Sodium Glucose Cotransporter-2 Inhibition in Heart Failure

Abstract

Despite current established therapy, heart failure (HF) remains a leading cause of hospitalization and mortality worldwide. Novel therapeutic targets are therefore needed to improve the prognosis of patients with HF. The EMPA-REG OUTCOME trial demonstrated significant reductions in mortality and HF hospitalization risk in patients with type 2 diabetes (T2D) and cardiovascular disease with the antihyperglycemic agent, empagliflozin – a sodium glucose co-transporter 2 (SGLT2) inhibitor. The CANVAS trial subsequently reported a reduction in 3-point MACE (major adverse cardiovascular events) and HF hospitalization risk. While SGLT2 inhibition may have potential application beyond T2D, including HF, the mechanisms responsible for the cardioprotective effects of SGLT2 inhibitors remain incompletely understood. SGLT2 inhibition promotes natriuresis and osmotic diuresis, leading to plasma volume contraction and reduced preload, as well as decreases in blood pressure, arterial stiffness and afterload, thereby improving subendocardial blood flow in patients with HF. SGLT2 inhibition is also associated with preservation of renal function. Based on data from mechanistic studies and clinical trials, large clinical trials with SGLT2 inhibitors are now investigating the potential use of SGLT2 inhibition in patients with HF with and without T2D. Accordingly, in this review, we summarize key pharmacodynamic effects of SGLT2 inhibitors and the clinical evidence which support the rationale for the use of SGLT2 inhibitors in HF patients with T2D. Since presumably these favorable effects occur independent of blood-glucose lowering, we also explore the potential use of SGLT2 inhibition in patients without T2D with HF or at risk of HF, such as in patients with coronary artery disease or hypertension. Finally, we provide a detailed overview and summary of ongoing cardiovascular outcome trials with SGLT2 inhibitors.

Observational research on sodium glucose co‐transporter‐2 inhibitors: A real breakthrough?

“…In terms of effectiveness, there is interest in verifying whether pharmacological modulation with SGLT2‐Is could be part of the armamentarium for treating patients with heart failure, with and without diabetes 43. Intriguingly, different large RCTs are ongoing (EMPEROR‐Preserved, EMPEROR‐Reduced, DAPA‐HF), which do not include diagnosis of T2DM in the inclusion criteria 44.…”

SGLT2 inhibition in a kidney with reduced nephron number: modeling and analysis of solute transport and metabolism

“…Most importantly and in addition to lowering blood sugar levels, SGLT2 inhibitors have also been reported to reduce blood pressure and protect from heart failure, even in patients with chronic kidney diseases and reduced GFR [estimated GFR (eGFR) Ն 30 ml•min Ϫ1 •1.73 m 2 ] (21a, 30,47). Moreover, new clinical trials have been initiated to explore the renocardiovascular benefits of SGLT2 inhibitors in nondiabetic patients (25). Hence another goal of this study is to determine if a persistent diuretic and natriuretic effect of SGLT2 inhibitors can be predicted when the nephron number and GFR are getting reduced in diabetes, and to which extent such beneficial effects may also extend to the nondiabetic setting.…”

Mechanisms of cardiovascular protection of non-insulin antidiabetic medications

“…Данные внутриклубочковые действия могут влиять на снижение альбуминурии. Если присутствует снижение СКФ (<45 мл/мин/1,73 м 2 ), сахароснижающий эффект ингибиторов SGLT2 снижается, хотя натрийуретический эффект может сохраняться: этот эффект, возможно, вносит наибольший вклад в кардиопротективный эффект данного класса препаратов, хотя существует несколько гипотез [82]. Определенно, сочетание стойкого сахароснижающего действия, осмотического диуреза и снижения массы тела положительно влияет на кардиопротекцию, которая наблюдалась в двух исследованиях сердечно-сосудистых исходов по ингибиторам SGLT2 (SGLT2i): EMPA-REG и CANVAS (Canaglifl ozin Cardiovascular Assessment Study Program) соответственно [83][84][85].…”