SGLT2 inhibition and heart failure—current concepts

Abstract

Type 2 diabetes mellitus (T2DM) is a major risk factor for several cardiovascular (CV) conditions, including heart failure (HF). However, until recently, no therapy to treat patients with diabetes could also reduce CV risks related to HF. The EMPA-REG OUTCOME trial with empagliflozin was the first to demonstrate significant cardioprotective benefits in this population. Its impressive 35% reduction in hospitalizations for HF drew the attention of the scientific community to the possibility that pharmacologic sodium-glucose cotransporter 2 (SGLT2) inhibition could be part of the armamentarium for treating patients with HF, with and without diabetes. The recently published CANVAS Program (with canagliflozin) and real-life data from the CVD-Real Study (using dapagliflozin, empagliflozin, and canagliflozin) further strengthened this hypothesis, suggesting that the observed benefit is not restricted to a particular drug, but is rather a class effect. This review explores the effects of pharmacologic SGLT2 inhibitors' use in cardiac function and discusses the potential role of this class of medication as a treatment for HF.

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

“…Intriguingly, different large RCTs are ongoing (EMPEROR‐Preserved, EMPEROR‐Reduced, DAPA‐HF), which do not include diagnosis of T2DM in the inclusion criteria 44. Clinicians might also wonder whether or not clinically significant differences exist among SGLT2‐Is through head‐to‐head comparative research.…”

“…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 Clinicians might also wonder whether or not clinically significant differences exist among SGLT2-Is through head-to-head comparative research. As discussed below, it appears that the existence of specific effects is a matter of safety rather than an efficacy issue, with the OBSERVE-4D MA of four US databases showing no difference in the estimates of HHF and BKAs.…”

Use of sodium–glucose co‐transporter‐2 inhibitors in patients with and without type 2 diabetes: implications for incident and prevalent heart failure

“…Other concurrent conditions including hypertension, obesity, hyperlipidaemia, and chronic kidney disease (CKD) may also play a role in the development of HF, making it difficult to determine the individual contribution of T2D to HF development . Many non‐atherosclerotic mechanisms for developing HF have been purported, including hyperglycaemia and elevated free fatty acids leading to left ventricular (LV) hypertrophy and remodelling . This is likely caused by changes in myocardial energetics that lead to reactive oxygen species‐related collagen deposition and fibrosis .…”

“…Possible mechanisms leading to improvement in heart failure (HF) outcomes with sodium–glucose co‐transporter‐2 inhibitors (SGLT‐2is) . A1C, glycated haemoglobin; AGT, angiotensinogen; BP, blood pressure; LV, left ventricular; NA + , sodium.…”

“…Sodium–glucose co‐transporter‐2 inhibitor therapy is associated with natriuresis and osmotic diuresis, even in individuals with normal kidney function without T2D . This contributes to decreases in intravascular volume, blood pressure, and arterial stiffness and ultimately reductions in cardiac preload and afterload . SGLT‐2is may decrease renal inflammation and tubular fibrosis through suppression of intrarenal angiotensinogen upregulation and oxidative stress .…”