SGLT2 inhibitor reduced HF outcomes independently of HF risk in diabetic patients

Effects of empagliflozin on risk for cardiovascular death and heart failure hospitalization across the spectrum of heart failure risk in the EMPA-REG OUTCOME trial

Literature - Fitchett D, Butler J, van de Borne P, et al, on behalf of the EMPA-REG OUTCOME trial investigators - Eur Heart J 2017; published online ahead of print


Patients with HF and T2DM are at particularly high risk of adverse outcomes, with an approximate doubling of mortality and HF hospitalization compared to those with T2DM or HF alone [1,2]. The EMPA-REG OUTCOME trial showed that the SGLT2 inhibitor empagliflozin reduced CV mortality by 38%, HF hospitalization by 35%, and the composite of CV mortality or HF hospitalization by 34% in patients with T2DM and CVD, independently of the diagnosis of HF at baseline [3,4].

In this analysis of the EMPA-REG OUTCOME trial, the effects of empagliflozin on clinical outcomes in patients across the spectrum of HF and HF risk were evaluated. In the EMPA-REG OUTCOME trial, approximately 7.000 patients with HbA1C of 7-10%, eGFR >30mL/min/1.73 m2) and established atherosclerotic CVD were randomized to empagliflozin 10mg or 25mg, or placebo once daily in addition to standard of care.

The 5-year risk for incident HF among the 89.9% of the trial cohort without baseline HF was assessed using the 9-variable Health ABC HF Risk score, which incorporates age, CAD, SBP, HR, LVH, smoking, serum albumin, fasting blood glucose, and creatinine [5,6]. The risk was then classified as low-to-average (5-year HF occurrence <10%), high (10–20%), and very high (≥20%). Patients with investigator-reported HF at baseline, those with at least one adjudicated HF hospitalization during the trial, and those with investigator-reported incident HF (but without a corresponding HF hospitalization) during the trial were grouped and defined as patients with ‘HF burden’.

Main results

  • The incident HF hospitalization rate or CV death risk per 100 patient-years (PY) in the placebo group increased with increasing HF risk profile (1.68 in the low-to-average risk group; 95%CI: 1.31 - 2.10; 4.03 in the high-risk group; 95%CI: 3.06 - 5.13; 7.0 in the very-high risk group; 95%CI: 4.33 - 10.29). In comparison, the incident HF hospitalization rate or CV death risk in those with prevalent baseline HF was 8.55 (95%CI: 6.33 - 11.11) per 100 PY.
  • In those without HF at baseline, regardless of their HF risk category, empagliflozin reduced the risk of HF hospitalization and CV death, as well as the individual components. A separation of the cumulative incidence curves appeared early and the reduction of risk persisted for the duration of the trial.
  • The CV mortality was also significantly reduced among the 13.6% (958 patients) in the trial with HF burden (HR: 0.67; 95% CI: 0.47 - 0.97), in whom absolute risk reduction was 4.9%.
  • The magnitude of relative benefit was similar in the 86.4% of patients without HF burden (HR: 0.63; 95% CI: 0.48–0.84) at baseline or during the trial.
  • The total number of deaths in the baseline or incident HF population comprised 37.9% of the overall CV deaths, whereas 62.1% occurred in the population without any HF burden.
  • Reductions in the risk for HF hospitalization with empagliflozin vs. placebo were observed by the first month and persisted for the duration of the trial. The HR stabilized as the number of patients with events increased over time.


Many T2DM patients with established CVD and without HF are at high or very high risk for HF outcomes. Empagliflozin reduced adverse HF outcomes both in patients at low or high HF risk.

Editorial comment

In his editorial article, Paneni [7] comments on the paper of Fitchett et al: ‘Taken together, these findings show for the first time that an SGLT-2 inhibitor, namely empagliflozin, reduces CV mortality and HHF in patients at both high and lower risk, as well as in patients with or without either baseline or incident HF.’

The author discusses the possible mechanisms leading to the reduction of CV mortality and HF hospitalization with empagliflozin, including osmotic diuresis, reduction in sympathetic nerve activation and increase of circulating ketone bodies, and he concludes: ‘Notably, the effect of SGLT-2 inhibitors on glucose elimination is proportional to glycaemic levels, being modest or even negligible in conditions of mild hyperglycaemia. This ‘self-limiting’ action of SGLT-2 inhibitors may suggest their use also in patients without diabetes (i.e. pre-diabetes, obesity, hypertension) to prevent adverse cardiac remodelling and dysfunction. Future studies will help us to characterize further and appreciate the potential of empagliflozin and other SGLT-2 inhibitors to fight the epidemic of HF.’


1. MacDonald MR, Petrie MC, Varyani F, Ostergren J, et al; CHARM Investigators. Impact of diabetes on outcomes in patients with low and preserved ejection fraction heart failure: an analysis of the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) programme. Eur Heart J 2008;29:1377–1385.

2. Cubbon RM, Adams B, Rajwani A, et al. Diabetes mellitus is associated with adverse prognosis in chronic heart failure of ischaemic and non-ischaemic aetiology. Diab Vasc Dis Res 2013;10:330–336.

3. Fitchett D, Zinman B, Wanner C, et al. EMPA REG OUTCOME Investigators. Heart failure outcomes

with empagliflozin in patients with type 2 diabetes at high cardiovascular risk: results of the EMPA-REG OUTCOMEVR trial. Eur Heart J 2016;37:1526–1534.

4. Zinman B, Inzucchi SE, Lachin JM, et al. Rationale, design, and baseline characteristics of a randomized, placebo controlled cardiovascular outcome trial of empagliflozin (EMPA-REG

OUTCOMETM). Cardiovasc Diabetol 2014;13:102.

5. Butler J, Kalogeropoulos A, Georgiopoulou V, et al. Incident heart failure prediction in the elderly: the health ABC heart failure score. Circ Heart Fail 2008;1:125–133.

6. Kalogeropoulos A, Psaty BM, Vasan RS, et al. Validation of the health ABC heart failure model for incident heart failure risk prediction: the Cardiovascular Health Study. Circ Heart Fail 2010;3:495–502.

7. Paneni F. Empagliflozin across the stages of diabetic heart disease. Eur Heart J 2017; published online ahead of print.

Find this article online at Eur Heart J

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