Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy

Vlado Perkovic, Meg J. Jardine, Bruce Neal, Severine Bompoint, Hiddo J.l. Heerspink, David M. Charytan, Robert Edwards, Rajiv Agarwal, George Bakris, Scott Bull, Christopher P. Cannon, George Capuano, Pei-ling Chu, Dick De Zeeuw, Tom Greene, Adeera Levin, Carol Pollock, David C. Wheeler, Yshai Yavin, Hong ZhangBernard Zinman, Gary Meininger, Barry M. Brenner, Kenneth W. Mahaffey, Srikanth Bellary

Research output: Contribution to journalArticle

Abstract

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to <90 ml per minute per 1.73 m 2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m 2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years.

Original languageEnglish
Pages (from-to)2295-2306
Number of pages12
JournalNew England Journal of Medicine
Volume380
Issue number24
DOIs
Publication statusPublished - 13 Jun 2019

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Type 2 Diabetes Mellitus
Kidney
Confidence Intervals
Chronic Kidney Failure
Creatinine
Placebos
Glomerular Filtration Rate
Renal Insufficiency
Clinical Trials Data Monitoring Committees
Albuminuria
Body Surface Area
Kidney Diseases
Random Allocation
Chronic Renal Insufficiency
Amputation
Canagliflozin
Dialysis
Cause of Death
Albumins
Hospitalization

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Perkovic, V., Jardine, M. J., Neal, B., Bompoint, S., Heerspink, H. J. L., Charytan, D. M., ... Bellary, S. (2019). Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. New England Journal of Medicine, 380(24), 2295-2306. https://doi.org/10.1056/NEJMoa1811744
Perkovic, Vlado ; Jardine, Meg J. ; Neal, Bruce ; Bompoint, Severine ; Heerspink, Hiddo J.l. ; Charytan, David M. ; Edwards, Robert ; Agarwal, Rajiv ; Bakris, George ; Bull, Scott ; Cannon, Christopher P. ; Capuano, George ; Chu, Pei-ling ; De Zeeuw, Dick ; Greene, Tom ; Levin, Adeera ; Pollock, Carol ; Wheeler, David C. ; Yavin, Yshai ; Zhang, Hong ; Zinman, Bernard ; Meininger, Gary ; Brenner, Barry M. ; Mahaffey, Kenneth W. ; Bellary, Srikanth. / Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. In: New England Journal of Medicine. 2019 ; Vol. 380, No. 24. pp. 2295-2306.
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abstract = "BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to <90 ml per minute per 1.73 m 2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m 2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30{\%} lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95{\%} confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34{\%} (hazard ratio, 0.66; 95{\%} CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32{\%} (hazard ratio, 0.68; 95{\%} CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95{\%} CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95{\%} CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years.",
author = "Vlado Perkovic and Jardine, {Meg J.} and Bruce Neal and Severine Bompoint and Heerspink, {Hiddo J.l.} and Charytan, {David M.} and Robert Edwards and Rajiv Agarwal and George Bakris and Scott Bull and Cannon, {Christopher P.} and George Capuano and Pei-ling Chu and {De Zeeuw}, Dick and Tom Greene and Adeera Levin and Carol Pollock and Wheeler, {David C.} and Yshai Yavin and Hong Zhang and Bernard Zinman and Gary Meininger and Brenner, {Barry M.} and Mahaffey, {Kenneth W.} and Srikanth Bellary",
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language = "English",
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Perkovic, V, Jardine, MJ, Neal, B, Bompoint, S, Heerspink, HJL, Charytan, DM, Edwards, R, Agarwal, R, Bakris, G, Bull, S, Cannon, CP, Capuano, G, Chu, P, De Zeeuw, D, Greene, T, Levin, A, Pollock, C, Wheeler, DC, Yavin, Y, Zhang, H, Zinman, B, Meininger, G, Brenner, BM, Mahaffey, KW & Bellary, S 2019, 'Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy', New England Journal of Medicine, vol. 380, no. 24, pp. 2295-2306. https://doi.org/10.1056/NEJMoa1811744

Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. / Perkovic, Vlado; Jardine, Meg J.; Neal, Bruce; Bompoint, Severine; Heerspink, Hiddo J.l.; Charytan, David M.; Edwards, Robert; Agarwal, Rajiv; Bakris, George; Bull, Scott; Cannon, Christopher P.; Capuano, George; Chu, Pei-ling; De Zeeuw, Dick; Greene, Tom; Levin, Adeera; Pollock, Carol; Wheeler, David C.; Yavin, Yshai; Zhang, Hong; Zinman, Bernard; Meininger, Gary; Brenner, Barry M.; Mahaffey, Kenneth W.; Bellary, Srikanth.

In: New England Journal of Medicine, Vol. 380, No. 24, 13.06.2019, p. 2295-2306.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy

AU - Perkovic, Vlado

AU - Jardine, Meg J.

AU - Neal, Bruce

AU - Bompoint, Severine

AU - Heerspink, Hiddo J.l.

AU - Charytan, David M.

AU - Edwards, Robert

AU - Agarwal, Rajiv

AU - Bakris, George

AU - Bull, Scott

AU - Cannon, Christopher P.

AU - Capuano, George

AU - Chu, Pei-ling

AU - De Zeeuw, Dick

AU - Greene, Tom

AU - Levin, Adeera

AU - Pollock, Carol

AU - Wheeler, David C.

AU - Yavin, Yshai

AU - Zhang, Hong

AU - Zinman, Bernard

AU - Meininger, Gary

AU - Brenner, Barry M.

AU - Mahaffey, Kenneth W.

AU - Bellary, Srikanth

PY - 2019/6/13

Y1 - 2019/6/13

N2 - BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to <90 ml per minute per 1.73 m 2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m 2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years.

AB - BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to <90 ml per minute per 1.73 m 2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m 2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years.

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Perkovic V, Jardine MJ, Neal B, Bompoint S, Heerspink HJL, Charytan DM et al. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. New England Journal of Medicine. 2019 Jun 13;380(24):2295-2306. https://doi.org/10.1056/NEJMoa1811744