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
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’.
- 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.
In his editorial article, Paneni  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.’