Short-Term Changes in Albuminuria and Risk of Cardiovascular and Renal Outcomes in Type 2 Diabetes Mellitus: A Post Hoc Analysis of the EMPA-REG OUTCOME Trial

Abstract

Background Early reduction in albuminuria with an SGLT2 (sodium-glucose cotransporter 2) inhibitor may be a positive indicator of long-term cardiovascular and renal benefits. We assessed changes in albuminuria during the first 12 weeks of treatment and subsequent long-term cardiovascular and renal risks associated with the SGLT2 inhibitor, empagliflozin, in the EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 diabetes Mellitus Patients) trial. Methods and Results We calculated the percentage urinary albumin creatinine ratio (UACR) change from baseline to week 12 in 6820 participants who did not experience a cardiovascular outcome (including 3-point major cardiovascular events and cardiovascular death or hospitalization for heart failure) or renal outcome (defined as 40% decline in estimated glomerular filtration rate from baseline, estimated glomerular filtration rate <15 mL/min per 1.73 m2, need for continuous renal-replacement therapy, or renal death) during the first 12 weeks. Multivariable Cox regression models were used to estimate the hazard ratio (HR) for each 30% reduction in UACR with outcomes. Empagliflozin reduced UACR by 18% (95% CI, 14-22) at week 12 compared with placebo, and increased the likelihood of a >30% reduction in UACR (odds ratio, 1.42; 95% CI, 1.27-1.58; P<0.001). During 3.0 years of follow-up, 704 major cardiovascular events, 440 cardiovascular deaths/hospitalizations for heart failure, and 168 renal outcomes were observed. Each 30% decrease in UACR during the first 12 weeks was statistically significantly associated with a lower hazard for major cardiovascular events (HR, 0.96; 95% CI, 0.93-0.99; P=0.012), cardiovascular deaths/hospitalizations for heart failure (HR, 0.94; 95% CI, 0.91-0.98; P=0.003), and renal outcomes (HR, 0.83; 95% CI, 0.78-0.89; P<0.001). Conclusions Short-term reduction in UACR was more common with empagliflozin and was statistically significantly associated with a decreased risk of long-term cardiovascular and renal outcomes. Registration URL: https://www.clinicaltrials.gov. Unique identifier: NCT01131676.

Keywords: cardiovascular outcomes; empagliflozin; kidney (diabetes); sodium‐glucose cotransporter 2 inhibitors.

Conflict of interest statement

Dr Inzucchi has participated on clinical trial executive/steering/publications committees and/or served as an advisor for Boehringer Ingelheim, AstraZeneca, Novo Nordisk, Sanofi/Lexicon, Abbott/Alere, and vTv Therapeutics. He has delivered lectures supported by Boehringer Ingelheim and Merck. Dr Zinman reports consultations and honoraria from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novo Nordisk, and Sanofi. Dr Inker reports funding from National Institutes of Health, National Kidney Foundation, Retrophin, Omeros, Dialysis Clinics, Inc., and Reata Pharmaceuticals for research and contracts to Tufts Medical Center and consulting agreements with Tricida and Omeros Corp. Dr Wanner reports serving on advisory boards for Bayer, Boehringer Ingelheim, and Merck and received speaker's honoraria from Boehringer Ingelheim, Merck Sharp & Dohme, Eli Lilly, and AstraZeneca. Dr Koitka‐Weber and M. Mattheus are Boehringer Ingelheim company employees. Dr von Eynatten was a Boehringer Ingelheim employee at the time the analysis was conducted. Dr Heerspink is supported by a VIDI (917.15.306) grant from the Netherlands Organisation for Scientific Research and has served as a consultant for AbbVie, Astellas, AstraZeneca, Boehringer Ingelheim, Fresenius, Gilead, Janssen, Merck, Mundipharma, Mitsubishi‐Tanabe, and Retrophin and reports grants for research support from AbbVie, AstraZeneca, Boehringer Ingelheim, and Janssen. The remaining authors have no disclosures to report.

Figures

Figure 1. Relationship between baseline UACR and (A) major adverse cardiovascular event, (B) cardiovascular death/hospitalization for heart failure, and (C) renal outcome and the event rate of (D) major adverse cardiovascular event, (E) cardiovascular death/hospitalization for heart failure, and (F) renal outcome across the entire patient cohort.

