The Year in Cardiology

Heart Failure: the Year in Cardiology 2019

John G.F. Cleland; Alexander R. Lyon; Theresa McDonagh; John J.V. McMurray


Eur Heart J. 2020;41(12):1232-1248. 

In This Article

Sodium-glucose Cotransporter-2 Inhibitors

Sodium-glucose cotransporter protein-2 (SGLT2) is found mainly in the proximal renal tubule and to a lesser extent in other organs. SGLT1 is abundant in the intestine and myocardium. SGLT2 inhibitors (SGLT2i) cause glycosuria, improving glycaemia, which led to their development for the treatment of T2DM, and an osmotic diuresis, leading to a contraction of plasma volume.[101,102] SGLT1 inhibitors reduce intestinal glucose absorption, which can cause diarrhoea but might have favourable effects on myocardial energy-utilization.[103] Most SGLT2i are highly selective, including dapagliflozin and empagliflozin, but sotagliflozin is less selective.[103]

EMPA-REG enrolled 7020 patients with T2DM, about 10% of whom had heart failure (LVEF was not measured) and showed that empagliflozin reduced the risk of hospitalization for heart failure and mortality.[104] Within a few weeks of initiating empagliflozin, body weight, and blood pressure fell and haematocrit rose, consistent with a diuretic effect. Subsequent RCTs of other SGLT2i in T2DM had similar findings. Meta-analyses suggested that SGLT2i were the hypoglycaemic agents most likely to reduce incident heart failure,[105–107] whilst observational data raises concerns about insulin therapy.[108] A meta-analysis of RCTs of empagliflozin, canagliflozin, and dapagliflozin for T2DM, including >30 000 patients, showed benefit, at least for those with established CV disease.[109] For the outcome of hospitalization for heart failure or CV death, the annual rate was about 0.6% for the 13 672 patients with multiple risk factors but without established CV disease, about 3% for the 20 650 patients with established atherosclerotic disease and about 6% for 3891 patients with heart failure at baseline; the relative risk reductions with SGLT2i in these populations were 16%, 24%, and 29%, respectively, without evidence of heterogeneity amongst agents. The largest of these trials, DECLARE,[110] included 17 160 patients of whom 671 had HFrEF and 1316 had HFpEF or an unspecified LVEF. In a subgroup analysis,[111] dapagliflozin reduced hospitalizations for heart failure and CV mortality for HFrEF but not for other patient-groups (Figure 5).

Figure 5.

Effect of dapagliflozin compared with placebo in type-2 diabetes mellitus in patients with heart failure with reduced ejection fraction, heart failure with preserved ejection fraction, or without heart failure in DECLARE. Reproduced with permission from ref.111

DAPA-HF[78,112] enrolled 4744 patients and followed them for a median of 18.3 months, demonstrating that addition of dapagliflozin to guideline-recommended therapy for HFrEF-reduced hospitalizations for heart failure by 30% and mortality (mainly cardiovascular) by 18%, preventing 3–5 hospitalizations and 1–2 deaths per 100 patients treated per year (Figure 6). Patients were somewhat less likely to experience serious adverse events, especially renal, with dapagliflozin compared with placebo. The benefits appeared consistent across subgroups, although patients with evidence of more severe congestion (worse NYHA class or higher NT-proBNP) may have received less benefit. Importantly, benefits were similar for those with and without T2DM and regardless of age.[113] Dapagliflozin also improved quality of life,[114] an effect that was confirmed in a smaller RCT (DEFINE)[115] that followed 263 patients for 12 weeks; about one in six patients got a meaningful benefit, either prevention of worsening or an improvement in symptoms, compared with placebo.

Figure 6.

Effect of dapagliflozin compared with placebo in patients with heart failure with reduced ejection fraction, with or without type-2 diabetesmellitus in DAPA-HF. Reproduced with permission from ref.78

In DAPA-HF, the placebo-corrected decline in weight between baseline and 8 months was 0.87 kg and this was associated with a small fall in NT-proBNP and systolic blood pressure and a small increase in haematocrit and serum creatinine. These findings are again consistent with the belief that SGLT2i exert at least some of their benefits by enhancing diuresis, either through an osmotic effect of glycosuria or by interfering with sodium-hydrogen exchange in the nephron.[116] The effects of SGLT2i appear early, consistent with an immediate haemodynamic effect. However, alternative or additional explanations for the effect of SGLT2i have been proposed. A small RCT suggested that empagliflozin stimulated production of erythropoietin leading to a rise in haematocrit and a fall in ferritin, a marker of inflammation and iron deficiency, although not transferrin saturation, a marker of iron deficiency alone.[117] However, administration of exogenous erythropoietin did not reduce morbidity or mortality in the RED-HF trial.[118] Others have suggested that SGLT2i increase the production of ketones, which may be a more efficient myocardial energy substrate, or block myocardial sodium–hydrogen exchanger-3, which may improve myocardial function and reduce fibrosis.[119,120] An RCT of empagliflozin in patients with T2DM but not heart failure[121] suggested little effect on cardiac function or remodelling; RCTs of the effects of SGLT2i on cardiac function in patients with HFrEF and HFpEF are awaited. Future trials will confirm whether the benefit observed in DAPA-HF is a class effect and whether they are effective for HFpEF or when congestion is severe.[122,123]