Benefits of SGLT2 Inhibitors Seen Across Patient Subgroups

Mitchel L. Zoler, PhD

October 30, 2020

Two different SGLT2 inhibitors produced broadly consistent beneficial effects across a spectrum of patients in two recent pivotal trials: one that enrolled patients with heart failure and the second that enrolled patients with chronic kidney disease (CKD).

In EMPEROR-Reduced, which assessed patients with heart failure and reduced ejection fraction, empagliflozin (Jardiance) cut the primary end point — cardiovascular death or heart failure hospitalizations — by 25% relative to placebo during a median follow-up of 16 months, according to results recently reported in the New England Journal of Medicine.

This benefit held steady across the wide range of renal function that the 3730 participants had at study enrollment, said Faiez Zannad, MD, from the University of Lorraine in Nancy, France.

He presented findings from a prespecified secondary analysis of EMPEROR-Reduced data, published simultaneously in Circulation, at Kidney Week 2020.

Renal function was not one of the criteria for enrollment in EMPEROR-Reduced, but about half the participants (47%) had some degree of CKD, defined as an estimated glomerular filtration rate (eGFR) below 60 mL/min per 1.73 m² or a urine-albumin-to-creatine ratio of at least 300 mg/g, and about half (53%) had higher levels of renal function.

Treatment with empagliflozin led to a significant 22% relative reduction in the primary end point in patients with CKD (95% CI, 0.65 - 0.93), and a significant 28% reduction in those without CKD (95% CI, 0.58 - 0.90), the prespecified analysis showed.

The effect on the primary end point was consistent "across the full spectrum of kidney function, down to an eGFR of 20 mL/min per 1.73 m²," said Zannad.

In addition, the rate of decline in eGFR was slower with empagliflozin than with placebo for patients with CKD at baseline (slowed by an annual rate of 1.11 mL/min per 1.73 m²) and for those without CKD at baseline (slowed by an annual rate of 2.41 mL/min per 1.73 m²).

"Slowing the rate of eGFR decline at low levels of kidney function is of high clinical importance," Zannad noted. "Thus, the numerically smaller difference among patients with CKD may be clinically even more important than the larger difference seen in patients without CKD."


In DAPA-CKD, which assessed 4304 patients with depressed kidney function, dapagliflozin led to a significant 39% reduction in the study's primary end point — a drop in eGFR of at least 50%, progression to end-stage kidney disease, or renal or cardiovascular death — compared with placebo during a median 2.4 years of follow-up, according to results recently reported in the New England Journal of Medicine.

The underlying cause of renal dysfunction did not change the effectiveness of dapagliflozin, a prespecified secondary analysis of the data showed, said David Wheeler, MBChB, MD, from the Royal Free Hospital in London, during his presentation.

The reduction in the primary end point was roughly the same whether the CKD was caused by diabetic nephropathy (58% of study participants), ischemic or hypertensive nephropathy (16%), glomerulonephridities (16%), or other or unknown causes (10%). The safety profile was also consistent across the patients in these four subgroups.

Outcome patterns in these subgroups were also consistent for a combined renal-specific end point, a combined cardiovascular end point, and for all-cause mortality. The findings showed no statistical signal of a heterogeneous response in any of these subgroups, Wheeler reported.

In an additional subgroup of 270 (6%) patients with nephropathy caused by renal accumulation of IgA, or Berger's disease, the primary outcome was a significant 71% lower with dapagliflozin than with placebo.

EMPEROR-Reduced was sponsored by Boehringer Ingelheim and Eli Lilly, the companies that market empagliflozin. DAPA-CKD was sponsored by AstraZeneca, the company that markets dapagliflozin. Zannad reports financial relationships with Boehringer Ingelheim and several other companies. Wheeler reports receiving honoraria or consultant fees from AstraZeneca, Boehringer Ingelheim, and several other companies.

Kidney Week 2020: American Society of Nephrology Annual Meeting: Abstracts FR OR52 and FR OR58. Presented October 23, 2020.

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