Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes.
BACKGROUND
Diabetes confers an increased risk of adverse cardiovascular and renal events. In the EMPA-REG OUTCOME trial, empagliflozin, a sodium-glucose cotransporter 2 inhibitor, reduced the risk of major adverse cardiovascular events in patients with type 2 diabetes at high risk for cardiovascular events. We wanted to determine the long-term renal effects of empagliflozin, an analysis that was a prespecified component of the secondary microvascular outcome of that trial.


METHODS
We randomly assigned patients with type 2 diabetes and an estimated glomerular filtration rate of at least 30 ml per minute per 1.73 m(2) of body-surface area to receive either empagliflozin (at a dose of 10 mg or 25 mg) or placebo once daily. Prespecified renal outcomes included incident or worsening nephropathy (progression to macroalbuminuria, doubling of the serum creatinine level, initiation of renal-replacement therapy, or death from renal disease) and incident albuminuria.


RESULTS
Incident or worsening nephropathy occurred in 525 of 4124 patients (12.7%) in the empagliflozin group and in 388 of 2061 (18.8%) in the placebo group (hazard ratio in the empagliflozin group, 0.61; 95% confidence interval, 0.53 to 0.70; P<0.001). Doubling of the serum creatinine level occurred in 70 of 4645 patients (1.5%) in the empagliflozin group and in 60 of 2323 (2.6%) in the placebo group, a significant relative risk reduction of 44%. Renal-replacement therapy was initiated in 13 of 4687 patients (0.3%) in the empagliflozin group and in 14 of 2333 patients (0.6%) in the placebo group, representing a 55% lower relative risk in the empagliflozin group. There was no significant between-group difference in the rate of incident albuminuria. The adverse-event profile of empagliflozin in patients with impaired kidney function at baseline was similar to that reported in the overall trial population.


