Recent clinical trials demonstrated that sodium–glucose co-transporter 2 inhibitors can reduce hospitalization for heart failure and improve hard kidney end points in patients with and without type 2 diabetes mellitus. These observations consolidate the view that organ protection is independent of blood glucose control and mitigation of traditional risk factors.
Refers to Packer, M. et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. N. Engl. J. Med. 383, 1413–1424 (2020) | Heerspink, H. J. L. Dapagliflozin in patients with chronic kidney disease. N. Engl. J. Med. 383, 1436–1446 (2020).
Cardiovascular outcome studies have definitively demonstrated that using sodium–glucose co-transporter 2 (SGLT2) inhibitors provides cardiovascular protection in patients with pre-existing, or at high risk of developing, cardiovascular disease (CVD)1,2,3. Furthermore, the CREDENCE study4 definitively demonstrated that canagliflozin reduced hard kidney end points and conferred cardiovascular protection in patients with diabetic kidney disease. The DAPA HF study5 further confirmed that dapagliflozin reduced hospitalization for heart failure (HHF) in patients with reduced ejection fraction, with and without type 2 diabetes mellitus (T2DM). Now, the EMPEROR-Reduced6 and DAPA-CKD7 trials provide further evidence that SGLT2 inhibition is not only beneficial to patients with T2DM — these drugs can reduce HHF and limit hard kidney outcomes in people with chronic kidney disease (CKD), respectively, even in patients without T2DM.
In the empagliflozin study (EMPEROR-Reduced)6, 73% of patients had an ejection fraction ≤30% and the mean estimated glomerular filtration rate (eGFR) was 62 ml/min/1.73 m2; 48% of patients had an eGFR <60 ml/min/1.73 m2. Importantly, half of the total 3,730 patients did not have T2DM. Patients treated with empagliflozin or placebo were matched for disease characteristics, co-morbidities and concomitant medication. The primary outcome — cardiovascular death or HHF — was reduced in patients treated with 10 mg empagliflozin compared with placebo (HR, 0.75; 95% CI 0.65–0.86; P < 0.001) and, notably, was equally beneficial in patients with and without T2DM. This effect was primarily driven by a reduction in total HHF in the group treated with empagliflozin (HR 0.70; 95% CI 0.58–0.85; P < 0.001), as cardiovascular death did not improve (HR 0.92; 95% CI 0.75–1.12)1. This lack of benefit on cardiovascular death is dissimilar to the 38% reduction observed in patients with high cardiovascular risk in the EMPA-REG1 study but is consistent with results observed in other cardiovascular outcome trials2,3. The reason for this discrepancy is unclear but the patient cohorts differed between studies — 10% of patients in EMPA-REG had heart failure and 100% had atherosclerotic vascular disease, whereas in EMPEROR-Reduced 100% of patients had heart failure that was non-ischaemic in origin in approximately 50% of cases.
In contrast to the earlier DAPA–HF study5, EMPEROR-Reduced6 was enriched in patients with a substantially reduced ejection fraction and increased levels of pro-brain natriuretic peptide, which indicates that patients in the EMPEROR-Reduced cohort had more advanced cardiac failure. Accordingly, the incidence of the primary composite outcome was 40% higher in EMPEROR-Reduced than in the DAPA-HF study5,8. However, the benefits observed in both the primary outcome and the secondary outcome (that is, HHF) were remarkably similar in both trials. Indeed, a reduction in HHF is highly consistent across all SGLT2 inhibitor trials1,2,3,4,5,6,7 and is now definitively demonstrated in two dedicated heart failure trials. In the EMPEROR-Reduced study, the rate of the eGFR decline (secondary end point) was lower in the empagliflozin treated group compared with placebo (−0.55 ± 0.23 and −2.28 ± 0.23 ml/min/1.73 m2 per year, respectively; P < 0.001). The kidney composite pre-specified end point (that is, chronic dialysis, transplantation or profound, sustained eGFR reduction) was also reduced (HR 0.50; 95% CI 0.32–0.77). Interestingly, in the DAPA-HF cohort treated with or without dapagliflozin, no differences were observed in the kidney composite end point, which included 50% reduction in eGFR, sustained eGFR <15 ml/min/1.73 m2, dialysis, transplantation, kidney or all-cause death5. However, a recent analysis of the DAPA-HF study9 showed that dapagliflozin reduced the risk of the exploratory end points of doubling of serum creatinine and attenuated the decrease in eGFR over time (−1.09 ml/min/1.73 m2 per year (95% CI −1.41 to −0.78) in the dapagliflozin group compared with −2.87 ml/min/1.73 m2 per year (95% CI −3.19 to −2.55) in the placebo group; P < 0.001 for difference in slopes). This slowing of eGFR decline was observed in patients with and without low eGFR and in those with and without T2DM. The EMPEROR-Preserved trial10, which is due for completion in April 2021, will assess the effects of empagliflozin on morbidity and mortality in patients with chronic heart failure and preserved ejection fraction, who are notoriously difficult to treat.
