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Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy
Vlado Perkovic1, Meg J Jardine1, Bruce Neal1
1From the George Institute for Global Health, University of New South Wales Sydney (V.P., M.J.J., B.N., S. Bompoint), the Royal North Shore Hospital (V.P.), Concord Repatriation General Hospital (M.J.J.), and the Charles Perkins Centre, University of Sydney (B.N.), Sydney, and the Kolling Institute of Medical Research, Sydney Medical School, University of Sydney, Royal North Shore Hospital, St. Leonards, NSW (C.P.) - all in Australia; Imperial College London (B.N.) and the Department of Renal Medicine, UCL Medical School (D.C.W.) - both in London; the Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands (H.J.L.H., D.Z.); the Nephrology Division, NYU School of Medicine and NYU Langone Medical Center, New York (D.M.C.); Baim Institute for Clinical Research (D.M.C., C.P.C., B.M.B.), the Cardiovascular Division (C.P.C.) and the Renal Division and Department of Medicine (B.M.B), Brigham and Women's Hospital, and Harvard Medical School (B.M.B.) - all in Boston; Janssen Research and Development, Raritan, NJ (R.E., S. Bull, G.C., P.-L.C., Y.Y., G.M.); Indiana University School of Medicine and Veterans Affairs Medical Center, Indianapolis (R.A.); the Department of Medicine, University of Chicago Medicine, Chicago (G.B.); the Division of Biostatistics, Department of Population Health Sciences, University of Utah, Salt Lake City (T.G.); the Division of Nephrology, University of British Columbia, Vancouver (A.L.), and the Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto (B.Z.) - all in Canada; the Renal Division, Peking University First Hospital, Beijing (H.Z.); and the Stanford Center for Clinical Research, Department of Medicine, Stanford University School of Medicine, Stanford, CA (K.W.M.).
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 m2 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 m2), 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. (Funded by Janssen Research and Development; CREDENCE ClinicalTrials.gov number, NCT02065791.).
Insights
Canagliflozin significantly reduced the risk of kidney failure and cardiovascular events in patients with type 2 diabetes and chronic kidney disease. This SGLT2 inhibitor offers a new treatment option for preserving kidney function.
Area of Science:
- Nephrology
- Endocrinology
- Cardiology
Background:
- Type 2 diabetes mellitus is a primary cause of kidney failure globally.
- Limited effective long-term treatments exist for diabetic kidney disease.
- Sodium-glucose cotransporter 2 (SGLT2) inhibitors show promise in improving renal outcomes.
Purpose of the Study:
- To evaluate the efficacy of canagliflozin in patients with type 2 diabetes and albuminuric chronic kidney disease.
- To assess the impact of canagliflozin on composite renal and cardiovascular outcomes.
Main Methods:
- A double-blind, randomized trial involving 4401 patients with type 2 diabetes and chronic kidney disease.
- Patients received either 100 mg daily of canagliflozin or a placebo, alongside renin-angiotensin system blockade.
- Primary outcome: composite of end-stage kidney disease, doubling of serum creatinine, or renal/cardiovascular death.
Main Results:
- Canagliflozin reduced the primary composite outcome by 30% (hazard ratio, 0.70; P=0.00001).
- Significant reductions were observed in renal-specific composite outcomes (34%) and end-stage kidney disease (32%).
- Canagliflozin also lowered the risk of cardiovascular death, myocardial infarction, stroke, and heart failure hospitalization.
Conclusions:
- Canagliflozin significantly lowers the risk of kidney failure and cardiovascular events in patients with type 2 diabetes and kidney disease.
- The study supports canagliflozin as a beneficial treatment for managing diabetic kidney disease.
- No significant differences in amputation or fracture rates were noted between groups.
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