SGLT2 inhibitor reduces adverse outcomes across the spectrum of heart failureHF risk in diabetics
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
The SGLT2 inhibitor empagliflozin reduces cardiovascular (CV) mortality and heart failure (HF) hospitalization in patients with type 2 diabetes (T2D) and CV disease . It is not known whether the clinical benefit of empagliflozin is consistent in diabetic patients with and without HF, and in those at higher and lower HF risk.
In the EMPA-REG OUTCOME trial, 7,020 patients with HbA1C between 7 and 10%, eGFR >30mL/min/1.73 m2, and established atherosclerotic CVD, were randomized to receive empagliflozin 10mg or 25mg, or placebo once daily in addition to standard of care, and followed for a median 3.1 years [2,3].
In this analysis of the EMPA-REG OUTCOME trial, the 5-year risk for incident HF was assessed in those without HF at baseline (89.9% of the study population), using the 9-variable Health ABC HF Risk score which incorporates age, coronary artery disease, systolic blood pressure, heart rate, left ventricular hypertrophy, smoking, serum albumin, fasting blood glucose, and creatinine [4,5].
The HF risk was 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 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; 95%CI: 1.31-2.10 in the low-to-average risk group; 4.03; 95%CI: 3.06-5.13 in the high-risk group; and 7.0; 4.33-10.29 in the very-high risk group).
- The incident HF hospitalization rate or CV death risk in those with HF at baseline was 8.55 (95%CI: 6.33-11.11) per 100 PY.
- The rate of CVD death and HF hospitalization per 1,000 PY in diabetic individuals without HF at baseline was consistently lower in the empagliflozin group compared with placebo: for low/average risk: 12.0 vs. 16.8; HR: 0.71; 95%CI: 0.52-0.96; for high risk: 20.7 vs. 40.3; HR: 0.52; 95%CI: 0.36-0.75; for very high risk: 38.0 vs. 70.0; HR: 0.55; 95%CI: 0.30-1.00. The beneficial effect started early (after 12 weeks) and persisted for the duration of the study.
- CV mortality was significantly reduced with empagliflozin as compared with placebo in the 13.6% of patients with HF burden (HR: 0.67; 95%CI: 0.47-0.97), and the absolute risk reduction was 4.9%. The relative benefit was similar in the 86.4% of patients without HF burden (overall HR: 0.63; 95%CI: 0.48–0.84; HR for low-to-average group: 0.65; 95%CI: 0.45-0.94; HR for high risk: 0.57; 95%CI: 0.38-0.88; HR for very high risk: 0.49; 95%CI: 0.24-1.02).
A sub-analysis of the EMPA-REG OUTCOME study showed that empagliflozin provides clinical benefit for diabetic patients with or without HF, and to those at high and low HF risk. This benefit occurred after 12 weeks of therapy and persisted throughout the study.
In his editorial article, Paneni  provides insights into the pathophysiology of early benefit of empagliflozin, which include its effects on glycemic control, osmotic diuresis and blood pressure, as well as the inhibition of the sodium-hydrogen exchange and the slower progression of kidney disease. He also notes the study limitations including that HF hospitalizations were not centrally adjudicated, the lack of specific cardiac measures like the ejection fraction, the possible underestimation of HF prevalence and incidence, and the low number of events in the HF risk subgroups.
The author concludes: ‘Overall, the present study provides novel insights to believe that empagliflozin, and perhaps other SGLTL-2 inhibitors, may act across the spectrum of diabetic heart disease, from early stages of diabetic cardiomyopathy to congestive HF.’ (…)‘This ‘”self-limiting’ 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.’