Sodium–glucose co‐transporter 2 inhibitors: ‘a tale of two sisters’, diabetes and heart failure
Authors: Dimitrios Farmakis, Javed Butler, Gerasimos Filippatos
Journal: European Journal of Heart Failure (2020)

This article refers to ‘Efficacy and safety of sodium–glucose co-transporter 2 inhibition according to left ventricular ejection fraction in DAPA-HF’ by P. Dewan et al., published in this issue on pages 1247–1258. Concerns regarding cardiovascular (CV) adverse events of certain anti-diabetic agents such as rosiglitazone led to a series of trials assessing the CV safety or type 2 diabetes mellitus (T2DM) therapies in patients with established CV disease or high CV risk.1 The so-called CV outcome trials addressed ‘hard’ endpoints including CV death, myocardial infarction (MI) and stroke.2 Three of these trials with sodium–glucose co-transporter 2 inhibitor (SGLT2i), however, yielded some unexpected findings. First, the EMPA-REG OUTCOME in T2DM patients with established CV disease, showed that empagliflozin was not only safe but also beneficial in reducing the composite of CV death/non-fatal MI/non-fatal stroke [3-point major adverse CV events (MACE)] by 14% and impressively, CV death by 38%, hospitalization for heart failure (HHF) by 35% and all-cause death by 32% compared to placebo.3 Some of these results were reproduced by the subsequent trials of canagliflozin and dapagliflozin in T2DM patients with high CV risk. In the CANVAS trial, canagliflozin reduced significantly the 3-point MACE by 14% and HHF by 33%,4 while in the DECLARE-TIMI 58 trial, dapagliflozin reduced HHF by 27%.5 Subgroup analyses of these trials showed that the observed benefits were consistent across patients with and without a baseline history of heart failure (HF).4, 6, 7 A constant finding in the above trials was the considerable reduction in the risk of HHF that was comparable or even numerically greater than that reported by neurohormonal inhibitors. Although HHF was not a primary endpoint in these trials and only 10% to 15% of patients enrolled had a history of HF, this unexpected finding and the mechanism of action of these agents led to the hypothesis that SGLT2i might represent an option to treat HF irrespectively of T2DM. A series of trials have thus been launched to test this hypothesis (Table 1). DAPA-HF was the first of these trials to report and showed that dapagliflozin reduced the primary composite endpoint of CV death/HHF/urgent HF visits by 26% compared to placebo in patients with chronic HF with reduced ejection fraction [HFrEF, defined as a left ventricular ejection fraction (LVEF) ≤40%]; the magnitude of benefit was similar in patients with or without diabetes.8 There was also a significant reduction in the components of the primary endpoint, including CV death (18% reduction) and worsening HF events (30% reduction), as well as all-cause death that was reduced by 17% compared to placebo. The drug further improved significantly symptoms and quality of life. A secondary analysis of DAPA-HF is presented in the current issue of the Journal.9 Dewan and colleagues analysed the results of the trial by baseline LVEF and show that the beneficial effects of dapagliflozin were consistent for all outcomes across the spectrum of reduced LVEF, ranging from 40% to <10%.9 The absolute risk of events was higher in patients with lower LVEF (i.e. LVEF <26% vs. >35%), and hence the absolute benefit of dapagliflozin is expected to be greater in these particular patients. In line with the findings of the present analysis, a secondary analysis of DECLARE-TIMI 58 that stratified T2DM patients according to HF history and LVEF at baseline, showed that although dapagliflozin reduced the composite of CV death/HHF as well as HHF consistently in all strata, the magnitude of benefit was greater for HFrEF patients (defined as a LVEF <45%), while CV death and all-cause death were reduced only in HFrEF.7 While the ongoing SGLT2i trials in HFrEF and HF with preserved ejection fraction are expected to provide more solid evidence in this regard, the results of the present analysis should be interpreted in the context of the specific HFrEF population studied that excluded patients with severe renal