Effect of Empagliflozin on Left Ventricular Volumes in Patients With Type 2 Diabetes, or Prediabetes, and Heart Failure With Reduced Ejection Fraction (SUGAR-DM-HF)

Abstract

Background: Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of heart failure hospitalization and cardiovascular death in patients with heart failure and reduced ejection fraction (HFrEF). However, their effects on cardiac structure and function in HFrEF are uncertain. Methods: We designed a multicenter randomized, double-blind, placebo-controlled trial to investigate the cardiac effects of empagliflozin in patients in NYHA functional class II to IV with a left ventricular (LV) ejection fraction ≤40% and type 2 diabetes or prediabetes. Patients were randomized 1:1 to empagliflozin 10 milligrams once daily or placebo, stratified by age (<65 and ≥65 years) and glycemic status (diabetes or prediabetes). The co-primary outcomes were change from baseline to 36 weeks in LV end-systolic volume indexed to body surface area (LVESVi) and LV global longitudinal strain (LV GLS) measured using cardiovascular magnetic resonance (CMR). Secondary efficacy outcomes included other CMR measures (LVEDVi, LVEF), diuretic intensification, symptoms (Kansas City Cardiomyopathy Questionnaire Total Symptom Score (KCCQ-TSS)), 6-minute walk distance (6MWD), B-lines on lung ultrasound and biomarkers (including NT-proBNP). Results: From April 2018 to August 2019, 105 patients were randomized: 77 (73.3%) male, mean age 68.7 [SD 11.1] years, 82 (78.1%) diabetes and 23 (21.9%) prediabetes, mean LVEF 32.5% [9.8%], and 81 (77.1%) NYHA II and 24 (22.9%) NYHA III. Patients received standard treatment for HFrEF. Compared with placebo, empagliflozin reduced LVESVi by 6.0 (-10.8 to -1.2) ml/m 2 (p=0.015). There was no difference in LV GLS. Empagliflozin reduced LVEDVi by 8.2 (-13.7 to -2.6) ml/m 2 (p=0.0042) and reduced NT-proBNP by 28 (2 to 47) %, p=0.038. There were no between-group differences in other CMR measures, KCCQ-TSS, 6MWD or B-lines. Conclusions: The SGLT2 inhibitor empagliflozin reduced LV volumes in patients with HFrEF and type 2 diabetes or prediabetes. Favorable reverse LV remodeling may be a mechanism by which SGLT2 inhibitors reduce HF hospitalization and mortality in HFrEF. Clinical Trial Registration: URL: https://www.clinicaltrials.gov Unique Identifier: NCT03485092.

Early initiation of SGLT2 inhibitors is important, irrespective of ejection fraction: SOLOIST‐WHF in perspective

“…44 SGLT2 inhibitors have also been shown to have favourable effects on left ventricular remodelling in people with and without diabetes and in those with systolic or diastolic dysfunction. [45][46][47][48] While most of these mechanisms have been described with SGLT2 inhibitors per se, it is important to point out that sotagliflozin also Figure 2 The natural history of worsening heart failure and the stages of worsening heart failure that have been evaluated in clinical trial settings. DAPA-HF, Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure; EF, ejection fraction; EMPEROR-Reduced, EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction; GDMT, guideline-directed medical therapy; HFrEF, heart failure with a reduced ejection fraction; MRA, mineralocorticoid receptor antagonists; RASi, renin-angiotensin system inhibitors; WHF, worsening heart failure.…”

“…Other relevant mechanisms may include an increase in erythropoietin, 43 inhibition of the sympathetic nervous system, 36 improved kidney function, changes in substrate utilization, 38 direct myocardial effects, modulation of autophagy/mitophagy, and a stimulation of a fasting transcriptional paradigm 44 . SGLT2 inhibitors have also been shown to have favourable effects on left ventricular remodelling in people with and without diabetes and in those with systolic or diastolic dysfunction 45–48 . While most of these mechanisms have been described with SGLT2 inhibitors per se, it is important to point out that sotagliflozin also inhibits SGLT1, which may have additional glycaemic and cardiovascular benefit 49 .…”

The year in cardiovascular medicine 2020: heart failure and cardiomyopathies

“…119 U studiji SUGAR-DM-HF emfagliflozin snizuje volumene lijeve klijetke mjereno magnetnom rezonancijom u bolesnika s HFrEF-om i tipom 2 dijabetesa ili preddijabetesa. 120 Mehanistička studija EMPA-TROPISM (ATRU-4) pokazuje povoljan učinak emfagliflozina u poboljšanju volumena i mase lijeve klijetke, sistoličke funkcije lijeve klijetke, funkcionalnog kapaciteta i kvalitete života, u bolesnika s HFrEF-om bez dijabetesa. 121 Ako se zbroje svi dokazi, može se utvrditi da SGLT-2 inhibitori snizuju ukupnu i CV smrtnost, poboljšavaju bubrežnu funkciju u bolesnika s HFrEF-om, podržavajući ulogu dapagliflozina i empagliflozina u smislu standardne skrbi za bolesnike s HFrEF-om.…”

“…119 In the SUGAR-DM-HF study, empagliflozin reduced LV volumes measured by CV magnetic resonance in patients with HFrEF and type 2 diabetes or prediabetes. 120 The mechanistic trial EMPA-TROPISM (ATRU-4) showed the beneficial effect of empagliflozin in improving LV volumes, LV mass, LV systolic function, functional capacity, and quality of life in non-diabetic patients with HFrEF 121 (ref). Taken the evidence together, SGLT-2 inhibitors reduce all-cause and CV mortality and improve renal outcomes in patients with HFrEF, supporting the role of dapagliflozin and empagliflozin as a new standard of care for patients with HFrEF.…”

Cardiovascular benefits of sodium-glucose cotransporter 2 inhibitors in diabetic and nondiabetic patients

“…Many clinical studies using cardiac magnetic resonance imaging or echocardiography have also shown that SGLT2i improve cardiac diastolic function and reduce left ventricular mass and volume [128][129][130][131]. However, most studies excluded individuals with overt HF and it, therefore, remains uncertain whether SGLT2i can attenuate advanced left ventricular remodeling.…”