Nan Ye1,2, Meg J Jardine1,3, Megumi Oshima1,4, Carinna Hockham1, Hiddo J L Heerspink5, Rajiv Agarwal6, George Bakris7, Aletta E Schutte1,8, Clare Arnott1,9, Tara I Chang10,11, Jose L Górriz12, Christopher P Cannon13,14, David M Charytan14,15, Dick de Zeeuw5, Adeera Levin16, Kenneth W Mahaffey17, Bruce Neal1,18, Carol Pollock19,20, David C Wheeler1,21, Gian Luca Di Tanna1, Hong Cheng2, Vlado Perkovic1,20, Brendon L Neuen1,22. 1. The George Institute for Global Health (N.Y., M.J.J., M.O., C.H., A.E.S., C.A., B.N., D.C.W., G.L.D.T., V.P., B.L.N.), University of New South Wales, Sydney, Australia. 2. Renal Division, Beijing Anzhen Hospital, Capital Medical University, China (N.Y., H.C.). 3. Concord Repatriation General Hospital, Sydney, Australia (M.J.J.). 4. Department of Nephrology and Laboratory Medicine, Kanazawa University, Ishikawa, Japan (M.O.). 5. Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, The Netherlands (H.J.L.H., D.d.Z.). 6. Indiana University School of Medicine and VA Medical Center, Indianapolis (R.A.). 7. Department of Medicine, University of Chicago Medicine, IL (G.B.). 8. School of Public Health and Community Medicine (A.E.S.), University of New South Wales, Sydney, Australia. 9. Department of Cardiology, Royal Prince Alfred Hospital, Sydney Medical School, Australia (C.A.). 10. Division of Nephrology (T.I.C.), Stanford University School of Medicine, CA. 11. Department of Medicine, Stanford Hypertension Center (T.I.C.), Stanford University School of Medicine, CA. 12. Department of Nephrology, Hospital Clínico Universitario, Valencia, Spain (J.L.G.). 13. Cardiovascular Division, Brigham and Women's Hospital, Boston, MA (C.P.C.). 14. Baim Institute for Clinical Research, Boston, MA (C.P.C., D.M.C.). 15. Nephrology Division, New York University Langone Medical Center, New York University School of Medicine, New York, NY (D.M.C.). 16. Division of Nephrology, University of British Columbia, Vancouver, Canada (A.L.). 17. Stanford Center for Clinical Research (K.W.M.), Stanford University School of Medicine, CA. 18. The Charles Perkins Centre (B.N.), University of Sydney, Australia. 19. Kolling Institute of Medical Research, Sydney Medical School (C.P.), University of Sydney, Australia. 20. Royal North Shore Hospital, Sydney, Australia (C.P., V.P.). 21. Department of Renal Medicine, University College London Medical School, United Kingdom (D.C.W.). 22. Imperial College London, United Kingdom (B.N.).
Abstract
BACKGROUND:People with type 2 diabetes and chronic kidney disease experience a high burden of hypertension, but the magnitude and consistency of blood pressure (BP) lowering with canagliflozin in this population are uncertain. Whether the effects of canagliflozin on kidney and cardiovascular outcomes vary by baseline BP or BP-lowering therapy is also unknown. METHODS: The CREDENCE trial (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation) randomized people with type 2 diabetes and chronic kidney disease to canagliflozin or placebo. In a post hoc analysis, we investigated the effect of canagliflozin on systolic BP across subgroups defined by baseline systolic BP, number of BP-lowering drug classes, and history of apparent treatment-resistant hypertension (BP ≥130/80 mm Hg while receiving ≥3 classes of BP-lowering drugs, including a diuretic). We also assessed whether effects on clinical outcomes differed across these subgroups. RESULTS: The trial included 4401 participants, of whom 3361 (76.4%) had baseline systolic BP ≥130 mm Hg, and 1371 (31.2%) had resistant hypertension. By week 3, canagliflozin reduced systolic BP by 3.50 mm Hg (95% CI, -4.27 to -2.72), an effect maintained over the duration of the trial, with similar reductions across BP and BP-lowering therapy subgroups (all P interaction ≥0.05). Canagliflozin also reduced the need for initiation of additional BP-lowering agents during the trial (hazard ratio, 0.68 [95% CI, 0.61-0.75]). The effect of canagliflozin on kidney failure, doubling of serum creatinine, or death caused by kidney or cardiovascular disease (hazard ratio, 0.70 [95% CI, 0.59-0.82]) was consistent across BP and BP-lowering therapy subgroups (all P interaction ≥0.35), as were effects on other key kidney, cardiovascular, and safety outcomes. CONCLUSIONS: In people with type 2 diabetes and chronic kidney disease, canagliflozin lowers systolic BP across all BP-defined subgroups and reduces the need for additional BP-lowering agents. These findings support use of canagliflozin for end-organ protection and as an adjunct BP-lowering therapy in people with chronic kidney disease. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02065791.
RCT Entities:
BACKGROUND:People with type 2 diabetes and chronic kidney disease experience a high burden of hypertension, but the magnitude and consistency of blood pressure (BP) lowering with canagliflozin in this population are uncertain. Whether the effects of canagliflozin on kidney and cardiovascular outcomes vary by baseline BP or BP-lowering therapy is also unknown. METHODS: The CREDENCE trial (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation) randomized people with type 2 diabetes and chronic kidney disease to canagliflozin or placebo. In a post hoc analysis, we investigated the effect of canagliflozin on systolic BP across subgroups defined by baseline systolic BP, number of BP-lowering drug classes, and history of apparent treatment-resistant hypertension (BP ≥130/80 mm Hg while receiving ≥3 classes of BP-lowering drugs, including a diuretic). We also assessed whether effects on clinical outcomes differed across these subgroups. RESULTS: The trial included 4401 participants, of whom 3361 (76.4%) had baseline systolic BP ≥130 mm Hg, and 1371 (31.2%) had resistant hypertension. By week 3, canagliflozin reduced systolic BP by 3.50 mm Hg (95% CI, -4.27 to -2.72), an effect maintained over the duration of the trial, with similar reductions across BP and BP-lowering therapy subgroups (all P interaction ≥0.05). Canagliflozin also reduced the need for initiation of additional BP-lowering agents during the trial (hazard ratio, 0.68 [95% CI, 0.61-0.75]). The effect of canagliflozin on kidney failure, doubling of serum creatinine, or death caused by kidney or cardiovascular disease (hazard ratio, 0.70 [95% CI, 0.59-0.82]) was consistent across BP and BP-lowering therapy subgroups (all P interaction ≥0.35), as were effects on other key kidney, cardiovascular, and safety outcomes. CONCLUSIONS: In people with type 2 diabetes and chronic kidney disease, canagliflozin lowers systolic BP across all BP-defined subgroups and reduces the need for additional BP-lowering agents. These findings support use of canagliflozin for end-organ protection and as an adjunct BP-lowering therapy in people with chronic kidney disease. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02065791.
Authors: Jan M Williams; Sydney R Murphy; Wenjie Wu; Jane J Border; Fan Fan; Richard J Roman Journal: Geroscience Date: 2022-06-29 Impact factor: 7.581
Authors: Anne Zanchi; Menno Pruijm; Marie-Eve Muller; Arlène Ghajarzadeh-Wurzner; Marc Maillard; Nathalie Dufour; Olivier Bonny; Grégoire Wuerzner; Michel Burnier Journal: Front Cardiovasc Med Date: 2022-03-22