“SGLT2 inhibitors can modify the trajectory of declining kidney function in … kidney disease unrelated to T2DM”
In the trial of dapagliflozin in patients with CKD (DAPA-CKD)7, 4,304 participants were randomly assigned to receive dapagliflozin (10 mg once daily) or placebo. Approximately one third of patients in each group did not have diabetic kidney disease. This trial extended our knowledge of the renoprotective benefits of SGLT2 inhibitors by including patients with a screening eGFR 25–75 ml/min/1.73 m2 — nearly 60% of patients had an eGFR <45 ml/min/1.73 m2, 14.5% had an eGFR <30 ml/min/1.73 m2 and the lowest eGFR was 25 ml/min/1.73 m2. The primary composite outcome, which included sustained eGFR decline ≥50%, kidney failure (also termed end-stage kidney disease) or death from kidney or cardiovascular causes, was lower in the dapagliflozin group irrespective of T2DM status (HR 0.61; 95% CI 0.51–0.72; P < 0.001)7. All secondary end points also favoured the use of dapagliflozin, including the kidney composite end point (that is, sustained eGFR decline ≥50%, kidney failure or death from kidney causes; HR 0.56; 95% CI 0.45–0.68; P < 0.001) and the composite of death from cardiovascular causes or HHF (HR 0.71; 95% CI 0.55–0.92; P = 0.009). All-cause death occurred less frequently in the group treated with dapagliflozin than in the placebo group (HR 0.69; 95% CI 0.53–0.88; P = 0.004)7.
DAPA-CKD7 fills an important knowledge gap and demonstrates that SGLT2 inhibitors can modify the trajectory of declining kidney function in patients with kidney disease unrelated to T2DM. Important data remain to be reported, particularly regarding cardiovascular outcomes in this population and analyses across subpopulations with different levels of baseline eGFR and albuminuria within the cohort. Cardiovascular outcome trials thus far have included up to 29% of patients with preserved eGFR and microalbuminuria, and have shown renoprotective benefits. EMPA-KIDNEY, a clinical trial due to report in mid-2022 (NCT03594110), will provide further insights into the renoprotective benefits of SGLT2 inhibitors in patients with lower levels of both eGFR and albuminuria.
“economic analyses of the cost–benefit ratios … will further inform health practitioners, patients and budget holders”
In summary, the EMPEROR-Reduced and DAPA-CKD clinical trials support the use of the SGLT2 inhibitor class of drugs in broad populations with few safety concerns. The patients who stand to benefit from the inclusion of SGLT2 inhibitors as part of their therapy include patients with T2DM who have, or are at risk of, atherosclerotic cardiovascular disease; patients with diabetic and non-diabetic kidney disease with an eGFR >25 ml/min/1.73 m2 and albuminuria levels above 200 mg/g at commencement of therapy; and patients with heart failure and reduced left ventricular ejection fraction (<40%), irrespective of the presence of T2DM and with an eGFR >20 ml/min/173 m2 (Fig. 1). Further interrogation of trial data, including economic analyses of the cost–benefit ratios of treatment with SGLT2 inhibitors, will further inform health practitioners, patients and budget holders as to their optimal use.
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Packer, M. et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. N. Engl. J. Med. 383, 1413–1424 (2020).
Heerspink, H. J. L. Dapagliflozin in patients with chronic kidney disease. N. Engl. J. Med. 383, 1436–1446 (2020).
Zannad, F. et al. SGLT2 inhibitors in patients with heart failure with reduced ejection fraction: a meta-analysis of the EMPEROR-Reduced and DAPA-HF trials. Lancet 396, 819–829 (2020).
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Anker, S. D. et al. Evaluation of the effects of sodium-glucose co-transporter 2 inhibition with empagliflozin on morbidity and mortality in patients with chronic heart failure and a preserved ejection fraction: rationale for and design of the EMPEROR Preserved Trial. Eur. J. Heart Fail. 21, 1279–1287 (2019).
C.P. is an Advisory Board member for Astra Zeneca and Boehringer Ingelheim, and a member of the Steering Committee of CREDENCE. U.P. declares no competing interests.
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Panchapakesan, U., Pollock, C. Organ protection beyond glycaemic control with SGLT2 inhibitors. Nat Rev Nephrol (2020). https://doi.org/10.1038/s41581-020-00373-4