMD and reserve FMD after 8 weeks of treatment and the change after 16 weeks of treatment in the following parameters: plasma levels of nitric oxide, vascular cell adhesion molecule-1 and isoprostane, high-density lipoprotein (HDL) and low-density lipoprotein subfractions profile, HDL function, blood pressure, body mass index, waist circumference and adipokines. Conclusion: This will be the first study to evaluate the add-on effect of PCSK9i on endothelial function of T2DM patients under regular use of empagliflozin. Trial registration: ClinicalTrials.gov identifier: NCT03932721

Evolocumab on top of empagliflozin improves endothelial function of individuals with diabetes: randomized active-controlled trial

“…Blinding of the study for the primary endpoint was implemented by performing offline assessments of the video recordings generated during the FMD examination, as described below. The study protocol has been previously described in detail elsewhere [ 13 ]. Briefly, individuals with T2D, aged 40–70 years, with a body mass index (BMI) < 40 kg/m2, were summoned by social media and newspaper campaigns to participate in the screening visit for medical evaluation, biochemical analysis, and screening for FMD.…”

The Reciprocal Relationship between LDL Metabolism and Type 2 Diabetes Mellitus

“…However, the addition of anti-PCSK9ab moderately reduced plasma ApoC-III levels (15%), and there was a more pronounced decrease in apoE concentration (33%) [135]. The prospective randomized clinical trial EXCEEDBHS3 was designed to investigate the effect of adding anti-PCSK9ab to sodium-glucose cotransporter 2 inhibitor (SGLT2i) therapy (which is reported to increase LDL levels) [137] on LDL subfractions; the trial is still ongoing [138]. In an animal model, treatment with anti-PCSK9ab reduced the size of atherosclerotic plaques and infiltration of pro-inflammatory macrophages, in addition to increasing circulating endothelial progenitor cells and angiogenic cells, suggesting that these results are secondary effects of LDL-C reduction [139].…”

Effects of SGLT-2 Inhibitors on Vascular Endothelial Function and Arterial Stiffness in Subjects With Type 2 Diabetes: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

“…Of these, 13 were excluded. We excluded three of them because the trials were ongoing, and the results were not published (n = 3) ( 17 – 19 ). Four articles had incomplete data, including PWV and FMD (n = 4) ( 20 – 23 )and two of them were not randomized or controlled (n = 2) ( 24 , 25 ).…”

“…The published literature suggests that research in the area is limited. It gave credit to some studies conducted but not published (17)(18)(19). There were few small randomized clinical trials with moderate heterogeneity.…”