The numbers above each circle (A through C) represent the number (percentage) of outcomes for each UACR category. The numbers above each bar represent the event rate (1000 patient×years). Cox regression models were adjusted for age, sex, smoking status, body mass index, systolic blood pressure, diastolic blood pressure, use of angiotensin‐converting enzyme inhibitor/angiotensin II receptor blocker, use of diuretics, treatment assignment (empagliflozin/placebo), region of residence, baseline glycated hemoglobin, estimated glomerular filtration rate, low‐density lipoprotein cholesterol, and high‐density lipoprotein cholesterol. UACR indicates urinary albumin creatinine ratio.

Figure 2. Relationship between change in UACR at week 12 and (A) major adverse cardiovascular event, (B) cardiovascular death/hospitalization for heart failure, and (C) renal outcome compared with the referent group (–30% to +30%).

The numbers above each circle represent the number (percentage) of outcomes for each change in UACR category. Cox regression models were adjusted for age, sex, smoking status, body mass index, baseline systolic and diastolic blood pressure, treatment assignment (empagliflozin/placebo), use of angiotensin‐converting enzyme inhibitor/angiotensin II receptor blocker, use of diuretics, region of residence, baseline UACR, glycated hemoglobin, estimated glomerular filtration rate, low‐density lipoprotein cholesterol and high‐density lipoprotein cholesterol, and percentage changes in estimated glomerular filtration rate, systolic blood pressure, glycated hemoglobin, and body weight at week 12. UACR indicates urinary albumin creatinine ratio.

Figure 3. Relationship between change in UACR at week 12 and (A) major adverse cardiovascular event, (B) cardiovascular death/hospitalization for heart failure, and (C) renal outcome in the placebo and empagliflozin groups.

Each point represents the median of each quartile change in albuminuria within the treatment group. Cox regression models were adjusted for age, sex, smoking status, body mass index, systolic blood pressure, diastolic blood pressure, use of angiotensin‐converting enzyme inhibitor/angiotensin II receptor blocker, use of diuretics, region of residence, baseline UACR, glycated hemoglobin, estimated glomerular filtration rate, low‐density lipoprotein cholesterol and high‐density lipoprotein cholesterol, percentage changes in estimated glomerular filtration rate, systolic blood pressure, glycated hemoglobin, and body weight at 12 weeks. UACR indicates urinary albumin creatinine ratio.

Figure 4. Adjusted HR for the association between >30% reduction in UACR from baseline to week 12 and cardiovascular and renal outcomes in all patients and within different subgroups.

Cox regression models were adjusted for age, sex, smoking status, body mass index, baseline systolic and diastolic blood pressure, treatment assignment (empagliflozin/placebo), use of ACEi/ARB, use of diuretics, region of residence, baseline UACR, glycated hemoglobin, eGFR, low‐density lipoprotein cholesterol and high‐density lipoprotein cholesterol, and percentage changes in eGFR, systolic blood pressure, glycated hemoglobin, and body weight at week 12. ACEi indicates angiotensin‐converting enzyme inhibitor; ARB, angiotensin II receptor blocker; CVD, cardiovascular death; eGFR, estimated glomerular filtration rate; HHF, hospitalization for heart failure; HR, hazard ratio; MACE, major adverse cardiovascular event; and UACR, urinary albumin creatinine ratio. *P value is the test of interaction between each subgroup.

Figure 5. Relationship between UACR at week 12 and (A) major adverse cardiovascular event, (B) cardiovascular death/hospitalization for heart failure, and (C) renal outcome, and the event rate of (D) major adverse cardiovascular event, (E) cardiovascular death/hospitalization for heart failure, and (F) renal outcome in both the empagliflozin and placebo groups.

The numbers above each circle (A through C) represent the number (percentage) of outcomes for each UACR category. The numbers above each bar represent the event rate (1000 patient×years). The <30 mg/g category in the placebo group was used as a reference for both the empagliflozin and placebo groups. Cox regression models were adjusted for age, sex, smoking status, body mass index, systolic blood pressure, diastolic blood pressure, use of angiotensin‐converting enzyme inhibitor/angiotensin II receptor blocker, use of diuretics, region of residence, baseline glycated hemoglobin, estimated glomerular filtration rate, low‐density lipoprotein cholesterol, and high‐density lipoprotein cholesterol. UACR indicates urinary albumin creatinine ratio.