CONCLUSIONS
In patients with type 2 diabetes at high cardiovascular risk, empagliflozin was associated with slower progression of kidney disease and lower rates of clinically relevant renal events than was placebo when added to standard care. (Funded by the Boehringer Ingelheim and Eli Lilly and Company Diabetes Alliance; EMPA-REG OUTCOME ClinicalTrials.gov number, NCT01131676.).
From the Department of Medicine, Division of Nephrology, Würzburg University Clinic, Würzburg (C.W.), and Boehringer Ingelheim Pharma, Ingelheim (M.E., M.M., H.J.W., U.C.B.) - both in Germany; the Section of Endocrinology, Yale University School of Medicine, New Haven, CT (S.E.I.); the Biostatistics Center, George Washington University, Rockville, MD (J.M.L.); the Divisions of Cardiology (D.F.) and Endocrinology (B.Z.), University of Toronto, and the Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital (B.Z.) - both in Toronto; and Boehringer Ingelheim Norway, Asker, Norway (O.E.J.).
Christoph
C
Wanner
From the Department of Medicine, Division of Nephrology, Würzburg University Clinic, Würzburg (C.W.), and Boehringer Ingelheim Pharma, Ingelheim (M.E., M.M., H.J.W., U.C.B.) - both in Germany; the Section of Endocrinology, Yale University School of Medicine, New Haven, CT (S.E.I.); the Biostatistics Center, George Washington University, Rockville, MD (J.M.L.); the Divisions of Cardiology (D.F.) and Endocrinology (B.Z.), University of Toronto, and the Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital (B.Z.) - both in Toronto; and Boehringer Ingelheim Norway, Asker, Norway (O.E.J.).
Silvio E
SE
Inzucchi
From the Department of Medicine, Division of Nephrology, Würzburg University Clinic, Würzburg (C.W.), and Boehringer Ingelheim Pharma, Ingelheim (M.E., M.M., H.J.W., U.C.B.) - both in Germany; the Section of Endocrinology, Yale University School of Medicine, New Haven, CT (S.E.I.); the Biostatistics Center, George Washington University, Rockville, MD (J.M.L.); the Divisions of Cardiology (D.F.) and Endocrinology (B.Z.), University of Toronto, and the Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital (B.Z.) - both in Toronto; and Boehringer Ingelheim Norway, Asker, Norway (O.E.J.).
John M
JM
Lachin
From the Department of Medicine, Division of Nephrology, Würzburg University Clinic, Würzburg (C.W.), and Boehringer Ingelheim Pharma, Ingelheim (M.E., M.M., H.J.W., U.C.B.) - both in Germany; the Section of Endocrinology, Yale University School of Medicine, New Haven, CT (S.E.I.); the Biostatistics Center, George Washington University, Rockville, MD (J.M.L.); the Divisions of Cardiology (D.F.) and Endocrinology (B.Z.), University of Toronto, and the Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital (B.Z.) - both in Toronto; and Boehringer Ingelheim Norway, Asker, Norway (O.E.J.).
David
D
Fitchett
From the Department of Medicine, Division of Nephrology, Würzburg University Clinic, Würzburg (C.W.), and Boehringer Ingelheim Pharma, Ingelheim (M.E., M.M., H.J.W., U.C.B.) - both in Germany; the Section of Endocrinology, Yale University School of Medicine, New Haven, CT (S.E.I.); the Biostatistics Center, George Washington University, Rockville, MD (J.M.L.); the Divisions of Cardiology (D.F.) and Endocrinology (B.Z.), University of Toronto, and the Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital (B.Z.) - both in Toronto; and Boehringer Ingelheim Norway, Asker, Norway (O.E.J.).
Maximilian
M
von Eynatten
From the Department of Medicine, Division of Nephrology, Würzburg University Clinic, Würzburg (C.W.), and Boehringer Ingelheim Pharma, Ingelheim (M.E., M.M., H.J.W., U.C.B.) - both in Germany; the Section of Endocrinology, Yale University School of Medicine, New Haven, CT (S.E.I.); the Biostatistics Center, George Washington University, Rockville, MD (J.M.L.); the Divisions of Cardiology (D.F.) and Endocrinology (B.Z.), University of Toronto, and the Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital (B.Z.) - both in Toronto; and Boehringer Ingelheim Norway, Asker, Norway (O.E.J.).
Michaela
M
Mattheus
From the Department of Medicine, Division of Nephrology, Würzburg University Clinic, Würzburg (C.W.), and Boehringer Ingelheim Pharma, Ingelheim (M.E., M.M., H.J.W., U.C.B.) - both in Germany; the Section of Endocrinology, Yale University School of Medicine, New Haven, CT (S.E.I.); the Biostatistics Center, George Washington University, Rockville, MD (J.M.L.); the Divisions of Cardiology (D.F.) and Endocrinology (B.Z.), University of Toronto, and the Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital (B.Z.) - both in Toronto; and Boehringer Ingelheim Norway, Asker, Norway (O.E.J.).
Odd Erik
OE
Johansen
From the Department of Medicine, Division of Nephrology, Würzburg University Clinic, Würzburg (C.W.), and Boehringer Ingelheim Pharma, Ingelheim (M.E., M.M., H.J.W., U.C.B.) - both in Germany; the Section of Endocrinology, Yale University School of Medicine, New Haven, CT (S.E.I.); the Biostatistics Center, George Washington University, Rockville, MD (J.M.L.); the Divisions of Cardiology (D.F.) and Endocrinology (B.Z.), University of Toronto, and the Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital (B.Z.) - both in Toronto; and Boehringer Ingelheim Norway, Asker, Norway (O.E.J.).
Hans J
HJ
Woerle
From the Department of Medicine, Division of Nephrology, Würzburg University Clinic, Würzburg (C.W.), and Boehringer Ingelheim Pharma, Ingelheim (M.E., M.M., H.J.W., U.C.B.) - both in Germany; the Section of Endocrinology, Yale University School of Medicine, New Haven, CT (S.E.I.); the Biostatistics Center, George Washington University, Rockville, MD (J.M.L.); the Divisions of Cardiology (D.F.) and Endocrinology (B.Z.), University of Toronto, and the Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital (B.Z.) - both in Toronto; and Boehringer Ingelheim Norway, Asker, Norway (O.E.J.).
Uli C
UC
Broedl
From the Department of Medicine, Division of Nephrology, Würzburg University Clinic, Würzburg (C.W.), and Boehringer Ingelheim Pharma, Ingelheim (M.E., M.M., H.J.W., U.C.B.) - both in Germany; the Section of Endocrinology, Yale University School of Medicine, New Haven, CT (S.E.I.); the Biostatistics Center, George Washington University, Rockville, MD (J.M.L.); the Divisions of Cardiology (D.F.) and Endocrinology (B.Z.), University of Toronto, and the Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital (B.Z.) - both in Toronto; and Boehringer Ingelheim Norway, Asker, Norway (O.E.J.).
Bernard
B
Zinman
D000368:Aged; D000419:Albuminuria; D001559:Benzhydryl Compounds / Q000009:adverse effects / Q000627:therapeutic use*; D002318:Cardiovascular Diseases / Q000209:etiology; D003924:Diabetes Mellitus, Type 2 / Q000150:complications* / Q000188:drug therapy; D003928:Diabetic Nephropathies / Q000188:drug therapy*; D018450:Disease Progression; D005260:Female; D005919:Glomerular Filtration Rate; D005960:Glucosides / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D057194:Intention to Treat Analysis; D053208:Kaplan-Meier Estimate; D007668:Kidney / Q000098:blood supply; D008297:Male; D055806:Microvessels / Q000187:drug effects; D008875:Middle Aged; D016016:Proportional Hazards Models; D012307:Risk Factors
D001559:Benzhydryl Compounds; D005960:Glucosides; D007004:Hypoglycemic Agents; C570240:empagliflozin