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American Journal of Kidney Diseases

Glucose Control and the Effect of Empagliflozin on Kidney Outcomes in Type 2 Diabetes: An Analysis From the EMPA-REG OUTCOME Trial

      To the Editor:
      The prevalence of diabetic kidney disease among US adults with diabetes has remained steady at ∼25% over the last 20 years despite increased use of glucose-lowering medications and renin-angiotensin-aldosterone system (RAAS) inhibitors.
      • Afkarian M.
      • Zelnick L.R.
      • Hall Y.N.
      • et al.
      Clinical manifestations of kidney disease among US adults with diabetes, 1988-2014.
      The presence of kidney disease is the main driver of the increased mortality observed in the type 2 diabetes mellitus (T2DM) population.
      • Afkarian M.
      • Sachs M.C.
      • Kestenbaum B.
      • et al.
      Kidney disease and increased mortality risk in type 2 diabetes.
      Thus, despite some evidence that intensified glycemic control and RAAS blockade mitigate aspects of diabetic microvascular sequelae, including progression of kidney disease,
      • Molitch M.E.
      • Adler A.I.
      • Flyvbjerg A.
      • et al.
      Diabetic kidney disease: a clinical update from Kidney Disease: Improving Global Outcomes.
      • Roscioni S.S.
      • Heerspink H.J.
      • de Zeeuw D.
      The effect of RAAS blockade on the progression of diabetic nephropathy.
      patients with T2DM and comorbid kidney disease still have an elevated risk for death and cardiorenal complications.
      • Afkarian M.
      • Zelnick L.R.
      • Hall Y.N.
      • et al.
      Clinical manifestations of kidney disease among US adults with diabetes, 1988-2014.
      SGLT2 inhibitors, the newest class of glucose-lowering medications, which elicit glucosuria by lowering the renal glucose threshold, have recently been demonstrated to reduce cardiovascular and renal risk. In the EMPA-REG OUTCOME trial of 7,020 patients with T2DM and established CV disease, empagliflozin, an SGLT2 inhibitor added to standard of care, reduced the risk for major adverse CV events by 14%, an effect driven by a 38% reduction in CV death.
      • Zinman B.
      • Wanner C.
      • Lachin J.M.
      • et al.
      Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.
      In a prespecified secondary analysis, incident or worsening nephropathy was reduced by 39% in the empagliflozin versus placebo group (12.7% vs 18.8%; HR, 0.61; 95% CI, 0.53-0.70; P < 0.001).
      • Heerspink H.J.
      • Desai M.
      • Jardine M.
      • Balis D.
      • Meininger G.
      • Perkovic V.
      Canagliflozin slows progression of renal function decline independently of glycemic effects.
      Prespecified subgroup analyses demonstrated that empagliflozin provided similar kidney benefits in patients with baseline HbA1c < 8.5% versus ≥8.5%.
      • Wanner C.
      • Inzucchi S.E.
      • Lachin J.M.
      • et al.
      Empagliflozin and progression of kidney disease in type 2 diabetes.
      We conducted an exploratory analysis to further examine whether the kidney benefits of empagliflozin were linked to its effect on HbA1c.
      In EMPA-REG OUTCOME, patients were randomly assigned (1:1:1) to empagliflozin, 10 mg; empagliflozin, 25 mg; or placebo once daily.
      • Zinman B.
      • Wanner C.
      • Lachin J.M.
      • et al.
      Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.
      For the first 12 weeks, background glucose-lowering therapy was to be unchanged. After 12 weeks, investigators were encouraged to adjust glucose-lowering therapy to reach glycemic control per local guidelines. The prespecified kidney outcome, incident or worsening nephropathy, was defined as progression to urinary albumin-creatinine ratio [UACR] > 300 mg/g; serum creatinine level doubling accompanied by eGFR ≤ 45 mL/min/1.73 m2 as calculated using the MDRD Study equation; initiation of renal replacement therapy; or death due to kidney disease.
      • Wanner C.
      • Inzucchi S.E.
      • Lachin J.M.
      • et al.
      Empagliflozin and progression of kidney disease in type 2 diabetes.
      An independent ethics committee or institutional review board approved the clinical protocol at each participating center. All patients provided written informed consent.
      • Zinman B.
      • Wanner C.
      • Lachin J.M.
      • et al.
      Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.
      We investigated the risk for incident or worsening nephropathy in the pooled empagliflozin group versus placebo after adjustment for baseline HbA1c and as a time-dependent variable of HbA1c control during the trial (<7.5%: defined based on the study population having long-standing diabetes and established CV disease), as well as by baseline HbA1c (<7%; 7%-<8%; 8%-<9%; ≥9%). The reduction in HbA1c from baseline to week 12 was assessed for the outcome of time from week 12 to incident or worsening nephropathy using 3 thresholds: (1) 0.5% (used by the ADA and EASD to categorize glucose-lowering efficacy as low vs intermediate), (2) 0.3% (the FDA definition for a minimal clinically meaningful reduction), and (3) the median reduction across all patients (0.4%). Thus, participants developing incident or worsening nephropathy before 12 weeks were excluded from this analysis; the baseline-to-week-12 HbA1c reduction was used for this analysis because background glucose-lowering medication was to be unchanged during this time. Differences in risk between treatment groups were assessed using a Cox proportional hazards model. For the time-dependent analysis, we performed linear interpolation for time points between 2 patient measurements and carried the last value forward. Based on these data, a binary variable of HbA1c control (<7.5%) was derived and added as a time-varying covariate to the Cox regression model including treatment, age, sex, and eGFR category, BMI category, and HbA1c (<7.5%) at baseline. P values were derived from tests of heterogeneity of treatment group differences without adjustment for multiple testing. Of note, because HbA1c reduction may be influenced by treatment, all models including the change in HbA1c or the time-dependent variable of HbA1c control are not appropriate to interpret a treatment effect.
      The median duration of treatment and observation time in EMPA-REG OUTCOME were 2.6 years and 3.1 years, respectively.
      • Zinman B.
      • Wanner C.
      • Lachin J.M.
      • et al.
      Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.
      We found that the relative reductions favoring empagliflozin compared to placebo when adjusted for HbA1c control at baseline and during the trial and across categories of baseline HbA1c were similar to those in the main analysis (Fig 1). At week 12, median HbA1c reduction was 0.4% (empagliflozin: 0.5%; placebo: 0.1%). At this time, the benefits of empagliflozin on kidney outcomes were evident regardless of whether the HbA1c reduction reached 0.5%, 0.3%, or the median (Fig 1).
      Figure thumbnail gr1
      Figure 1Incident or worsening nephropathy adjusted for HbA1c control at baseline and as a time-dependent variable, by HbA1c at baseline, and by changes at week 12 (ΔHbA1c). At week 12, the median HbA1c reduction with empagliflozin was 0.4% (empagliflozin: 0.5%; placebo: 0.1%). Cox regression analyses in patients treated with 1 or more dose of study drug. One patient was excluded because the subgroup variable was missing. Abbreviations: BL, baseline; CI, confidence interval; HbA1c, glycated hemoglobin; HR, hazard ratio; pt, patient.
      This study extends similar findings from a post hoc analysis of a phase 3 trial of canagliflozin.
      • Heerspink H.J.
      • Desai M.
      • Jardine M.
      • Balis D.
      • Meininger G.
      • Perkovic V.
      Canagliflozin slows progression of renal function decline independently of glycemic effects.
      The latter analysis indicated that relative to glimepiride, canagliflozin slowed kidney function decline over 52 weeks independently of HbA1c level.
      • Heerspink H.J.
      • Desai M.
      • Jardine M.
      • Balis D.
      • Meininger G.
      • Perkovic V.
      Canagliflozin slows progression of renal function decline independently of glycemic effects.
      The present study adds to those findings by providing data from a larger longer trial that measured hard kidney outcomes. In addition, it has been previously reported that UACR-lowering effects in EMPA-REG OUTCOME were also largely independent of changes in HbA1c levels.
      • Cherney D.Z.I.
      • Zinman B.
      • Inzucchi S.E.
      • et al.
      Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease: an exploratory analysis from the EMPA-REG OUTCOME randomised, placebo-controlled trial.
      Together, these data support the concept that empagliflozin may exert its kidney-protective effects independently of glucose lowering.
      In conclusion, in the EMPA-REG OUTCOME trial, the beneficial effect of empagliflozin on kidney outcomes was consistent irrespective of HbA1c levels before and during therapy or degree of reduction in HbA1c levels in patients with T2DM and established CV disease. Two large placebo-controlled, event-driven clinical trials, EMPA-KIDNEY (empagliflozin) and DAPA-CKD (dapagliflozin), will likely provide additional insights into potential glycemia-independent kidney effects by investigating thoroughly the effects of SGLT2 inhibition on the progression of kidney disease and the occurrence of CV death in patients with established chronic kidney disease with and without diabetes.

