Changes in Cardiovascular Biomarkers Associated With the Sodium–Glucose Cotransporter 2 (SGLT2) Inhibitor Ertugliflozin in Patients With Chronic Kidney Disease and Type 2 Diabetes

Abstract

Patients with type 2 diabetes are at high risk of developing renal and cardiovascular complications. Sodium–glucose cotransporter 2 (SGLT2) inhibitors have garnered interest due to their glucoseindependent cardiorenal protective effects, as reported in trials including participants with andwithout diabetes, such as Dapagliflozin And Prevention of Adverse outcomes inChronic KidneyDisease (DAPA-CKD) (1,2). These trials have demonstrated that SGLT2 inhibitors reduce cardiovascular disease (CVD) risk, especially hospitalization for heart failure (1,2). Despite these clinical benefits, the underlying physiological mechanisms of SGLT2 inhibitors are incompletely understood, particularly in patients with chronic kidney disease (CKD). Accordingly, this analysis examined the impact of treatment with an SGLT2 inhibitor, ertugliflozin, on markers of plasma volume contractionandmyocardial strain inparticipants with type 2 diabetes and moderate CKD. We performed a post hoc exploratory analysis in a subset of 231 participants from the eValuation of ERTugliflozin efficacy and Safety (VERTIS) RENAL trial (clinical trial reg. no. NCT01986855, ClinicalTrials.gov) with type 2 diabetes and stage 3 CKD (estimated glomerular filtrationrate[eGFR]30–59mL/min/1.73m) who were randomized to SGLT2 inhibitor therapy with ertugliflozin (5 mg or 15 mg daily; pooled herein) or placebo (3). Clinical and biomarker measurements were obtained at baseline and 26 weeks and 52 weeks postrandomization. Biomarkers were quantified with Luminex xMAP (cardiac troponin, renin, and N-terminal pro B-type natriuretic peptide [NT-proBNP]) or ELISA (atrial natriuretic peptide [ANP], human erythropoietin [EPO], ACE, and ACE2). Aldosterone was quantified by DiaSorin LIAISON XL Analyzer based on competitive chemiluminescent immunoassay. Differences in longitudinal changes in biomarkers among participants receiving either placebo or ertugliflozin were analyzed with use of linear mixed-effects models.Weperformedacorrelationanalysis between changes in hematocrit (HCT) and biomarkers using the Spearman correlation coefficient. Median age of participants (49% of whom were male) was 67 years and duration of type 2 diabetes 12.9 years, with 49% having a history of CVD. The median glycated hemoglobin (HbA1c) level was 8.0%, eGFR 47.8 mL/min/1.73 m, systolic blood pressure 133.5 mmHg, and urine albumin-to-creatinine ratio 28.1 mg/g. The majority (97%) of study participants wereonantihypertensive therapy (reninangiotensin-aldosterone system inhibitors 87%, diuretics 59%, a-/b-blockers 62%). Among participants randomized to ertugliflozin, compared with placebo, plasma aldosteronewas significantly higher at 26 weeks (P 5 0.005) (Fig. 1), an effect thatwasno longer significant at 52weeks. NT-proBNP was lower among those randomized to ertugliflozin at 26 and 52 weeks (P 5 0.020 and P 5 0.035, respectively). Plasma renin and ANP showed similar, nonsignificant directional