dysfunction, low systolic blood pressure or other serious comorbidities, which may actually be frequent in HFrEF, particularly at the lower end of LVEF spectrum. Another relevant issue is the long-term preciseness of LVEF measurements. In DAPA-HF, the baseline LVEF was allowed to be assessed up to 12 months prior to enrolment. LVEF trajectory in HFrEF has been reported to show a rise within 1 year that is more pronounced in women, patients with non-ischaemic HF aetiology and those with early-onset HF (of less than 12 months).10 Thus, the true baseline LVEF in DAPA-HF may not be what is reported. There is an ongoing discussion regarding the underlying mechanisms that mediate the observed benefit of SGLT2i. Several different actions of these drugs have been considered including renal, metabolic, and CV (Figure 1).11 The improvement of ventricular loading conditions due to a decrease in preload and afterload accomplished by osmotic diuresis/natriuresis and blood pressure reduction, the attenuation of glycaemia-induced cardiotoxicity and the improvement of myocardial energetics due to the increase in circulating ketonic substrates for cardiomyocyte metabolism have been proposed as potential mechanisms, based on SGLT2i mode of action and observed effects in extracardiac organs.12 These mechanisms have however been questioned.12, 13 The beneficial effects of these agents develop early, are present in patients with and without diabetes, do not correlate with glycaemia control or blood pressure change, and are seen across the spectrum of renal function with estimated glomerular filtration rates (eGFRs) between 30 and >90 mL/min/1.73 m2 (the glucose lowering efficacy of SGLT2i declines at low eGFR). Moreover, SGLT2i do not seem to reduce significantly natriuretic peptides in acute or chronic HF or improve dyspnoea, diuretic response or hospitalization length in acute HF.14, 15 In addition, HF patients have increased circulating levels and utilization of ketonic bodies even without SGLT2i,13 while animal experiments do not favour an increased myocardial utilization of ketone bodies in the presence of SGLT2i, despite the increase in their circulating levels.16 In contrast to renal and metabolic actions of SGLT2i, attention has lately been focused on their cardiac effects provided by a series of mechanistic in vitro, experimental in vivo, or clinical studies. These effects include reduction in myocardial inflammation, oxidative stress, apoptosis, fibrosis and hypertrophy, improvement of coronary endothelial function, reduction in aortic stiffness and enhancement of diastolic function.17-20 Particular attention has been placed on the inhibition of myocardial sodium/hydrogen exchanger 1 that has been indicated by in silico and in vivo animal studies21, 22 and is thought to result in attenuation of cardiomyocyte calcium overload.23 Another interesting mechanism is the attenuation in the expansion and inflammation of epicardial adipose tissue, that results in reduction of adipokine synthesis, such as leptin, which exerts detrimental paracrine effects on the myocardium, including inflammation and fibrosis.24 These studies provide some evidence on direct cardiac effects of SGLT2i with potentials for cardio-protection. While several ongoing trials are expected to provide a wealth of evidence on SGLT2i across the whole spectrum of HF phenotypes, the quest for the better understanding of the mode of action of these agents in HF continues. The figure was created using artwork provided by Servier Medical Art, licensed under a Creative Commons Attribution 3.0 Unported License. Conflict of interest: D.F.: lecture honoraria or consulting fees from Abbott Laboratories, Bayer, Boehringer Ingelheim, Menarini, Novartis, Orion Pharma and Roche Diagnostics. J.B.: consultant to Abbott, Adrenomed, Amgen, Applied Therapeutics, Array, AstraZeneca, Bayer, BerlinCures, Boehringer Ingelheim, Cardior, CVRx, Foundry, G3 Pharma, Imbria, Impulse Dynamics, Innolife, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, NovoNordisk, Relypsa, Roche, Sanofi, Sequana Medical, V-Wave Limited, and Vifor. G.F.: committee member in trials and registries sponsored by Novartis, Vifor, Medtronic, Servier and Boehringer Ingelheim.