Empagliflozin and Cardiovascular and Kidney Outcomes across KDIGO Risk Categories: Post Hoc Analysis of a Randomized, Double-Blind, Placebo-Controlled, Multinational Trial

Abstract

Background and objectives: In the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG Outcome), empagliflozin, in addition to standard of care, significantly reduced risk of cardiovascular death by 38%, hospitalization for heart failure by 35%, and incident or worsening nephropathy by 39% compared with placebo in patients with type 2 diabetes and established cardiovascular disease. Using EMPA-REG Outcome data, we assessed whether the Kidney Disease Improving Global Outcomes (KDIGO) CKD classification had an influence on the treatment effect of empagliflozin.

Design, setting, participants, & measurements: Patients with type 2 diabetes, established atherosclerotic cardiovascular disease, and eGFR≥30 ml/min per 1.73 m² at screening were randomized to receive empagliflozin 10 mg, empagliflozin 25 mg, or placebo once daily in addition to standard of care. Post hoc, we analyzed cardiovascular and kidney outcomes, and safety, using the two-dimensional KDIGO classification framework.

Results: Of 6952 patients with baseline eGFR and urinary albumin-creatinine ratio values, 47%, 29%, 15%, and 8% were classified into low, moderately increased, high, and very high KDIGO risk categories, respectively. Empagliflozin showed consistent risk reductions across KDIGO categories for cardiovascular outcomes (P values for treatment by subgroup interactions ranged from 0.26 to 0.85) and kidney outcomes (P values for treatment by subgroup interactions ranged from 0.16 to 0.60). In all KDIGO risk categories, placebo and empagliflozin had similar adverse event rates, the notable exception being genital infection events, which were more common with empagliflozin for each category.

Conclusions: The observed effects of empagliflozin versus placebo on cardiovascular and kidney outcomes were consistent across the KDIGO risk categories, indicating that the effect of treatment benefit of empagliflozin was unaffected by baseline CKD status.

Clinical trial registry name and registration number: EMPA-REG OUTCOME, NCT01131676.

Keywords: KDIGO; SGLT2 inhibition; diabetic nephropathy; empagliflozin; glomerular filtration rate; kidney disease.

Graphical abstract

Figure 1.

Proportions of patients by Kidney Disease Improving Global Outcomes (KDIGO) risk category in the overall trial population, showing that almost half of patients (47%) were in the low-risk category. The KDIGO “heat map” showing prognosis of CKD by GFR and albuminuria category is shown for reference (3). Of all treated patients, baseline eGFR and urine albumin-creatinine ratio measurements were available for 4635 patients on empagliflozin (98.9%) and 2317 patients on placebo (99.3%). Reprinted from ref. , with permission.

Figure 2.

Forest plot showing that the risk reduction of cardiovascular outcomes with empagliflozin versus placebo is consistent across KDIGO risk categories. *Sixty-eight patients were excluded as the subgroup variable was missing. 95% CI, 95% confidence interval; MACE, major adverse cardiovascular event; MI, myocardial infarction.

Figure 3.

Forest plot showing that the risk reduction of kidney outcomes with empagliflozin versus placebo is consistent across KDIGO risk categories. Cox regression analysis in patients treated with one or more doses of study drug. *Sixty-eight patients were excluded as the subgroup variable was missing. ^†Accompanied by eGFR≤45 ml/min per 1.73 m². Macroalbuminuria: urine albumin-creatinine ratio >300 mg/g.

Figure 4.

Empagliflozin consistently slowed the long-term annual decline in eGFR across all patient subgroups regardless of KDIGO risk category, as assessed by mean eGFR (Modification of Diet in Renal Disease [MDRD]) slopes on the basis of random intercept/random coefficient models. Adjusted mean eGFR across subgroups of KDIGO risk category. Empa, empagliflozin.

Figure 4.

Empagliflozin consistently slowed the long-term annual decline in eGFR across all patient subgroups regardless of KDIGO risk category, as assessed by mean eGFR (Modification of Diet in Renal Disease [MDRD]) slopes on the basis of random intercept/random coefficient models. Adjusted mean eGFR across subgroups of KDIGO risk category. Empa, empagliflozin.

Figure 5.

Adverse event (AE) incidence rate ratios were similar or lower with empagliflozin compared with placebo except for genital infections. Data are from patients treated with one or more doses of study drug, including all events that occurred within 7 days after the last receipt of the study drug. Medical Dictionary for Drug Regulatory Activities version used for reporting: 18.0.