      Article Information

      Authors’ Contributions

      Research idea and study design: all authors; data acquisition: SH; data analysis/interpretation: all authors. Each author contributed important intellectual content during manuscript drafting or revision and accepts accountability for the overall work by ensuring that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved.

      Support

      The EMPA-REG OUTCOME trial was sponsored by the Boehringer Ingelheim and Eli Lilly and Company Diabetes Alliance. Boehringer Ingelheim was involved in the design and conduct of the study; collection, analysis, and interpretation of data; preparation of this article; and the decision to submit the report for publication. Medical writing assistance, supported financially by Boehringer Ingelheim , was provided by Malcolm Darkes, PhD, of Envision Pharma Group, Horsham, UK, during the preparation of this manuscript. Eli Lilly’s involvement was limited to cofunding of the study.

      Financial Disclosure

      MEC has received fees for advisory services to Boehringer Ingelheim, AstraZeneca, Sanofi, Bayer, Merck, Novartis, and Servier. SEI reports honoraria from AstraZeneca , Boehringer Ingelheim , Daiichi-Sankyo , Eisai , Janssen , Novo Nordisk , Sanofi /Lexicon, VTV Therapeutics, and Intarcia . BZ has received research grants awarded to his institution from Boehringer Ingelheim , AstraZeneca , and Novo Nordisk ; and honoraria from Janssen , Sanofi , Eli Lilly and Company , Boehringer Ingelheim , Novo Nordisk , and Merck . CW reports honoraria from Boehringer Ingelheim , Janssen , Lilly , and Mitsubishi . SH, MvE, and AK-W are employed by Boehringer Ingelheim.

      Acknowledgements

      The authors thank the staff and participants of this study for important contributions.

      Peer Review

      Received October 2, 2018. Evaluated by 2 external peer reviewers, with direct editorial input from a Statistics/Methods Editor, an Associate Editor, and the Editor-in-Chief. Accepted in revised form March 31, 2019.

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