Canagliflozin and Cardiovascular and Renal Outcomes in Type 2 Diabetes Mellitus and Chronic Kidney Disease in Primary and Secondary Cardiovascular Prevention Groups

Kenneth W Mahaffey; Meg J Jardine; Severine Bompoint; Christopher P Cannon; Bruce Neal; Hiddo J L Heerspink; David M Charytan; Robert Edwards; Rajiv Agarwal; George Bakris; Scott Bull; George Capuano; Dick de Zeeuw; Tom Greene; Adeera Levin; Carol Pollock; Tao Sun; David C Wheeler; Yshai Yavin; Hong Zhang; Bernard Zinman; Norman Rosenthal; Barry M Brenner; Vlado Perkovic

doi:10.1161/CIRCULATIONAHA.119.042007

Canagliflozin and Cardiovascular and Renal Outcomes in Type 2 Diabetes Mellitus and Chronic Kidney Disease in Primary and Secondary Cardiovascular Prevention Groups

Circulation. 2019 Aug 27;140(9):739-750. doi: 10.1161/CIRCULATIONAHA.119.042007. Epub 2019 Jul 11.

Authors

Kenneth W Mahaffey¹, Meg J Jardine^{2

3}, Severine Bompoint², Christopher P Cannon^{4

5}, Bruce Neal^{2

6

7}, Hiddo J L Heerspink^{2

8}, David M Charytan^{9

5}, Robert Edwards¹⁰, Rajiv Agarwal¹¹, George Bakris¹², Scott Bull¹⁰, George Capuano¹⁰, Dick de Zeeuw⁸, Tom Greene¹³, Adeera Levin¹⁴, Carol Pollock¹⁵, Tao Sun¹⁰, David C Wheeler¹⁶, Yshai Yavin¹⁰, Hong Zhang¹⁷, Bernard Zinman¹⁸, Norman Rosenthal¹⁰, Barry M Brenner^{5

19}, Vlado Perkovic^{2

20}

Affiliations

¹ Stanford Center for Clinical Research, Department of Medicine, Stanford University School of Medicine, CA (K.W.M.).
² George Institute for Global Health, University of New South Wales, Sydney, Australia (M.J.J., S.B., B.N., H.J.L.H., V.P.).
³ Concord Repatriation General Hospital, Sydney, Australia (M.J.J.).
⁴ Cardiovascular Division, Brigham & Women's Hospital, Boston, MA (C.P.C.).
⁵ Baim Institute for Clinical Research, Boston, MA (D.M.C., C.P.C., B.M.B.).
⁶ Charles Perkins Centre, University of Sydney, Australia (B.N.).
⁷ Imperial College London, UK (B.N.).
⁸ Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, The Netherlands (H.J.L.H., D.d.Z.).
⁹ Nephrology Division, NYU School of Medicine and NYU Langone Medical Center, New York (D.M.C.).
¹⁰ Janssen Research & Development, LLC, Raritan, NJ (R.E., S.B., G.C., T.S., Y.Y., N.R.).
¹¹ Indiana University School of Medicine and VA Medical Center, Indianapolis (R.A.).
¹² Department of Medicine, University of Chicago Medicine, IL (G.B.).
¹³ Division of Biostatistics, Department of Population Health Sciences, University of Utah, Salt Lake City (T.G.).
¹⁴ Division of Nephrology, University of British Columbia, Vancouver, Canada (A.L.).
¹⁵ Kolling Institute of Medical Research, Sydney Medical School, University of Sydney, Royal North Shore Hospital, St. Leonards, NSW, Australia (C.P.).
¹⁶ Department of Renal Medicine, UCL Medical School, London, UK (D.C.W.).
¹⁷ Renal Division of Peking University First Hospital, Beijing, China (H.Z.).
¹⁸ Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, University of Toronto, ON, Canada (B.Z.).
¹⁹ Renal Division and Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (B.M.B.).
²⁰ Royal North Shore Hospital, Sydney, Australia (V.P.).

Abstract

Background: Canagliflozin reduces the risk of kidney failure in patients with type 2 diabetes mellitus and chronic kidney disease, but effects on specific cardiovascular outcomes are uncertain, as are effects in people without previous cardiovascular disease (primary prevention).

Methods: In CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation), 4401 participants with type 2 diabetes mellitus and chronic kidney disease were randomly assigned to canagliflozin or placebo on a background of optimized standard of care.

Results: Primary prevention participants (n=2181, 49.6%) were younger (61 versus 65 years), were more often female (37% versus 31%), and had shorter duration of diabetes mellitus (15 years versus 16 years) compared with secondary prevention participants (n=2220, 50.4%). Canagliflozin reduced the risk of major cardiovascular events overall (hazard ratio [HR], 0.80 [95% CI, 0.67-0.95]; P=0.01), with consistent reductions in both the primary (HR, 0.68 [95% CI, 0.49-0.94]) and secondary (HR, 0.85 [95% CI, 0.69-1.06]) prevention groups (P for interaction=0.25). Effects were also similar for the components of the composite including cardiovascular death (HR, 0.78 [95% CI, 0.61-1.00]), nonfatal myocardial infarction (HR, 0.81 [95% CI, 0.59-1.10]), and nonfatal stroke (HR, 0.80 [95% CI, 0.56-1.15]). The risk of the primary composite renal outcome and the composite of cardiovascular death or hospitalization for heart failure were also consistently reduced in both the primary and secondary prevention groups (P for interaction >0.5 for each outcome).

Conclusions: Canagliflozin significantly reduced major cardiovascular events and kidney failure in patients with type 2 diabetes mellitus and chronic kidney disease, including in participants who did not have previous cardiovascular disease.

Clinical trial registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02065791.

Keywords: canagliflozin; clinical trial; diabetes mellitus; primary prevention; renal insufficiency, chronic; secondary prevention.

Publication types

Multicenter Study
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

MeSH terms

Canagliflozin / therapeutic use*
Cardiovascular Diseases / prevention & control*
Diabetes Mellitus, Type 2 / pathology*
Double-Blind Method
Female
Humans
Kidney Failure, Chronic / prevention & control
Male
Middle Aged
Placebo Effect
Proportional Hazards Models
Renal Insufficiency, Chronic / pathology*
Risk
Secondary Prevention
Sodium-Glucose Transporter 2 Inhibitors / therapeutic use*
Treatment Outcome

Substances

Sodium-Glucose Transporter 2 Inhibitors
Canagliflozin

Associated data

ClinicalTrials.gov/NCT02065791